Community Translations

The US Food and Drug Administration awarded regulatory approval this spring to the third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of patients with exon 19 deletion- or exon21 L858R mutation-positive advanced non–small-cell lung cancer (NSCLC) not previously treated for advanced disease.

Osimertinib is designed to target both sensitizing and resistant mutant forms of EGFR, but not the wildtype protein, in an effort to improve safety and efficacy compared with other standard of care (SoC) EGFR inhibitors. It was previously approved in the second-line setting in NSCLC following failure of prior EGFR inhibitor therapy in 2015. The current approval represents a paradigm shift in the front-line treatment of advanced NSCLC, reinforcing the role of osimertinib, which has been recommended in this setting by the National Comprehensive Cancer Network Guidelines in Oncology for more than a year.

Approval was based on the phase 3, multicenter, international, randomized, double-blind, active-controlled FLAURA trial. A total of 556 patients were randomized 1:1 to receive an oral daily dose of 80 mg osimertinib or gefitinib 250 mg or erlotinib 150 mg. The trial was conducted during December 2014 through March 2016 at 132 sites in 29 countries.

Eligible patients were aged 18 or over and had locally advanced or metastatic NSCLC, had not previously received treatment for advanced disease, were eligible for first-line treatment with erlotinib or gefitinib, had locally or centrally confirmed EGFR exon 19 deletion or L858R mutations alone or concurrently with other EGFR mutations, and a World Health Organization Performance Status of 0 (fully active, able to carry on all predisease performance without restriction) or 1 (restricted in strenuous activity but ambulatory and able to carry out light work), and a minimum life expectancy of 12 weeks.

Patients with central nervous system metastases were eligible if their condition was neurologically stable. Patients who had previous definitive treatment or glucocorticoid therapy had to have completed it at least 2 weeks before the start of the trial. Patients were excluded from the trial if they had any previous treatment with any systemic anticancer therapy for advanced NSCLC, had major surgery within 4 weeks of the first dose of the study drug, had radiation therapy to more than 30% of the bone marrow or a wide field of radiation within 4 weeks of the first dose of the study drug, or were currently receiving potent inhibitors or inducers of cytochrome P450 3A4.

Osimertinib cut the risk of disease progression or death by more than 50% compared with standard TKI therapy. The estimated median progression-free survival (PFS) was 18.9 months with osimertinib, compared with 10.2 months for erlotinib or gefitinib (hazard ratio [HR]: 0.46; P < .0001). PFS benefit extended across all prespecified subgroups, including patients with CNS metastases (median PFS: 15.2 months vs 9.6 months; HR: 0.47; P = .0009). Confirmed overall response rate was 77% and 69% in the study and SoC groups, respectively, and estimated duration of response (DoR) was 17.6 months and 9.6 months. At the time of analysis, there were too few deaths to compare overall survival.

The most common adverse events (AEs) experienced by patients treated with osimertinib were diarrhea, rash, dry skin, nail toxicity, stomatitis, and reduced appetite. Serious AEs occurred in 4% of patients treated with osimertinib, most commonly involving pneumonia, interstitial lung disease/pneumonitis, and pulmonary embolism (PE). The rate of grade 3/4 AEs was 33.7% in the osimertinib group and 44.8% in the SoC group. Patients treated with osimertinib were less likely to discontinue treatment due to AEs (13.3% vs 18.1% of those receiving SoC).

The US Food and Drug Administration awarded regulatory approval this spring to the third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of patients with exon 19 deletion- or exon21 L858R mutation-positive advanced non–small-cell lung cancer (NSCLC) not previously treated for advanced disease.

Osimertinib is designed to target both sensitizing and resistant mutant forms of EGFR, but not the wildtype protein, in an effort to improve safety and efficacy compared with other standard of care (SoC) EGFR inhibitors. It was previously approved in the second-line setting in NSCLC following failure of prior EGFR inhibitor therapy in 2015. The current approval represents a paradigm shift in the front-line treatment of advanced NSCLC, reinforcing the role of osimertinib, which has been recommended in this setting by the National Comprehensive Cancer Network Guidelines in Oncology for more than a year.

Approval was based on the phase 3, multicenter, international, randomized, double-blind, active-controlled FLAURA trial. A total of 556 patients were randomized 1:1 to receive an oral daily dose of 80 mg osimertinib or gefitinib 250 mg or erlotinib 150 mg. The trial was conducted during December 2014 through March 2016 at 132 sites in 29 countries.

Eligible patients were aged 18 or over and had locally advanced or metastatic NSCLC, had not previously received treatment for advanced disease, were eligible for first-line treatment with erlotinib or gefitinib, had locally or centrally confirmed EGFR exon 19 deletion or L858R mutations alone or concurrently with other EGFR mutations, and a World Health Organization Performance Status of 0 (fully active, able to carry on all predisease performance without restriction) or 1 (restricted in strenuous activity but ambulatory and able to carry out light work), and a minimum life expectancy of 12 weeks.

Patients with central nervous system metastases were eligible if their condition was neurologically stable. Patients who had previous definitive treatment or glucocorticoid therapy had to have completed it at least 2 weeks before the start of the trial. Patients were excluded from the trial if they had any previous treatment with any systemic anticancer therapy for advanced NSCLC, had major surgery within 4 weeks of the first dose of the study drug, had radiation therapy to more than 30% of the bone marrow or a wide field of radiation within 4 weeks of the first dose of the study drug, or were currently receiving potent inhibitors or inducers of cytochrome P450 3A4.

Osimertinib cut the risk of disease progression or death by more than 50% compared with standard TKI therapy. The estimated median progression-free survival (PFS) was 18.9 months with osimertinib, compared with 10.2 months for erlotinib or gefitinib (hazard ratio [HR]: 0.46; P < .0001). PFS benefit extended across all prespecified subgroups, including patients with CNS metastases (median PFS: 15.2 months vs 9.6 months; HR: 0.47; P = .0009). Confirmed overall response rate was 77% and 69% in the study and SoC groups, respectively, and estimated duration of response (DoR) was 17.6 months and 9.6 months. At the time of analysis, there were too few deaths to compare overall survival.

The most common adverse events (AEs) experienced by patients treated with osimertinib were diarrhea, rash, dry skin, nail toxicity, stomatitis, and reduced appetite. Serious AEs occurred in 4% of patients treated with osimertinib, most commonly involving pneumonia, interstitial lung disease/pneumonitis, and pulmonary embolism (PE). The rate of grade 3/4 AEs was 33.7% in the osimertinib group and 44.8% in the SoC group. Patients treated with osimertinib were less likely to discontinue treatment due to AEs (13.3% vs 18.1% of those receiving SoC).

The US Food and Drug Administration awarded regulatory approval this spring to the third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of patients with exon 19 deletion- or exon21 L858R mutation-positive advanced non–small-cell lung cancer (NSCLC) not previously treated for advanced disease.

Osimertinib is designed to target both sensitizing and resistant mutant forms of EGFR, but not the wildtype protein, in an effort to improve safety and efficacy compared with other standard of care (SoC) EGFR inhibitors. It was previously approved in the second-line setting in NSCLC following failure of prior EGFR inhibitor therapy in 2015. The current approval represents a paradigm shift in the front-line treatment of advanced NSCLC, reinforcing the role of osimertinib, which has been recommended in this setting by the National Comprehensive Cancer Network Guidelines in Oncology for more than a year.

Approval was based on the phase 3, multicenter, international, randomized, double-blind, active-controlled FLAURA trial. A total of 556 patients were randomized 1:1 to receive an oral daily dose of 80 mg osimertinib or gefitinib 250 mg or erlotinib 150 mg. The trial was conducted during December 2014 through March 2016 at 132 sites in 29 countries.

Eligible patients were aged 18 or over and had locally advanced or metastatic NSCLC, had not previously received treatment for advanced disease, were eligible for first-line treatment with erlotinib or gefitinib, had locally or centrally confirmed EGFR exon 19 deletion or L858R mutations alone or concurrently with other EGFR mutations, and a World Health Organization Performance Status of 0 (fully active, able to carry on all predisease performance without restriction) or 1 (restricted in strenuous activity but ambulatory and able to carry out light work), and a minimum life expectancy of 12 weeks.

Patients with central nervous system metastases were eligible if their condition was neurologically stable. Patients who had previous definitive treatment or glucocorticoid therapy had to have completed it at least 2 weeks before the start of the trial. Patients were excluded from the trial if they had any previous treatment with any systemic anticancer therapy for advanced NSCLC, had major surgery within 4 weeks of the first dose of the study drug, had radiation therapy to more than 30% of the bone marrow or a wide field of radiation within 4 weeks of the first dose of the study drug, or were currently receiving potent inhibitors or inducers of cytochrome P450 3A4.

Osimertinib cut the risk of disease progression or death by more than 50% compared with standard TKI therapy. The estimated median progression-free survival (PFS) was 18.9 months with osimertinib, compared with 10.2 months for erlotinib or gefitinib (hazard ratio [HR]: 0.46; P < .0001). PFS benefit extended across all prespecified subgroups, including patients with CNS metastases (median PFS: 15.2 months vs 9.6 months; HR: 0.47; P = .0009). Confirmed overall response rate was 77% and 69% in the study and SoC groups, respectively, and estimated duration of response (DoR) was 17.6 months and 9.6 months. At the time of analysis, there were too few deaths to compare overall survival.

The most common adverse events (AEs) experienced by patients treated with osimertinib were diarrhea, rash, dry skin, nail toxicity, stomatitis, and reduced appetite. Serious AEs occurred in 4% of patients treated with osimertinib, most commonly involving pneumonia, interstitial lung disease/pneumonitis, and pulmonary embolism (PE). The rate of grade 3/4 AEs was 33.7% in the osimertinib group and 44.8% in the SoC group. Patients treated with osimertinib were less likely to discontinue treatment due to AEs (13.3% vs 18.1% of those receiving SoC).

On April 30, 2018, the US Food and Drug Administration expanded the indication for the combined use of dabrafenib and trametinib to include adjuvant treatment of BRAF-mutant melanoma following complete surgical resection. Dabrafenib is an inhibitor of the BRAF kinase, and trametinib is an inhibitor of the MEK kinase, both of which are components of the mitogen-activated protein kinase (MAPK) signaling pathway. The 2 drugs are already approved as both single agents and in combination for the treatment of BRAF-mutated metastatic melanoma.

The current approval was based on data from a phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial. The COMBI-AD trial was carried out from January 2013 through December 2014 at 169 sites in 26 countries. A total of 870 patients with stage III melanoma and BRAF V600E/K mutations and pathologic involvement of regional lymph nodes following complete resection were randomly assigned to receive dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily, or 2 matched placebos for up to 1 year. Randomization was stratified according to BRAF mutation status (V600E or V600K) and disease stage (IIIA, IIIB or IIIC).

Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (on a scale of 1-5, with higher scores indicating greater disability). Patients who had undergone previous systemic anticancer therapy or radiotherapy were excluded from the study.

The primary endpoint was relapse-free survival (RFS), defined as the time from randomization to disease recurrence or death from any cause. Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety. Clinical examination and imaging by computed tomography, magnetic resonance imaging, or both was performed every 3 months for the first 2 years and then every 6 months until disease recurrence or trial completion.

As of the data cut-off, the combination of dabrafenib and trametinib reduced the risk of disease recurrence or death by 53% compared with placebo (hazard ratio [HR], 0.47; P < .001). Median RFS was not yet reached in the combination arm, compared with 16.6 months in the placebo arm. The RFS benefit was observed across all prespecified subgroups, and the combination was also found to improve OS, DMFS, and FFR.

The most common adverse events (AEs) included pyrexia, fatigue, nausea, rash, vomiting, diarrhea, chills, and myalgia. Overall, 97% of patients experienced an AE, 41% experienced a grade 3/4 AE, and 26% had an AE that led to treatment discontinuation. In patients treated with placebo, those numbers were 88%, 14%, and 3%, respectively.

On April 30, 2018, the US Food and Drug Administration expanded the indication for the combined use of dabrafenib and trametinib to include adjuvant treatment of BRAF-mutant melanoma following complete surgical resection. Dabrafenib is an inhibitor of the BRAF kinase, and trametinib is an inhibitor of the MEK kinase, both of which are components of the mitogen-activated protein kinase (MAPK) signaling pathway. The 2 drugs are already approved as both single agents and in combination for the treatment of BRAF-mutated metastatic melanoma.

The current approval was based on data from a phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial. The COMBI-AD trial was carried out from January 2013 through December 2014 at 169 sites in 26 countries. A total of 870 patients with stage III melanoma and BRAF V600E/K mutations and pathologic involvement of regional lymph nodes following complete resection were randomly assigned to receive dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily, or 2 matched placebos for up to 1 year. Randomization was stratified according to BRAF mutation status (V600E or V600K) and disease stage (IIIA, IIIB or IIIC).

Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (on a scale of 1-5, with higher scores indicating greater disability). Patients who had undergone previous systemic anticancer therapy or radiotherapy were excluded from the study.

The primary endpoint was relapse-free survival (RFS), defined as the time from randomization to disease recurrence or death from any cause. Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety. Clinical examination and imaging by computed tomography, magnetic resonance imaging, or both was performed every 3 months for the first 2 years and then every 6 months until disease recurrence or trial completion.

As of the data cut-off, the combination of dabrafenib and trametinib reduced the risk of disease recurrence or death by 53% compared with placebo (hazard ratio [HR], 0.47; P < .001). Median RFS was not yet reached in the combination arm, compared with 16.6 months in the placebo arm. The RFS benefit was observed across all prespecified subgroups, and the combination was also found to improve OS, DMFS, and FFR.

The most common adverse events (AEs) included pyrexia, fatigue, nausea, rash, vomiting, diarrhea, chills, and myalgia. Overall, 97% of patients experienced an AE, 41% experienced a grade 3/4 AE, and 26% had an AE that led to treatment discontinuation. In patients treated with placebo, those numbers were 88%, 14%, and 3%, respectively.

On April 30, 2018, the US Food and Drug Administration expanded the indication for the combined use of dabrafenib and trametinib to include adjuvant treatment of BRAF-mutant melanoma following complete surgical resection. Dabrafenib is an inhibitor of the BRAF kinase, and trametinib is an inhibitor of the MEK kinase, both of which are components of the mitogen-activated protein kinase (MAPK) signaling pathway. The 2 drugs are already approved as both single agents and in combination for the treatment of BRAF-mutated metastatic melanoma.

The current approval was based on data from a phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial. The COMBI-AD trial was carried out from January 2013 through December 2014 at 169 sites in 26 countries. A total of 870 patients with stage III melanoma and BRAF V600E/K mutations and pathologic involvement of regional lymph nodes following complete resection were randomly assigned to receive dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily, or 2 matched placebos for up to 1 year. Randomization was stratified according to BRAF mutation status (V600E or V600K) and disease stage (IIIA, IIIB or IIIC).

Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (on a scale of 1-5, with higher scores indicating greater disability). Patients who had undergone previous systemic anticancer therapy or radiotherapy were excluded from the study.

The primary endpoint was relapse-free survival (RFS), defined as the time from randomization to disease recurrence or death from any cause. Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety. Clinical examination and imaging by computed tomography, magnetic resonance imaging, or both was performed every 3 months for the first 2 years and then every 6 months until disease recurrence or trial completion.

As of the data cut-off, the combination of dabrafenib and trametinib reduced the risk of disease recurrence or death by 53% compared with placebo (hazard ratio [HR], 0.47; P < .001). Median RFS was not yet reached in the combination arm, compared with 16.6 months in the placebo arm. The RFS benefit was observed across all prespecified subgroups, and the combination was also found to improve OS, DMFS, and FFR.

The most common adverse events (AEs) included pyrexia, fatigue, nausea, rash, vomiting, diarrhea, chills, and myalgia. Overall, 97% of patients experienced an AE, 41% experienced a grade 3/4 AE, and 26% had an AE that led to treatment discontinuation. In patients treated with placebo, those numbers were 88%, 14%, and 3%, respectively.

The approval of Bcl-2 inhibitor venetoclax was expanded by the US Food and Drug Administration in June 2018 to include the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), regardless of their genotype, who have received at least 1 prior therapy.¹ It was previously approved in 2016 for the treatment of patients who had a chromosome 17p deletion, which leads to loss of the tumor-suppressor gene TP53.

Approval was based on the positive results of the phase 3, randomized, multicenter, open-label MURANO trial in which 389 patients were randomized 1:1 to receive a combination of venetoclax and the CD20-targeting monoclonal antibody rituximab (venetoclax–rituximab) or bendamustine in combination with rituximab (bendamustine–rituximab).

Eligible patients were 18 years of age or older, had been diagnosed with relapsed/refractory CLL that required treatment, had received 1-3 prior therapies (including at least 1 chemotherapy regimen), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (on a 5-point scale, with 5 indicating the greatest level of disability), and had adequate bone marrow, renal, and hepatic function.

Patients who had received prior bendamustine treatment were eligible for the trial provided they had experienced a duration of response of 24 months or longer. However, patients with transformed CLL, central nervous system involvement, prior treatment with allogeneic or autologous stem cell transplant, major organ dysfunction, other active malignancy, or who were pregnant or breastfeeding, were excluded from the study.

Patients in the venetoclax arm received a 5-week ramp-up schedule, followed by a dose of 400 mg once daily for 24 months. Rituximab treatment started at the end of the venetoclax ramp-up period and was administered at a dose of 375 mg/m² intravenously on cycle 1 day 1 and 500 mg/m² on day 1 of cycles 2-6. In the control arm, patients received 6 cycles with the same rituximab dosing and schedule as the study group and bendamustine at a dose of 70 mg/m² on days 1 and 2 of each 28-day cycle.

The primary endpoint was progression-free survival (PFS), as assessed by an independent review committee over a median follow-up of 23 months. Median PFS was significantly improved in the venetoclax arm (not yet reached versus 18.1 months in the bendamustine arm [HR, 0.19; P < .001]). In addition, objective response rate (ORR) and event-free survival (EFS) also favored the venetoclax arm; ORR was 92% compared with 72%, respectively, and 2-year EFS was 84.9% compared with 34.8%. There was also a trend toward improved 24-month overall survival (OS) rate (91.9% vs 86.6%), however this did not achieve statistical significance, nor did median OS.

The most common adverse events (AEs) in patients treated with venetoclax were neutropenia, diarrhea, upper-respiratory tract infection, fatigue, cough, and nausea. Grade 3/4 neutropenia occurred in 64% of patients, and serious AEs in 46% of patients. Serious infections occurred in 21% of patients, most commonly pneumonia. Ten deaths in the venetoclax arm were attributed to treatment, compared with 11 deaths in the bendamustine arm.²

The prescribing information details warnings and precautions relating to the risk of tumor lysis syndrome, which is increased in patients with higher tumor burden, reduced renal function, or in receipt of strong or moderate CYP3A inhibitors or P-gp inhibitors during the ramp-up stage. Patients should receive appropriate preventive strategies, including hydration and antihyperuricemics, blood chemistry should be monitored and abnormalities managed promptly, and dosing should be interrupted or adjusted as necessary.

Other warnings relate to neutropenia (complete blood counts should be monitored throughout treatment and venetoclax treatment interrupted or dose reduced for severe neutropenia, alongside possible use of supportive measures), immunization (live vaccines should not be administered before or during treatment or after treatment until B-cell recovery, and patients should be advised of the potentially reduced efficacy of vaccines), and embryofetal toxicity (patients should be advised of the risks and the need for effective contraception during and after treatment). Venetoclax is marketed as Venclexta by Genentech.³

The approval of Bcl-2 inhibitor venetoclax was expanded by the US Food and Drug Administration in June 2018 to include the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), regardless of their genotype, who have received at least 1 prior therapy.¹ It was previously approved in 2016 for the treatment of patients who had a chromosome 17p deletion, which leads to loss of the tumor-suppressor gene TP53.

Approval was based on the positive results of the phase 3, randomized, multicenter, open-label MURANO trial in which 389 patients were randomized 1:1 to receive a combination of venetoclax and the CD20-targeting monoclonal antibody rituximab (venetoclax–rituximab) or bendamustine in combination with rituximab (bendamustine–rituximab).

Eligible patients were 18 years of age or older, had been diagnosed with relapsed/refractory CLL that required treatment, had received 1-3 prior therapies (including at least 1 chemotherapy regimen), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (on a 5-point scale, with 5 indicating the greatest level of disability), and had adequate bone marrow, renal, and hepatic function.

Patients who had received prior bendamustine treatment were eligible for the trial provided they had experienced a duration of response of 24 months or longer. However, patients with transformed CLL, central nervous system involvement, prior treatment with allogeneic or autologous stem cell transplant, major organ dysfunction, other active malignancy, or who were pregnant or breastfeeding, were excluded from the study.

Patients in the venetoclax arm received a 5-week ramp-up schedule, followed by a dose of 400 mg once daily for 24 months. Rituximab treatment started at the end of the venetoclax ramp-up period and was administered at a dose of 375 mg/m² intravenously on cycle 1 day 1 and 500 mg/m² on day 1 of cycles 2-6. In the control arm, patients received 6 cycles with the same rituximab dosing and schedule as the study group and bendamustine at a dose of 70 mg/m² on days 1 and 2 of each 28-day cycle.

The primary endpoint was progression-free survival (PFS), as assessed by an independent review committee over a median follow-up of 23 months. Median PFS was significantly improved in the venetoclax arm (not yet reached versus 18.1 months in the bendamustine arm [HR, 0.19; P < .001]). In addition, objective response rate (ORR) and event-free survival (EFS) also favored the venetoclax arm; ORR was 92% compared with 72%, respectively, and 2-year EFS was 84.9% compared with 34.8%. There was also a trend toward improved 24-month overall survival (OS) rate (91.9% vs 86.6%), however this did not achieve statistical significance, nor did median OS.

The most common adverse events (AEs) in patients treated with venetoclax were neutropenia, diarrhea, upper-respiratory tract infection, fatigue, cough, and nausea. Grade 3/4 neutropenia occurred in 64% of patients, and serious AEs in 46% of patients. Serious infections occurred in 21% of patients, most commonly pneumonia. Ten deaths in the venetoclax arm were attributed to treatment, compared with 11 deaths in the bendamustine arm.²

The prescribing information details warnings and precautions relating to the risk of tumor lysis syndrome, which is increased in patients with higher tumor burden, reduced renal function, or in receipt of strong or moderate CYP3A inhibitors or P-gp inhibitors during the ramp-up stage. Patients should receive appropriate preventive strategies, including hydration and antihyperuricemics, blood chemistry should be monitored and abnormalities managed promptly, and dosing should be interrupted or adjusted as necessary.

Other warnings relate to neutropenia (complete blood counts should be monitored throughout treatment and venetoclax treatment interrupted or dose reduced for severe neutropenia, alongside possible use of supportive measures), immunization (live vaccines should not be administered before or during treatment or after treatment until B-cell recovery, and patients should be advised of the potentially reduced efficacy of vaccines), and embryofetal toxicity (patients should be advised of the risks and the need for effective contraception during and after treatment). Venetoclax is marketed as Venclexta by Genentech.³

The approval of Bcl-2 inhibitor venetoclax was expanded by the US Food and Drug Administration in June 2018 to include the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), regardless of their genotype, who have received at least 1 prior therapy.¹ It was previously approved in 2016 for the treatment of patients who had a chromosome 17p deletion, which leads to loss of the tumor-suppressor gene TP53.

Approval was based on the positive results of the phase 3, randomized, multicenter, open-label MURANO trial in which 389 patients were randomized 1:1 to receive a combination of venetoclax and the CD20-targeting monoclonal antibody rituximab (venetoclax–rituximab) or bendamustine in combination with rituximab (bendamustine–rituximab).

Eligible patients were 18 years of age or older, had been diagnosed with relapsed/refractory CLL that required treatment, had received 1-3 prior therapies (including at least 1 chemotherapy regimen), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (on a 5-point scale, with 5 indicating the greatest level of disability), and had adequate bone marrow, renal, and hepatic function.

Patients who had received prior bendamustine treatment were eligible for the trial provided they had experienced a duration of response of 24 months or longer. However, patients with transformed CLL, central nervous system involvement, prior treatment with allogeneic or autologous stem cell transplant, major organ dysfunction, other active malignancy, or who were pregnant or breastfeeding, were excluded from the study.

Patients in the venetoclax arm received a 5-week ramp-up schedule, followed by a dose of 400 mg once daily for 24 months. Rituximab treatment started at the end of the venetoclax ramp-up period and was administered at a dose of 375 mg/m² intravenously on cycle 1 day 1 and 500 mg/m² on day 1 of cycles 2-6. In the control arm, patients received 6 cycles with the same rituximab dosing and schedule as the study group and bendamustine at a dose of 70 mg/m² on days 1 and 2 of each 28-day cycle.

The primary endpoint was progression-free survival (PFS), as assessed by an independent review committee over a median follow-up of 23 months. Median PFS was significantly improved in the venetoclax arm (not yet reached versus 18.1 months in the bendamustine arm [HR, 0.19; P < .001]). In addition, objective response rate (ORR) and event-free survival (EFS) also favored the venetoclax arm; ORR was 92% compared with 72%, respectively, and 2-year EFS was 84.9% compared with 34.8%. There was also a trend toward improved 24-month overall survival (OS) rate (91.9% vs 86.6%), however this did not achieve statistical significance, nor did median OS.

The most common adverse events (AEs) in patients treated with venetoclax were neutropenia, diarrhea, upper-respiratory tract infection, fatigue, cough, and nausea. Grade 3/4 neutropenia occurred in 64% of patients, and serious AEs in 46% of patients. Serious infections occurred in 21% of patients, most commonly pneumonia. Ten deaths in the venetoclax arm were attributed to treatment, compared with 11 deaths in the bendamustine arm.²

The prescribing information details warnings and precautions relating to the risk of tumor lysis syndrome, which is increased in patients with higher tumor burden, reduced renal function, or in receipt of strong or moderate CYP3A inhibitors or P-gp inhibitors during the ramp-up stage. Patients should receive appropriate preventive strategies, including hydration and antihyperuricemics, blood chemistry should be monitored and abnormalities managed promptly, and dosing should be interrupted or adjusted as necessary.

Other warnings relate to neutropenia (complete blood counts should be monitored throughout treatment and venetoclax treatment interrupted or dose reduced for severe neutropenia, alongside possible use of supportive measures), immunization (live vaccines should not be administered before or during treatment or after treatment until B-cell recovery, and patients should be advised of the potentially reduced efficacy of vaccines), and embryofetal toxicity (patients should be advised of the risks and the need for effective contraception during and after treatment). Venetoclax is marketed as Venclexta by Genentech.³

In April 2018, the US Food and Drug Administration expanded the approval of the combination of nivolumab and ipilimumab into a new indication, following a previous approval in patients with metastatic melanoma. The double immune checkpoint inhibitor combination was approved on the basis of the phase 3 CheckMate-214 study for the treatment of patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma (RCC).¹

Nivolumab monotherapy is already approved in the second-line setting for the treatment of advanced RCC, and the demonstration of significantly improved overall survival (OS) in this study suggests that the combination should supplant sunitinib in the front-line setting in the treatment of this type of cancer.

A total of 1,096 patients at 175 sites in 28 countries were randomized 1:1 to receive nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) intravenously every 3 weeks for 4 doses in an induction phase, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks in a maintenance phase or sunitinib (50 mg) orally daily for 4 weeks of each 6-week cycle.

Eligible patients were 18 years or older, had previously untreated advanced RCC with a clear-cell component, had measurable disease according to Response Evaluation Criteria in Solid Tumors (version 1.1), and had a Karnofsky performance status of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability). Patients with central nervous system metastases or autoimmune disease who were being treated with glucocorticoids and immunosuppressants were excluded from the study.

Around three-quarters of patients with advanced RCC have intermediate- or poor-risk disease and experience worse outcomes than patients with favorable-risk disease. Patients in CheckMate-214 were stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk score as favorable (score of 0), intermediate (score of 1 or 2) or poor risk (score of 3-6), according to the number of risk factors present.

Risk factors included a Karnofsky performance score of 70, time from initial diagnosis to randomization of <1 year, a hemoglobin level below the lower limit of normal, a corrected serum calcium concentration of >10 mg/dL, or an absolute neutrophil count or platelet count above the upper limit of normal. Patients were also stratified according to geographic region (United States versus Canada and Europe versus the rest of the world).

The coprimary endpoints were objective response rate (ORR), progression-free survival (PFS), and OS in a subset of 847 intermediate- and poor-risk patients. Over a median follow-up of 25.2 months, there was a statistically significant improvement in OS and ORR in patients treated with nivolumab and ipilimumab (mPFS not reached; ORR, 41.6%), compared with sunitinib (OS, 25.9 months; ORR, 26.5%), with P <.001 for both. The immunotherapy combination was favored across subgroups.

The most common adverse events (AEs) in patients treated with nivolumab and ipilimumab included fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The combination was associated with fewer grade 3/4 AEs (63% vs 46% for sunitinib), but a higher rate of treatment discontinuations because of AEs (31% vs 21%, respectively). There were 8 deaths in the combination arm, and 4 in the sunitinib arm that were reported to be treatment related.²

The warnings and precautions related to nivolumab–ipilimumab combination therapy outlined in the prescribing information include mostly immune-mediated AEs, such as immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. There are also warnings relating to the risk of infusion reactions and the potential for embryofetal toxicity.

Patients should be monitored for hyperglycemia and for changes in liver, thyroid, renal, and neurologic function. Treatment with nivolumab and ipilimumab should be withheld for moderate and permanently discontinued for severe or life-threatening immune-mediated pneumonitis, colitis, and hepatitis, as well as transaminase or total bilirubin elevation. It should also be withheld for moderate or severe hypophysitis and serum creatinine elevation, moderate adrenal insufficiency and severe hyperglycemia, and permanently discontinued for life-threatening hypophysitis and serum creatinine elevation, severe or life-threatening adrenal insufficiency, and life-threatening hyperglycemia.

New-onset moderate to severe neurologic signs or symptoms warrant treatment being withheld, and immune-mediated encephalitis should lead to treatment discontinuation. For mild or moderate infusion reactions, the infusion rate can be slowed or interrupted, and infusions should be discontinued in the event of severe or life-threatening infusion reactions. Patients should be advised of the potential for fetal harm and the need for effective contraception during and after treatment. Ipilimumab and nivolumab are marketed as Yervoy and Opdivo, respectively, by Bristol-Myers Squibb.^3,4

In April 2018, the US Food and Drug Administration expanded the approval of the combination of nivolumab and ipilimumab into a new indication, following a previous approval in patients with metastatic melanoma. The double immune checkpoint inhibitor combination was approved on the basis of the phase 3 CheckMate-214 study for the treatment of patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma (RCC).¹

Nivolumab monotherapy is already approved in the second-line setting for the treatment of advanced RCC, and the demonstration of significantly improved overall survival (OS) in this study suggests that the combination should supplant sunitinib in the front-line setting in the treatment of this type of cancer.

A total of 1,096 patients at 175 sites in 28 countries were randomized 1:1 to receive nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) intravenously every 3 weeks for 4 doses in an induction phase, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks in a maintenance phase or sunitinib (50 mg) orally daily for 4 weeks of each 6-week cycle.

Eligible patients were 18 years or older, had previously untreated advanced RCC with a clear-cell component, had measurable disease according to Response Evaluation Criteria in Solid Tumors (version 1.1), and had a Karnofsky performance status of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability). Patients with central nervous system metastases or autoimmune disease who were being treated with glucocorticoids and immunosuppressants were excluded from the study.

Around three-quarters of patients with advanced RCC have intermediate- or poor-risk disease and experience worse outcomes than patients with favorable-risk disease. Patients in CheckMate-214 were stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk score as favorable (score of 0), intermediate (score of 1 or 2) or poor risk (score of 3-6), according to the number of risk factors present.

Risk factors included a Karnofsky performance score of 70, time from initial diagnosis to randomization of <1 year, a hemoglobin level below the lower limit of normal, a corrected serum calcium concentration of >10 mg/dL, or an absolute neutrophil count or platelet count above the upper limit of normal. Patients were also stratified according to geographic region (United States versus Canada and Europe versus the rest of the world).

The coprimary endpoints were objective response rate (ORR), progression-free survival (PFS), and OS in a subset of 847 intermediate- and poor-risk patients. Over a median follow-up of 25.2 months, there was a statistically significant improvement in OS and ORR in patients treated with nivolumab and ipilimumab (mPFS not reached; ORR, 41.6%), compared with sunitinib (OS, 25.9 months; ORR, 26.5%), with P <.001 for both. The immunotherapy combination was favored across subgroups.

The most common adverse events (AEs) in patients treated with nivolumab and ipilimumab included fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The combination was associated with fewer grade 3/4 AEs (63% vs 46% for sunitinib), but a higher rate of treatment discontinuations because of AEs (31% vs 21%, respectively). There were 8 deaths in the combination arm, and 4 in the sunitinib arm that were reported to be treatment related.²

The warnings and precautions related to nivolumab–ipilimumab combination therapy outlined in the prescribing information include mostly immune-mediated AEs, such as immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. There are also warnings relating to the risk of infusion reactions and the potential for embryofetal toxicity.

Patients should be monitored for hyperglycemia and for changes in liver, thyroid, renal, and neurologic function. Treatment with nivolumab and ipilimumab should be withheld for moderate and permanently discontinued for severe or life-threatening immune-mediated pneumonitis, colitis, and hepatitis, as well as transaminase or total bilirubin elevation. It should also be withheld for moderate or severe hypophysitis and serum creatinine elevation, moderate adrenal insufficiency and severe hyperglycemia, and permanently discontinued for life-threatening hypophysitis and serum creatinine elevation, severe or life-threatening adrenal insufficiency, and life-threatening hyperglycemia.

New-onset moderate to severe neurologic signs or symptoms warrant treatment being withheld, and immune-mediated encephalitis should lead to treatment discontinuation. For mild or moderate infusion reactions, the infusion rate can be slowed or interrupted, and infusions should be discontinued in the event of severe or life-threatening infusion reactions. Patients should be advised of the potential for fetal harm and the need for effective contraception during and after treatment. Ipilimumab and nivolumab are marketed as Yervoy and Opdivo, respectively, by Bristol-Myers Squibb.^3,4

In April 2018, the US Food and Drug Administration expanded the approval of the combination of nivolumab and ipilimumab into a new indication, following a previous approval in patients with metastatic melanoma. The double immune checkpoint inhibitor combination was approved on the basis of the phase 3 CheckMate-214 study for the treatment of patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma (RCC).¹

Nivolumab monotherapy is already approved in the second-line setting for the treatment of advanced RCC, and the demonstration of significantly improved overall survival (OS) in this study suggests that the combination should supplant sunitinib in the front-line setting in the treatment of this type of cancer.

A total of 1,096 patients at 175 sites in 28 countries were randomized 1:1 to receive nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) intravenously every 3 weeks for 4 doses in an induction phase, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks in a maintenance phase or sunitinib (50 mg) orally daily for 4 weeks of each 6-week cycle.

Eligible patients were 18 years or older, had previously untreated advanced RCC with a clear-cell component, had measurable disease according to Response Evaluation Criteria in Solid Tumors (version 1.1), and had a Karnofsky performance status of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability). Patients with central nervous system metastases or autoimmune disease who were being treated with glucocorticoids and immunosuppressants were excluded from the study.

Around three-quarters of patients with advanced RCC have intermediate- or poor-risk disease and experience worse outcomes than patients with favorable-risk disease. Patients in CheckMate-214 were stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk score as favorable (score of 0), intermediate (score of 1 or 2) or poor risk (score of 3-6), according to the number of risk factors present.

Risk factors included a Karnofsky performance score of 70, time from initial diagnosis to randomization of <1 year, a hemoglobin level below the lower limit of normal, a corrected serum calcium concentration of >10 mg/dL, or an absolute neutrophil count or platelet count above the upper limit of normal. Patients were also stratified according to geographic region (United States versus Canada and Europe versus the rest of the world).

The coprimary endpoints were objective response rate (ORR), progression-free survival (PFS), and OS in a subset of 847 intermediate- and poor-risk patients. Over a median follow-up of 25.2 months, there was a statistically significant improvement in OS and ORR in patients treated with nivolumab and ipilimumab (mPFS not reached; ORR, 41.6%), compared with sunitinib (OS, 25.9 months; ORR, 26.5%), with P <.001 for both. The immunotherapy combination was favored across subgroups.

The most common adverse events (AEs) in patients treated with nivolumab and ipilimumab included fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The combination was associated with fewer grade 3/4 AEs (63% vs 46% for sunitinib), but a higher rate of treatment discontinuations because of AEs (31% vs 21%, respectively). There were 8 deaths in the combination arm, and 4 in the sunitinib arm that were reported to be treatment related.²

The warnings and precautions related to nivolumab–ipilimumab combination therapy outlined in the prescribing information include mostly immune-mediated AEs, such as immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. There are also warnings relating to the risk of infusion reactions and the potential for embryofetal toxicity.

Patients should be monitored for hyperglycemia and for changes in liver, thyroid, renal, and neurologic function. Treatment with nivolumab and ipilimumab should be withheld for moderate and permanently discontinued for severe or life-threatening immune-mediated pneumonitis, colitis, and hepatitis, as well as transaminase or total bilirubin elevation. It should also be withheld for moderate or severe hypophysitis and serum creatinine elevation, moderate adrenal insufficiency and severe hyperglycemia, and permanently discontinued for life-threatening hypophysitis and serum creatinine elevation, severe or life-threatening adrenal insufficiency, and life-threatening hyperglycemia.

New-onset moderate to severe neurologic signs or symptoms warrant treatment being withheld, and immune-mediated encephalitis should lead to treatment discontinuation. For mild or moderate infusion reactions, the infusion rate can be slowed or interrupted, and infusions should be discontinued in the event of severe or life-threatening infusion reactions. Patients should be advised of the potential for fetal harm and the need for effective contraception during and after treatment. Ipilimumab and nivolumab are marketed as Yervoy and Opdivo, respectively, by Bristol-Myers Squibb.^3,4

The small-molecule tyrosine kinase inhibitor neratinib is now approved for the extended adjuvant treatment of patients with early-stage HER2 [human epidermal growth factor receptor]-positive breast cancer following postoperative trastuzumab. Trastuzumab is a HER2-targeted monoclonal antibody that has become standard of care in combination with chemotherapy for the treatment of this patient population in which it significantly improves survival. However, disease recurrence will occur in about a quarter of trastuzumab-treated patients owing to the development of resistance.

Neratinib may help overcome trastuzumab resistance thanks to its potent inhibition of the downstream phosphorylation of HER2 and other members of the HER family. Its approval was based on the phase 3 ExteNET trial, in which extended adjuvant treatment with neratinib was compared with placebo among 2,840 patients who remained disease free after 1 year of adjuvant trastuzumab.¹

The ExteNET trial was performed at 495 centers in Europe, Asia, Australia, New Zealand, and South America. Patients aged 18 years or older (≥20 years in Japan), with stage 1-3 HER2-positive breast cancer, who completed neoadjuvant and adjuvant trastuzumab therapy up to 1 year before randomization were eligible. Patients also had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), normal organ function, and a left ventricular ejection fraction within normal institutional range. Patients with clinically significant cardiac, gastrointesintal or psychiatric comorbidities and those who were not able to swallow oral medication were excluded from the study.

Patients randomly received oral neratinib 240 mg per day or matching placebo, and randomization was stratified according to HR status (positive or negative), nodal status (0, 1-3, or ≥4) and trastuzumab-adjuvant regimen (sequentially or concurrently with chemotherapy).

The primary outcome was invasive disease-free survival (iDFS). The 2-year iDFS rate was 93.9% for neratinib, compared with 91.6% for placebo (hazard ratio [HR], 0.66; P < .008). Recently, a 5-year analysis of the ExteNET trial showed that after a median follow-up of 5.2 years, the iDFS rates were 90.2% vs 87.7% (HR, 0.73; P = .0083).²

Adverse events

The most common adverse event (AE) was diarrhea, in 95% of patients, 40% of whom had grade 3 diarrhea, leading to dose reduction in 26% of patients and discontinuation in 16.8% of patients. Serious AEs occurred in 7% of patients in the neratinib and 6% of those in the placebo arms. In the 5-year analysis, there was no evidence of increased risk of long-term toxicity or adverse consequences of neratinib-associated diarrhea. Furthermore, the ongoing, open-label phase 2 CONTROL trial suggests that the occurrence and severity of neratinib-associated diarrhea can be effectively controlled with antidiarrheal prophylaxis, with drugs such as loperamide.³

At the January 2017 cut-off, 137 patients treated with neratinib (240 mg/day) for 1 year had also received treatment with loperamide monotherapy, 64 patients had received loperamide and budesonide, and 10 patients had received loperamide and colestipol. The safety data from the loperamide monotherapy arm were compared with the safety data from the ExteNET trial, which was based in a similar population of patients who did not receive antidiarrheal prophylaxis. The incidence of all-grade diarrhea was 77% vs 95%, respectively, for those who received antidiarrheal prophylaxis in the CONTROL trial compared with those in the ExteNET trial who did not, and the repective rates of grade 3 diarrhea were 31% and 40%. The rate of dose reductions and holds owing to diarrhea were also lower among those who received antidiarrheal prophylaxis, but the rate of discontinuation due to diarrhea was higher in the loperamide-treated cohort.
 

Warnings and precautions

Neratinib is marketed as Nerlynx by Puma Biotechnology Inc. The prescribing information describes warnings and precautions relating to diarrhea, hepatotoxicity, and embryofetal toxicity. Patients should be monitored for diarrhea and treated with antidiarrheals as needed. Severe diarrhea with dehydration should be treated with fluids and electrolytes as needed, treatment should be interrupted and resumed at a reduced dose. For grade 3/4 diarrhea or diarrhea with complicating features (eg, dehydration, fever, neutropenia), stool cultures should be performed to rule out infectious causes.

Total bilirubin, aspartate and alanine aminotransferase, and alkaline phosphatase levels should be measured before starting treatment, every 3 months during treatment, or as clinically indicated. Neratinib can cause fetal harm, so pregnant women should be advised of the risk to the fetus and patients of reproductive potential should be counseled on the need for effective contraception during treatment and for at least 1 month after the last dose.⁴

The small-molecule tyrosine kinase inhibitor neratinib is now approved for the extended adjuvant treatment of patients with early-stage HER2 [human epidermal growth factor receptor]-positive breast cancer following postoperative trastuzumab. Trastuzumab is a HER2-targeted monoclonal antibody that has become standard of care in combination with chemotherapy for the treatment of this patient population in which it significantly improves survival. However, disease recurrence will occur in about a quarter of trastuzumab-treated patients owing to the development of resistance.

Neratinib may help overcome trastuzumab resistance thanks to its potent inhibition of the downstream phosphorylation of HER2 and other members of the HER family. Its approval was based on the phase 3 ExteNET trial, in which extended adjuvant treatment with neratinib was compared with placebo among 2,840 patients who remained disease free after 1 year of adjuvant trastuzumab.¹

The ExteNET trial was performed at 495 centers in Europe, Asia, Australia, New Zealand, and South America. Patients aged 18 years or older (≥20 years in Japan), with stage 1-3 HER2-positive breast cancer, who completed neoadjuvant and adjuvant trastuzumab therapy up to 1 year before randomization were eligible. Patients also had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), normal organ function, and a left ventricular ejection fraction within normal institutional range. Patients with clinically significant cardiac, gastrointesintal or psychiatric comorbidities and those who were not able to swallow oral medication were excluded from the study.

Patients randomly received oral neratinib 240 mg per day or matching placebo, and randomization was stratified according to HR status (positive or negative), nodal status (0, 1-3, or ≥4) and trastuzumab-adjuvant regimen (sequentially or concurrently with chemotherapy).

The primary outcome was invasive disease-free survival (iDFS). The 2-year iDFS rate was 93.9% for neratinib, compared with 91.6% for placebo (hazard ratio [HR], 0.66; P < .008). Recently, a 5-year analysis of the ExteNET trial showed that after a median follow-up of 5.2 years, the iDFS rates were 90.2% vs 87.7% (HR, 0.73; P = .0083).²

Adverse events

The most common adverse event (AE) was diarrhea, in 95% of patients, 40% of whom had grade 3 diarrhea, leading to dose reduction in 26% of patients and discontinuation in 16.8% of patients. Serious AEs occurred in 7% of patients in the neratinib and 6% of those in the placebo arms. In the 5-year analysis, there was no evidence of increased risk of long-term toxicity or adverse consequences of neratinib-associated diarrhea. Furthermore, the ongoing, open-label phase 2 CONTROL trial suggests that the occurrence and severity of neratinib-associated diarrhea can be effectively controlled with antidiarrheal prophylaxis, with drugs such as loperamide.³

At the January 2017 cut-off, 137 patients treated with neratinib (240 mg/day) for 1 year had also received treatment with loperamide monotherapy, 64 patients had received loperamide and budesonide, and 10 patients had received loperamide and colestipol. The safety data from the loperamide monotherapy arm were compared with the safety data from the ExteNET trial, which was based in a similar population of patients who did not receive antidiarrheal prophylaxis. The incidence of all-grade diarrhea was 77% vs 95%, respectively, for those who received antidiarrheal prophylaxis in the CONTROL trial compared with those in the ExteNET trial who did not, and the repective rates of grade 3 diarrhea were 31% and 40%. The rate of dose reductions and holds owing to diarrhea were also lower among those who received antidiarrheal prophylaxis, but the rate of discontinuation due to diarrhea was higher in the loperamide-treated cohort.
 

Warnings and precautions

Neratinib is marketed as Nerlynx by Puma Biotechnology Inc. The prescribing information describes warnings and precautions relating to diarrhea, hepatotoxicity, and embryofetal toxicity. Patients should be monitored for diarrhea and treated with antidiarrheals as needed. Severe diarrhea with dehydration should be treated with fluids and electrolytes as needed, treatment should be interrupted and resumed at a reduced dose. For grade 3/4 diarrhea or diarrhea with complicating features (eg, dehydration, fever, neutropenia), stool cultures should be performed to rule out infectious causes.

Total bilirubin, aspartate and alanine aminotransferase, and alkaline phosphatase levels should be measured before starting treatment, every 3 months during treatment, or as clinically indicated. Neratinib can cause fetal harm, so pregnant women should be advised of the risk to the fetus and patients of reproductive potential should be counseled on the need for effective contraception during treatment and for at least 1 month after the last dose.⁴

The small-molecule tyrosine kinase inhibitor neratinib is now approved for the extended adjuvant treatment of patients with early-stage HER2 [human epidermal growth factor receptor]-positive breast cancer following postoperative trastuzumab. Trastuzumab is a HER2-targeted monoclonal antibody that has become standard of care in combination with chemotherapy for the treatment of this patient population in which it significantly improves survival. However, disease recurrence will occur in about a quarter of trastuzumab-treated patients owing to the development of resistance.

Neratinib may help overcome trastuzumab resistance thanks to its potent inhibition of the downstream phosphorylation of HER2 and other members of the HER family. Its approval was based on the phase 3 ExteNET trial, in which extended adjuvant treatment with neratinib was compared with placebo among 2,840 patients who remained disease free after 1 year of adjuvant trastuzumab.¹

The ExteNET trial was performed at 495 centers in Europe, Asia, Australia, New Zealand, and South America. Patients aged 18 years or older (≥20 years in Japan), with stage 1-3 HER2-positive breast cancer, who completed neoadjuvant and adjuvant trastuzumab therapy up to 1 year before randomization were eligible. Patients also had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), normal organ function, and a left ventricular ejection fraction within normal institutional range. Patients with clinically significant cardiac, gastrointesintal or psychiatric comorbidities and those who were not able to swallow oral medication were excluded from the study.

Patients randomly received oral neratinib 240 mg per day or matching placebo, and randomization was stratified according to HR status (positive or negative), nodal status (0, 1-3, or ≥4) and trastuzumab-adjuvant regimen (sequentially or concurrently with chemotherapy).

The primary outcome was invasive disease-free survival (iDFS). The 2-year iDFS rate was 93.9% for neratinib, compared with 91.6% for placebo (hazard ratio [HR], 0.66; P < .008). Recently, a 5-year analysis of the ExteNET trial showed that after a median follow-up of 5.2 years, the iDFS rates were 90.2% vs 87.7% (HR, 0.73; P = .0083).²

Adverse events

The most common adverse event (AE) was diarrhea, in 95% of patients, 40% of whom had grade 3 diarrhea, leading to dose reduction in 26% of patients and discontinuation in 16.8% of patients. Serious AEs occurred in 7% of patients in the neratinib and 6% of those in the placebo arms. In the 5-year analysis, there was no evidence of increased risk of long-term toxicity or adverse consequences of neratinib-associated diarrhea. Furthermore, the ongoing, open-label phase 2 CONTROL trial suggests that the occurrence and severity of neratinib-associated diarrhea can be effectively controlled with antidiarrheal prophylaxis, with drugs such as loperamide.³

At the January 2017 cut-off, 137 patients treated with neratinib (240 mg/day) for 1 year had also received treatment with loperamide monotherapy, 64 patients had received loperamide and budesonide, and 10 patients had received loperamide and colestipol. The safety data from the loperamide monotherapy arm were compared with the safety data from the ExteNET trial, which was based in a similar population of patients who did not receive antidiarrheal prophylaxis. The incidence of all-grade diarrhea was 77% vs 95%, respectively, for those who received antidiarrheal prophylaxis in the CONTROL trial compared with those in the ExteNET trial who did not, and the repective rates of grade 3 diarrhea were 31% and 40%. The rate of dose reductions and holds owing to diarrhea were also lower among those who received antidiarrheal prophylaxis, but the rate of discontinuation due to diarrhea was higher in the loperamide-treated cohort.
 

Warnings and precautions

Neratinib is marketed as Nerlynx by Puma Biotechnology Inc. The prescribing information describes warnings and precautions relating to diarrhea, hepatotoxicity, and embryofetal toxicity. Patients should be monitored for diarrhea and treated with antidiarrheals as needed. Severe diarrhea with dehydration should be treated with fluids and electrolytes as needed, treatment should be interrupted and resumed at a reduced dose. For grade 3/4 diarrhea or diarrhea with complicating features (eg, dehydration, fever, neutropenia), stool cultures should be performed to rule out infectious causes.

Total bilirubin, aspartate and alanine aminotransferase, and alkaline phosphatase levels should be measured before starting treatment, every 3 months during treatment, or as clinically indicated. Neratinib can cause fetal harm, so pregnant women should be advised of the risk to the fetus and patients of reproductive potential should be counseled on the need for effective contraception during treatment and for at least 1 month after the last dose.⁴

Biosimilars are copies of FDA-approved biologic drugs (those generally derived from a living organism) that cannot be identical to the reference drug but demonstrate a high similarity to it. As patents on the reference drugs expire, biosimilars are being developed to increase competition in the marketplace to reduce costs and improve patient access to therapy. Although the US Food and Drug Administration (FDA) has no regulatory power over drug prices, it recently announced efforts to streamline the biosimilar approval process to facilitate access to therapies and curb the associated skyrocketing costs.

Several biosimilars have been approved by the agency in recent years, and earlier this year they were joined by 2 more: the approval in May of epoetin alfa-epbx (Retacrit; Hospira, a Pfizer company) for all indications of the reference product (epoetin alfa; Epogen/Procrit, Amgen), including the treatment of anemia caused by myelosuppressive chemotherapy, when there is a minimum of 2 additional months of planned chemotherapy;¹ and the June approval of pegfilgrastim-jmdb (Fulphila, Mylan and Biocon) for the treatment of patients undergoing myelosuppressive chemotherapy to help reduce the chance of infection as suggested by febrile neutropenia (fever, often with other signs of infection, associated with an abnormally low number of infection-fighting white blood cells).² The reference product for pegfilgrastim-jmdb is pegfilgrastim (Neulasta, Amgen).

The approval of both biosimilars was based on a review of a body of evidence that included structural and functional characterization, animal study data, human pharmacokinetic (PK) and pharmacodynamic (PD) data, clinical immunogenicity data, and other clinical safety and efficacy data. This evidence established that the biosimilars were highly similar to the already FDA-approved reference products, with no clinically relevant differences.



Biocon and Mylan-GmBH, which jointly developed pegfilgrastim-jmdb, originally filed for approval in 2017; and Hospira Inc, a Pfizer company that developed epoetin alfa-epbx, filed for the first time in 2015. They subsequently received complete response letters from the FDA, twice in the case of the epoetin alfa biosimilar, rejecting their approval. For pegfilgrastim-jmdb, the complete response letter was related to a pending update of the Biologic License Application as the result of requalification activities taken because of modifications at their manufacturing plant. For epoetin alfa-epbx, the FDA expressed concerns relating to a manufacturing facility. The companies addressed the concerns in the complete response letters and submitted corrective and preventive action plans.^3,4

Pegfilgrastim-jmdb

The results from a phase 3, multicenter, randomized, double-blind parallel-group trial of pegfilgrastim-jmdb compared with European Union-approved pegfilgrastim were published in 2016. Chemotherapy and radiation-naïve patients with newly diagnosed breast cancer (n = 194) received the biosimilar or reference product every 3 weeks for 6 cycles. The primary endpoint was duration of severe neutropenia in cycle 1, defined as days with absolute neutrophil count <0.5 x 10⁹/L. The mean standard deviation was 1.2 [0.93] in the pegfilgrastim-jmdb arm and 1.2 [1.10] in the EU-pegfilgrastim arm, and the 95% confidence interval of least squares means differences was within the -1 day, +1 day range, indicating equivalency.⁵

A characterization and similarity assessment of pegfilgrastim-jmdb compared with US- and EU-approved pegfilgrastim was presented at the 2018 Annual Meeting of the American Society of Clinical Oncology. G-CSF receptor (G-CSFR) binding was assessed by surface plasmon resonance and potency was measured by in vitro stimulated proliferation in a mouse myelogenous leukemia cell line. In vivo rodent studies were also performed and included a PD study with a single dose of up to 3 mg/kg.⁶

There was high similarity in the structure, molecular mass, impurities and functional activity of the biosimilar and reference products, as well as similar G-CSFR binding and equivalent relative potency. Neutrophil and leukocyte counts were increased to a similar degree, and toxicology and drug kinetics were also comparable.

The recommended dose of pegfilgrastim-jmdb is a 6 mg/0.6 ml injection in a single-dose prefilled syringe for manual use only, administered subcutaneously once per chemotherapy cycle. The prescribing information also has dosing guidelines for administration in pediatric patients who weigh less than 45 kg. Pegfilgrastim-jmdb should not be administered between 14 days before and 24 hours after administration of chemotherapy.

The prescribing information details warnings and precautions relating to splenic rupture, acute respiratory distress syndrome (ARDS), serious allergic reactions, potential for severe/fatal sickle cell crises in patients with sickle cell disorders, glomerulonephritis, leukocytosis, capillary leak syndrome, and the potential for tumor growth or recurrence.⁷

Patients should be evaluated for an enlarged spleen or splenic rupture if they report upper left abdominal or shoulder pain. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated for ARDS and treatment discontinued if a diagnosis is confirmed. Pegfilgrastim-jmdb should be permanently discontinued in patients who develop serious allergic reactions and should not be used in patients with a history of serious allergic reactions to pegfilgrastim or filgrastim products.

Dose-reduction or interruption should be considered in patients who develop glomerulonephritis. Complete blood counts should be monitored throughout treatment. Patients should be monitored closely for capillary leak syndrome and treated with standard therapy. Pegfilgrastim-jmdb is marketed as Fulphila.

Epoetin alfa-epbx

Epoetin alfa-epbx was evaluated in 2 clinical trials in healthy individuals. The EPOE-12-02 trial established the PK and PD following a single subcutaneous dose of 100 U/kg in 81 participants. The EPOE-14-1 study was designed to determine the PK and PD of multiple doses of subcutaneous 100 U/kg 3 times weekly for 3 weeks in 129 participants. Both studies met prespecified criteria for PK and PD similarity to US-approved epoetin alfa, including geometric mean of area under the curve (AUC)0-120h, AUC0-inf, C_max (maximum serum concentration achieved by a drug in a specified area of the body) and E_max (maximum response achievable for a drug dose).

Evidence of efficacy and safety were also evaluated using pooled data from EPOE-10-13 and EPOE-10-01, conducted in patients with chronic kidney disease, which was considered the most sensitive population in which to evaluate clinically meaningful differences between the biosimilar and reference product.^8,9

There were no clinically meaningful differences in efficacy and a similar adverse event profile. The most common side effects include high blood pressure, joint pain, muscle spasm, fever, dizziness, respiratory infection, and cough, among others.

The recommended dose of epoetin alfa-epbx, which is marketed as Retacrit, is 40,000 Units weekly or 150 U/kg 3 times weekly in adults and 600 U/kg intravenously weekly in pediatric patients aged 5 years or younger. Epoetin alfa-epbx comes with a boxed warning to alert health care providers to the increased risks of death, heart problems, stroke, and tumor growth, or recurrence. The prescribing information also details warnings and precautions relating to these risks, as well as hypertension, seizures, lack or loss of hemoglobin response, pure red cell aplasia, serious allergic reactions, and severe cutaneous reactions.⁹

Blood pressure should be appropriately controlled before treatment initiation, treatment should be reduced or withheld if it becomes uncontrollable, and patients should be advised of the importance of compliance with anti-hypertensive medication and dietary restrictions. Patients should be monitored closely for premonitory neurologic symptoms and advised to contact their provider in the event of new-onset seizures, premonitory symptoms, or change in seizure frequency.

The prescribing information has dosing recommendations for lack or loss of hemoglobin response to epoetin alfa-epbx. If severe anemia or low reticulocyte count occur, treatment should be withheld and patients evaluated for neutralizing antibodies to erythropoietin and, in the event that PRCA is confirmed, treatment should be permanently discontinued. Treatment should be immediately and permanently discontinued for serious allergic reactions or severe cutaneous reactions.

Biosimilars are copies of FDA-approved biologic drugs (those generally derived from a living organism) that cannot be identical to the reference drug but demonstrate a high similarity to it. As patents on the reference drugs expire, biosimilars are being developed to increase competition in the marketplace to reduce costs and improve patient access to therapy. Although the US Food and Drug Administration (FDA) has no regulatory power over drug prices, it recently announced efforts to streamline the biosimilar approval process to facilitate access to therapies and curb the associated skyrocketing costs.

Several biosimilars have been approved by the agency in recent years, and earlier this year they were joined by 2 more: the approval in May of epoetin alfa-epbx (Retacrit; Hospira, a Pfizer company) for all indications of the reference product (epoetin alfa; Epogen/Procrit, Amgen), including the treatment of anemia caused by myelosuppressive chemotherapy, when there is a minimum of 2 additional months of planned chemotherapy;¹ and the June approval of pegfilgrastim-jmdb (Fulphila, Mylan and Biocon) for the treatment of patients undergoing myelosuppressive chemotherapy to help reduce the chance of infection as suggested by febrile neutropenia (fever, often with other signs of infection, associated with an abnormally low number of infection-fighting white blood cells).² The reference product for pegfilgrastim-jmdb is pegfilgrastim (Neulasta, Amgen).

The approval of both biosimilars was based on a review of a body of evidence that included structural and functional characterization, animal study data, human pharmacokinetic (PK) and pharmacodynamic (PD) data, clinical immunogenicity data, and other clinical safety and efficacy data. This evidence established that the biosimilars were highly similar to the already FDA-approved reference products, with no clinically relevant differences.



Biocon and Mylan-GmBH, which jointly developed pegfilgrastim-jmdb, originally filed for approval in 2017; and Hospira Inc, a Pfizer company that developed epoetin alfa-epbx, filed for the first time in 2015. They subsequently received complete response letters from the FDA, twice in the case of the epoetin alfa biosimilar, rejecting their approval. For pegfilgrastim-jmdb, the complete response letter was related to a pending update of the Biologic License Application as the result of requalification activities taken because of modifications at their manufacturing plant. For epoetin alfa-epbx, the FDA expressed concerns relating to a manufacturing facility. The companies addressed the concerns in the complete response letters and submitted corrective and preventive action plans.^3,4

Pegfilgrastim-jmdb

The results from a phase 3, multicenter, randomized, double-blind parallel-group trial of pegfilgrastim-jmdb compared with European Union-approved pegfilgrastim were published in 2016. Chemotherapy and radiation-naïve patients with newly diagnosed breast cancer (n = 194) received the biosimilar or reference product every 3 weeks for 6 cycles. The primary endpoint was duration of severe neutropenia in cycle 1, defined as days with absolute neutrophil count <0.5 x 10⁹/L. The mean standard deviation was 1.2 [0.93] in the pegfilgrastim-jmdb arm and 1.2 [1.10] in the EU-pegfilgrastim arm, and the 95% confidence interval of least squares means differences was within the -1 day, +1 day range, indicating equivalency.⁵

A characterization and similarity assessment of pegfilgrastim-jmdb compared with US- and EU-approved pegfilgrastim was presented at the 2018 Annual Meeting of the American Society of Clinical Oncology. G-CSF receptor (G-CSFR) binding was assessed by surface plasmon resonance and potency was measured by in vitro stimulated proliferation in a mouse myelogenous leukemia cell line. In vivo rodent studies were also performed and included a PD study with a single dose of up to 3 mg/kg.⁶

There was high similarity in the structure, molecular mass, impurities and functional activity of the biosimilar and reference products, as well as similar G-CSFR binding and equivalent relative potency. Neutrophil and leukocyte counts were increased to a similar degree, and toxicology and drug kinetics were also comparable.

The recommended dose of pegfilgrastim-jmdb is a 6 mg/0.6 ml injection in a single-dose prefilled syringe for manual use only, administered subcutaneously once per chemotherapy cycle. The prescribing information also has dosing guidelines for administration in pediatric patients who weigh less than 45 kg. Pegfilgrastim-jmdb should not be administered between 14 days before and 24 hours after administration of chemotherapy.

The prescribing information details warnings and precautions relating to splenic rupture, acute respiratory distress syndrome (ARDS), serious allergic reactions, potential for severe/fatal sickle cell crises in patients with sickle cell disorders, glomerulonephritis, leukocytosis, capillary leak syndrome, and the potential for tumor growth or recurrence.⁷

Patients should be evaluated for an enlarged spleen or splenic rupture if they report upper left abdominal or shoulder pain. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated for ARDS and treatment discontinued if a diagnosis is confirmed. Pegfilgrastim-jmdb should be permanently discontinued in patients who develop serious allergic reactions and should not be used in patients with a history of serious allergic reactions to pegfilgrastim or filgrastim products.

Dose-reduction or interruption should be considered in patients who develop glomerulonephritis. Complete blood counts should be monitored throughout treatment. Patients should be monitored closely for capillary leak syndrome and treated with standard therapy. Pegfilgrastim-jmdb is marketed as Fulphila.

Epoetin alfa-epbx

Epoetin alfa-epbx was evaluated in 2 clinical trials in healthy individuals. The EPOE-12-02 trial established the PK and PD following a single subcutaneous dose of 100 U/kg in 81 participants. The EPOE-14-1 study was designed to determine the PK and PD of multiple doses of subcutaneous 100 U/kg 3 times weekly for 3 weeks in 129 participants. Both studies met prespecified criteria for PK and PD similarity to US-approved epoetin alfa, including geometric mean of area under the curve (AUC)0-120h, AUC0-inf, C_max (maximum serum concentration achieved by a drug in a specified area of the body) and E_max (maximum response achievable for a drug dose).

Evidence of efficacy and safety were also evaluated using pooled data from EPOE-10-13 and EPOE-10-01, conducted in patients with chronic kidney disease, which was considered the most sensitive population in which to evaluate clinically meaningful differences between the biosimilar and reference product.^8,9

There were no clinically meaningful differences in efficacy and a similar adverse event profile. The most common side effects include high blood pressure, joint pain, muscle spasm, fever, dizziness, respiratory infection, and cough, among others.

The recommended dose of epoetin alfa-epbx, which is marketed as Retacrit, is 40,000 Units weekly or 150 U/kg 3 times weekly in adults and 600 U/kg intravenously weekly in pediatric patients aged 5 years or younger. Epoetin alfa-epbx comes with a boxed warning to alert health care providers to the increased risks of death, heart problems, stroke, and tumor growth, or recurrence. The prescribing information also details warnings and precautions relating to these risks, as well as hypertension, seizures, lack or loss of hemoglobin response, pure red cell aplasia, serious allergic reactions, and severe cutaneous reactions.⁹

Blood pressure should be appropriately controlled before treatment initiation, treatment should be reduced or withheld if it becomes uncontrollable, and patients should be advised of the importance of compliance with anti-hypertensive medication and dietary restrictions. Patients should be monitored closely for premonitory neurologic symptoms and advised to contact their provider in the event of new-onset seizures, premonitory symptoms, or change in seizure frequency.

The prescribing information has dosing recommendations for lack or loss of hemoglobin response to epoetin alfa-epbx. If severe anemia or low reticulocyte count occur, treatment should be withheld and patients evaluated for neutralizing antibodies to erythropoietin and, in the event that PRCA is confirmed, treatment should be permanently discontinued. Treatment should be immediately and permanently discontinued for serious allergic reactions or severe cutaneous reactions.

Biosimilars are copies of FDA-approved biologic drugs (those generally derived from a living organism) that cannot be identical to the reference drug but demonstrate a high similarity to it. As patents on the reference drugs expire, biosimilars are being developed to increase competition in the marketplace to reduce costs and improve patient access to therapy. Although the US Food and Drug Administration (FDA) has no regulatory power over drug prices, it recently announced efforts to streamline the biosimilar approval process to facilitate access to therapies and curb the associated skyrocketing costs.

Several biosimilars have been approved by the agency in recent years, and earlier this year they were joined by 2 more: the approval in May of epoetin alfa-epbx (Retacrit; Hospira, a Pfizer company) for all indications of the reference product (epoetin alfa; Epogen/Procrit, Amgen), including the treatment of anemia caused by myelosuppressive chemotherapy, when there is a minimum of 2 additional months of planned chemotherapy;¹ and the June approval of pegfilgrastim-jmdb (Fulphila, Mylan and Biocon) for the treatment of patients undergoing myelosuppressive chemotherapy to help reduce the chance of infection as suggested by febrile neutropenia (fever, often with other signs of infection, associated with an abnormally low number of infection-fighting white blood cells).² The reference product for pegfilgrastim-jmdb is pegfilgrastim (Neulasta, Amgen).

The approval of both biosimilars was based on a review of a body of evidence that included structural and functional characterization, animal study data, human pharmacokinetic (PK) and pharmacodynamic (PD) data, clinical immunogenicity data, and other clinical safety and efficacy data. This evidence established that the biosimilars were highly similar to the already FDA-approved reference products, with no clinically relevant differences.



Biocon and Mylan-GmBH, which jointly developed pegfilgrastim-jmdb, originally filed for approval in 2017; and Hospira Inc, a Pfizer company that developed epoetin alfa-epbx, filed for the first time in 2015. They subsequently received complete response letters from the FDA, twice in the case of the epoetin alfa biosimilar, rejecting their approval. For pegfilgrastim-jmdb, the complete response letter was related to a pending update of the Biologic License Application as the result of requalification activities taken because of modifications at their manufacturing plant. For epoetin alfa-epbx, the FDA expressed concerns relating to a manufacturing facility. The companies addressed the concerns in the complete response letters and submitted corrective and preventive action plans.^3,4

Pegfilgrastim-jmdb

The results from a phase 3, multicenter, randomized, double-blind parallel-group trial of pegfilgrastim-jmdb compared with European Union-approved pegfilgrastim were published in 2016. Chemotherapy and radiation-naïve patients with newly diagnosed breast cancer (n = 194) received the biosimilar or reference product every 3 weeks for 6 cycles. The primary endpoint was duration of severe neutropenia in cycle 1, defined as days with absolute neutrophil count <0.5 x 10⁹/L. The mean standard deviation was 1.2 [0.93] in the pegfilgrastim-jmdb arm and 1.2 [1.10] in the EU-pegfilgrastim arm, and the 95% confidence interval of least squares means differences was within the -1 day, +1 day range, indicating equivalency.⁵

A characterization and similarity assessment of pegfilgrastim-jmdb compared with US- and EU-approved pegfilgrastim was presented at the 2018 Annual Meeting of the American Society of Clinical Oncology. G-CSF receptor (G-CSFR) binding was assessed by surface plasmon resonance and potency was measured by in vitro stimulated proliferation in a mouse myelogenous leukemia cell line. In vivo rodent studies were also performed and included a PD study with a single dose of up to 3 mg/kg.⁶

There was high similarity in the structure, molecular mass, impurities and functional activity of the biosimilar and reference products, as well as similar G-CSFR binding and equivalent relative potency. Neutrophil and leukocyte counts were increased to a similar degree, and toxicology and drug kinetics were also comparable.

The recommended dose of pegfilgrastim-jmdb is a 6 mg/0.6 ml injection in a single-dose prefilled syringe for manual use only, administered subcutaneously once per chemotherapy cycle. The prescribing information also has dosing guidelines for administration in pediatric patients who weigh less than 45 kg. Pegfilgrastim-jmdb should not be administered between 14 days before and 24 hours after administration of chemotherapy.

The prescribing information details warnings and precautions relating to splenic rupture, acute respiratory distress syndrome (ARDS), serious allergic reactions, potential for severe/fatal sickle cell crises in patients with sickle cell disorders, glomerulonephritis, leukocytosis, capillary leak syndrome, and the potential for tumor growth or recurrence.⁷

Patients should be evaluated for an enlarged spleen or splenic rupture if they report upper left abdominal or shoulder pain. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated for ARDS and treatment discontinued if a diagnosis is confirmed. Pegfilgrastim-jmdb should be permanently discontinued in patients who develop serious allergic reactions and should not be used in patients with a history of serious allergic reactions to pegfilgrastim or filgrastim products.

Dose-reduction or interruption should be considered in patients who develop glomerulonephritis. Complete blood counts should be monitored throughout treatment. Patients should be monitored closely for capillary leak syndrome and treated with standard therapy. Pegfilgrastim-jmdb is marketed as Fulphila.

Epoetin alfa-epbx

Epoetin alfa-epbx was evaluated in 2 clinical trials in healthy individuals. The EPOE-12-02 trial established the PK and PD following a single subcutaneous dose of 100 U/kg in 81 participants. The EPOE-14-1 study was designed to determine the PK and PD of multiple doses of subcutaneous 100 U/kg 3 times weekly for 3 weeks in 129 participants. Both studies met prespecified criteria for PK and PD similarity to US-approved epoetin alfa, including geometric mean of area under the curve (AUC)0-120h, AUC0-inf, C_max (maximum serum concentration achieved by a drug in a specified area of the body) and E_max (maximum response achievable for a drug dose).

Evidence of efficacy and safety were also evaluated using pooled data from EPOE-10-13 and EPOE-10-01, conducted in patients with chronic kidney disease, which was considered the most sensitive population in which to evaluate clinically meaningful differences between the biosimilar and reference product.^8,9

There were no clinically meaningful differences in efficacy and a similar adverse event profile. The most common side effects include high blood pressure, joint pain, muscle spasm, fever, dizziness, respiratory infection, and cough, among others.

The recommended dose of epoetin alfa-epbx, which is marketed as Retacrit, is 40,000 Units weekly or 150 U/kg 3 times weekly in adults and 600 U/kg intravenously weekly in pediatric patients aged 5 years or younger. Epoetin alfa-epbx comes with a boxed warning to alert health care providers to the increased risks of death, heart problems, stroke, and tumor growth, or recurrence. The prescribing information also details warnings and precautions relating to these risks, as well as hypertension, seizures, lack or loss of hemoglobin response, pure red cell aplasia, serious allergic reactions, and severe cutaneous reactions.⁹

Blood pressure should be appropriately controlled before treatment initiation, treatment should be reduced or withheld if it becomes uncontrollable, and patients should be advised of the importance of compliance with anti-hypertensive medication and dietary restrictions. Patients should be monitored closely for premonitory neurologic symptoms and advised to contact their provider in the event of new-onset seizures, premonitory symptoms, or change in seizure frequency.

The prescribing information has dosing recommendations for lack or loss of hemoglobin response to epoetin alfa-epbx. If severe anemia or low reticulocyte count occur, treatment should be withheld and patients evaluated for neutralizing antibodies to erythropoietin and, in the event that PRCA is confirmed, treatment should be permanently discontinued. Treatment should be immediately and permanently discontinued for serious allergic reactions or severe cutaneous reactions.

There were a number of landmark approvals by the US Food and Drug Administration (FDA) in 2017 for cancer therapies, among them, the approval of the first two chimeric antigen receptor (CAR) T-cell therapies for cancer: tisagenlecleucel (in August) and axicabtagene ciloluecel (in October).¹ CAR T-cells are a type of adoptive cell therapy or immunotherapy, in which the patient’s own immune cells are genetically engineered to target a tumor-associated antigen, in this case CD19. In tisagenlecleucel, CD19 proteins on B cells are targeted in the treatment of B-cell precursor acute lymphoblastic leukemia. Axicabtagene ciloluecel, the second anti-CD19 CAR T-cell therapy, was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma.

Tisagenlecleucel

Tisagenlecleucel was approved for the treatment of pediatric patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) whose disease is refractory to treatment or who have relapsed after second-line therapy or beyond.² Approval was based on the pivotal ELIANA trial, a single-arm, global phase 2 trial conducted at 25 centers worldwide during April 2015 through April 2017. Patients were eligible for enrollment if they had relapsed or refractory B-cell ALL and were at least 3 years of age at screening and no older than 21 years of age at diagnosis, had at least 5% lymphoblasts in the bone marrow at screening, had tumor expression of CD19, had adequate organ function, and a Karnofsky (adult) or Lansky (child) Performance Status of ≥50 (with the worst allowable score, 50, indicating a patient who requires considerable assistance and frequent medical care [Karnofsky] and lying around much of the day, but gets dressed; no active playing but participates in all quiet play and activities [Lansky]). Exclusion criteria included previous receipt of anti-CD19 therapy, concomitant genetic syndromes associated with bone marrow failure, previous malignancy, and/or active or latent hepatitis B or C virus (HBV/HCV) infection.

The overall remission rate (ORR) was evaluated in 75 patients who were given a single dose of tisagenlecleucel (a median weight-adjusted dose of 3.1 x 10⁶ transduced viable T cells per kg of body weight) within 14 days of completing a lymphodepleting chemotherapy regimen. The confirmed ORR after at least 3 months of follow-up, as assessed by independent central review, was 81%, which included 60% of patients in complete remission (CR) and 21% in complete remission with incomplete hematologic recovery, all of whom were negative for minimal residual disease.

The most common adverse events (AEs) associated with tisagenlecleucel treatment were cytokine release syndrome (CRS), hypogammaglobulinemia, infection, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium. AEs were of grade 3/4 severity in 84% of patients.³

To combat serious safety issues, including CRS and neurologic toxicities, the FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (REMS) that, in part, requires health care providers who administer the drug to be trained in their management. It also requires the facility where treatment is administered to have immediate, onsite access to the drug tocilizumab, which was approved in conjunction with tisagenlecleucel for the treatment of patients who experience CRS.

In addition to information about the REMS, the prescribing information details warnings and precautions relating to several other common toxicities. These include hypersensitivity reactions, serious infections, prolonged cytopenias, and hypogammaglobulinemia.

Patients should be monitored for signs and symptoms of infection and treated appropriately. Viral reactivation can occur after tisagenlecleucel treatment, so patients should be screened for HBV, HCV, and human immunodeficiency virus before collection of cells.

The administration of myeloid growth factors is not recommended during the first 3 weeks after infusion or until CRS has resolved. Immunoglobulin levels should be monitored after treatment and hypogammaglobulinemia managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement according to standard guidelines.

Patients treated with tisagenlecleucel should also be monitored for life for secondary malignancies, should not be treated with live vaccines from 2 weeks before the start of lymphodepleting chemotherapy until immune recovery after tisagenlecleucel infusion, and should be aware of the potential for neurological events to impact their ability to drive and use dangerous machinery.⁴

Tisagenlecleucel is marketed as Kymriah by Novartis Pharmaceuticals. The recommended dose is 1 infusion of 0.2-5 x 10⁶ CAR-positive viable T cells per kilogram of body weight intravenously (for patients ≤50kg) and 0.1-2.5 x 10⁸ cells/kg (for patients >50kg), administered 2-14 days after lymphodepleting chemotherapy.

Axicabtagene ciloleucel

Axicabtagene ciloleucel was approved for the treatment of adult patients with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.⁵ It is not indicated for the treatment of patients with primary central nervous system lymphoma.

Approval followed positive results from the phase 2 single-arm, multicenter ZUMA-1 trial.⁶ Patients were included if they were aged 18 years of age and older, had histologically confirmed aggressive B-cell non-Hodgkin lymphoma that was chemotherapy refractory, had received adequate previous therapy, had at least 1 measurable lesion, had completed radiation or systemic therapy at least 2 weeks before, had resolved toxicities related to previous therapy, and had an Eastern Cooperative Oncology Group Performance Status of 0 (asymptomatic) or 1 (symptomatic), an absolute neutrophil count of ≥1000/µL, a platelet count of ≥50,000/µL, and adequate hepatic, renal and cardiac function. They were treated with a single infusion of axicabtagene ciloleucel after lymphodepleting chemotherapy.

Patients who had received previous CD19-targeted therapy, who had concomitant genetic syndromes associated with bone marrow failure, who had previous malignancy, and who had active or latent HBV/HCV infection were among those excluded from the study.

Patients were enrolled in 2 cohorts; those with DLBCL (n = 77) and those with PMBCL or transformed follicular lymphoma (n = 24). The primary endpoint was objective response rate, and after a primary analysis at a minimum of 6 months follow-up, the objective response rate was 82%, with a CR rate of 52%. Among patients who achieved CR, the median duration of response was not reached after a median follow-up of 7.9 months.

A subsequent updated analysis was performed when 108 patients had been followed for a minimum of 1 year. The objective response rate was 82%, and the CR rate was 58%, with some patients having CR in the absence of additional therapies as late as 15 months after treatment. At this updated analysis, 42% of patients continued to have a response, 40% of whom remained in CR.

The most common grade 3 or higher AEs included febrile neutropenia, fever, CRS, encephalopathy, infections, hypotension, and hypoxia. Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias, and serious infections. Grade 3 or higher CRS or neurologic toxicities occurred in 13% and 28% of patients, respectively. Three patients died during treatment.

To mitigate the risk of CRS and neurologic toxicity, axicabtagene ciloleucel is approved with an REMS that requires appropriate certification and training before hospitals are cleared to administer the therapy.

Other warnings and precautions in the prescribing information relate to serious infections (monitor for signs and symptoms and treat appropriately), prolonged cytopenias (monitor blood counts), hypogammaglobulinemia (monitor immunoglobulin levels and manage appropriately), secondary malignancies (life-long monitoring), and the potential effects of neurologic events on a patient’s ability to drive and operate dangerous machinery (avoid for at least 8 weeks after infusion).⁷

Axicabtagene ciloleucel is marketed as Yescarta by Kite Pharma Inc. The recommended dose is a single intravenous infusion with a target of 2 x 10⁶ CAR-positive viable T cells per kilogram of body weight, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.

There were a number of landmark approvals by the US Food and Drug Administration (FDA) in 2017 for cancer therapies, among them, the approval of the first two chimeric antigen receptor (CAR) T-cell therapies for cancer: tisagenlecleucel (in August) and axicabtagene ciloluecel (in October).¹ CAR T-cells are a type of adoptive cell therapy or immunotherapy, in which the patient’s own immune cells are genetically engineered to target a tumor-associated antigen, in this case CD19. In tisagenlecleucel, CD19 proteins on B cells are targeted in the treatment of B-cell precursor acute lymphoblastic leukemia. Axicabtagene ciloluecel, the second anti-CD19 CAR T-cell therapy, was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma.

Tisagenlecleucel

Tisagenlecleucel was approved for the treatment of pediatric patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) whose disease is refractory to treatment or who have relapsed after second-line therapy or beyond.² Approval was based on the pivotal ELIANA trial, a single-arm, global phase 2 trial conducted at 25 centers worldwide during April 2015 through April 2017. Patients were eligible for enrollment if they had relapsed or refractory B-cell ALL and were at least 3 years of age at screening and no older than 21 years of age at diagnosis, had at least 5% lymphoblasts in the bone marrow at screening, had tumor expression of CD19, had adequate organ function, and a Karnofsky (adult) or Lansky (child) Performance Status of ≥50 (with the worst allowable score, 50, indicating a patient who requires considerable assistance and frequent medical care [Karnofsky] and lying around much of the day, but gets dressed; no active playing but participates in all quiet play and activities [Lansky]). Exclusion criteria included previous receipt of anti-CD19 therapy, concomitant genetic syndromes associated with bone marrow failure, previous malignancy, and/or active or latent hepatitis B or C virus (HBV/HCV) infection.

The overall remission rate (ORR) was evaluated in 75 patients who were given a single dose of tisagenlecleucel (a median weight-adjusted dose of 3.1 x 10⁶ transduced viable T cells per kg of body weight) within 14 days of completing a lymphodepleting chemotherapy regimen. The confirmed ORR after at least 3 months of follow-up, as assessed by independent central review, was 81%, which included 60% of patients in complete remission (CR) and 21% in complete remission with incomplete hematologic recovery, all of whom were negative for minimal residual disease.

The most common adverse events (AEs) associated with tisagenlecleucel treatment were cytokine release syndrome (CRS), hypogammaglobulinemia, infection, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium. AEs were of grade 3/4 severity in 84% of patients.³

To combat serious safety issues, including CRS and neurologic toxicities, the FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (REMS) that, in part, requires health care providers who administer the drug to be trained in their management. It also requires the facility where treatment is administered to have immediate, onsite access to the drug tocilizumab, which was approved in conjunction with tisagenlecleucel for the treatment of patients who experience CRS.

In addition to information about the REMS, the prescribing information details warnings and precautions relating to several other common toxicities. These include hypersensitivity reactions, serious infections, prolonged cytopenias, and hypogammaglobulinemia.

Patients should be monitored for signs and symptoms of infection and treated appropriately. Viral reactivation can occur after tisagenlecleucel treatment, so patients should be screened for HBV, HCV, and human immunodeficiency virus before collection of cells.

The administration of myeloid growth factors is not recommended during the first 3 weeks after infusion or until CRS has resolved. Immunoglobulin levels should be monitored after treatment and hypogammaglobulinemia managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement according to standard guidelines.

Patients treated with tisagenlecleucel should also be monitored for life for secondary malignancies, should not be treated with live vaccines from 2 weeks before the start of lymphodepleting chemotherapy until immune recovery after tisagenlecleucel infusion, and should be aware of the potential for neurological events to impact their ability to drive and use dangerous machinery.⁴

Tisagenlecleucel is marketed as Kymriah by Novartis Pharmaceuticals. The recommended dose is 1 infusion of 0.2-5 x 10⁶ CAR-positive viable T cells per kilogram of body weight intravenously (for patients ≤50kg) and 0.1-2.5 x 10⁸ cells/kg (for patients >50kg), administered 2-14 days after lymphodepleting chemotherapy.

Axicabtagene ciloleucel

Axicabtagene ciloleucel was approved for the treatment of adult patients with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.⁵ It is not indicated for the treatment of patients with primary central nervous system lymphoma.

Approval followed positive results from the phase 2 single-arm, multicenter ZUMA-1 trial.⁶ Patients were included if they were aged 18 years of age and older, had histologically confirmed aggressive B-cell non-Hodgkin lymphoma that was chemotherapy refractory, had received adequate previous therapy, had at least 1 measurable lesion, had completed radiation or systemic therapy at least 2 weeks before, had resolved toxicities related to previous therapy, and had an Eastern Cooperative Oncology Group Performance Status of 0 (asymptomatic) or 1 (symptomatic), an absolute neutrophil count of ≥1000/µL, a platelet count of ≥50,000/µL, and adequate hepatic, renal and cardiac function. They were treated with a single infusion of axicabtagene ciloleucel after lymphodepleting chemotherapy.

Patients who had received previous CD19-targeted therapy, who had concomitant genetic syndromes associated with bone marrow failure, who had previous malignancy, and who had active or latent HBV/HCV infection were among those excluded from the study.

Patients were enrolled in 2 cohorts; those with DLBCL (n = 77) and those with PMBCL or transformed follicular lymphoma (n = 24). The primary endpoint was objective response rate, and after a primary analysis at a minimum of 6 months follow-up, the objective response rate was 82%, with a CR rate of 52%. Among patients who achieved CR, the median duration of response was not reached after a median follow-up of 7.9 months.

A subsequent updated analysis was performed when 108 patients had been followed for a minimum of 1 year. The objective response rate was 82%, and the CR rate was 58%, with some patients having CR in the absence of additional therapies as late as 15 months after treatment. At this updated analysis, 42% of patients continued to have a response, 40% of whom remained in CR.

The most common grade 3 or higher AEs included febrile neutropenia, fever, CRS, encephalopathy, infections, hypotension, and hypoxia. Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias, and serious infections. Grade 3 or higher CRS or neurologic toxicities occurred in 13% and 28% of patients, respectively. Three patients died during treatment.

To mitigate the risk of CRS and neurologic toxicity, axicabtagene ciloleucel is approved with an REMS that requires appropriate certification and training before hospitals are cleared to administer the therapy.

Other warnings and precautions in the prescribing information relate to serious infections (monitor for signs and symptoms and treat appropriately), prolonged cytopenias (monitor blood counts), hypogammaglobulinemia (monitor immunoglobulin levels and manage appropriately), secondary malignancies (life-long monitoring), and the potential effects of neurologic events on a patient’s ability to drive and operate dangerous machinery (avoid for at least 8 weeks after infusion).⁷

Axicabtagene ciloleucel is marketed as Yescarta by Kite Pharma Inc. The recommended dose is a single intravenous infusion with a target of 2 x 10⁶ CAR-positive viable T cells per kilogram of body weight, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.

There were a number of landmark approvals by the US Food and Drug Administration (FDA) in 2017 for cancer therapies, among them, the approval of the first two chimeric antigen receptor (CAR) T-cell therapies for cancer: tisagenlecleucel (in August) and axicabtagene ciloluecel (in October).¹ CAR T-cells are a type of adoptive cell therapy or immunotherapy, in which the patient’s own immune cells are genetically engineered to target a tumor-associated antigen, in this case CD19. In tisagenlecleucel, CD19 proteins on B cells are targeted in the treatment of B-cell precursor acute lymphoblastic leukemia. Axicabtagene ciloluecel, the second anti-CD19 CAR T-cell therapy, was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma.

Tisagenlecleucel

Tisagenlecleucel was approved for the treatment of pediatric patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) whose disease is refractory to treatment or who have relapsed after second-line therapy or beyond.² Approval was based on the pivotal ELIANA trial, a single-arm, global phase 2 trial conducted at 25 centers worldwide during April 2015 through April 2017. Patients were eligible for enrollment if they had relapsed or refractory B-cell ALL and were at least 3 years of age at screening and no older than 21 years of age at diagnosis, had at least 5% lymphoblasts in the bone marrow at screening, had tumor expression of CD19, had adequate organ function, and a Karnofsky (adult) or Lansky (child) Performance Status of ≥50 (with the worst allowable score, 50, indicating a patient who requires considerable assistance and frequent medical care [Karnofsky] and lying around much of the day, but gets dressed; no active playing but participates in all quiet play and activities [Lansky]). Exclusion criteria included previous receipt of anti-CD19 therapy, concomitant genetic syndromes associated with bone marrow failure, previous malignancy, and/or active or latent hepatitis B or C virus (HBV/HCV) infection.

The overall remission rate (ORR) was evaluated in 75 patients who were given a single dose of tisagenlecleucel (a median weight-adjusted dose of 3.1 x 10⁶ transduced viable T cells per kg of body weight) within 14 days of completing a lymphodepleting chemotherapy regimen. The confirmed ORR after at least 3 months of follow-up, as assessed by independent central review, was 81%, which included 60% of patients in complete remission (CR) and 21% in complete remission with incomplete hematologic recovery, all of whom were negative for minimal residual disease.

The most common adverse events (AEs) associated with tisagenlecleucel treatment were cytokine release syndrome (CRS), hypogammaglobulinemia, infection, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium. AEs were of grade 3/4 severity in 84% of patients.³

To combat serious safety issues, including CRS and neurologic toxicities, the FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (REMS) that, in part, requires health care providers who administer the drug to be trained in their management. It also requires the facility where treatment is administered to have immediate, onsite access to the drug tocilizumab, which was approved in conjunction with tisagenlecleucel for the treatment of patients who experience CRS.

In addition to information about the REMS, the prescribing information details warnings and precautions relating to several other common toxicities. These include hypersensitivity reactions, serious infections, prolonged cytopenias, and hypogammaglobulinemia.

Patients should be monitored for signs and symptoms of infection and treated appropriately. Viral reactivation can occur after tisagenlecleucel treatment, so patients should be screened for HBV, HCV, and human immunodeficiency virus before collection of cells.

The administration of myeloid growth factors is not recommended during the first 3 weeks after infusion or until CRS has resolved. Immunoglobulin levels should be monitored after treatment and hypogammaglobulinemia managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement according to standard guidelines.

Patients treated with tisagenlecleucel should also be monitored for life for secondary malignancies, should not be treated with live vaccines from 2 weeks before the start of lymphodepleting chemotherapy until immune recovery after tisagenlecleucel infusion, and should be aware of the potential for neurological events to impact their ability to drive and use dangerous machinery.⁴

Tisagenlecleucel is marketed as Kymriah by Novartis Pharmaceuticals. The recommended dose is 1 infusion of 0.2-5 x 10⁶ CAR-positive viable T cells per kilogram of body weight intravenously (for patients ≤50kg) and 0.1-2.5 x 10⁸ cells/kg (for patients >50kg), administered 2-14 days after lymphodepleting chemotherapy.

Axicabtagene ciloleucel

Axicabtagene ciloleucel was approved for the treatment of adult patients with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.⁵ It is not indicated for the treatment of patients with primary central nervous system lymphoma.

Approval followed positive results from the phase 2 single-arm, multicenter ZUMA-1 trial.⁶ Patients were included if they were aged 18 years of age and older, had histologically confirmed aggressive B-cell non-Hodgkin lymphoma that was chemotherapy refractory, had received adequate previous therapy, had at least 1 measurable lesion, had completed radiation or systemic therapy at least 2 weeks before, had resolved toxicities related to previous therapy, and had an Eastern Cooperative Oncology Group Performance Status of 0 (asymptomatic) or 1 (symptomatic), an absolute neutrophil count of ≥1000/µL, a platelet count of ≥50,000/µL, and adequate hepatic, renal and cardiac function. They were treated with a single infusion of axicabtagene ciloleucel after lymphodepleting chemotherapy.

Patients who had received previous CD19-targeted therapy, who had concomitant genetic syndromes associated with bone marrow failure, who had previous malignancy, and who had active or latent HBV/HCV infection were among those excluded from the study.

Patients were enrolled in 2 cohorts; those with DLBCL (n = 77) and those with PMBCL or transformed follicular lymphoma (n = 24). The primary endpoint was objective response rate, and after a primary analysis at a minimum of 6 months follow-up, the objective response rate was 82%, with a CR rate of 52%. Among patients who achieved CR, the median duration of response was not reached after a median follow-up of 7.9 months.

A subsequent updated analysis was performed when 108 patients had been followed for a minimum of 1 year. The objective response rate was 82%, and the CR rate was 58%, with some patients having CR in the absence of additional therapies as late as 15 months after treatment. At this updated analysis, 42% of patients continued to have a response, 40% of whom remained in CR.

The most common grade 3 or higher AEs included febrile neutropenia, fever, CRS, encephalopathy, infections, hypotension, and hypoxia. Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias, and serious infections. Grade 3 or higher CRS or neurologic toxicities occurred in 13% and 28% of patients, respectively. Three patients died during treatment.

To mitigate the risk of CRS and neurologic toxicity, axicabtagene ciloleucel is approved with an REMS that requires appropriate certification and training before hospitals are cleared to administer the therapy.

Other warnings and precautions in the prescribing information relate to serious infections (monitor for signs and symptoms and treat appropriately), prolonged cytopenias (monitor blood counts), hypogammaglobulinemia (monitor immunoglobulin levels and manage appropriately), secondary malignancies (life-long monitoring), and the potential effects of neurologic events on a patient’s ability to drive and operate dangerous machinery (avoid for at least 8 weeks after infusion).⁷

Axicabtagene ciloleucel is marketed as Yescarta by Kite Pharma Inc. The recommended dose is a single intravenous infusion with a target of 2 x 10⁶ CAR-positive viable T cells per kilogram of body weight, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.

The treatment of multiple myeloma has been revolutionized in the past few decades, with the introduction of numerous novel drug classes that have more than doubled median survival times. The immunomodulatory drug (IMiD), lenalidomide, forms the backbone of the majority of treatment paradigms, first receiving US Food and Drug Administration approval in 2006 for use in combination with dexamethasone in previously treated patients with multiple myeloma. Since then, approved indications for lenalidomide in multiple myeloma have continued to expand.

Most recently, on February 22, 2017, lenalidomide was approved for use as maintenance therapy following autologous stem cell transplant (ASCT), making it the first and only treatment available in this setting. This approval was based on 2 randomized, controlled trials that evaluated the efficacy and safety of lenalidomide in more than 1,000 patients in this setting and demonstrated a significant advantage in progression-free survival (PFS) compared with patients receiving placebo.

CALGB 100104¹ and IFM 2005-02² were randomized, double-blind phase 3 trials conducted at 47 locations across the United States and 78 centers in France, Belgium, and Switzerland, respectively. In the CALGB trial, eligible patients were 18-70 years of age, with a European Cooperative Oncology Group (ECOG) performance status of 0 or 1, symptomatic disease requiring treatment (Durie-Salmon stage ≥1), and who received any induction therapy of 2-12 months duration. In the IFM trial, eligible patients were younger than 65 years, with multiple myeloma that had not progressed in the interval between first-line ASCT, performed within the previous 6 months, and randomization, and who had normal liver function tests and blood cell counts.

In CALGB 100104, after undergoing ASCT, 460 patients were randomly assigned to lenalidomide (starting at a dose of 10 mg/day) or placebo between day 100 and day 110 after transplantation. In IFM 2005-02, after undergoing ASCT, 614 patients were randomized 1:1 to receive either consolidation treatment with lenalidomide (at a dose of 25 mg/day on days 1-21 of each 28-day cycle for 2 cycles) followed by maintenance with lenalidomide (10 mg/day for the first 3 months, increasing to 15 mg if tolerated), or the same consolidation treatment followed by maintenance therapy with placebo.

The primary endpoint of CALGB 100104 was time to progression (TTP) and lenalidomide was associated with a significantly longer TTP. Median PFS was also improved by around 15 months (hazard ratio [HR], 0.38; P < .001). In a more recent long-term PFS analysis, median PFS was 5.7 years in the lenalidomide arm compared with 1.9 years with placebo, a difference of 3.8 years (HR, 0.38).³

The primary endpoint for IFM 2005-02 was PFS and lenalidomide maintenance therapy resulted in a significant improvement in PFS in both the originally published study (18-month PFS advantage) and long-term follow-up. The most recent PFS analysis demonstrated a PFS of 3.9 years for lenalidomide, compared with 2 years for no maintenance, a difference of 1.9 years (HR, 0.53). Although the studies were not powered for an overall survival (OS) endpoint, a descriptive analysis showed a median OS of 9.3 years, compared with 7 years in CALGB 100104, and 8.8 years compared with 7.3 years in IFM 2005-02.

In a meta-analysis of data pooled from these 2 studies and a third randomized trial (GIMEMA-RVMM-PI-209),⁴ which was presented at the 2016 annual meeting of the American Society of Clinical Oncology, maintenance therapy with lenalidomide following frontline treatment with high-dose melphalan and ASCT reduced the risk of death by 26% compared with placebo or no maintenance therapy, prompting suggestions that lenalidomide become standard of care in this setting.

The safety profile of lenalidomide in this setting was similar to that previously described in other studies. The most frequently reported adverse events (AEs), across both studies, were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm, and pyrexia. The most common grade 3/4 AEs included neutropenia, thrombocytopenia, and leukopenia. AEs were generally most common in the first 6 months of treatment and subsequently declined in frequency over time or remained stable.

The prescribing information carries warnings and precautions about embryo-fetal toxicity, hematologic toxicity, venous/arterial thromboembolic events, secondary primary malignancies, hepatotoxicity, allergic reactions, tumor lysis syndrome, and thyroid disorders.⁵ Given its teratogenic effects, lenalidomide is only available through a restricted program under a risk evaluation mitigation strategy.

Patients with neutropenia should be monitored for signs of infections, patients advised to look for signs of bleeding or bruising, and weekly complete blood count performed for the first 2 cycles, on days 1 and 15 of cycle 3 and every 4 weeks thereafter.

Action should be taken to try to reduce the risk of venous and arterial thromboembolic events where possible and thrombophylaxis is recommended, based on the assessment of the underlying risk. Since lenalidomide can increase the risk of secondary primary malignancies, each case should be evaluated for risk-to-benefit ratio.

Liver enzymes should be monitored periodically and treatment interrupted upon their elevation, resuming at a lower dose if levels return to baseline values. Patients who have a history of grade 4 rash following thalidomide treatment should not receive lenalidomide. If grade 2-3 skin rash occurs, treatment interruption or discontinuation should be considered and lenalidomide should be discontinued in the event of angioedema, grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome or toxic epidermal necrolysis are suspected.

Patients with high tumor burden prior to treatment are at highest risk of tumor lysis syndrome and should be monitored closely and appropriate precautions taken, and thyroid function should be measured before and during lenalidomide treatment to address potential thyroid disorders. Lenalidomide is marketed as Revlimid by Celgene Corporation.

The treatment of multiple myeloma has been revolutionized in the past few decades, with the introduction of numerous novel drug classes that have more than doubled median survival times. The immunomodulatory drug (IMiD), lenalidomide, forms the backbone of the majority of treatment paradigms, first receiving US Food and Drug Administration approval in 2006 for use in combination with dexamethasone in previously treated patients with multiple myeloma. Since then, approved indications for lenalidomide in multiple myeloma have continued to expand.

Most recently, on February 22, 2017, lenalidomide was approved for use as maintenance therapy following autologous stem cell transplant (ASCT), making it the first and only treatment available in this setting. This approval was based on 2 randomized, controlled trials that evaluated the efficacy and safety of lenalidomide in more than 1,000 patients in this setting and demonstrated a significant advantage in progression-free survival (PFS) compared with patients receiving placebo.

CALGB 100104¹ and IFM 2005-02² were randomized, double-blind phase 3 trials conducted at 47 locations across the United States and 78 centers in France, Belgium, and Switzerland, respectively. In the CALGB trial, eligible patients were 18-70 years of age, with a European Cooperative Oncology Group (ECOG) performance status of 0 or 1, symptomatic disease requiring treatment (Durie-Salmon stage ≥1), and who received any induction therapy of 2-12 months duration. In the IFM trial, eligible patients were younger than 65 years, with multiple myeloma that had not progressed in the interval between first-line ASCT, performed within the previous 6 months, and randomization, and who had normal liver function tests and blood cell counts.

In CALGB 100104, after undergoing ASCT, 460 patients were randomly assigned to lenalidomide (starting at a dose of 10 mg/day) or placebo between day 100 and day 110 after transplantation. In IFM 2005-02, after undergoing ASCT, 614 patients were randomized 1:1 to receive either consolidation treatment with lenalidomide (at a dose of 25 mg/day on days 1-21 of each 28-day cycle for 2 cycles) followed by maintenance with lenalidomide (10 mg/day for the first 3 months, increasing to 15 mg if tolerated), or the same consolidation treatment followed by maintenance therapy with placebo.

The primary endpoint of CALGB 100104 was time to progression (TTP) and lenalidomide was associated with a significantly longer TTP. Median PFS was also improved by around 15 months (hazard ratio [HR], 0.38; P < .001). In a more recent long-term PFS analysis, median PFS was 5.7 years in the lenalidomide arm compared with 1.9 years with placebo, a difference of 3.8 years (HR, 0.38).³

The primary endpoint for IFM 2005-02 was PFS and lenalidomide maintenance therapy resulted in a significant improvement in PFS in both the originally published study (18-month PFS advantage) and long-term follow-up. The most recent PFS analysis demonstrated a PFS of 3.9 years for lenalidomide, compared with 2 years for no maintenance, a difference of 1.9 years (HR, 0.53). Although the studies were not powered for an overall survival (OS) endpoint, a descriptive analysis showed a median OS of 9.3 years, compared with 7 years in CALGB 100104, and 8.8 years compared with 7.3 years in IFM 2005-02.

In a meta-analysis of data pooled from these 2 studies and a third randomized trial (GIMEMA-RVMM-PI-209),⁴ which was presented at the 2016 annual meeting of the American Society of Clinical Oncology, maintenance therapy with lenalidomide following frontline treatment with high-dose melphalan and ASCT reduced the risk of death by 26% compared with placebo or no maintenance therapy, prompting suggestions that lenalidomide become standard of care in this setting.

The safety profile of lenalidomide in this setting was similar to that previously described in other studies. The most frequently reported adverse events (AEs), across both studies, were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm, and pyrexia. The most common grade 3/4 AEs included neutropenia, thrombocytopenia, and leukopenia. AEs were generally most common in the first 6 months of treatment and subsequently declined in frequency over time or remained stable.

The prescribing information carries warnings and precautions about embryo-fetal toxicity, hematologic toxicity, venous/arterial thromboembolic events, secondary primary malignancies, hepatotoxicity, allergic reactions, tumor lysis syndrome, and thyroid disorders.⁵ Given its teratogenic effects, lenalidomide is only available through a restricted program under a risk evaluation mitigation strategy.

Patients with neutropenia should be monitored for signs of infections, patients advised to look for signs of bleeding or bruising, and weekly complete blood count performed for the first 2 cycles, on days 1 and 15 of cycle 3 and every 4 weeks thereafter.

Action should be taken to try to reduce the risk of venous and arterial thromboembolic events where possible and thrombophylaxis is recommended, based on the assessment of the underlying risk. Since lenalidomide can increase the risk of secondary primary malignancies, each case should be evaluated for risk-to-benefit ratio.

Liver enzymes should be monitored periodically and treatment interrupted upon their elevation, resuming at a lower dose if levels return to baseline values. Patients who have a history of grade 4 rash following thalidomide treatment should not receive lenalidomide. If grade 2-3 skin rash occurs, treatment interruption or discontinuation should be considered and lenalidomide should be discontinued in the event of angioedema, grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome or toxic epidermal necrolysis are suspected.

Patients with high tumor burden prior to treatment are at highest risk of tumor lysis syndrome and should be monitored closely and appropriate precautions taken, and thyroid function should be measured before and during lenalidomide treatment to address potential thyroid disorders. Lenalidomide is marketed as Revlimid by Celgene Corporation.

The treatment of multiple myeloma has been revolutionized in the past few decades, with the introduction of numerous novel drug classes that have more than doubled median survival times. The immunomodulatory drug (IMiD), lenalidomide, forms the backbone of the majority of treatment paradigms, first receiving US Food and Drug Administration approval in 2006 for use in combination with dexamethasone in previously treated patients with multiple myeloma. Since then, approved indications for lenalidomide in multiple myeloma have continued to expand.

Most recently, on February 22, 2017, lenalidomide was approved for use as maintenance therapy following autologous stem cell transplant (ASCT), making it the first and only treatment available in this setting. This approval was based on 2 randomized, controlled trials that evaluated the efficacy and safety of lenalidomide in more than 1,000 patients in this setting and demonstrated a significant advantage in progression-free survival (PFS) compared with patients receiving placebo.

CALGB 100104¹ and IFM 2005-02² were randomized, double-blind phase 3 trials conducted at 47 locations across the United States and 78 centers in France, Belgium, and Switzerland, respectively. In the CALGB trial, eligible patients were 18-70 years of age, with a European Cooperative Oncology Group (ECOG) performance status of 0 or 1, symptomatic disease requiring treatment (Durie-Salmon stage ≥1), and who received any induction therapy of 2-12 months duration. In the IFM trial, eligible patients were younger than 65 years, with multiple myeloma that had not progressed in the interval between first-line ASCT, performed within the previous 6 months, and randomization, and who had normal liver function tests and blood cell counts.

In CALGB 100104, after undergoing ASCT, 460 patients were randomly assigned to lenalidomide (starting at a dose of 10 mg/day) or placebo between day 100 and day 110 after transplantation. In IFM 2005-02, after undergoing ASCT, 614 patients were randomized 1:1 to receive either consolidation treatment with lenalidomide (at a dose of 25 mg/day on days 1-21 of each 28-day cycle for 2 cycles) followed by maintenance with lenalidomide (10 mg/day for the first 3 months, increasing to 15 mg if tolerated), or the same consolidation treatment followed by maintenance therapy with placebo.

The primary endpoint of CALGB 100104 was time to progression (TTP) and lenalidomide was associated with a significantly longer TTP. Median PFS was also improved by around 15 months (hazard ratio [HR], 0.38; P < .001). In a more recent long-term PFS analysis, median PFS was 5.7 years in the lenalidomide arm compared with 1.9 years with placebo, a difference of 3.8 years (HR, 0.38).³

The primary endpoint for IFM 2005-02 was PFS and lenalidomide maintenance therapy resulted in a significant improvement in PFS in both the originally published study (18-month PFS advantage) and long-term follow-up. The most recent PFS analysis demonstrated a PFS of 3.9 years for lenalidomide, compared with 2 years for no maintenance, a difference of 1.9 years (HR, 0.53). Although the studies were not powered for an overall survival (OS) endpoint, a descriptive analysis showed a median OS of 9.3 years, compared with 7 years in CALGB 100104, and 8.8 years compared with 7.3 years in IFM 2005-02.

In a meta-analysis of data pooled from these 2 studies and a third randomized trial (GIMEMA-RVMM-PI-209),⁴ which was presented at the 2016 annual meeting of the American Society of Clinical Oncology, maintenance therapy with lenalidomide following frontline treatment with high-dose melphalan and ASCT reduced the risk of death by 26% compared with placebo or no maintenance therapy, prompting suggestions that lenalidomide become standard of care in this setting.

The safety profile of lenalidomide in this setting was similar to that previously described in other studies. The most frequently reported adverse events (AEs), across both studies, were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm, and pyrexia. The most common grade 3/4 AEs included neutropenia, thrombocytopenia, and leukopenia. AEs were generally most common in the first 6 months of treatment and subsequently declined in frequency over time or remained stable.

The prescribing information carries warnings and precautions about embryo-fetal toxicity, hematologic toxicity, venous/arterial thromboembolic events, secondary primary malignancies, hepatotoxicity, allergic reactions, tumor lysis syndrome, and thyroid disorders.⁵ Given its teratogenic effects, lenalidomide is only available through a restricted program under a risk evaluation mitigation strategy.

Patients with neutropenia should be monitored for signs of infections, patients advised to look for signs of bleeding or bruising, and weekly complete blood count performed for the first 2 cycles, on days 1 and 15 of cycle 3 and every 4 weeks thereafter.

Action should be taken to try to reduce the risk of venous and arterial thromboembolic events where possible and thrombophylaxis is recommended, based on the assessment of the underlying risk. Since lenalidomide can increase the risk of secondary primary malignancies, each case should be evaluated for risk-to-benefit ratio.

Liver enzymes should be monitored periodically and treatment interrupted upon their elevation, resuming at a lower dose if levels return to baseline values. Patients who have a history of grade 4 rash following thalidomide treatment should not receive lenalidomide. If grade 2-3 skin rash occurs, treatment interruption or discontinuation should be considered and lenalidomide should be discontinued in the event of angioedema, grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome or toxic epidermal necrolysis are suspected.

Patients with high tumor burden prior to treatment are at highest risk of tumor lysis syndrome and should be monitored closely and appropriate precautions taken, and thyroid function should be measured before and during lenalidomide treatment to address potential thyroid disorders. Lenalidomide is marketed as Revlimid by Celgene Corporation.