Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

jcom02509400_t1.JPG

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

jcom02509400_t1.JPG

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

jcom02509400_t1.JPG

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.

Design. International randomized phase 3 trial.

Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.

Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.

Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.

Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.

Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).

Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.

Commentary

Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].

In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.

Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.

Applications for Clinical Practice

The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.

Design. International randomized phase 3 trial.

Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.

Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.

Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.

Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.

Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).

Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.

Commentary

Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].

In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.

Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.

Applications for Clinical Practice

The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.

Design. International randomized phase 3 trial.

Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.

Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.

Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.

Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.

Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).

Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.

Commentary

Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].

In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.

Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.

Applications for Clinical Practice

The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.

Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.

Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.

Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m² and cyclophosphamide 500 mg/m² given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x10⁶ CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.

Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.

Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.

Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.

Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.

Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.

Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.

Commentary

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.

Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.

One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.

The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.

Applications for Clinical Practice

CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.

Study Overview

Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.

Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.

Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.

Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m² and cyclophosphamide 500 mg/m² given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x10⁶ CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.

Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.

Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.

Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.

Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.

Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.

Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.

Commentary

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.

Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.

One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.

The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.

Applications for Clinical Practice

CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.

Study Overview

Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.

Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.

Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.

Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m² and cyclophosphamide 500 mg/m² given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x10⁶ CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.

Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.

Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.

Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.

Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.

Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.

Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.

Commentary

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.

Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.

One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.

The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.

Applications for Clinical Practice

CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.

Study Overview

Objective. To compare the efficacy of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) with that of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage III or IV classic Hodgkin’s lymphoma.

Design. The ECHELON-1 trial, an international, openlabel, randomized phase 3 trial.

Setting and participants. In this multicenter international trial, a total of 1334 patients underwent randomization from November 2012 through January
2016. Eligible patients were 18 years of age older and had newly diagnosed and histologically proven classic Hodgkin’s lymphoma, Ann Arbor stage III or IV. Patients were eligible only if they had not received prior systemic chemotherapy or radiotherapy. All patients were required to have an ECOG performance status of ≤ 2 and adequate hematologic parameters (hemoglobin ≥ 8, ANC ≥ 1500, and platelet count ≥ 75,000). Patients with nodular lymphocyte predominant Hodgkin’s lymphoma, pre-existing peripheral sensory neuropathy, or known cerebral or meningeal disease were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive A+AVD (brentuximab vedotin 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2 and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2 and dacarbazine 375 mg/m2) IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. A PET scan was done at the end of the second cycle (PET2) and if this showed increased uptake at any site or uptake at a new site of disease (Deauville score 5) patients could be switched to an alternative frontline therapy at the treating physician’s discretion.

Main outcome measures. The primary endpoint of this study was modified progression-free survival (mPFS), defined as time to disease progression, death, or modified progression (noncomplete response after completion of frontline therapy—Deauville score 3, 4, or 5 on PET). Modified progression was incorporated as an endpoint in order to assess the effectiveness of frontline therapy. A secondary endpoint of the study was overall survival (OS).

Results. The baseline characteristics were well balanced between the treatment arms. 58% of the patients were male and 64% had stage IV disease. The median age was 36 years and 9% in each group were over the age of 65. After a median follow-up of 24.9 months, the independently assessed 2-year mPFS was 82.1% and 77.2% in the A+AVD and ABVD groups, respectively (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.6–0.98). The 2-year mPFS rate according to investigator assessment was 81% and 74.4% in the A+AVD and ABVD groups, respectively. Modified progression (failure to achieve a complete response after completion of frontline therapy resulting in treatment with subsequent therapy) occurred in 9 and 22 patients in the
A+AVD and ABVD groups, respectively. A pre-specified subgroup analysis showed that patients from North America, male patients, patients with involvement of more than 1 extranodal site, patients with a high IPSS score (4–7), patients < 60 years old and those with stage IV disease appeared to benefit more from A+AVD. The rate of PET2 negativity was 89% with A+AVD and 86% with ABVD. The 2-year overall survival was 96.6% in the A+AVD group and 94.9% in the ABVD group (HR 0.72; 95% CI 0.44–1.17). Fewer patients in the A+AVD group received subsequent cancer-directed therapy.

Neutropenia was more commonly reported in the A+AVD group (58% vs. 45%). Moreover, febrile neutropenia was reported in 19% and 8% of patients in the A+AVD and ABVD groups, respectively. Discontinuation rates in either arm for febrile neutropenia was ≤ 1%. The rate of infections was 55% in the A+AVD group and 50% in the ABVD group (grade 3 or higher: 18% and 10%, respectively). After review of the rates of febrile neutropenia, the safety monitoring committee recommended that primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) be used for patients who were yet to be enrolled. The rate of febrile neutropenia in the 83 patients in the A+AVD group who received primary prophylaxis was lower than those who did not (11% vs. 18%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and 42% in the ABVD group (grade 3 or higher: 11% vs 2%, respectively). Neuropathy lead to discontinuation of a study drug in 10% of patients in the A+AVD group. 67% of patients with peripheral neuropathy in the A+AVD group had resolution or improvement by one grade of their neuropathy at the time of last follow up. Pulmonary toxicity was reported in 2% of patients in the A+AVD group and 7% of the ABVD group (grade 3 or higher: < 1% vs. 3%, respectively). During treatment, 9 deaths were reported in the A+AVD group and 13 deaths in the ABVD group. Of the deaths in the ABVD group, 11 were associated with pulmonary toxicity.

Conclusion. A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin’s lymphoma.

Commentary

Hodgkin’s lymphoma (HL) accounts for approximately 10% of all lymphomas in the world annually [1]. While outcomes with frontline therapy for patients with HL have dramatically improved with ABVD, up to 30% of patients have either refractory disease or relapse after initial therapy [2,3]. One particular area of concern in the current treatment of HL with ABVD is the associated pulmonary toxicity of bleomycin. Pulmonary toxicity from bleomycin occurs in approximately 20%–30% of patients and can lead to long-term morbidity [4,5]. In addition, approximately 15% or more of HL patients are elderly and may have co-existing pulmonary disease. In the previously published E2496 trial, the risk of bleomycin lung toxicity in the elderly was 24% [3]. Although the risk of clinically relevant lung toxicity remains low, there is considerable concern about this amongst clinicians. Recent data has challenged the benefit of bleomycin as a component of ABVD. For example, Johnson and colleagues have shown that in patients with a negtive PET scan after 2 cycles of ABVD, the omission of bleomycin (ie, continuation of AVD) resulted in only a 1.6% reduction in 3-year progression-free survival with a decrease in pulmonary toxicity [6].

Recently, there have been notable advances in the treatment of patients with relapsed or refractory HL, including the incorporation of the PD-1 inhibitor
nivolumab as well as the immunotoxin conjugated CD30 monoclonal antibody brentuximab vedotin (BV). Given the activity of such agents in relapsed and refractory patients, there has been much enthusiasm about incorporation of such agents into the frontline setting. In the current ECHELON-1 trial, Connors and colleagues present the results of a randomized phase 3 trial comparing ABVD, the current standard of care, to A+AVD, which replaces bleomycin with BV. The trial used a primary endpoint of modified progression-free survival, where a noncomplete response and after primary therapy and subsequent treatment with anticancer therapy was considered disease progression. Notably, this trial did meet its primary endpoint of improved
modified PFS, with a 4.9% lower risk of progression, death, or noncomplete response and subsequent need for treatment at 2 years. Overall survival was not significantly different at the time of analysis.

There are some noteworthy findings in addition to this. First, A+AVD was associated with a higher risk of febrile neutropenia and infectious complications; however, following the incorporation of G-CSF prophylaxis this risk was lowered. The pulmonary toxicity was lower in the A+AVD group (2% vs. 7%). A+AVD was associated with an increased risk of peripheral neuropathy, which appeared to improve or resolve following discontinuation of therapy. The neuropathy was mainly low grade with only 11% being grade 3 or higher. Although it remains early and follow-up short, A+AVD did appear to have superior efficacy with a decrease in the risk of pulmonary toxicity in this study. It is worth noting that the risk of neurotoxicity was higher, albeit reversible with drug discontinuation. Given these results, A+AVD warrants consideration as frontline therapy in newly diagnosed patients with advanced stage classic Hodgkin’s lymphoma.

Applications for Clinical Practice

The results of this trial suggest that A+AVD with G-CSF support compares favorably to ABVD and may represent an acceptable first-line treatment strategy, particularly for patients at higher risk for pulmonary toxicity, although follow-up remains short at this time.

—Daniel Isaac, DO, MS

Study Overview

Objective. To compare the efficacy of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) with that of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage III or IV classic Hodgkin’s lymphoma.

Design. The ECHELON-1 trial, an international, openlabel, randomized phase 3 trial.

Setting and participants. In this multicenter international trial, a total of 1334 patients underwent randomization from November 2012 through January
2016. Eligible patients were 18 years of age older and had newly diagnosed and histologically proven classic Hodgkin’s lymphoma, Ann Arbor stage III or IV. Patients were eligible only if they had not received prior systemic chemotherapy or radiotherapy. All patients were required to have an ECOG performance status of ≤ 2 and adequate hematologic parameters (hemoglobin ≥ 8, ANC ≥ 1500, and platelet count ≥ 75,000). Patients with nodular lymphocyte predominant Hodgkin’s lymphoma, pre-existing peripheral sensory neuropathy, or known cerebral or meningeal disease were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive A+AVD (brentuximab vedotin 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2 and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2 and dacarbazine 375 mg/m2) IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. A PET scan was done at the end of the second cycle (PET2) and if this showed increased uptake at any site or uptake at a new site of disease (Deauville score 5) patients could be switched to an alternative frontline therapy at the treating physician’s discretion.

Main outcome measures. The primary endpoint of this study was modified progression-free survival (mPFS), defined as time to disease progression, death, or modified progression (noncomplete response after completion of frontline therapy—Deauville score 3, 4, or 5 on PET). Modified progression was incorporated as an endpoint in order to assess the effectiveness of frontline therapy. A secondary endpoint of the study was overall survival (OS).

Results. The baseline characteristics were well balanced between the treatment arms. 58% of the patients were male and 64% had stage IV disease. The median age was 36 years and 9% in each group were over the age of 65. After a median follow-up of 24.9 months, the independently assessed 2-year mPFS was 82.1% and 77.2% in the A+AVD and ABVD groups, respectively (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.6–0.98). The 2-year mPFS rate according to investigator assessment was 81% and 74.4% in the A+AVD and ABVD groups, respectively. Modified progression (failure to achieve a complete response after completion of frontline therapy resulting in treatment with subsequent therapy) occurred in 9 and 22 patients in the
A+AVD and ABVD groups, respectively. A pre-specified subgroup analysis showed that patients from North America, male patients, patients with involvement of more than 1 extranodal site, patients with a high IPSS score (4–7), patients < 60 years old and those with stage IV disease appeared to benefit more from A+AVD. The rate of PET2 negativity was 89% with A+AVD and 86% with ABVD. The 2-year overall survival was 96.6% in the A+AVD group and 94.9% in the ABVD group (HR 0.72; 95% CI 0.44–1.17). Fewer patients in the A+AVD group received subsequent cancer-directed therapy.

Neutropenia was more commonly reported in the A+AVD group (58% vs. 45%). Moreover, febrile neutropenia was reported in 19% and 8% of patients in the A+AVD and ABVD groups, respectively. Discontinuation rates in either arm for febrile neutropenia was ≤ 1%. The rate of infections was 55% in the A+AVD group and 50% in the ABVD group (grade 3 or higher: 18% and 10%, respectively). After review of the rates of febrile neutropenia, the safety monitoring committee recommended that primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) be used for patients who were yet to be enrolled. The rate of febrile neutropenia in the 83 patients in the A+AVD group who received primary prophylaxis was lower than those who did not (11% vs. 18%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and 42% in the ABVD group (grade 3 or higher: 11% vs 2%, respectively). Neuropathy lead to discontinuation of a study drug in 10% of patients in the A+AVD group. 67% of patients with peripheral neuropathy in the A+AVD group had resolution or improvement by one grade of their neuropathy at the time of last follow up. Pulmonary toxicity was reported in 2% of patients in the A+AVD group and 7% of the ABVD group (grade 3 or higher: < 1% vs. 3%, respectively). During treatment, 9 deaths were reported in the A+AVD group and 13 deaths in the ABVD group. Of the deaths in the ABVD group, 11 were associated with pulmonary toxicity.

Conclusion. A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin’s lymphoma.

Commentary

Hodgkin’s lymphoma (HL) accounts for approximately 10% of all lymphomas in the world annually [1]. While outcomes with frontline therapy for patients with HL have dramatically improved with ABVD, up to 30% of patients have either refractory disease or relapse after initial therapy [2,3]. One particular area of concern in the current treatment of HL with ABVD is the associated pulmonary toxicity of bleomycin. Pulmonary toxicity from bleomycin occurs in approximately 20%–30% of patients and can lead to long-term morbidity [4,5]. In addition, approximately 15% or more of HL patients are elderly and may have co-existing pulmonary disease. In the previously published E2496 trial, the risk of bleomycin lung toxicity in the elderly was 24% [3]. Although the risk of clinically relevant lung toxicity remains low, there is considerable concern about this amongst clinicians. Recent data has challenged the benefit of bleomycin as a component of ABVD. For example, Johnson and colleagues have shown that in patients with a negtive PET scan after 2 cycles of ABVD, the omission of bleomycin (ie, continuation of AVD) resulted in only a 1.6% reduction in 3-year progression-free survival with a decrease in pulmonary toxicity [6].

Recently, there have been notable advances in the treatment of patients with relapsed or refractory HL, including the incorporation of the PD-1 inhibitor
nivolumab as well as the immunotoxin conjugated CD30 monoclonal antibody brentuximab vedotin (BV). Given the activity of such agents in relapsed and refractory patients, there has been much enthusiasm about incorporation of such agents into the frontline setting. In the current ECHELON-1 trial, Connors and colleagues present the results of a randomized phase 3 trial comparing ABVD, the current standard of care, to A+AVD, which replaces bleomycin with BV. The trial used a primary endpoint of modified progression-free survival, where a noncomplete response and after primary therapy and subsequent treatment with anticancer therapy was considered disease progression. Notably, this trial did meet its primary endpoint of improved
modified PFS, with a 4.9% lower risk of progression, death, or noncomplete response and subsequent need for treatment at 2 years. Overall survival was not significantly different at the time of analysis.

There are some noteworthy findings in addition to this. First, A+AVD was associated with a higher risk of febrile neutropenia and infectious complications; however, following the incorporation of G-CSF prophylaxis this risk was lowered. The pulmonary toxicity was lower in the A+AVD group (2% vs. 7%). A+AVD was associated with an increased risk of peripheral neuropathy, which appeared to improve or resolve following discontinuation of therapy. The neuropathy was mainly low grade with only 11% being grade 3 or higher. Although it remains early and follow-up short, A+AVD did appear to have superior efficacy with a decrease in the risk of pulmonary toxicity in this study. It is worth noting that the risk of neurotoxicity was higher, albeit reversible with drug discontinuation. Given these results, A+AVD warrants consideration as frontline therapy in newly diagnosed patients with advanced stage classic Hodgkin’s lymphoma.

Applications for Clinical Practice

The results of this trial suggest that A+AVD with G-CSF support compares favorably to ABVD and may represent an acceptable first-line treatment strategy, particularly for patients at higher risk for pulmonary toxicity, although follow-up remains short at this time.

—Daniel Isaac, DO, MS

Study Overview

Objective. To compare the efficacy of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) with that of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage III or IV classic Hodgkin’s lymphoma.

Design. The ECHELON-1 trial, an international, openlabel, randomized phase 3 trial.

Setting and participants. In this multicenter international trial, a total of 1334 patients underwent randomization from November 2012 through January
2016. Eligible patients were 18 years of age older and had newly diagnosed and histologically proven classic Hodgkin’s lymphoma, Ann Arbor stage III or IV. Patients were eligible only if they had not received prior systemic chemotherapy or radiotherapy. All patients were required to have an ECOG performance status of ≤ 2 and adequate hematologic parameters (hemoglobin ≥ 8, ANC ≥ 1500, and platelet count ≥ 75,000). Patients with nodular lymphocyte predominant Hodgkin’s lymphoma, pre-existing peripheral sensory neuropathy, or known cerebral or meningeal disease were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive A+AVD (brentuximab vedotin 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2 and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2 and dacarbazine 375 mg/m2) IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. A PET scan was done at the end of the second cycle (PET2) and if this showed increased uptake at any site or uptake at a new site of disease (Deauville score 5) patients could be switched to an alternative frontline therapy at the treating physician’s discretion.

Main outcome measures. The primary endpoint of this study was modified progression-free survival (mPFS), defined as time to disease progression, death, or modified progression (noncomplete response after completion of frontline therapy—Deauville score 3, 4, or 5 on PET). Modified progression was incorporated as an endpoint in order to assess the effectiveness of frontline therapy. A secondary endpoint of the study was overall survival (OS).

Results. The baseline characteristics were well balanced between the treatment arms. 58% of the patients were male and 64% had stage IV disease. The median age was 36 years and 9% in each group were over the age of 65. After a median follow-up of 24.9 months, the independently assessed 2-year mPFS was 82.1% and 77.2% in the A+AVD and ABVD groups, respectively (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.6–0.98). The 2-year mPFS rate according to investigator assessment was 81% and 74.4% in the A+AVD and ABVD groups, respectively. Modified progression (failure to achieve a complete response after completion of frontline therapy resulting in treatment with subsequent therapy) occurred in 9 and 22 patients in the
A+AVD and ABVD groups, respectively. A pre-specified subgroup analysis showed that patients from North America, male patients, patients with involvement of more than 1 extranodal site, patients with a high IPSS score (4–7), patients < 60 years old and those with stage IV disease appeared to benefit more from A+AVD. The rate of PET2 negativity was 89% with A+AVD and 86% with ABVD. The 2-year overall survival was 96.6% in the A+AVD group and 94.9% in the ABVD group (HR 0.72; 95% CI 0.44–1.17). Fewer patients in the A+AVD group received subsequent cancer-directed therapy.

Neutropenia was more commonly reported in the A+AVD group (58% vs. 45%). Moreover, febrile neutropenia was reported in 19% and 8% of patients in the A+AVD and ABVD groups, respectively. Discontinuation rates in either arm for febrile neutropenia was ≤ 1%. The rate of infections was 55% in the A+AVD group and 50% in the ABVD group (grade 3 or higher: 18% and 10%, respectively). After review of the rates of febrile neutropenia, the safety monitoring committee recommended that primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) be used for patients who were yet to be enrolled. The rate of febrile neutropenia in the 83 patients in the A+AVD group who received primary prophylaxis was lower than those who did not (11% vs. 18%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and 42% in the ABVD group (grade 3 or higher: 11% vs 2%, respectively). Neuropathy lead to discontinuation of a study drug in 10% of patients in the A+AVD group. 67% of patients with peripheral neuropathy in the A+AVD group had resolution or improvement by one grade of their neuropathy at the time of last follow up. Pulmonary toxicity was reported in 2% of patients in the A+AVD group and 7% of the ABVD group (grade 3 or higher: < 1% vs. 3%, respectively). During treatment, 9 deaths were reported in the A+AVD group and 13 deaths in the ABVD group. Of the deaths in the ABVD group, 11 were associated with pulmonary toxicity.

Conclusion. A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin’s lymphoma.

Commentary

Hodgkin’s lymphoma (HL) accounts for approximately 10% of all lymphomas in the world annually [1]. While outcomes with frontline therapy for patients with HL have dramatically improved with ABVD, up to 30% of patients have either refractory disease or relapse after initial therapy [2,3]. One particular area of concern in the current treatment of HL with ABVD is the associated pulmonary toxicity of bleomycin. Pulmonary toxicity from bleomycin occurs in approximately 20%–30% of patients and can lead to long-term morbidity [4,5]. In addition, approximately 15% or more of HL patients are elderly and may have co-existing pulmonary disease. In the previously published E2496 trial, the risk of bleomycin lung toxicity in the elderly was 24% [3]. Although the risk of clinically relevant lung toxicity remains low, there is considerable concern about this amongst clinicians. Recent data has challenged the benefit of bleomycin as a component of ABVD. For example, Johnson and colleagues have shown that in patients with a negtive PET scan after 2 cycles of ABVD, the omission of bleomycin (ie, continuation of AVD) resulted in only a 1.6% reduction in 3-year progression-free survival with a decrease in pulmonary toxicity [6].

Recently, there have been notable advances in the treatment of patients with relapsed or refractory HL, including the incorporation of the PD-1 inhibitor
nivolumab as well as the immunotoxin conjugated CD30 monoclonal antibody brentuximab vedotin (BV). Given the activity of such agents in relapsed and refractory patients, there has been much enthusiasm about incorporation of such agents into the frontline setting. In the current ECHELON-1 trial, Connors and colleagues present the results of a randomized phase 3 trial comparing ABVD, the current standard of care, to A+AVD, which replaces bleomycin with BV. The trial used a primary endpoint of modified progression-free survival, where a noncomplete response and after primary therapy and subsequent treatment with anticancer therapy was considered disease progression. Notably, this trial did meet its primary endpoint of improved
modified PFS, with a 4.9% lower risk of progression, death, or noncomplete response and subsequent need for treatment at 2 years. Overall survival was not significantly different at the time of analysis.

There are some noteworthy findings in addition to this. First, A+AVD was associated with a higher risk of febrile neutropenia and infectious complications; however, following the incorporation of G-CSF prophylaxis this risk was lowered. The pulmonary toxicity was lower in the A+AVD group (2% vs. 7%). A+AVD was associated with an increased risk of peripheral neuropathy, which appeared to improve or resolve following discontinuation of therapy. The neuropathy was mainly low grade with only 11% being grade 3 or higher. Although it remains early and follow-up short, A+AVD did appear to have superior efficacy with a decrease in the risk of pulmonary toxicity in this study. It is worth noting that the risk of neurotoxicity was higher, albeit reversible with drug discontinuation. Given these results, A+AVD warrants consideration as frontline therapy in newly diagnosed patients with advanced stage classic Hodgkin’s lymphoma.

Applications for Clinical Practice

The results of this trial suggest that A+AVD with G-CSF support compares favorably to ABVD and may represent an acceptable first-line treatment strategy, particularly for patients at higher risk for pulmonary toxicity, although follow-up remains short at this time.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the PD-L1 anti­body durvalumab in the treatment of patients with unresectable stage III non-small-cell lung cancer (NSCLC) following completion of standard chemoradiotherapy.

Design. Interim analysis of the phase III PACIFIC study, a randomized, double-blind, international study.

Setting and participants. A total of 709 patients underwent randomization between May 2014 and April 2016. Eligible patients had histologically proven stage III, locally advanced and unresectable NSCLC with no evidence of disease progression following chemoradiotherapy. The enrolled patients had received at least 2 cycles of platinum-based chemotherapy concurrently with definitive radiation therapy (54 Gy to 66 Gy). Initially, patients were randomized within 2 weeks of completing radiation; however, the protocol was amended to allow randomization up to 42 days following completion of therapy. Patients were not eligible if they had previous exposure to anti-PD-1 or PD-L1 antibodies or active or prior autoimmune disease in the last 2 years. All patients were required to have an WHO performance status of 0 or 1. The patients were stratified at randomization by age (< 65 or > 65 years), sex and smoking status. Enrollment was not restricted to level of PD-L1 expression.

Intervention. Patients were randomized in a 2:1 ratio to receive consolidation durvalumab 10 mg/kg or placebo every 2 weeks for up to 12 months. The intervention was discontinued if there was evidence of confirmed disease progression, treatment with an alternative anticancer therapy, toxicity or patient preference. The response to treatment was assessed every 8 weeks for the first year and then every 12 weeks thereafter.

Main outcome measures. The primary endpoints of the study were progression-free survival (PFS) by blinded independent review and overall survival (OS). Secondary endpoints were the percentage of patients alive without disease progression at 12 and 18 months, objective response rate, duration of response, safety, and time to death or metastasis. Patients were given the option to provide archived tumor specimens for PD-L1 testing.

Results. The baseline characteristics were balanced. The median age at enrollment was 64 years and 91% of the patients were current or former smokers. The vast majority of patients (> 99% in both groups) received concurrent chemoradiotherapy. The response to initial concurrent therapy was similar in both groups with complete response rates of 1.9% and 3% in the durvalumab and placebo groups, respectively, and partial response rates of 48.7% and 46.8%. Archived tumor samples showed ≥ 25% PD-L1 expression in 22.3% of patients (24% in durvalumab group versus 18.6% in placebo group) and < 25% in 41% of patients (39.3%% in durvalumab group versus 44.3% in placebo group). PD-L1 status was unknown in 36.7% of the enrolled patients. Of note, 6% of patients enrolled had EGFR mutations.

After a median follow-up of 14.5 months, the median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (P < 0.001; hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.42–0.65). The 12-month PFS rate was 55.9% and 35.3% in the durvalumab and placebo group, respectively. The 18-month PFS rate was 44.2% and 27% in the durvalumab and placebo group, respectively. The PFS results were consistent across all subgroups. The PFS benefit was observed regardless of PD-L1 expression. The median time to death or metastasis was 23.2 months in the durvalumab group versus 14.6 months with placebo (HR 0.52; 95% CI 0.39–0.69). The objective response rate was significantly higher in the durvalumab group (28.4% vs. 16%, P < 0.001). The median duration of response was longer with durvalumab. Of the patients who responded to durvalumab, 73% had ongoing response at 18 months compared with 47% in the placebo group. OS was not assessed at this interm analysis.

Adverse events (AE) of any grade occurred in over approximately 95% in both groups. Grade 3 or 4 AE occurred in 29.9% in the durvalumab group and 26.1% in the placebo group. The most common grade 3 or 4 AE was pneumonia, occurring in about 4% of patients in each group. More patients in the durvalumab group discontinued treatment (15.4% vs 9.8%). Death due to an AE occurred in 4.4% of the durvalumab group and 5.6% of the placebo group. The most frequent AE leading to discontinuation was pneumonitis or radiation pneumonitis and pneumonia. Pneumonitis or radiation pneumonitis occurred in 33.9% (3.4% grade 3 or 4) and 24.8% (2.6% grade 3 or 4) of the durvalumab and placebo groups, respectively. Immune-mediated AE of any grade were more common in the duvalumab group occurring in 24% of patients (vs. 8% in placebo). Of these, 14% of patients in the durvalumab group required glucocorticoids compared with 4.3% in the placebo group. The most AE of interest was diarrhea, which occurred in 18% of the patients in both groups.

Conclusion. The addition of consolidative durvalumab following completion of concurrent chemoradiotherapy in patients with stage III, locally advanced NSCLC significantly improved PFS without a significant increase in treatment-related adverse events.

Commentary

Pre-clinical evidence has suggested that chemotherapy and radiation therapy may lead to upregulation of PD-L1 expression by tumor cells leading to increased PD-L1 mediated T cell apoptosis [1,2]. Given prior studies documenting PD-L1 expression as a predictive biomarker for response to durvalumab, the authors of the current trial hypothesized that the addition of durvalumab after chemoradiotherapy would provide clinical benefit likely mediated by upregulation of PD-L1. The results from this pre-planned interim analysis show a significant improvement in progression-free survival with the addition of durvalumab with a 48% decrease in the risk of progression. This benefit was noted across all patient subgroups. In addition, responses to durvalumab were durable, with 72% of the patients who responded having an ongoing response at 18 months. Interestingly, the response to durvalumab was independent of PD-L1 expression, which is in contrast to previous studies showing PD-L1 expression to be a good biomarker for durvalumab response [3].

The results of the PACIFIC trial represent a clinically meaningful benefit and suggests an excellent option for patients with unresectable stage III NSCLC. One important point to highlight is that the addition of durvalumab was well tolerated and did not appear to significantly increase the rate of severe adverse events. Of particular interest is the similar rates of grade 3 or 4 pneumonitis, which appeared to be around 3% for each group. Overall survival data remain immature at the time of this analysis; however, given the acceptable toxicity profile and improved PFS this combination should be considered for these patients in clinical practice. Ongoing trials are underway to evaluate the role of single-agent durvalumab in the front-line setting for NSCLC.

Applications for Clinical Practice

In patients with unresectable stage III NSCLC who have no evidence of disease progression following completion of chemoradiotherapy, the addition of durvalumab provided a significant and clinically meaningful improvement in progression-free survival without an increase in serious adverse events. While the overall survival data is immature, the 48% improvement in progression-free survival supports the incorporation of durvalumab into standard practice in this patient population.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the PD-L1 anti­body durvalumab in the treatment of patients with unresectable stage III non-small-cell lung cancer (NSCLC) following completion of standard chemoradiotherapy.

Design. Interim analysis of the phase III PACIFIC study, a randomized, double-blind, international study.

Setting and participants. A total of 709 patients underwent randomization between May 2014 and April 2016. Eligible patients had histologically proven stage III, locally advanced and unresectable NSCLC with no evidence of disease progression following chemoradiotherapy. The enrolled patients had received at least 2 cycles of platinum-based chemotherapy concurrently with definitive radiation therapy (54 Gy to 66 Gy). Initially, patients were randomized within 2 weeks of completing radiation; however, the protocol was amended to allow randomization up to 42 days following completion of therapy. Patients were not eligible if they had previous exposure to anti-PD-1 or PD-L1 antibodies or active or prior autoimmune disease in the last 2 years. All patients were required to have an WHO performance status of 0 or 1. The patients were stratified at randomization by age (< 65 or > 65 years), sex and smoking status. Enrollment was not restricted to level of PD-L1 expression.

Intervention. Patients were randomized in a 2:1 ratio to receive consolidation durvalumab 10 mg/kg or placebo every 2 weeks for up to 12 months. The intervention was discontinued if there was evidence of confirmed disease progression, treatment with an alternative anticancer therapy, toxicity or patient preference. The response to treatment was assessed every 8 weeks for the first year and then every 12 weeks thereafter.

Main outcome measures. The primary endpoints of the study were progression-free survival (PFS) by blinded independent review and overall survival (OS). Secondary endpoints were the percentage of patients alive without disease progression at 12 and 18 months, objective response rate, duration of response, safety, and time to death or metastasis. Patients were given the option to provide archived tumor specimens for PD-L1 testing.

Results. The baseline characteristics were balanced. The median age at enrollment was 64 years and 91% of the patients were current or former smokers. The vast majority of patients (> 99% in both groups) received concurrent chemoradiotherapy. The response to initial concurrent therapy was similar in both groups with complete response rates of 1.9% and 3% in the durvalumab and placebo groups, respectively, and partial response rates of 48.7% and 46.8%. Archived tumor samples showed ≥ 25% PD-L1 expression in 22.3% of patients (24% in durvalumab group versus 18.6% in placebo group) and < 25% in 41% of patients (39.3%% in durvalumab group versus 44.3% in placebo group). PD-L1 status was unknown in 36.7% of the enrolled patients. Of note, 6% of patients enrolled had EGFR mutations.

After a median follow-up of 14.5 months, the median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (P < 0.001; hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.42–0.65). The 12-month PFS rate was 55.9% and 35.3% in the durvalumab and placebo group, respectively. The 18-month PFS rate was 44.2% and 27% in the durvalumab and placebo group, respectively. The PFS results were consistent across all subgroups. The PFS benefit was observed regardless of PD-L1 expression. The median time to death or metastasis was 23.2 months in the durvalumab group versus 14.6 months with placebo (HR 0.52; 95% CI 0.39–0.69). The objective response rate was significantly higher in the durvalumab group (28.4% vs. 16%, P < 0.001). The median duration of response was longer with durvalumab. Of the patients who responded to durvalumab, 73% had ongoing response at 18 months compared with 47% in the placebo group. OS was not assessed at this interm analysis.

Adverse events (AE) of any grade occurred in over approximately 95% in both groups. Grade 3 or 4 AE occurred in 29.9% in the durvalumab group and 26.1% in the placebo group. The most common grade 3 or 4 AE was pneumonia, occurring in about 4% of patients in each group. More patients in the durvalumab group discontinued treatment (15.4% vs 9.8%). Death due to an AE occurred in 4.4% of the durvalumab group and 5.6% of the placebo group. The most frequent AE leading to discontinuation was pneumonitis or radiation pneumonitis and pneumonia. Pneumonitis or radiation pneumonitis occurred in 33.9% (3.4% grade 3 or 4) and 24.8% (2.6% grade 3 or 4) of the durvalumab and placebo groups, respectively. Immune-mediated AE of any grade were more common in the duvalumab group occurring in 24% of patients (vs. 8% in placebo). Of these, 14% of patients in the durvalumab group required glucocorticoids compared with 4.3% in the placebo group. The most AE of interest was diarrhea, which occurred in 18% of the patients in both groups.

Conclusion. The addition of consolidative durvalumab following completion of concurrent chemoradiotherapy in patients with stage III, locally advanced NSCLC significantly improved PFS without a significant increase in treatment-related adverse events.

Commentary

Pre-clinical evidence has suggested that chemotherapy and radiation therapy may lead to upregulation of PD-L1 expression by tumor cells leading to increased PD-L1 mediated T cell apoptosis [1,2]. Given prior studies documenting PD-L1 expression as a predictive biomarker for response to durvalumab, the authors of the current trial hypothesized that the addition of durvalumab after chemoradiotherapy would provide clinical benefit likely mediated by upregulation of PD-L1. The results from this pre-planned interim analysis show a significant improvement in progression-free survival with the addition of durvalumab with a 48% decrease in the risk of progression. This benefit was noted across all patient subgroups. In addition, responses to durvalumab were durable, with 72% of the patients who responded having an ongoing response at 18 months. Interestingly, the response to durvalumab was independent of PD-L1 expression, which is in contrast to previous studies showing PD-L1 expression to be a good biomarker for durvalumab response [3].

The results of the PACIFIC trial represent a clinically meaningful benefit and suggests an excellent option for patients with unresectable stage III NSCLC. One important point to highlight is that the addition of durvalumab was well tolerated and did not appear to significantly increase the rate of severe adverse events. Of particular interest is the similar rates of grade 3 or 4 pneumonitis, which appeared to be around 3% for each group. Overall survival data remain immature at the time of this analysis; however, given the acceptable toxicity profile and improved PFS this combination should be considered for these patients in clinical practice. Ongoing trials are underway to evaluate the role of single-agent durvalumab in the front-line setting for NSCLC.

Applications for Clinical Practice

In patients with unresectable stage III NSCLC who have no evidence of disease progression following completion of chemoradiotherapy, the addition of durvalumab provided a significant and clinically meaningful improvement in progression-free survival without an increase in serious adverse events. While the overall survival data is immature, the 48% improvement in progression-free survival supports the incorporation of durvalumab into standard practice in this patient population.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the PD-L1 anti­body durvalumab in the treatment of patients with unresectable stage III non-small-cell lung cancer (NSCLC) following completion of standard chemoradiotherapy.

Design. Interim analysis of the phase III PACIFIC study, a randomized, double-blind, international study.

Setting and participants. A total of 709 patients underwent randomization between May 2014 and April 2016. Eligible patients had histologically proven stage III, locally advanced and unresectable NSCLC with no evidence of disease progression following chemoradiotherapy. The enrolled patients had received at least 2 cycles of platinum-based chemotherapy concurrently with definitive radiation therapy (54 Gy to 66 Gy). Initially, patients were randomized within 2 weeks of completing radiation; however, the protocol was amended to allow randomization up to 42 days following completion of therapy. Patients were not eligible if they had previous exposure to anti-PD-1 or PD-L1 antibodies or active or prior autoimmune disease in the last 2 years. All patients were required to have an WHO performance status of 0 or 1. The patients were stratified at randomization by age (< 65 or > 65 years), sex and smoking status. Enrollment was not restricted to level of PD-L1 expression.

Intervention. Patients were randomized in a 2:1 ratio to receive consolidation durvalumab 10 mg/kg or placebo every 2 weeks for up to 12 months. The intervention was discontinued if there was evidence of confirmed disease progression, treatment with an alternative anticancer therapy, toxicity or patient preference. The response to treatment was assessed every 8 weeks for the first year and then every 12 weeks thereafter.

Main outcome measures. The primary endpoints of the study were progression-free survival (PFS) by blinded independent review and overall survival (OS). Secondary endpoints were the percentage of patients alive without disease progression at 12 and 18 months, objective response rate, duration of response, safety, and time to death or metastasis. Patients were given the option to provide archived tumor specimens for PD-L1 testing.

Results. The baseline characteristics were balanced. The median age at enrollment was 64 years and 91% of the patients were current or former smokers. The vast majority of patients (> 99% in both groups) received concurrent chemoradiotherapy. The response to initial concurrent therapy was similar in both groups with complete response rates of 1.9% and 3% in the durvalumab and placebo groups, respectively, and partial response rates of 48.7% and 46.8%. Archived tumor samples showed ≥ 25% PD-L1 expression in 22.3% of patients (24% in durvalumab group versus 18.6% in placebo group) and < 25% in 41% of patients (39.3%% in durvalumab group versus 44.3% in placebo group). PD-L1 status was unknown in 36.7% of the enrolled patients. Of note, 6% of patients enrolled had EGFR mutations.

After a median follow-up of 14.5 months, the median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (P < 0.001; hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.42–0.65). The 12-month PFS rate was 55.9% and 35.3% in the durvalumab and placebo group, respectively. The 18-month PFS rate was 44.2% and 27% in the durvalumab and placebo group, respectively. The PFS results were consistent across all subgroups. The PFS benefit was observed regardless of PD-L1 expression. The median time to death or metastasis was 23.2 months in the durvalumab group versus 14.6 months with placebo (HR 0.52; 95% CI 0.39–0.69). The objective response rate was significantly higher in the durvalumab group (28.4% vs. 16%, P < 0.001). The median duration of response was longer with durvalumab. Of the patients who responded to durvalumab, 73% had ongoing response at 18 months compared with 47% in the placebo group. OS was not assessed at this interm analysis.

Adverse events (AE) of any grade occurred in over approximately 95% in both groups. Grade 3 or 4 AE occurred in 29.9% in the durvalumab group and 26.1% in the placebo group. The most common grade 3 or 4 AE was pneumonia, occurring in about 4% of patients in each group. More patients in the durvalumab group discontinued treatment (15.4% vs 9.8%). Death due to an AE occurred in 4.4% of the durvalumab group and 5.6% of the placebo group. The most frequent AE leading to discontinuation was pneumonitis or radiation pneumonitis and pneumonia. Pneumonitis or radiation pneumonitis occurred in 33.9% (3.4% grade 3 or 4) and 24.8% (2.6% grade 3 or 4) of the durvalumab and placebo groups, respectively. Immune-mediated AE of any grade were more common in the duvalumab group occurring in 24% of patients (vs. 8% in placebo). Of these, 14% of patients in the durvalumab group required glucocorticoids compared with 4.3% in the placebo group. The most AE of interest was diarrhea, which occurred in 18% of the patients in both groups.

Conclusion. The addition of consolidative durvalumab following completion of concurrent chemoradiotherapy in patients with stage III, locally advanced NSCLC significantly improved PFS without a significant increase in treatment-related adverse events.

Commentary

Pre-clinical evidence has suggested that chemotherapy and radiation therapy may lead to upregulation of PD-L1 expression by tumor cells leading to increased PD-L1 mediated T cell apoptosis [1,2]. Given prior studies documenting PD-L1 expression as a predictive biomarker for response to durvalumab, the authors of the current trial hypothesized that the addition of durvalumab after chemoradiotherapy would provide clinical benefit likely mediated by upregulation of PD-L1. The results from this pre-planned interim analysis show a significant improvement in progression-free survival with the addition of durvalumab with a 48% decrease in the risk of progression. This benefit was noted across all patient subgroups. In addition, responses to durvalumab were durable, with 72% of the patients who responded having an ongoing response at 18 months. Interestingly, the response to durvalumab was independent of PD-L1 expression, which is in contrast to previous studies showing PD-L1 expression to be a good biomarker for durvalumab response [3].

The results of the PACIFIC trial represent a clinically meaningful benefit and suggests an excellent option for patients with unresectable stage III NSCLC. One important point to highlight is that the addition of durvalumab was well tolerated and did not appear to significantly increase the rate of severe adverse events. Of particular interest is the similar rates of grade 3 or 4 pneumonitis, which appeared to be around 3% for each group. Overall survival data remain immature at the time of this analysis; however, given the acceptable toxicity profile and improved PFS this combination should be considered for these patients in clinical practice. Ongoing trials are underway to evaluate the role of single-agent durvalumab in the front-line setting for NSCLC.

Applications for Clinical Practice

In patients with unresectable stage III NSCLC who have no evidence of disease progression following completion of chemoradiotherapy, the addition of durvalumab provided a significant and clinically meaningful improvement in progression-free survival without an increase in serious adverse events. While the overall survival data is immature, the 48% improvement in progression-free survival supports the incorporation of durvalumab into standard practice in this patient population.

—Daniel Isaac, DO, MS

Study Overview

Objective. To examine the heterogeneity in colorectal cancer (CRC) incidence in intermediate-risk patients and the effect of surveillance on CRC incidence.

Design. Retrospective, multicenter cohort study.

Setting and participants. Study patients underwent colonoscopy between 1 January 1990 and 21 December 2010 at 17 hospitals in the United Kingdom. Patients  were eligible for the study if they had a baseline colonoscopy with a newly diagnosed intermediate-risk adenoma. Intermediate-risk adenomas (as defined by the UK guidelines) included 1 to 2 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size. Patients with a history of prior resections, colorectal cancer, inflammatory bowel disease or a family history of CRC were excluded from the study. Patient, procedural, and polyp characteristics were assessed at baseline.

Main outcome measures. The primary outcome was inci-dence of CRC. Additional factors assessed included age at first polyp detection, sex, completeness of colonoscopy, preparation quality, number of adenomas, size of largest adenoma, histology, and location. Proximal polyps were defined as those proximal to the descending colon. Information regarding social history (eg, smoking status) was not available.

Results. The authors identified 253,798 patients who underwent colonoscopy between 1 January 1990 and 21 December 2010. Of those, 223,539 were excluded based on not meeting the pre-specified inclusion criteria, resulting in 30,259 eligible patients for analysis. Review of histological data confirmed intermediate-risk adenomas in 11,995 (40%) of the patients. The median age in this study was 66 years and 55% were men. Fifty-eight percent attended 1 or more follow-up surveillance visits while 42% had no follow-up surveillance colonoscopy. Those who attended more than 1 follow-up surveillance visits were younger, had a greater proportion of large adenomas (> 20 mm), or had an adenoma with high-grade dysplasia. Both groups had similar rates of villous histology (9% vs. 10%).

After a median follow-up of 7.9 years, 210 CRCs were diagnosed and 32% of patients died. In the group with no follow-up surveillance, 46% died and 2% were diagnosed with cancer. In the group who had 1 or more follow-up colonoscopies, 21% died and 1% were diagnosed with cancer. One or 2 surveillance visits were associated with a significant reduction in CRC incidence (HR 0.57 [95% confidence interval {CI} 0.4–0.8) and 0.51 [95% CI 0.31–0.84], respectively). Three or more surveillance exams were also associated with a similar reduction in CRC incidence (HR 0.54; CI 0.29–0.99). Characteristics associated with increased CRC incidence were older age, adenomas > 20 mm, high-grade dysplasia, proximal polyps, and colonoscopies that were either incomplete or with poor preparation. The number of adenomas was not independently associated with CRC incidence.

The authors divided the cohort into higher-risk (74%) and lower-risk (26%)  subgroups based on polyp and procedural characteristics. The higher-risk group included patients with baseline adenomas ≥ 20 mm, high-grade dysplasia, proximal polyps, or suboptimal evaluation. The lower-risk group included all others. CRC incidence was higher in the “higher-risk” subgroup (247 CRC per 100,000 vs. 93 CRC per 100,000). In the higher-risk group, risk of CRC decreased with more surveillance visits, a finding that was not observed in the lower-risk group. The 10-year incidence of CRC in the cohort overall was 2.7%, in the higher-risk group was 3.3% and in the lower risk group was 1.1%. CRC incidence was significantly higher in the higher-risk subgroup compared with the general population.

Conclusion. Colonoscopy surveillance significantly reducedthe incidence of CRC in intermediate-risk patients (1 to 3 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size) who were offered surveillance at 3-year intervals. Moreover, the benefit of surveillance was particularly noted in a sub-group of patients who had large adenomas (≥ 20 mm), high-grade dysplasia, proximal polyps or poor endoscopic evaluation at the time of initial screening.

Commentary

Screening colonoscopy with removal of adenomatous polyps prevents many CRCs and has been shown to reduce mortality [1]. The results of this retrospective study suggest that patients with intermediate-risk adenomas who underwent at least 1 surveillance colonoscopy at 3-year intervals had a significant reduction in the incidence of CRC. The authors have identified a subgroup of patients at higher risk for CRC, which included those who had a suboptimal initial colonoscopy including poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia, or proximal adenomas. In particular, ongoing surveillance in this high-risk cohort was associated with significant reductions in CRC incidence. Conversely, those in the lower-risk group had a CRC incidence lower than that of the general population,  raising some questions as to whether this group benefits from ongoing surveillance. However, definitive conclusions are difficult to make given the relatively low incidence of CRC in this group.

The risk of neoplasia in patients with colorectal ade-nomas has been evaluated in multiple studies. A pooled analysis by Martinez and colleagues examined over 9000 patients and noted advanced adenomas were found during follow up in 11.2% of the population, with 0.6% of the population developing invasive CRC [2]. Compared with adenomas < 5 mm, those with baseline adenomas 10–19 mm had a higher risk of advanced neoplasia (15.9% vs 7.7%; OR 2.2). Moreover, those with a baseline polyp ≥ 20 mm had a risk of advanced neoplasia at follow-up of 19.3% (OR 2.99). The results of the current investigation also suggest an increased risk of neoplasia with increased polyp size. Interestingly, the polyp size that conferred a higher risk in this study was ≥ 20 mm. The authors of this study suggest that polyps ≥ 20 mm along with the previously mentioned high-risk features may identify a subgroup within the intermediate-risk population who may benefit from close surveillance. One particularly interesting finding in this study was the identification of proximal colon polyps as a risk factor. While less well defined, previous investigations have noted a similar finding suggesting a risk of advanced neoplasia of up to 80% in patients with proximal polyps [3]. Given such, intensive surveillance may not be appropriate for all intermediate-risk patients and a more refined risk-adapted approach may be preferred.

There are some important limitations of the current study that warrant discussion. First, it should be emphasized that this study is observational in nature and therefore, definitive conclusions cannot be made despite the significant effect of surveillance colonoscopy in patients with high-risk features. In addition, the median follow-up in this study was 7.9 years and one could argue that longer-follow up is needed in order to validate the findings of this study, particularly in patients in the lower-risk cohort. Nevertheless, this study does suggest that there may be a population of patients that harbor higher-risk features and close surveillance limited to this group may be more appropriate. Furthermore, the duration of surveillance remains an important clinical question that requires further research.

Applications for Clinical Practice

In 2012, the United States Multi-Society Task Force (MSTF) on CRC issued updated guidelines defining adenoma risk and postpolypectomy surveillance. Low-risk adenomas (1 to 2 tubular adenomas ≤ 10 mm at baseline) should have repeat surveillance colonoscopy in 5 to 10 years. Advanced adenomas (≥ 10 mm, villous histology, or high-grade dysplasia) or those with 3 to 10 adenomas at baseline should undergo first surveillance in 3 years [4]. The authors of the current study suggest that surveillance colonoscopy at 3-year intervals for patients with particularly high-risk features including those with poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia or proximal adenomas benefit the greatest from at least 1 surveillance colonoscopy. Those with lower- risk features may not require such rigorous follow-up; however, further work to define which high-risk cohorts should undergo close surveillance is warranted. It is vital that the primary care provider understand such guidelines in order to facilitate the appropriate follow-up.

—Daniel Isaac, DO, MS, Michigan State University, East Lansing, MI

Study Overview

Objective. To examine the heterogeneity in colorectal cancer (CRC) incidence in intermediate-risk patients and the effect of surveillance on CRC incidence.

Design. Retrospective, multicenter cohort study.

Setting and participants. Study patients underwent colonoscopy between 1 January 1990 and 21 December 2010 at 17 hospitals in the United Kingdom. Patients  were eligible for the study if they had a baseline colonoscopy with a newly diagnosed intermediate-risk adenoma. Intermediate-risk adenomas (as defined by the UK guidelines) included 1 to 2 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size. Patients with a history of prior resections, colorectal cancer, inflammatory bowel disease or a family history of CRC were excluded from the study. Patient, procedural, and polyp characteristics were assessed at baseline.

Main outcome measures. The primary outcome was inci-dence of CRC. Additional factors assessed included age at first polyp detection, sex, completeness of colonoscopy, preparation quality, number of adenomas, size of largest adenoma, histology, and location. Proximal polyps were defined as those proximal to the descending colon. Information regarding social history (eg, smoking status) was not available.

Results. The authors identified 253,798 patients who underwent colonoscopy between 1 January 1990 and 21 December 2010. Of those, 223,539 were excluded based on not meeting the pre-specified inclusion criteria, resulting in 30,259 eligible patients for analysis. Review of histological data confirmed intermediate-risk adenomas in 11,995 (40%) of the patients. The median age in this study was 66 years and 55% were men. Fifty-eight percent attended 1 or more follow-up surveillance visits while 42% had no follow-up surveillance colonoscopy. Those who attended more than 1 follow-up surveillance visits were younger, had a greater proportion of large adenomas (> 20 mm), or had an adenoma with high-grade dysplasia. Both groups had similar rates of villous histology (9% vs. 10%).

After a median follow-up of 7.9 years, 210 CRCs were diagnosed and 32% of patients died. In the group with no follow-up surveillance, 46% died and 2% were diagnosed with cancer. In the group who had 1 or more follow-up colonoscopies, 21% died and 1% were diagnosed with cancer. One or 2 surveillance visits were associated with a significant reduction in CRC incidence (HR 0.57 [95% confidence interval {CI} 0.4–0.8) and 0.51 [95% CI 0.31–0.84], respectively). Three or more surveillance exams were also associated with a similar reduction in CRC incidence (HR 0.54; CI 0.29–0.99). Characteristics associated with increased CRC incidence were older age, adenomas > 20 mm, high-grade dysplasia, proximal polyps, and colonoscopies that were either incomplete or with poor preparation. The number of adenomas was not independently associated with CRC incidence.

The authors divided the cohort into higher-risk (74%) and lower-risk (26%)  subgroups based on polyp and procedural characteristics. The higher-risk group included patients with baseline adenomas ≥ 20 mm, high-grade dysplasia, proximal polyps, or suboptimal evaluation. The lower-risk group included all others. CRC incidence was higher in the “higher-risk” subgroup (247 CRC per 100,000 vs. 93 CRC per 100,000). In the higher-risk group, risk of CRC decreased with more surveillance visits, a finding that was not observed in the lower-risk group. The 10-year incidence of CRC in the cohort overall was 2.7%, in the higher-risk group was 3.3% and in the lower risk group was 1.1%. CRC incidence was significantly higher in the higher-risk subgroup compared with the general population.

Conclusion. Colonoscopy surveillance significantly reducedthe incidence of CRC in intermediate-risk patients (1 to 3 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size) who were offered surveillance at 3-year intervals. Moreover, the benefit of surveillance was particularly noted in a sub-group of patients who had large adenomas (≥ 20 mm), high-grade dysplasia, proximal polyps or poor endoscopic evaluation at the time of initial screening.

Commentary

Screening colonoscopy with removal of adenomatous polyps prevents many CRCs and has been shown to reduce mortality [1]. The results of this retrospective study suggest that patients with intermediate-risk adenomas who underwent at least 1 surveillance colonoscopy at 3-year intervals had a significant reduction in the incidence of CRC. The authors have identified a subgroup of patients at higher risk for CRC, which included those who had a suboptimal initial colonoscopy including poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia, or proximal adenomas. In particular, ongoing surveillance in this high-risk cohort was associated with significant reductions in CRC incidence. Conversely, those in the lower-risk group had a CRC incidence lower than that of the general population,  raising some questions as to whether this group benefits from ongoing surveillance. However, definitive conclusions are difficult to make given the relatively low incidence of CRC in this group.

The risk of neoplasia in patients with colorectal ade-nomas has been evaluated in multiple studies. A pooled analysis by Martinez and colleagues examined over 9000 patients and noted advanced adenomas were found during follow up in 11.2% of the population, with 0.6% of the population developing invasive CRC [2]. Compared with adenomas < 5 mm, those with baseline adenomas 10–19 mm had a higher risk of advanced neoplasia (15.9% vs 7.7%; OR 2.2). Moreover, those with a baseline polyp ≥ 20 mm had a risk of advanced neoplasia at follow-up of 19.3% (OR 2.99). The results of the current investigation also suggest an increased risk of neoplasia with increased polyp size. Interestingly, the polyp size that conferred a higher risk in this study was ≥ 20 mm. The authors of this study suggest that polyps ≥ 20 mm along with the previously mentioned high-risk features may identify a subgroup within the intermediate-risk population who may benefit from close surveillance. One particularly interesting finding in this study was the identification of proximal colon polyps as a risk factor. While less well defined, previous investigations have noted a similar finding suggesting a risk of advanced neoplasia of up to 80% in patients with proximal polyps [3]. Given such, intensive surveillance may not be appropriate for all intermediate-risk patients and a more refined risk-adapted approach may be preferred.

There are some important limitations of the current study that warrant discussion. First, it should be emphasized that this study is observational in nature and therefore, definitive conclusions cannot be made despite the significant effect of surveillance colonoscopy in patients with high-risk features. In addition, the median follow-up in this study was 7.9 years and one could argue that longer-follow up is needed in order to validate the findings of this study, particularly in patients in the lower-risk cohort. Nevertheless, this study does suggest that there may be a population of patients that harbor higher-risk features and close surveillance limited to this group may be more appropriate. Furthermore, the duration of surveillance remains an important clinical question that requires further research.

Applications for Clinical Practice

In 2012, the United States Multi-Society Task Force (MSTF) on CRC issued updated guidelines defining adenoma risk and postpolypectomy surveillance. Low-risk adenomas (1 to 2 tubular adenomas ≤ 10 mm at baseline) should have repeat surveillance colonoscopy in 5 to 10 years. Advanced adenomas (≥ 10 mm, villous histology, or high-grade dysplasia) or those with 3 to 10 adenomas at baseline should undergo first surveillance in 3 years [4]. The authors of the current study suggest that surveillance colonoscopy at 3-year intervals for patients with particularly high-risk features including those with poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia or proximal adenomas benefit the greatest from at least 1 surveillance colonoscopy. Those with lower- risk features may not require such rigorous follow-up; however, further work to define which high-risk cohorts should undergo close surveillance is warranted. It is vital that the primary care provider understand such guidelines in order to facilitate the appropriate follow-up.

—Daniel Isaac, DO, MS, Michigan State University, East Lansing, MI

Study Overview

Objective. To examine the heterogeneity in colorectal cancer (CRC) incidence in intermediate-risk patients and the effect of surveillance on CRC incidence.

Design. Retrospective, multicenter cohort study.

Setting and participants. Study patients underwent colonoscopy between 1 January 1990 and 21 December 2010 at 17 hospitals in the United Kingdom. Patients  were eligible for the study if they had a baseline colonoscopy with a newly diagnosed intermediate-risk adenoma. Intermediate-risk adenomas (as defined by the UK guidelines) included 1 to 2 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size. Patients with a history of prior resections, colorectal cancer, inflammatory bowel disease or a family history of CRC were excluded from the study. Patient, procedural, and polyp characteristics were assessed at baseline.

Main outcome measures. The primary outcome was inci-dence of CRC. Additional factors assessed included age at first polyp detection, sex, completeness of colonoscopy, preparation quality, number of adenomas, size of largest adenoma, histology, and location. Proximal polyps were defined as those proximal to the descending colon. Information regarding social history (eg, smoking status) was not available.

Results. The authors identified 253,798 patients who underwent colonoscopy between 1 January 1990 and 21 December 2010. Of those, 223,539 were excluded based on not meeting the pre-specified inclusion criteria, resulting in 30,259 eligible patients for analysis. Review of histological data confirmed intermediate-risk adenomas in 11,995 (40%) of the patients. The median age in this study was 66 years and 55% were men. Fifty-eight percent attended 1 or more follow-up surveillance visits while 42% had no follow-up surveillance colonoscopy. Those who attended more than 1 follow-up surveillance visits were younger, had a greater proportion of large adenomas (> 20 mm), or had an adenoma with high-grade dysplasia. Both groups had similar rates of villous histology (9% vs. 10%).

After a median follow-up of 7.9 years, 210 CRCs were diagnosed and 32% of patients died. In the group with no follow-up surveillance, 46% died and 2% were diagnosed with cancer. In the group who had 1 or more follow-up colonoscopies, 21% died and 1% were diagnosed with cancer. One or 2 surveillance visits were associated with a significant reduction in CRC incidence (HR 0.57 [95% confidence interval {CI} 0.4–0.8) and 0.51 [95% CI 0.31–0.84], respectively). Three or more surveillance exams were also associated with a similar reduction in CRC incidence (HR 0.54; CI 0.29–0.99). Characteristics associated with increased CRC incidence were older age, adenomas > 20 mm, high-grade dysplasia, proximal polyps, and colonoscopies that were either incomplete or with poor preparation. The number of adenomas was not independently associated with CRC incidence.

The authors divided the cohort into higher-risk (74%) and lower-risk (26%)  subgroups based on polyp and procedural characteristics. The higher-risk group included patients with baseline adenomas ≥ 20 mm, high-grade dysplasia, proximal polyps, or suboptimal evaluation. The lower-risk group included all others. CRC incidence was higher in the “higher-risk” subgroup (247 CRC per 100,000 vs. 93 CRC per 100,000). In the higher-risk group, risk of CRC decreased with more surveillance visits, a finding that was not observed in the lower-risk group. The 10-year incidence of CRC in the cohort overall was 2.7%, in the higher-risk group was 3.3% and in the lower risk group was 1.1%. CRC incidence was significantly higher in the higher-risk subgroup compared with the general population.

Conclusion. Colonoscopy surveillance significantly reducedthe incidence of CRC in intermediate-risk patients (1 to 3 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size) who were offered surveillance at 3-year intervals. Moreover, the benefit of surveillance was particularly noted in a sub-group of patients who had large adenomas (≥ 20 mm), high-grade dysplasia, proximal polyps or poor endoscopic evaluation at the time of initial screening.

Commentary

Screening colonoscopy with removal of adenomatous polyps prevents many CRCs and has been shown to reduce mortality [1]. The results of this retrospective study suggest that patients with intermediate-risk adenomas who underwent at least 1 surveillance colonoscopy at 3-year intervals had a significant reduction in the incidence of CRC. The authors have identified a subgroup of patients at higher risk for CRC, which included those who had a suboptimal initial colonoscopy including poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia, or proximal adenomas. In particular, ongoing surveillance in this high-risk cohort was associated with significant reductions in CRC incidence. Conversely, those in the lower-risk group had a CRC incidence lower than that of the general population,  raising some questions as to whether this group benefits from ongoing surveillance. However, definitive conclusions are difficult to make given the relatively low incidence of CRC in this group.

The risk of neoplasia in patients with colorectal ade-nomas has been evaluated in multiple studies. A pooled analysis by Martinez and colleagues examined over 9000 patients and noted advanced adenomas were found during follow up in 11.2% of the population, with 0.6% of the population developing invasive CRC [2]. Compared with adenomas < 5 mm, those with baseline adenomas 10–19 mm had a higher risk of advanced neoplasia (15.9% vs 7.7%; OR 2.2). Moreover, those with a baseline polyp ≥ 20 mm had a risk of advanced neoplasia at follow-up of 19.3% (OR 2.99). The results of the current investigation also suggest an increased risk of neoplasia with increased polyp size. Interestingly, the polyp size that conferred a higher risk in this study was ≥ 20 mm. The authors of this study suggest that polyps ≥ 20 mm along with the previously mentioned high-risk features may identify a subgroup within the intermediate-risk population who may benefit from close surveillance. One particularly interesting finding in this study was the identification of proximal colon polyps as a risk factor. While less well defined, previous investigations have noted a similar finding suggesting a risk of advanced neoplasia of up to 80% in patients with proximal polyps [3]. Given such, intensive surveillance may not be appropriate for all intermediate-risk patients and a more refined risk-adapted approach may be preferred.

There are some important limitations of the current study that warrant discussion. First, it should be emphasized that this study is observational in nature and therefore, definitive conclusions cannot be made despite the significant effect of surveillance colonoscopy in patients with high-risk features. In addition, the median follow-up in this study was 7.9 years and one could argue that longer-follow up is needed in order to validate the findings of this study, particularly in patients in the lower-risk cohort. Nevertheless, this study does suggest that there may be a population of patients that harbor higher-risk features and close surveillance limited to this group may be more appropriate. Furthermore, the duration of surveillance remains an important clinical question that requires further research.

Applications for Clinical Practice

In 2012, the United States Multi-Society Task Force (MSTF) on CRC issued updated guidelines defining adenoma risk and postpolypectomy surveillance. Low-risk adenomas (1 to 2 tubular adenomas ≤ 10 mm at baseline) should have repeat surveillance colonoscopy in 5 to 10 years. Advanced adenomas (≥ 10 mm, villous histology, or high-grade dysplasia) or those with 3 to 10 adenomas at baseline should undergo first surveillance in 3 years [4]. The authors of the current study suggest that surveillance colonoscopy at 3-year intervals for patients with particularly high-risk features including those with poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia or proximal adenomas benefit the greatest from at least 1 surveillance colonoscopy. Those with lower- risk features may not require such rigorous follow-up; however, further work to define which high-risk cohorts should undergo close surveillance is warranted. It is vital that the primary care provider understand such guidelines in order to facilitate the appropriate follow-up.

—Daniel Isaac, DO, MS, Michigan State University, East Lansing, MI

Study Overview

Objective. To compare the effect of 4 commonly recommended treatments for cancer-related fatigue (CRF): exercise, psychological, combined exercise and psychological, and pharmaceutical.

Design. Meta-analysis.

Study selection. The authors searched electronic databases (PubMed, PsycINFO, CINAHL, EMBASE and Cochrane Library) for randomized controlled trials published on or before 31 May 2016 that tested exercise, psychological treatment, exercise plus psychological, and pharmaceutical intervention and used CRF severity as a study outcome. Other inclusion criteria included randomized controlled study design, age > 18 with cancer, and CRF assessment independent of cancer treatment. Studies that included use of erythropoietin drugs as the pharmacological intervention, alternative physical modalities (eg, yoga, tai chi) as the exercise therapy, and reduced energy, vitality, or vigor as the fatigue outcome were excluded. Article review was performed independently by 3 reviewers. Independent third-party reviewers resolved all discrepancies. The methodologic quality of the selected studies were evaluated using the previously validated Physiotherapy Evidence-Based Database (PEDro) scale. This scale ranks studies numerically from 0–12 with 12 being the highest quality. Exercise interventions were defined as aerobic, anaerobic, or both based on the provided description in the original published article. Similarly, psychological interventions were categorized as cognitive behavioral, psychoeducational, or eclectic based on the original study.

Main outcome measure. Severity of CRF.

Results. The authors identified 17,033 potential studies during the screening period. After applying exclusion criteria, 351 articles were selected for full review. Of the selected articles, 113 studies were included and analyzed in this meta-analysis. Fourteen articles had more than 1 intervention arm, which resulted in a total of 127 effect sizes: 69 evaluated exercise, 34 evaluated psychological intervention, 10 evaluated the combination of exercise and psychological interventions, and 14 evaluated pharmaceutical intervention. The pooled analysis of all 113 studies yielded a sample size of 11,525 participants. Of these, 78% were female and 22% were male. The majority of included studies were conducted on a cohort of women with breast cancer (~47%). 44% of the studies enrolled patients with nonmetastatic cancer while only 10% enrolled patients with metastatic disease.

Pharmaceutical interventions included the use of paroxetine hydrochloride (n = 2 studies), modafinil or armo-dafinil (4), methylphenidate or dexymethylphenidate (5), dexamphetamine (1) and methylprednisolone (1). Exercise studies used aerobic modes (36), anaerobic modes (13), and a combination of aerobic and anaerobic modes (20). Psychological interventions included cognitive behavioral therapy (19), psychoeducational methods (14), and a combination of psychotherapeutic methods (1). There were 10 studies that assessed the combination of combined exercise plus psychological interventions.

The authors found a significant improvement in CRF across all included studies. The studies that used exercise as their intervention had the greatest improvement in CRF (P < 0.001). Psychological interventions also yielded significant improvements in CRF (P < 0.001). When combined, exercise and psychological interventions also showed significant improvement of CRF (P < 0.001). On the other hand, pharmaceutical interventions yielded a much smaller albeit significantimprovement in CRF (P = 0.05). Comparison across all interventions types showed that pharmaceutical interventions yielded the least improvement in CRF.

Further analysis of independent variables showed that the greatest effect was seen in patients with early stage, nonmetastatic disease who had completed their primary treatment. Group-based and in-person intervention methods were found to be more effective than individual interventions. Of the psychological interventions used, cognitive behavioral therapy was the most effective. This intervention was particularly effective in those who had early stage disease who had completed their primary treatment. Type of cancer, patient age, and exercise modality were not associated with treatment effectiveness.

Conclusion. The results of this study suggest that exercise with or without psychological interventions are effective at reducing CRF with greater improvement than with pharmaceutical interventions.

Commentary

Fatigue has been recognized as one of the most common symptoms associated with cancer and CRF. Some authors have estimated the prevalence of CRF may vary from 60% to 90% [1]. Moreover, the type of anti-cancer therapy appears to impact the severity of CRF. For example, patients receiving chemotherapy have reported CRF more commonly than those undergoing radiation therapy [1]. It is vital that the treating oncologist as well as the primary care provider be able to recognize CRF early in the treatment course and intervene in order to improve quality of life in this patient population.

According to the authors, this study is one of the first and most comprehensive attempts to examine the influence of various interventions on CRF. The results of this meta-analysis suggest that exercise (both aerobic and anaerobic), psychological therapy, or the combination of exercise and psychological therapy are more effective means to improve CRF compared with pharmacologic interventions. Notably, these results may suggest that specific interventions may be more effective depending on where the patient is in their treatment course. For example, the effect of exercise seemed greatest for patients who were receiving their primary treatment while the addition of psychological interventions may be best reserved for those who have completed their primary therapy. In addition, the greatest effect seemed to be seen in patients who had early stage disease following completion of definitive therapy.

Numerous authors have sought to assess the impact of various interventions on CRF; however, such studies have had small sample sizes and were often limited to a certain group of patients (eg, breast cancer). Despite these limitations, numerous trials have demonstrated improved fatigue, decreased emotional distress, and improved sleep and better quality of life with exercise [2–4]. This study corroborates the effects of exercise noted previously and further supports evidence that pharmacological therapy offers limited clinical benefit in the management of CRF.

There are some noteworthy limitations to the current meta-analysis. Most of the studies included in this analysis were among patients with breast cancer or patients who had completed primary therapy for breast cancer. Furthermore, the severity of fatigue was not quantified in many of the included trials. This analysis excluded pharmaceutical interventions that evaluated the use of an erythropoietin-stimulating agents (ESAs). ESAs have been widely studied in cancer patients and are currently recommended for patients with a hemoglobin less than 10 g/dL due to chemotherapy who being treated for a nonhematologic malignancy and have no other treatable cause of anemia. Numerous randomized trials have shown decreased red blood cell transfusion with the use of ESAs; however, the impact on CRF has been difficult to correlate. A meta-analysis by Cella and colleagues failed to demonstrated an improvement in fatigue-related symptoms with the use of ESAs in cancer patients [5]. In general, the use of ESAs is controversial in patients who are receiving myelosuppressive therapy for curative intent. This is largely related to the associated thromboembolic risks as well as data suggesting higher mortality rates. Finally, this analysis included patients with primarily non-metastatic disease and the effect of such interventions on patients with advance cancer requires further analysis.

Applications for Clinical Practice

CRF remains a common problem encountered in clinical practice. The treating oncologist and primary care provider must be astute at recognizing and promptly intervening in order to improve quality of life in patients with cancer. This study and prior trials continue to demonstrate the clinical benefits of exercise and psychological interventions in improving quality of life measures in this patient population and these interventions should be recommended. Pharmacologic therapies continue to offer little in the management of CRF and should be reserved for those who fail other intervention strategies. Such an approach is reinforced by the NCCN guidelines, which recommend nonpharmacologic interventions such as physical activity, psychosocial interventions, and nutrition counseling as front-line therapy (category 1) while reserving psychostimulants for those who do not derive benefit from these interventions [6].

—Daniel Isaac, DO, MS

Study Overview

Objective. To compare the effect of 4 commonly recommended treatments for cancer-related fatigue (CRF): exercise, psychological, combined exercise and psychological, and pharmaceutical.

Design. Meta-analysis.

Study selection. The authors searched electronic databases (PubMed, PsycINFO, CINAHL, EMBASE and Cochrane Library) for randomized controlled trials published on or before 31 May 2016 that tested exercise, psychological treatment, exercise plus psychological, and pharmaceutical intervention and used CRF severity as a study outcome. Other inclusion criteria included randomized controlled study design, age > 18 with cancer, and CRF assessment independent of cancer treatment. Studies that included use of erythropoietin drugs as the pharmacological intervention, alternative physical modalities (eg, yoga, tai chi) as the exercise therapy, and reduced energy, vitality, or vigor as the fatigue outcome were excluded. Article review was performed independently by 3 reviewers. Independent third-party reviewers resolved all discrepancies. The methodologic quality of the selected studies were evaluated using the previously validated Physiotherapy Evidence-Based Database (PEDro) scale. This scale ranks studies numerically from 0–12 with 12 being the highest quality. Exercise interventions were defined as aerobic, anaerobic, or both based on the provided description in the original published article. Similarly, psychological interventions were categorized as cognitive behavioral, psychoeducational, or eclectic based on the original study.

Main outcome measure. Severity of CRF.

Results. The authors identified 17,033 potential studies during the screening period. After applying exclusion criteria, 351 articles were selected for full review. Of the selected articles, 113 studies were included and analyzed in this meta-analysis. Fourteen articles had more than 1 intervention arm, which resulted in a total of 127 effect sizes: 69 evaluated exercise, 34 evaluated psychological intervention, 10 evaluated the combination of exercise and psychological interventions, and 14 evaluated pharmaceutical intervention. The pooled analysis of all 113 studies yielded a sample size of 11,525 participants. Of these, 78% were female and 22% were male. The majority of included studies were conducted on a cohort of women with breast cancer (~47%). 44% of the studies enrolled patients with nonmetastatic cancer while only 10% enrolled patients with metastatic disease.

Pharmaceutical interventions included the use of paroxetine hydrochloride (n = 2 studies), modafinil or armo-dafinil (4), methylphenidate or dexymethylphenidate (5), dexamphetamine (1) and methylprednisolone (1). Exercise studies used aerobic modes (36), anaerobic modes (13), and a combination of aerobic and anaerobic modes (20). Psychological interventions included cognitive behavioral therapy (19), psychoeducational methods (14), and a combination of psychotherapeutic methods (1). There were 10 studies that assessed the combination of combined exercise plus psychological interventions.

The authors found a significant improvement in CRF across all included studies. The studies that used exercise as their intervention had the greatest improvement in CRF (P < 0.001). Psychological interventions also yielded significant improvements in CRF (P < 0.001). When combined, exercise and psychological interventions also showed significant improvement of CRF (P < 0.001). On the other hand, pharmaceutical interventions yielded a much smaller albeit significantimprovement in CRF (P = 0.05). Comparison across all interventions types showed that pharmaceutical interventions yielded the least improvement in CRF.

Further analysis of independent variables showed that the greatest effect was seen in patients with early stage, nonmetastatic disease who had completed their primary treatment. Group-based and in-person intervention methods were found to be more effective than individual interventions. Of the psychological interventions used, cognitive behavioral therapy was the most effective. This intervention was particularly effective in those who had early stage disease who had completed their primary treatment. Type of cancer, patient age, and exercise modality were not associated with treatment effectiveness.

Conclusion. The results of this study suggest that exercise with or without psychological interventions are effective at reducing CRF with greater improvement than with pharmaceutical interventions.

Commentary

Fatigue has been recognized as one of the most common symptoms associated with cancer and CRF. Some authors have estimated the prevalence of CRF may vary from 60% to 90% [1]. Moreover, the type of anti-cancer therapy appears to impact the severity of CRF. For example, patients receiving chemotherapy have reported CRF more commonly than those undergoing radiation therapy [1]. It is vital that the treating oncologist as well as the primary care provider be able to recognize CRF early in the treatment course and intervene in order to improve quality of life in this patient population.

According to the authors, this study is one of the first and most comprehensive attempts to examine the influence of various interventions on CRF. The results of this meta-analysis suggest that exercise (both aerobic and anaerobic), psychological therapy, or the combination of exercise and psychological therapy are more effective means to improve CRF compared with pharmacologic interventions. Notably, these results may suggest that specific interventions may be more effective depending on where the patient is in their treatment course. For example, the effect of exercise seemed greatest for patients who were receiving their primary treatment while the addition of psychological interventions may be best reserved for those who have completed their primary therapy. In addition, the greatest effect seemed to be seen in patients who had early stage disease following completion of definitive therapy.

Numerous authors have sought to assess the impact of various interventions on CRF; however, such studies have had small sample sizes and were often limited to a certain group of patients (eg, breast cancer). Despite these limitations, numerous trials have demonstrated improved fatigue, decreased emotional distress, and improved sleep and better quality of life with exercise [2–4]. This study corroborates the effects of exercise noted previously and further supports evidence that pharmacological therapy offers limited clinical benefit in the management of CRF.

There are some noteworthy limitations to the current meta-analysis. Most of the studies included in this analysis were among patients with breast cancer or patients who had completed primary therapy for breast cancer. Furthermore, the severity of fatigue was not quantified in many of the included trials. This analysis excluded pharmaceutical interventions that evaluated the use of an erythropoietin-stimulating agents (ESAs). ESAs have been widely studied in cancer patients and are currently recommended for patients with a hemoglobin less than 10 g/dL due to chemotherapy who being treated for a nonhematologic malignancy and have no other treatable cause of anemia. Numerous randomized trials have shown decreased red blood cell transfusion with the use of ESAs; however, the impact on CRF has been difficult to correlate. A meta-analysis by Cella and colleagues failed to demonstrated an improvement in fatigue-related symptoms with the use of ESAs in cancer patients [5]. In general, the use of ESAs is controversial in patients who are receiving myelosuppressive therapy for curative intent. This is largely related to the associated thromboembolic risks as well as data suggesting higher mortality rates. Finally, this analysis included patients with primarily non-metastatic disease and the effect of such interventions on patients with advance cancer requires further analysis.

Applications for Clinical Practice

CRF remains a common problem encountered in clinical practice. The treating oncologist and primary care provider must be astute at recognizing and promptly intervening in order to improve quality of life in patients with cancer. This study and prior trials continue to demonstrate the clinical benefits of exercise and psychological interventions in improving quality of life measures in this patient population and these interventions should be recommended. Pharmacologic therapies continue to offer little in the management of CRF and should be reserved for those who fail other intervention strategies. Such an approach is reinforced by the NCCN guidelines, which recommend nonpharmacologic interventions such as physical activity, psychosocial interventions, and nutrition counseling as front-line therapy (category 1) while reserving psychostimulants for those who do not derive benefit from these interventions [6].

—Daniel Isaac, DO, MS

Study Overview

Objective. To compare the effect of 4 commonly recommended treatments for cancer-related fatigue (CRF): exercise, psychological, combined exercise and psychological, and pharmaceutical.

Design. Meta-analysis.

Study selection. The authors searched electronic databases (PubMed, PsycINFO, CINAHL, EMBASE and Cochrane Library) for randomized controlled trials published on or before 31 May 2016 that tested exercise, psychological treatment, exercise plus psychological, and pharmaceutical intervention and used CRF severity as a study outcome. Other inclusion criteria included randomized controlled study design, age > 18 with cancer, and CRF assessment independent of cancer treatment. Studies that included use of erythropoietin drugs as the pharmacological intervention, alternative physical modalities (eg, yoga, tai chi) as the exercise therapy, and reduced energy, vitality, or vigor as the fatigue outcome were excluded. Article review was performed independently by 3 reviewers. Independent third-party reviewers resolved all discrepancies. The methodologic quality of the selected studies were evaluated using the previously validated Physiotherapy Evidence-Based Database (PEDro) scale. This scale ranks studies numerically from 0–12 with 12 being the highest quality. Exercise interventions were defined as aerobic, anaerobic, or both based on the provided description in the original published article. Similarly, psychological interventions were categorized as cognitive behavioral, psychoeducational, or eclectic based on the original study.

Main outcome measure. Severity of CRF.

Results. The authors identified 17,033 potential studies during the screening period. After applying exclusion criteria, 351 articles were selected for full review. Of the selected articles, 113 studies were included and analyzed in this meta-analysis. Fourteen articles had more than 1 intervention arm, which resulted in a total of 127 effect sizes: 69 evaluated exercise, 34 evaluated psychological intervention, 10 evaluated the combination of exercise and psychological interventions, and 14 evaluated pharmaceutical intervention. The pooled analysis of all 113 studies yielded a sample size of 11,525 participants. Of these, 78% were female and 22% were male. The majority of included studies were conducted on a cohort of women with breast cancer (~47%). 44% of the studies enrolled patients with nonmetastatic cancer while only 10% enrolled patients with metastatic disease.

Pharmaceutical interventions included the use of paroxetine hydrochloride (n = 2 studies), modafinil or armo-dafinil (4), methylphenidate or dexymethylphenidate (5), dexamphetamine (1) and methylprednisolone (1). Exercise studies used aerobic modes (36), anaerobic modes (13), and a combination of aerobic and anaerobic modes (20). Psychological interventions included cognitive behavioral therapy (19), psychoeducational methods (14), and a combination of psychotherapeutic methods (1). There were 10 studies that assessed the combination of combined exercise plus psychological interventions.

The authors found a significant improvement in CRF across all included studies. The studies that used exercise as their intervention had the greatest improvement in CRF (P < 0.001). Psychological interventions also yielded significant improvements in CRF (P < 0.001). When combined, exercise and psychological interventions also showed significant improvement of CRF (P < 0.001). On the other hand, pharmaceutical interventions yielded a much smaller albeit significantimprovement in CRF (P = 0.05). Comparison across all interventions types showed that pharmaceutical interventions yielded the least improvement in CRF.

Further analysis of independent variables showed that the greatest effect was seen in patients with early stage, nonmetastatic disease who had completed their primary treatment. Group-based and in-person intervention methods were found to be more effective than individual interventions. Of the psychological interventions used, cognitive behavioral therapy was the most effective. This intervention was particularly effective in those who had early stage disease who had completed their primary treatment. Type of cancer, patient age, and exercise modality were not associated with treatment effectiveness.

Conclusion. The results of this study suggest that exercise with or without psychological interventions are effective at reducing CRF with greater improvement than with pharmaceutical interventions.

Commentary

Fatigue has been recognized as one of the most common symptoms associated with cancer and CRF. Some authors have estimated the prevalence of CRF may vary from 60% to 90% [1]. Moreover, the type of anti-cancer therapy appears to impact the severity of CRF. For example, patients receiving chemotherapy have reported CRF more commonly than those undergoing radiation therapy [1]. It is vital that the treating oncologist as well as the primary care provider be able to recognize CRF early in the treatment course and intervene in order to improve quality of life in this patient population.

According to the authors, this study is one of the first and most comprehensive attempts to examine the influence of various interventions on CRF. The results of this meta-analysis suggest that exercise (both aerobic and anaerobic), psychological therapy, or the combination of exercise and psychological therapy are more effective means to improve CRF compared with pharmacologic interventions. Notably, these results may suggest that specific interventions may be more effective depending on where the patient is in their treatment course. For example, the effect of exercise seemed greatest for patients who were receiving their primary treatment while the addition of psychological interventions may be best reserved for those who have completed their primary therapy. In addition, the greatest effect seemed to be seen in patients who had early stage disease following completion of definitive therapy.

Numerous authors have sought to assess the impact of various interventions on CRF; however, such studies have had small sample sizes and were often limited to a certain group of patients (eg, breast cancer). Despite these limitations, numerous trials have demonstrated improved fatigue, decreased emotional distress, and improved sleep and better quality of life with exercise [2–4]. This study corroborates the effects of exercise noted previously and further supports evidence that pharmacological therapy offers limited clinical benefit in the management of CRF.

There are some noteworthy limitations to the current meta-analysis. Most of the studies included in this analysis were among patients with breast cancer or patients who had completed primary therapy for breast cancer. Furthermore, the severity of fatigue was not quantified in many of the included trials. This analysis excluded pharmaceutical interventions that evaluated the use of an erythropoietin-stimulating agents (ESAs). ESAs have been widely studied in cancer patients and are currently recommended for patients with a hemoglobin less than 10 g/dL due to chemotherapy who being treated for a nonhematologic malignancy and have no other treatable cause of anemia. Numerous randomized trials have shown decreased red blood cell transfusion with the use of ESAs; however, the impact on CRF has been difficult to correlate. A meta-analysis by Cella and colleagues failed to demonstrated an improvement in fatigue-related symptoms with the use of ESAs in cancer patients [5]. In general, the use of ESAs is controversial in patients who are receiving myelosuppressive therapy for curative intent. This is largely related to the associated thromboembolic risks as well as data suggesting higher mortality rates. Finally, this analysis included patients with primarily non-metastatic disease and the effect of such interventions on patients with advance cancer requires further analysis.

Applications for Clinical Practice

CRF remains a common problem encountered in clinical practice. The treating oncologist and primary care provider must be astute at recognizing and promptly intervening in order to improve quality of life in patients with cancer. This study and prior trials continue to demonstrate the clinical benefits of exercise and psychological interventions in improving quality of life measures in this patient population and these interventions should be recommended. Pharmacologic therapies continue to offer little in the management of CRF and should be reserved for those who fail other intervention strategies. Such an approach is reinforced by the NCCN guidelines, which recommend nonpharmacologic interventions such as physical activity, psychosocial interventions, and nutrition counseling as front-line therapy (category 1) while reserving psychostimulants for those who do not derive benefit from these interventions [6].

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy and safety of the CDK4/6 inhibitor ribociclib in combination with letrozole as initial therapy in patients with hormone-receptor (HR)–positive, human epidermal growth factor receptor 2 (HER-2)–negative advanced breast cancer.

Design. Pre-planned interim analysis of a randomized, double-blind, phase 3 clinical trial.

Setting and participants. This study enrolled patients in 29 countries at 223 centers. A total of 668 postmenopausal women underwent randomization, with 334 assigned to receive ribociclib plus letrozole and 334 assigned to receive placebo plus letrozole. All women had HR-positive, HER-2 negative recurrent or metastatic breast cancer and had not received prior systemic therapy. Enrolled patients had either measurable disease on imaging or at least 1 lytic bone lesion. All patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were excluded if they had received prior therapy with a CDK4/6 inhibitor, previous systemic chemotherapy or endocrine therapy. If a patient received an aromatase inhibitor for neoadjuvant or adjuvant therapy, the disease-free interval needed to be more than 12 months to be included in the study. Patients with inflammatory breast cancer or central nervous system involvement were also excluded. Normal cardiac function (normal QT interval) was required for enrollment. The randomization was stratified by presence of liver or lung metastases.

Intervention. The patients were randomized to oral ribociclib 600 mg per day 3 weeks on, 1 week off in a 28-day treatment cycle plus letrozole 2.5 mg daily or placebo plus letrozole. The dosing of ribociclib was based on a prior phase 1 study [1]. Treatment was continued until disease progression, unacceptable toxicity, discontinuation, or death. Dose reductions of ribociclib were allowed; however, dose reductions of letrozole were not permitted. Crossover between treatment arms was not allowed. Patients were assessed with computed tomo-graphy at the time of randomization, every 8 weeks for the first 18 months and every 12 weeks there-after. Patients were monitored for hematological toxicity each cycle. Electrocardiographic assessment was done at screening, on day 15 of cycle 1 and on day 1 of all subsequent cycles to monitor for QT prolongation.

Main outcome measures. The primary outcome was progression-free survival. The secondary outcomes were overall survival, overall response rate (complete or partial response), clinical benefit rate, and safety. Clinical benefit rate was defined as overall response plus stable disease lasting 24 weeks or more. A prespecified interim analysis was planned after disease progression or death was reported in 211 of 302 patients (70%).

Results. The baseline characteristics were balanced between the 2 groups. Visceral disease was present in 58.8% and bone-only disease in 22% of the patients. The median duration of therapy exposure was 13 months in the ribociclib group and 12.4 months in the placebo group. The median duration of follow-up was 15.3 months. After 18 months, progression-free survival was 63% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib/letrozole group versus 42.2% (95% CI, 34.8 to 49.5) in the placebo group (P < 0.001). The median progression-free survival was not met in the combination group (95% CI, 19.3 to not reached) versus 14.7 months (95% CI, 13.0 to 16.5) in the placebo group. The improved progression-free survival was seen across all subgroups. The overall response rate was higher in the combination arm (52.7% vs. 37.1%) as was the clinical benefit rate (80.1% vs. 71.8%). Serious adverse events occurred in 21.3% of patients in the ribociclib group and 11.8% in the placebo group. Serious adverse events were attributed to the study drug in 7.5% of the ribociclib group and 1.5% of the placebo group. The most common adverse events were myelosuppression, nausea, fatigue and diarrhea. Grade 3 and 4 neutropenia was noted in 59.3% in the ribociclib group versus < 1% in the placebo arm. The discontinuation rate due to adverse events in the ribociclib and placebo groups was 7.5% versus 2.1%, respectively. The most common reason for discontinuation was disease progression in 26% in the ribociclib group and 43.7% in the placebo group. Three deaths occurred in the ribociclib group and one in the placebo group. Interruptions in ribociclib occurred in 76.9% of patients. Dose reductions occurred in 53.9% of patients in the ribociclib group versus 7% in the placebo group. The most common reason a dose reduction occurred was neutropenia.

Conclusion. First-line treatment with ribociclib plus letrozole in postmenopausal women with HR-positive, HER-2 negative advanced breast cancer was associated with significantly longer progression-free survival compared with letrozole plus placebo. The improved progression-free survival was seen across all subgroups.

Commentary

Nearly 80% of all breast cancers express hormone receptor positivity. Hormonal therapy has been an important component of treatment for women with hormone-positive breast cancer in both the local and metastatic setting. Many tumors will eventually develop resistance to such therapy with the median progression-free survival with first-line endocrine therapy alone being around 9 months [2]. Cyclin dependent kinases 4 and 6 (CDK4/6) play an important role in estrogen-receptor signaling and cell cycle progression. CDK 4/6 mediates progression through the cell cycle from G1 to S phase via phosphorylation and inactivation of the retinoblastoma tumor suppressor protein [3]. Overexpression of CDK 4/6 in hormone receptor positive breast cancer is thought to play an important role in the development of endocrine therapy resistance [4].

The previously published PALOMA-2 trial, which compared treatment with the CDK 4/6 inhibitor palbociclib plus letrozole with letrozole alone, reported a significant improvement in progression-free survival with the addition of palbociclib (24.8 months vs. 14.5 months) in the front-line setting for women with advanced, hormone-positive breast cancer [5]. The improved progression-free survival with palbociclib was seen across all subgroups with a favorable toxicity profile. The current study represents the second randomized trial to show that the addition of CDK4/6 inhibitor to endocrine-based therapy significantly improves progression-free survival. This benefit was also seen across all patient subgroups including those with liver and lung metastases. In addition, the combination of ribociclib and letrozole also show significantly higher rates of overall response compared with placebo. In general, the addition of ribociclib to letrozole was well tolerated with a very low rate (7.5%) of discontinuation of therapy. Although neutropenia was a frequent complication in the ribociclib group febrile neutropenia occurred in only 1.5% of patients.

The incorporation of CDK4/6 inhibitors to endocrine-based therapy in the front-line setting has proven effective with an impressive early separation of the progression-free survival curves. Both the PALOMA-2 trial and the current MONALEESA-2 trial have shown similar results with approximately 40% improvement in progression-free survival. Whether the results seen in these trials will translate into an improvement in overall survival is yet to be determined. The results of these 2 trial suggest that CDK4/6 inhibitors have activity in both patients who have not received previous treatment with endocrine therapy and in those who received adjuvant endocrine therapy with late (> 12 months) relapse. Further determination of the subset of women who would benefit from the addition of CDK4/6 inhibitors remains an important clinical question. There are currently no clinical biomarkers that can be used to predict whether a patient would benefit from the addition of these medications.

Applications for Clinical Practice

The results of the current trial represent an exciting step forward in the treatment of advanced breast cancer. Palbociclib in combination with endocrine therapy is currently incorporated into clinical practice. The cost of these agents remains a concern; however, most insurance policies will cover them. Clinical trials are ongoing in the neoadjuvant and adjuvant setting for early breast cancer.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy and safety of the CDK4/6 inhibitor ribociclib in combination with letrozole as initial therapy in patients with hormone-receptor (HR)–positive, human epidermal growth factor receptor 2 (HER-2)–negative advanced breast cancer.

Design. Pre-planned interim analysis of a randomized, double-blind, phase 3 clinical trial.

Setting and participants. This study enrolled patients in 29 countries at 223 centers. A total of 668 postmenopausal women underwent randomization, with 334 assigned to receive ribociclib plus letrozole and 334 assigned to receive placebo plus letrozole. All women had HR-positive, HER-2 negative recurrent or metastatic breast cancer and had not received prior systemic therapy. Enrolled patients had either measurable disease on imaging or at least 1 lytic bone lesion. All patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were excluded if they had received prior therapy with a CDK4/6 inhibitor, previous systemic chemotherapy or endocrine therapy. If a patient received an aromatase inhibitor for neoadjuvant or adjuvant therapy, the disease-free interval needed to be more than 12 months to be included in the study. Patients with inflammatory breast cancer or central nervous system involvement were also excluded. Normal cardiac function (normal QT interval) was required for enrollment. The randomization was stratified by presence of liver or lung metastases.

Intervention. The patients were randomized to oral ribociclib 600 mg per day 3 weeks on, 1 week off in a 28-day treatment cycle plus letrozole 2.5 mg daily or placebo plus letrozole. The dosing of ribociclib was based on a prior phase 1 study [1]. Treatment was continued until disease progression, unacceptable toxicity, discontinuation, or death. Dose reductions of ribociclib were allowed; however, dose reductions of letrozole were not permitted. Crossover between treatment arms was not allowed. Patients were assessed with computed tomo-graphy at the time of randomization, every 8 weeks for the first 18 months and every 12 weeks there-after. Patients were monitored for hematological toxicity each cycle. Electrocardiographic assessment was done at screening, on day 15 of cycle 1 and on day 1 of all subsequent cycles to monitor for QT prolongation.

Main outcome measures. The primary outcome was progression-free survival. The secondary outcomes were overall survival, overall response rate (complete or partial response), clinical benefit rate, and safety. Clinical benefit rate was defined as overall response plus stable disease lasting 24 weeks or more. A prespecified interim analysis was planned after disease progression or death was reported in 211 of 302 patients (70%).

Results. The baseline characteristics were balanced between the 2 groups. Visceral disease was present in 58.8% and bone-only disease in 22% of the patients. The median duration of therapy exposure was 13 months in the ribociclib group and 12.4 months in the placebo group. The median duration of follow-up was 15.3 months. After 18 months, progression-free survival was 63% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib/letrozole group versus 42.2% (95% CI, 34.8 to 49.5) in the placebo group (P < 0.001). The median progression-free survival was not met in the combination group (95% CI, 19.3 to not reached) versus 14.7 months (95% CI, 13.0 to 16.5) in the placebo group. The improved progression-free survival was seen across all subgroups. The overall response rate was higher in the combination arm (52.7% vs. 37.1%) as was the clinical benefit rate (80.1% vs. 71.8%). Serious adverse events occurred in 21.3% of patients in the ribociclib group and 11.8% in the placebo group. Serious adverse events were attributed to the study drug in 7.5% of the ribociclib group and 1.5% of the placebo group. The most common adverse events were myelosuppression, nausea, fatigue and diarrhea. Grade 3 and 4 neutropenia was noted in 59.3% in the ribociclib group versus < 1% in the placebo arm. The discontinuation rate due to adverse events in the ribociclib and placebo groups was 7.5% versus 2.1%, respectively. The most common reason for discontinuation was disease progression in 26% in the ribociclib group and 43.7% in the placebo group. Three deaths occurred in the ribociclib group and one in the placebo group. Interruptions in ribociclib occurred in 76.9% of patients. Dose reductions occurred in 53.9% of patients in the ribociclib group versus 7% in the placebo group. The most common reason a dose reduction occurred was neutropenia.

Conclusion. First-line treatment with ribociclib plus letrozole in postmenopausal women with HR-positive, HER-2 negative advanced breast cancer was associated with significantly longer progression-free survival compared with letrozole plus placebo. The improved progression-free survival was seen across all subgroups.

Commentary

Nearly 80% of all breast cancers express hormone receptor positivity. Hormonal therapy has been an important component of treatment for women with hormone-positive breast cancer in both the local and metastatic setting. Many tumors will eventually develop resistance to such therapy with the median progression-free survival with first-line endocrine therapy alone being around 9 months [2]. Cyclin dependent kinases 4 and 6 (CDK4/6) play an important role in estrogen-receptor signaling and cell cycle progression. CDK 4/6 mediates progression through the cell cycle from G1 to S phase via phosphorylation and inactivation of the retinoblastoma tumor suppressor protein [3]. Overexpression of CDK 4/6 in hormone receptor positive breast cancer is thought to play an important role in the development of endocrine therapy resistance [4].

The previously published PALOMA-2 trial, which compared treatment with the CDK 4/6 inhibitor palbociclib plus letrozole with letrozole alone, reported a significant improvement in progression-free survival with the addition of palbociclib (24.8 months vs. 14.5 months) in the front-line setting for women with advanced, hormone-positive breast cancer [5]. The improved progression-free survival with palbociclib was seen across all subgroups with a favorable toxicity profile. The current study represents the second randomized trial to show that the addition of CDK4/6 inhibitor to endocrine-based therapy significantly improves progression-free survival. This benefit was also seen across all patient subgroups including those with liver and lung metastases. In addition, the combination of ribociclib and letrozole also show significantly higher rates of overall response compared with placebo. In general, the addition of ribociclib to letrozole was well tolerated with a very low rate (7.5%) of discontinuation of therapy. Although neutropenia was a frequent complication in the ribociclib group febrile neutropenia occurred in only 1.5% of patients.

The incorporation of CDK4/6 inhibitors to endocrine-based therapy in the front-line setting has proven effective with an impressive early separation of the progression-free survival curves. Both the PALOMA-2 trial and the current MONALEESA-2 trial have shown similar results with approximately 40% improvement in progression-free survival. Whether the results seen in these trials will translate into an improvement in overall survival is yet to be determined. The results of these 2 trial suggest that CDK4/6 inhibitors have activity in both patients who have not received previous treatment with endocrine therapy and in those who received adjuvant endocrine therapy with late (> 12 months) relapse. Further determination of the subset of women who would benefit from the addition of CDK4/6 inhibitors remains an important clinical question. There are currently no clinical biomarkers that can be used to predict whether a patient would benefit from the addition of these medications.

Applications for Clinical Practice

The results of the current trial represent an exciting step forward in the treatment of advanced breast cancer. Palbociclib in combination with endocrine therapy is currently incorporated into clinical practice. The cost of these agents remains a concern; however, most insurance policies will cover them. Clinical trials are ongoing in the neoadjuvant and adjuvant setting for early breast cancer.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy and safety of the CDK4/6 inhibitor ribociclib in combination with letrozole as initial therapy in patients with hormone-receptor (HR)–positive, human epidermal growth factor receptor 2 (HER-2)–negative advanced breast cancer.

Design. Pre-planned interim analysis of a randomized, double-blind, phase 3 clinical trial.

Setting and participants. This study enrolled patients in 29 countries at 223 centers. A total of 668 postmenopausal women underwent randomization, with 334 assigned to receive ribociclib plus letrozole and 334 assigned to receive placebo plus letrozole. All women had HR-positive, HER-2 negative recurrent or metastatic breast cancer and had not received prior systemic therapy. Enrolled patients had either measurable disease on imaging or at least 1 lytic bone lesion. All patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were excluded if they had received prior therapy with a CDK4/6 inhibitor, previous systemic chemotherapy or endocrine therapy. If a patient received an aromatase inhibitor for neoadjuvant or adjuvant therapy, the disease-free interval needed to be more than 12 months to be included in the study. Patients with inflammatory breast cancer or central nervous system involvement were also excluded. Normal cardiac function (normal QT interval) was required for enrollment. The randomization was stratified by presence of liver or lung metastases.

Intervention. The patients were randomized to oral ribociclib 600 mg per day 3 weeks on, 1 week off in a 28-day treatment cycle plus letrozole 2.5 mg daily or placebo plus letrozole. The dosing of ribociclib was based on a prior phase 1 study [1]. Treatment was continued until disease progression, unacceptable toxicity, discontinuation, or death. Dose reductions of ribociclib were allowed; however, dose reductions of letrozole were not permitted. Crossover between treatment arms was not allowed. Patients were assessed with computed tomo-graphy at the time of randomization, every 8 weeks for the first 18 months and every 12 weeks there-after. Patients were monitored for hematological toxicity each cycle. Electrocardiographic assessment was done at screening, on day 15 of cycle 1 and on day 1 of all subsequent cycles to monitor for QT prolongation.

Main outcome measures. The primary outcome was progression-free survival. The secondary outcomes were overall survival, overall response rate (complete or partial response), clinical benefit rate, and safety. Clinical benefit rate was defined as overall response plus stable disease lasting 24 weeks or more. A prespecified interim analysis was planned after disease progression or death was reported in 211 of 302 patients (70%).

Results. The baseline characteristics were balanced between the 2 groups. Visceral disease was present in 58.8% and bone-only disease in 22% of the patients. The median duration of therapy exposure was 13 months in the ribociclib group and 12.4 months in the placebo group. The median duration of follow-up was 15.3 months. After 18 months, progression-free survival was 63% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib/letrozole group versus 42.2% (95% CI, 34.8 to 49.5) in the placebo group (P < 0.001). The median progression-free survival was not met in the combination group (95% CI, 19.3 to not reached) versus 14.7 months (95% CI, 13.0 to 16.5) in the placebo group. The improved progression-free survival was seen across all subgroups. The overall response rate was higher in the combination arm (52.7% vs. 37.1%) as was the clinical benefit rate (80.1% vs. 71.8%). Serious adverse events occurred in 21.3% of patients in the ribociclib group and 11.8% in the placebo group. Serious adverse events were attributed to the study drug in 7.5% of the ribociclib group and 1.5% of the placebo group. The most common adverse events were myelosuppression, nausea, fatigue and diarrhea. Grade 3 and 4 neutropenia was noted in 59.3% in the ribociclib group versus < 1% in the placebo arm. The discontinuation rate due to adverse events in the ribociclib and placebo groups was 7.5% versus 2.1%, respectively. The most common reason for discontinuation was disease progression in 26% in the ribociclib group and 43.7% in the placebo group. Three deaths occurred in the ribociclib group and one in the placebo group. Interruptions in ribociclib occurred in 76.9% of patients. Dose reductions occurred in 53.9% of patients in the ribociclib group versus 7% in the placebo group. The most common reason a dose reduction occurred was neutropenia.

Conclusion. First-line treatment with ribociclib plus letrozole in postmenopausal women with HR-positive, HER-2 negative advanced breast cancer was associated with significantly longer progression-free survival compared with letrozole plus placebo. The improved progression-free survival was seen across all subgroups.

Commentary

Nearly 80% of all breast cancers express hormone receptor positivity. Hormonal therapy has been an important component of treatment for women with hormone-positive breast cancer in both the local and metastatic setting. Many tumors will eventually develop resistance to such therapy with the median progression-free survival with first-line endocrine therapy alone being around 9 months [2]. Cyclin dependent kinases 4 and 6 (CDK4/6) play an important role in estrogen-receptor signaling and cell cycle progression. CDK 4/6 mediates progression through the cell cycle from G1 to S phase via phosphorylation and inactivation of the retinoblastoma tumor suppressor protein [3]. Overexpression of CDK 4/6 in hormone receptor positive breast cancer is thought to play an important role in the development of endocrine therapy resistance [4].

The previously published PALOMA-2 trial, which compared treatment with the CDK 4/6 inhibitor palbociclib plus letrozole with letrozole alone, reported a significant improvement in progression-free survival with the addition of palbociclib (24.8 months vs. 14.5 months) in the front-line setting for women with advanced, hormone-positive breast cancer [5]. The improved progression-free survival with palbociclib was seen across all subgroups with a favorable toxicity profile. The current study represents the second randomized trial to show that the addition of CDK4/6 inhibitor to endocrine-based therapy significantly improves progression-free survival. This benefit was also seen across all patient subgroups including those with liver and lung metastases. In addition, the combination of ribociclib and letrozole also show significantly higher rates of overall response compared with placebo. In general, the addition of ribociclib to letrozole was well tolerated with a very low rate (7.5%) of discontinuation of therapy. Although neutropenia was a frequent complication in the ribociclib group febrile neutropenia occurred in only 1.5% of patients.

The incorporation of CDK4/6 inhibitors to endocrine-based therapy in the front-line setting has proven effective with an impressive early separation of the progression-free survival curves. Both the PALOMA-2 trial and the current MONALEESA-2 trial have shown similar results with approximately 40% improvement in progression-free survival. Whether the results seen in these trials will translate into an improvement in overall survival is yet to be determined. The results of these 2 trial suggest that CDK4/6 inhibitors have activity in both patients who have not received previous treatment with endocrine therapy and in those who received adjuvant endocrine therapy with late (> 12 months) relapse. Further determination of the subset of women who would benefit from the addition of CDK4/6 inhibitors remains an important clinical question. There are currently no clinical biomarkers that can be used to predict whether a patient would benefit from the addition of these medications.

Applications for Clinical Practice

The results of the current trial represent an exciting step forward in the treatment of advanced breast cancer. Palbociclib in combination with endocrine therapy is currently incorporated into clinical practice. The cost of these agents remains a concern; however, most insurance policies will cover them. Clinical trials are ongoing in the neoadjuvant and adjuvant setting for early breast cancer.

—Daniel Isaac, DO, MS