TBD Meeting (4748-19)

BARCELONA – In postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer, the combination of ribociclib (Kisqali) and fulvestrant (Faslodex) was associated with a significant survival benefit, compared with fulvestrant alone, investigators reported.­

Neil Osterweil/MDedge News

Among 726 postmenopausal patients in MONALEESA-3 randomly assigned to receive either ribociclib or placebo plus fulvestrant who were followed for a median of 39.4 months, the median overall survival (OS) was not reached for patients assigned to ribociclib, compared with 40 months for patients in the control (fulvestrant-only) arm, reported Dennis J. Slamon, MD, PhD from the University of California, Los Angeles

“The combined data set of MONALEESA-3 and MONALEESA-7 represent some 1,400 patients, and the largest body of evidence for overall survival for any [cyclin-dependent kinases 4/6] inhibitor, and these data demonstrate a consistent, meaningful prolongation of survival irrespective of menopausal status, pre or post, and irrespective of whether the patient is treated in the first line or the second line,” he said at the European Society for Medical Oncology Congress.

Results of the MONALEESA-7 trial, which showed an overall survival advantage for adding ribociclib to endocrine therapy in premenopausal women with hormone receptor–positive, HER2-negative breast cancer, were reported at the 2019 annual meeting of the American Society of Clinical Oncology.

MONALEESA-3 investigators enrolled 726 postmenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer who had received not more than one prior line of endocrine therapy for advanced disease, stratified them by the presence of liver and/or lung metastases and prior endocrine therapy, and then randomly assigned them to receive intramuscular fulvestrant 500 mg every 28 days, with an additional dose on day 15 of cycle one, plus either ribociclib 600 mg per day, 3 weeks on and 1 week off for every cycle, or placebo.

Dr. Slamon presented results of the primary endpoint of progression-free survival at the 2018 ASCO annual meeting, which showed a median PFS with ribociclib plus fulvestrant of 20.5 months versus 12.8 months for fulvestrant alone (hazard ratio, 5.93; P less than .0001). The overall survival data presented by Dr. Slamon at ESMO 2019 were not mature at that time.

As noted, at a median follow-up of 39.4 months, median overall survival was not reached in the combination arm, compared with 40 months in the fulvestrant/placebo arm, translating into a HR for risk of death with ribociclib of 0.724 (P = .00455).

Estimated OS rates at 36 months were 67% in the ribociclib arm versus 58.2% in the placebo arm, and at 42 months were 57.8% and 45.9%, respectively.

The survival benefit appeared consistent both for patients treated in the first line (median OS not reached vs. 45.1 months; HR, 0.70) and for those treated after early relapse of therapy for early breast or in the second line (median OS, 40.2 vs. 32.5 months, respectively; HR, 0.73). In both comparisons, however, the 95% confidence interval crossed 1, indicating that the results were not statistically significant.

An analysis of OS by subgroup indicated significant benefit or trends for most categories except Asian race, and treatment in Asia or Latin America, although the numbers of patients in each of those subgroups was less than 20, making it difficult to draw significant inferences from the findings, Dr. Slamon cautioned.

A descriptive analysis of updated PFS results were very similar to those previously reported, with a median of 20.6 months with ribociclib versus 12.8 months with placebo (HR, 0.587). Median PFS by line of therapy was 33.6 versus 19.2 months, respectively, in the first line, and 14.5 versus 9.1 months in the second line (HR, 0.546 and 0.571; P values not shown).

Neil Osterweil/MDedge News

“CDK4/6 inhibitors not only improve progression-free survival in first- and second-line metastatic breast cancer, it also translates into an overall survival improvement. What more do we really want?” said invited discussant Sybil Loibl, MD, from Goethe University in Frankfurt, Germany.

“Outcome improves irrespective of pretreatment, menopausal status, endocrine sensitivity and site of metastases, which is good knowledge for our patients,” she said.

To date there are no biomarkers identified that can select subgroups that could experience particular benefit from CDK4/6 inhibitors. It may require a meta-analysis of all available clinical trial data on these agents in both the first and second line therapy to reveal potential differences among subgroups, she said.

MONALEESA-3 is supported by Novartis. Dr. Slamon disclosed a consulting or advisory role, research funding, honoraria, and travel expenses from Novartis and others. Dr. Loibl disclosed honoraria and research grants from Novartis and others.

SOURCE: Slamon DJ et al. ESMO 2019, Abstract LBA7_PR.

BARCELONA – In postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer, the combination of ribociclib (Kisqali) and fulvestrant (Faslodex) was associated with a significant survival benefit, compared with fulvestrant alone, investigators reported.­

Neil Osterweil/MDedge News

Among 726 postmenopausal patients in MONALEESA-3 randomly assigned to receive either ribociclib or placebo plus fulvestrant who were followed for a median of 39.4 months, the median overall survival (OS) was not reached for patients assigned to ribociclib, compared with 40 months for patients in the control (fulvestrant-only) arm, reported Dennis J. Slamon, MD, PhD from the University of California, Los Angeles

“The combined data set of MONALEESA-3 and MONALEESA-7 represent some 1,400 patients, and the largest body of evidence for overall survival for any [cyclin-dependent kinases 4/6] inhibitor, and these data demonstrate a consistent, meaningful prolongation of survival irrespective of menopausal status, pre or post, and irrespective of whether the patient is treated in the first line or the second line,” he said at the European Society for Medical Oncology Congress.

Results of the MONALEESA-7 trial, which showed an overall survival advantage for adding ribociclib to endocrine therapy in premenopausal women with hormone receptor–positive, HER2-negative breast cancer, were reported at the 2019 annual meeting of the American Society of Clinical Oncology.

MONALEESA-3 investigators enrolled 726 postmenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer who had received not more than one prior line of endocrine therapy for advanced disease, stratified them by the presence of liver and/or lung metastases and prior endocrine therapy, and then randomly assigned them to receive intramuscular fulvestrant 500 mg every 28 days, with an additional dose on day 15 of cycle one, plus either ribociclib 600 mg per day, 3 weeks on and 1 week off for every cycle, or placebo.

Dr. Slamon presented results of the primary endpoint of progression-free survival at the 2018 ASCO annual meeting, which showed a median PFS with ribociclib plus fulvestrant of 20.5 months versus 12.8 months for fulvestrant alone (hazard ratio, 5.93; P less than .0001). The overall survival data presented by Dr. Slamon at ESMO 2019 were not mature at that time.

As noted, at a median follow-up of 39.4 months, median overall survival was not reached in the combination arm, compared with 40 months in the fulvestrant/placebo arm, translating into a HR for risk of death with ribociclib of 0.724 (P = .00455).

Estimated OS rates at 36 months were 67% in the ribociclib arm versus 58.2% in the placebo arm, and at 42 months were 57.8% and 45.9%, respectively.

The survival benefit appeared consistent both for patients treated in the first line (median OS not reached vs. 45.1 months; HR, 0.70) and for those treated after early relapse of therapy for early breast or in the second line (median OS, 40.2 vs. 32.5 months, respectively; HR, 0.73). In both comparisons, however, the 95% confidence interval crossed 1, indicating that the results were not statistically significant.

An analysis of OS by subgroup indicated significant benefit or trends for most categories except Asian race, and treatment in Asia or Latin America, although the numbers of patients in each of those subgroups was less than 20, making it difficult to draw significant inferences from the findings, Dr. Slamon cautioned.

A descriptive analysis of updated PFS results were very similar to those previously reported, with a median of 20.6 months with ribociclib versus 12.8 months with placebo (HR, 0.587). Median PFS by line of therapy was 33.6 versus 19.2 months, respectively, in the first line, and 14.5 versus 9.1 months in the second line (HR, 0.546 and 0.571; P values not shown).

Neil Osterweil/MDedge News

“CDK4/6 inhibitors not only improve progression-free survival in first- and second-line metastatic breast cancer, it also translates into an overall survival improvement. What more do we really want?” said invited discussant Sybil Loibl, MD, from Goethe University in Frankfurt, Germany.

“Outcome improves irrespective of pretreatment, menopausal status, endocrine sensitivity and site of metastases, which is good knowledge for our patients,” she said.

To date there are no biomarkers identified that can select subgroups that could experience particular benefit from CDK4/6 inhibitors. It may require a meta-analysis of all available clinical trial data on these agents in both the first and second line therapy to reveal potential differences among subgroups, she said.

MONALEESA-3 is supported by Novartis. Dr. Slamon disclosed a consulting or advisory role, research funding, honoraria, and travel expenses from Novartis and others. Dr. Loibl disclosed honoraria and research grants from Novartis and others.

SOURCE: Slamon DJ et al. ESMO 2019, Abstract LBA7_PR.

BARCELONA – In postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer, the combination of ribociclib (Kisqali) and fulvestrant (Faslodex) was associated with a significant survival benefit, compared with fulvestrant alone, investigators reported.­

Neil Osterweil/MDedge News

Among 726 postmenopausal patients in MONALEESA-3 randomly assigned to receive either ribociclib or placebo plus fulvestrant who were followed for a median of 39.4 months, the median overall survival (OS) was not reached for patients assigned to ribociclib, compared with 40 months for patients in the control (fulvestrant-only) arm, reported Dennis J. Slamon, MD, PhD from the University of California, Los Angeles

“The combined data set of MONALEESA-3 and MONALEESA-7 represent some 1,400 patients, and the largest body of evidence for overall survival for any [cyclin-dependent kinases 4/6] inhibitor, and these data demonstrate a consistent, meaningful prolongation of survival irrespective of menopausal status, pre or post, and irrespective of whether the patient is treated in the first line or the second line,” he said at the European Society for Medical Oncology Congress.

Results of the MONALEESA-7 trial, which showed an overall survival advantage for adding ribociclib to endocrine therapy in premenopausal women with hormone receptor–positive, HER2-negative breast cancer, were reported at the 2019 annual meeting of the American Society of Clinical Oncology.

MONALEESA-3 investigators enrolled 726 postmenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer who had received not more than one prior line of endocrine therapy for advanced disease, stratified them by the presence of liver and/or lung metastases and prior endocrine therapy, and then randomly assigned them to receive intramuscular fulvestrant 500 mg every 28 days, with an additional dose on day 15 of cycle one, plus either ribociclib 600 mg per day, 3 weeks on and 1 week off for every cycle, or placebo.

Dr. Slamon presented results of the primary endpoint of progression-free survival at the 2018 ASCO annual meeting, which showed a median PFS with ribociclib plus fulvestrant of 20.5 months versus 12.8 months for fulvestrant alone (hazard ratio, 5.93; P less than .0001). The overall survival data presented by Dr. Slamon at ESMO 2019 were not mature at that time.

As noted, at a median follow-up of 39.4 months, median overall survival was not reached in the combination arm, compared with 40 months in the fulvestrant/placebo arm, translating into a HR for risk of death with ribociclib of 0.724 (P = .00455).

Estimated OS rates at 36 months were 67% in the ribociclib arm versus 58.2% in the placebo arm, and at 42 months were 57.8% and 45.9%, respectively.

The survival benefit appeared consistent both for patients treated in the first line (median OS not reached vs. 45.1 months; HR, 0.70) and for those treated after early relapse of therapy for early breast or in the second line (median OS, 40.2 vs. 32.5 months, respectively; HR, 0.73). In both comparisons, however, the 95% confidence interval crossed 1, indicating that the results were not statistically significant.

An analysis of OS by subgroup indicated significant benefit or trends for most categories except Asian race, and treatment in Asia or Latin America, although the numbers of patients in each of those subgroups was less than 20, making it difficult to draw significant inferences from the findings, Dr. Slamon cautioned.

A descriptive analysis of updated PFS results were very similar to those previously reported, with a median of 20.6 months with ribociclib versus 12.8 months with placebo (HR, 0.587). Median PFS by line of therapy was 33.6 versus 19.2 months, respectively, in the first line, and 14.5 versus 9.1 months in the second line (HR, 0.546 and 0.571; P values not shown).

Neil Osterweil/MDedge News

“CDK4/6 inhibitors not only improve progression-free survival in first- and second-line metastatic breast cancer, it also translates into an overall survival improvement. What more do we really want?” said invited discussant Sybil Loibl, MD, from Goethe University in Frankfurt, Germany.

“Outcome improves irrespective of pretreatment, menopausal status, endocrine sensitivity and site of metastases, which is good knowledge for our patients,” she said.

To date there are no biomarkers identified that can select subgroups that could experience particular benefit from CDK4/6 inhibitors. It may require a meta-analysis of all available clinical trial data on these agents in both the first and second line therapy to reveal potential differences among subgroups, she said.

MONALEESA-3 is supported by Novartis. Dr. Slamon disclosed a consulting or advisory role, research funding, honoraria, and travel expenses from Novartis and others. Dr. Loibl disclosed honoraria and research grants from Novartis and others.

SOURCE: Slamon DJ et al. ESMO 2019, Abstract LBA7_PR.

BARCELONA – Ivosidenib, a first-in-class, oral, small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) protein, significantly improved progression-free survival, compared with placebo, for the treatment of advanced cholangiocarcinoma in the global, randomized, phase 3 ClarIDHy trial.

A trend toward favorable overall survival was also seen in the pivotal double-blind trial, Ghassan K. Abou-Alfa, MD, of Memorial Sloan-Kettering Cancer Center, New York, reported at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) in 124 patients randomized to receive 500 mg of ivosidenib (IVO) once daily was 2.7 months, compared with 1.4 months in 61 patients who received placebo (hazard ratio, 0.37).

The primary study endpoint – PFS by central review – was reached, Dr. Abou-Alfa said, noting that the PFS rates at 6 and 12 months were 32% and 22% in the IVO arm, whereas none of the patients in the placebo arm were progression-free for 6 or more months.

Although the 1.3-month difference in PFS between the treatment and placebo arms “may seem short and some people may question whether this is clinically meaningful,” this outcome actually represents an important breakthrough for patients with a disease that has few treatment options, Angela Lamarca, MD, PhD, of the Christie NHS Foundation Trust, Manchester, England, explained in a press release about the study.

“A treatment that increases the chance of being free from progression by 32% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families,” said Dr. Lamarca, representing the ESMO Press & Media Affairs Committee.

Indeed, the overall response rate in the IVO arm was 2.4%, representing three partial responses, and the stable disease rate was 50.8%. The overall response rate and stable disease rates in the placebo arm were 0% and 28%, Dr. Abou-Alfa said.

Median overall survival in the intent-to-treat population, including the 57% of placebo arm patients who crossed over to the treatment arm at the time of radiographic progression as allowed by study protocol, was 10.8 months, compared with 9.7 months in the placebo arm, respectively (HR, 0.69), Dr. Abou-Alfa said.

Crossover-adjusted overall survival was 6 months for the placebo arm (HR, 0.46) as assessed using rank-preserving structural failure time analysis, which suggested that the overall survival benefit would have been statistically significant had there been no crossover.

Study subjects had unresectable or metastatic mIDH1 cholangiocarcinoma, good performance status, and measurable disease. They had a median age of 62 years, and 68 were men. Most had intrahepatic disease (91%) and metastatic disease (92%), and 43% had two prior therapies, he noted.

They were randomized 2:1 to the treatment and placebo arms, respectively.

Since IVO targets mIDH1, which occurs in about 20% of patients with cholangiocarcinoma and results in production of the oncogenesis-promoting oncometabolite D-2-hydroxyglutarate, and since the IVO has shown encouraging activity in smaller prior studies, ClarIDHy was designed to evaluate it in the advanced mIDH1 cholangiocarcinoma setting because patients with this aggressive disease have generally poor prognosis and few treatment options beyond chemotherapy, he explained.

In addition to providing significant, clinically meaningful survival benefit, the treatment also was generally well tolerated, he noted.

Treatment-emergent adverse events occurring in more than 15% of patients in the IVO arm included nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), and vomiting (16.0%). Grade 3 or higher adverse events were reported in 46% and 36% of the IVO and placebo patients, respectively.

The findings are notable, in part because of the unmet need and also because this is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in patients with advanced mIDH1 cholangiocarcinoma, he said, concluding that “these pivotal data demonstrate the clinical relevance and benefit of ivosidenib in mIDH1 cholangiocarcinoma ... [and] establish the role for genomic testing in this rare cancer with a high unmet need.”

He also said studies should investigate IVO in the first-line setting for IDH1-mutated cholangiocarcinoma, in addition to its use in combination therapy and as adjuvant therapy.

In the ESMO press release, Chris Verslype, MD, of University Hospital Leuven (Belgium) called the findings of this study unprecedented given the lack of treatment options in those who fail systemic therapy, which has led to very limited survival.

The findings are “very likely to change clinical practice” and “will, for sure, drive the further development of targeted therapy for the disease,” he said.

Despite being limited by the requirement that patients have good performance status after prior chemotherapy (which means the findings may not be representative of all patients), ClarIDHy is “still a strong study because of the randomization to placebo.”

“It showed a real effect,” he said.

ClarIDHy was funded by Agios Pharmaceuticals. Dr. Abou-Alfa reported both personal and institutional relationships with industry. These include advisory /consulting roles and research grants/funding from numerous pharmaceutical companies.

SOURCE: Abou-Alfa GK et al. ESMO 2019, Abstract LBA10-PR.

BARCELONA – Ivosidenib, a first-in-class, oral, small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) protein, significantly improved progression-free survival, compared with placebo, for the treatment of advanced cholangiocarcinoma in the global, randomized, phase 3 ClarIDHy trial.

A trend toward favorable overall survival was also seen in the pivotal double-blind trial, Ghassan K. Abou-Alfa, MD, of Memorial Sloan-Kettering Cancer Center, New York, reported at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) in 124 patients randomized to receive 500 mg of ivosidenib (IVO) once daily was 2.7 months, compared with 1.4 months in 61 patients who received placebo (hazard ratio, 0.37).

The primary study endpoint – PFS by central review – was reached, Dr. Abou-Alfa said, noting that the PFS rates at 6 and 12 months were 32% and 22% in the IVO arm, whereas none of the patients in the placebo arm were progression-free for 6 or more months.

Although the 1.3-month difference in PFS between the treatment and placebo arms “may seem short and some people may question whether this is clinically meaningful,” this outcome actually represents an important breakthrough for patients with a disease that has few treatment options, Angela Lamarca, MD, PhD, of the Christie NHS Foundation Trust, Manchester, England, explained in a press release about the study.

“A treatment that increases the chance of being free from progression by 32% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families,” said Dr. Lamarca, representing the ESMO Press & Media Affairs Committee.

Indeed, the overall response rate in the IVO arm was 2.4%, representing three partial responses, and the stable disease rate was 50.8%. The overall response rate and stable disease rates in the placebo arm were 0% and 28%, Dr. Abou-Alfa said.

Median overall survival in the intent-to-treat population, including the 57% of placebo arm patients who crossed over to the treatment arm at the time of radiographic progression as allowed by study protocol, was 10.8 months, compared with 9.7 months in the placebo arm, respectively (HR, 0.69), Dr. Abou-Alfa said.

Crossover-adjusted overall survival was 6 months for the placebo arm (HR, 0.46) as assessed using rank-preserving structural failure time analysis, which suggested that the overall survival benefit would have been statistically significant had there been no crossover.

Study subjects had unresectable or metastatic mIDH1 cholangiocarcinoma, good performance status, and measurable disease. They had a median age of 62 years, and 68 were men. Most had intrahepatic disease (91%) and metastatic disease (92%), and 43% had two prior therapies, he noted.

They were randomized 2:1 to the treatment and placebo arms, respectively.

Since IVO targets mIDH1, which occurs in about 20% of patients with cholangiocarcinoma and results in production of the oncogenesis-promoting oncometabolite D-2-hydroxyglutarate, and since the IVO has shown encouraging activity in smaller prior studies, ClarIDHy was designed to evaluate it in the advanced mIDH1 cholangiocarcinoma setting because patients with this aggressive disease have generally poor prognosis and few treatment options beyond chemotherapy, he explained.

In addition to providing significant, clinically meaningful survival benefit, the treatment also was generally well tolerated, he noted.

Treatment-emergent adverse events occurring in more than 15% of patients in the IVO arm included nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), and vomiting (16.0%). Grade 3 or higher adverse events were reported in 46% and 36% of the IVO and placebo patients, respectively.

The findings are notable, in part because of the unmet need and also because this is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in patients with advanced mIDH1 cholangiocarcinoma, he said, concluding that “these pivotal data demonstrate the clinical relevance and benefit of ivosidenib in mIDH1 cholangiocarcinoma ... [and] establish the role for genomic testing in this rare cancer with a high unmet need.”

He also said studies should investigate IVO in the first-line setting for IDH1-mutated cholangiocarcinoma, in addition to its use in combination therapy and as adjuvant therapy.

In the ESMO press release, Chris Verslype, MD, of University Hospital Leuven (Belgium) called the findings of this study unprecedented given the lack of treatment options in those who fail systemic therapy, which has led to very limited survival.

The findings are “very likely to change clinical practice” and “will, for sure, drive the further development of targeted therapy for the disease,” he said.

Despite being limited by the requirement that patients have good performance status after prior chemotherapy (which means the findings may not be representative of all patients), ClarIDHy is “still a strong study because of the randomization to placebo.”

“It showed a real effect,” he said.

ClarIDHy was funded by Agios Pharmaceuticals. Dr. Abou-Alfa reported both personal and institutional relationships with industry. These include advisory /consulting roles and research grants/funding from numerous pharmaceutical companies.

SOURCE: Abou-Alfa GK et al. ESMO 2019, Abstract LBA10-PR.

BARCELONA – Ivosidenib, a first-in-class, oral, small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) protein, significantly improved progression-free survival, compared with placebo, for the treatment of advanced cholangiocarcinoma in the global, randomized, phase 3 ClarIDHy trial.

A trend toward favorable overall survival was also seen in the pivotal double-blind trial, Ghassan K. Abou-Alfa, MD, of Memorial Sloan-Kettering Cancer Center, New York, reported at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) in 124 patients randomized to receive 500 mg of ivosidenib (IVO) once daily was 2.7 months, compared with 1.4 months in 61 patients who received placebo (hazard ratio, 0.37).

The primary study endpoint – PFS by central review – was reached, Dr. Abou-Alfa said, noting that the PFS rates at 6 and 12 months were 32% and 22% in the IVO arm, whereas none of the patients in the placebo arm were progression-free for 6 or more months.

Although the 1.3-month difference in PFS between the treatment and placebo arms “may seem short and some people may question whether this is clinically meaningful,” this outcome actually represents an important breakthrough for patients with a disease that has few treatment options, Angela Lamarca, MD, PhD, of the Christie NHS Foundation Trust, Manchester, England, explained in a press release about the study.

“A treatment that increases the chance of being free from progression by 32% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families,” said Dr. Lamarca, representing the ESMO Press & Media Affairs Committee.

Indeed, the overall response rate in the IVO arm was 2.4%, representing three partial responses, and the stable disease rate was 50.8%. The overall response rate and stable disease rates in the placebo arm were 0% and 28%, Dr. Abou-Alfa said.

Median overall survival in the intent-to-treat population, including the 57% of placebo arm patients who crossed over to the treatment arm at the time of radiographic progression as allowed by study protocol, was 10.8 months, compared with 9.7 months in the placebo arm, respectively (HR, 0.69), Dr. Abou-Alfa said.

Crossover-adjusted overall survival was 6 months for the placebo arm (HR, 0.46) as assessed using rank-preserving structural failure time analysis, which suggested that the overall survival benefit would have been statistically significant had there been no crossover.

Study subjects had unresectable or metastatic mIDH1 cholangiocarcinoma, good performance status, and measurable disease. They had a median age of 62 years, and 68 were men. Most had intrahepatic disease (91%) and metastatic disease (92%), and 43% had two prior therapies, he noted.

They were randomized 2:1 to the treatment and placebo arms, respectively.

Since IVO targets mIDH1, which occurs in about 20% of patients with cholangiocarcinoma and results in production of the oncogenesis-promoting oncometabolite D-2-hydroxyglutarate, and since the IVO has shown encouraging activity in smaller prior studies, ClarIDHy was designed to evaluate it in the advanced mIDH1 cholangiocarcinoma setting because patients with this aggressive disease have generally poor prognosis and few treatment options beyond chemotherapy, he explained.

In addition to providing significant, clinically meaningful survival benefit, the treatment also was generally well tolerated, he noted.

Treatment-emergent adverse events occurring in more than 15% of patients in the IVO arm included nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), and vomiting (16.0%). Grade 3 or higher adverse events were reported in 46% and 36% of the IVO and placebo patients, respectively.

The findings are notable, in part because of the unmet need and also because this is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in patients with advanced mIDH1 cholangiocarcinoma, he said, concluding that “these pivotal data demonstrate the clinical relevance and benefit of ivosidenib in mIDH1 cholangiocarcinoma ... [and] establish the role for genomic testing in this rare cancer with a high unmet need.”

He also said studies should investigate IVO in the first-line setting for IDH1-mutated cholangiocarcinoma, in addition to its use in combination therapy and as adjuvant therapy.

In the ESMO press release, Chris Verslype, MD, of University Hospital Leuven (Belgium) called the findings of this study unprecedented given the lack of treatment options in those who fail systemic therapy, which has led to very limited survival.

The findings are “very likely to change clinical practice” and “will, for sure, drive the further development of targeted therapy for the disease,” he said.

Despite being limited by the requirement that patients have good performance status after prior chemotherapy (which means the findings may not be representative of all patients), ClarIDHy is “still a strong study because of the randomization to placebo.”

“It showed a real effect,” he said.

ClarIDHy was funded by Agios Pharmaceuticals. Dr. Abou-Alfa reported both personal and institutional relationships with industry. These include advisory /consulting roles and research grants/funding from numerous pharmaceutical companies.

SOURCE: Abou-Alfa GK et al. ESMO 2019, Abstract LBA10-PR.

BARCELONA – PARP inhibitors may be able to do for men with advanced castration-resistant prostate cancer what they currently do for women with breast or ovarian cancers linked to BRCA mutations, investigators report.

Neil Osterweil/MDedge News

Among men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed on prior therapy with either abiraterone (Zytiga) or enzalutamide (Xtandi) and that bore DNA-repair mutations (BRCA1, BRCA2, or ATM), those who were randomized in the PROfound trial to receive olaparib (Lynparza) had significant improvement in radiographic progression-free survival (rPFS) compared with patients assigned to the physician’s choice of a new hormonal agent, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago.

“PROfound is the first positive biomarker-selected phase 3 study evaluating a molecularly-targeted therapy in men with metastatic castration-resistant prostate cancer, highlighting the importance of genomic testing in this population, and also importantly highlighting the feasibility of precision-medicine trials in this disease,” she said at the European Society for Medical Oncology (ESMO) Congress.

Approximately 25% of men with mCRPC have loss-of-function mutations or alterations in homologous recombinant repair (HRR) genes, especially BRCA1, BRCA2, and ATM. Breast and ovarian cancers bearing these mutations are known to be sensitive to PARP (poly ADP ribose polymerase) inhibitors such as olaparib.

To see whether men with mCRPC could derive a similar benefit, the investigators enrolled patients who had experienced disease progression on abiraterone or enzalutamiude and whose tumors had one or more alterations in any qualifying gene with direct or indirect role in homologous recombinant DNA repair.

Patients were stratified by previous taxane use and measurable disease, and then two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (in BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L).

The median age in cohort A was 68, and in cohort B it was 67, with men 86 years of age at the upper end of the range.

“I think it’s remarkable that men in their late 80s and even early 90s were eligible, were able to be enter this study and be treated on it, and I think that’s an important point here,” Dr. Hussain said.

Nearly one-fourth of patients in the trial had metastatic disease at their initial diagnosis, she noted.

Patients in each cohort were randomized on a 2:1 basis to receive either open-label olaparib 300 mg twice daily, or the treating physician’s choice of abireraterone or enzalutamide, plus predisone.

Upon blinded independent central review (BICR) showing disease progression, patients were allowed to cross over to the olaparib arm, which more than 80% of patients eventually did.

Radiographic PFS in the BRCA1, BRCA2 and ATM cohort according to BICR, the primary endpoint, was a median of 7.39 months with olaparib, compared with 3.55 months with the other therapies, for a hazard ratio (HR) for progression on olaparib of 0.34 (P less than .0001).

A somewhat smaller but still significant benefit was seen for olaparib in the overall population (both cohorts), with a median rPFS of 5.82 months vs. 3.52 months, respectively (HR 0.49, P less than .0001).

Among patients in cohort A, the objective response rate was 33.3% with olaparib, compared with 2.3% for the other agents, resulting in an odds ratio for response of 20.86 (P less than .0001)

Olaparib was also associated with longer time to pain progression in patients in cohort A, with the median not reached compared with 9.92 months with the hormonal agents (HR 0.44, P = .0192).

Among patients in the physician’s choice arm who had disease progression, 80.6% in cohort A and 84.6% in cohort B were crossed over to olaparib.

At this interim analysis, median overall survival was 18.5 months with olaparib, compared with 15.11 months with the other agents, but this difference was not statistically significant. Further follow-up will be needed before a difference in overall survival becomes evident, Dr. Hussain said.

“I think this study has demonstrated that now prostate cancer can be treated with a targeted therapy approach,” said Ignacio Duran, MD, of Hospital Universitario Marques de Valdecilla in Santander, Spain. He was the invited discussant and moderator of a briefing where Dr. Hussain outlined the study details prior to presentation in a symposium.

Neil Osterweil/MDedge News

“Not all prostate cancer patients have the same tumors, and this is the first time we’ve been able to identify that we can more precisely characterize the molecular biology, the genetic background of these tumors, and that is going to determine how we treat them,” he said.

The PROfound trial made “a double hit: superiority in terms of efficacy, and it has proved a new concept that in prostate cancer has not been proved before,” he added.

“This is a truly practice-changing study, not just for our practice and our patients, but also for the study design,” said Eleni Efstathiou, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, who was the invited discussant at the symposium where Dr. Hussain presented the full trial data.

Neil Osterweil/MDedge News

She lauded the use of a validated genomic testing tissue-based assay (FoundationOne CDx next-generation sequencing test) to identify patients who might benefit from olaparib.

She said that the PARP inhibition-specific strategy of the trial appears to have paid off, with statistically significant, clinically meaningful improvement in outcomes and an acceptable safety profile.

“And when it comes to a prostate cancer therapy strategry? Well, we’re starting to enter into the targeted therapy era,” she said.

The PROfound trial was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck. Dr. Hussain disclosed travel and/or accommodation support, honoraria, consulting/advisory fees and research support from AstraZeneca and others. Dr. Duran disclosed advisory board fees from Roche and BMS, and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck. Dr. Efstathiou disclosed research support and honoraria from various companies, not including AstraZeneca or Merck.

SOURCE: Hussain M et al. ESMO 2019, Abstract LBA-12.

BARCELONA – PARP inhibitors may be able to do for men with advanced castration-resistant prostate cancer what they currently do for women with breast or ovarian cancers linked to BRCA mutations, investigators report.

Neil Osterweil/MDedge News

Among men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed on prior therapy with either abiraterone (Zytiga) or enzalutamide (Xtandi) and that bore DNA-repair mutations (BRCA1, BRCA2, or ATM), those who were randomized in the PROfound trial to receive olaparib (Lynparza) had significant improvement in radiographic progression-free survival (rPFS) compared with patients assigned to the physician’s choice of a new hormonal agent, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago.

“PROfound is the first positive biomarker-selected phase 3 study evaluating a molecularly-targeted therapy in men with metastatic castration-resistant prostate cancer, highlighting the importance of genomic testing in this population, and also importantly highlighting the feasibility of precision-medicine trials in this disease,” she said at the European Society for Medical Oncology (ESMO) Congress.

Approximately 25% of men with mCRPC have loss-of-function mutations or alterations in homologous recombinant repair (HRR) genes, especially BRCA1, BRCA2, and ATM. Breast and ovarian cancers bearing these mutations are known to be sensitive to PARP (poly ADP ribose polymerase) inhibitors such as olaparib.

To see whether men with mCRPC could derive a similar benefit, the investigators enrolled patients who had experienced disease progression on abiraterone or enzalutamiude and whose tumors had one or more alterations in any qualifying gene with direct or indirect role in homologous recombinant DNA repair.

Patients were stratified by previous taxane use and measurable disease, and then two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (in BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L).

The median age in cohort A was 68, and in cohort B it was 67, with men 86 years of age at the upper end of the range.

“I think it’s remarkable that men in their late 80s and even early 90s were eligible, were able to be enter this study and be treated on it, and I think that’s an important point here,” Dr. Hussain said.

Nearly one-fourth of patients in the trial had metastatic disease at their initial diagnosis, she noted.

Patients in each cohort were randomized on a 2:1 basis to receive either open-label olaparib 300 mg twice daily, or the treating physician’s choice of abireraterone or enzalutamide, plus predisone.

Upon blinded independent central review (BICR) showing disease progression, patients were allowed to cross over to the olaparib arm, which more than 80% of patients eventually did.

Radiographic PFS in the BRCA1, BRCA2 and ATM cohort according to BICR, the primary endpoint, was a median of 7.39 months with olaparib, compared with 3.55 months with the other therapies, for a hazard ratio (HR) for progression on olaparib of 0.34 (P less than .0001).

A somewhat smaller but still significant benefit was seen for olaparib in the overall population (both cohorts), with a median rPFS of 5.82 months vs. 3.52 months, respectively (HR 0.49, P less than .0001).

Among patients in cohort A, the objective response rate was 33.3% with olaparib, compared with 2.3% for the other agents, resulting in an odds ratio for response of 20.86 (P less than .0001)

Olaparib was also associated with longer time to pain progression in patients in cohort A, with the median not reached compared with 9.92 months with the hormonal agents (HR 0.44, P = .0192).

Among patients in the physician’s choice arm who had disease progression, 80.6% in cohort A and 84.6% in cohort B were crossed over to olaparib.

At this interim analysis, median overall survival was 18.5 months with olaparib, compared with 15.11 months with the other agents, but this difference was not statistically significant. Further follow-up will be needed before a difference in overall survival becomes evident, Dr. Hussain said.

“I think this study has demonstrated that now prostate cancer can be treated with a targeted therapy approach,” said Ignacio Duran, MD, of Hospital Universitario Marques de Valdecilla in Santander, Spain. He was the invited discussant and moderator of a briefing where Dr. Hussain outlined the study details prior to presentation in a symposium.

Neil Osterweil/MDedge News

“Not all prostate cancer patients have the same tumors, and this is the first time we’ve been able to identify that we can more precisely characterize the molecular biology, the genetic background of these tumors, and that is going to determine how we treat them,” he said.

The PROfound trial made “a double hit: superiority in terms of efficacy, and it has proved a new concept that in prostate cancer has not been proved before,” he added.

“This is a truly practice-changing study, not just for our practice and our patients, but also for the study design,” said Eleni Efstathiou, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, who was the invited discussant at the symposium where Dr. Hussain presented the full trial data.

Neil Osterweil/MDedge News

She lauded the use of a validated genomic testing tissue-based assay (FoundationOne CDx next-generation sequencing test) to identify patients who might benefit from olaparib.

She said that the PARP inhibition-specific strategy of the trial appears to have paid off, with statistically significant, clinically meaningful improvement in outcomes and an acceptable safety profile.

“And when it comes to a prostate cancer therapy strategry? Well, we’re starting to enter into the targeted therapy era,” she said.

The PROfound trial was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck. Dr. Hussain disclosed travel and/or accommodation support, honoraria, consulting/advisory fees and research support from AstraZeneca and others. Dr. Duran disclosed advisory board fees from Roche and BMS, and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck. Dr. Efstathiou disclosed research support and honoraria from various companies, not including AstraZeneca or Merck.

SOURCE: Hussain M et al. ESMO 2019, Abstract LBA-12.

BARCELONA – PARP inhibitors may be able to do for men with advanced castration-resistant prostate cancer what they currently do for women with breast or ovarian cancers linked to BRCA mutations, investigators report.

Neil Osterweil/MDedge News

Among men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed on prior therapy with either abiraterone (Zytiga) or enzalutamide (Xtandi) and that bore DNA-repair mutations (BRCA1, BRCA2, or ATM), those who were randomized in the PROfound trial to receive olaparib (Lynparza) had significant improvement in radiographic progression-free survival (rPFS) compared with patients assigned to the physician’s choice of a new hormonal agent, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago.

“PROfound is the first positive biomarker-selected phase 3 study evaluating a molecularly-targeted therapy in men with metastatic castration-resistant prostate cancer, highlighting the importance of genomic testing in this population, and also importantly highlighting the feasibility of precision-medicine trials in this disease,” she said at the European Society for Medical Oncology (ESMO) Congress.

Approximately 25% of men with mCRPC have loss-of-function mutations or alterations in homologous recombinant repair (HRR) genes, especially BRCA1, BRCA2, and ATM. Breast and ovarian cancers bearing these mutations are known to be sensitive to PARP (poly ADP ribose polymerase) inhibitors such as olaparib.

To see whether men with mCRPC could derive a similar benefit, the investigators enrolled patients who had experienced disease progression on abiraterone or enzalutamiude and whose tumors had one or more alterations in any qualifying gene with direct or indirect role in homologous recombinant DNA repair.

Patients were stratified by previous taxane use and measurable disease, and then two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (in BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L).

The median age in cohort A was 68, and in cohort B it was 67, with men 86 years of age at the upper end of the range.

“I think it’s remarkable that men in their late 80s and even early 90s were eligible, were able to be enter this study and be treated on it, and I think that’s an important point here,” Dr. Hussain said.

Nearly one-fourth of patients in the trial had metastatic disease at their initial diagnosis, she noted.

Patients in each cohort were randomized on a 2:1 basis to receive either open-label olaparib 300 mg twice daily, or the treating physician’s choice of abireraterone or enzalutamide, plus predisone.

Upon blinded independent central review (BICR) showing disease progression, patients were allowed to cross over to the olaparib arm, which more than 80% of patients eventually did.

Radiographic PFS in the BRCA1, BRCA2 and ATM cohort according to BICR, the primary endpoint, was a median of 7.39 months with olaparib, compared with 3.55 months with the other therapies, for a hazard ratio (HR) for progression on olaparib of 0.34 (P less than .0001).

A somewhat smaller but still significant benefit was seen for olaparib in the overall population (both cohorts), with a median rPFS of 5.82 months vs. 3.52 months, respectively (HR 0.49, P less than .0001).

Among patients in cohort A, the objective response rate was 33.3% with olaparib, compared with 2.3% for the other agents, resulting in an odds ratio for response of 20.86 (P less than .0001)

Olaparib was also associated with longer time to pain progression in patients in cohort A, with the median not reached compared with 9.92 months with the hormonal agents (HR 0.44, P = .0192).

Among patients in the physician’s choice arm who had disease progression, 80.6% in cohort A and 84.6% in cohort B were crossed over to olaparib.

At this interim analysis, median overall survival was 18.5 months with olaparib, compared with 15.11 months with the other agents, but this difference was not statistically significant. Further follow-up will be needed before a difference in overall survival becomes evident, Dr. Hussain said.

“I think this study has demonstrated that now prostate cancer can be treated with a targeted therapy approach,” said Ignacio Duran, MD, of Hospital Universitario Marques de Valdecilla in Santander, Spain. He was the invited discussant and moderator of a briefing where Dr. Hussain outlined the study details prior to presentation in a symposium.

Neil Osterweil/MDedge News

“Not all prostate cancer patients have the same tumors, and this is the first time we’ve been able to identify that we can more precisely characterize the molecular biology, the genetic background of these tumors, and that is going to determine how we treat them,” he said.

The PROfound trial made “a double hit: superiority in terms of efficacy, and it has proved a new concept that in prostate cancer has not been proved before,” he added.

“This is a truly practice-changing study, not just for our practice and our patients, but also for the study design,” said Eleni Efstathiou, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, who was the invited discussant at the symposium where Dr. Hussain presented the full trial data.

Neil Osterweil/MDedge News

She lauded the use of a validated genomic testing tissue-based assay (FoundationOne CDx next-generation sequencing test) to identify patients who might benefit from olaparib.

She said that the PARP inhibition-specific strategy of the trial appears to have paid off, with statistically significant, clinically meaningful improvement in outcomes and an acceptable safety profile.

“And when it comes to a prostate cancer therapy strategry? Well, we’re starting to enter into the targeted therapy era,” she said.

The PROfound trial was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck. Dr. Hussain disclosed travel and/or accommodation support, honoraria, consulting/advisory fees and research support from AstraZeneca and others. Dr. Duran disclosed advisory board fees from Roche and BMS, and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck. Dr. Efstathiou disclosed research support and honoraria from various companies, not including AstraZeneca or Merck.

SOURCE: Hussain M et al. ESMO 2019, Abstract LBA-12.

BARCELONA – Adding the CDK4/6 inhibitor abemaciclib to fulvestrant significantly improves overall survival in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer patients who progressed on prior endocrine therapy, according to findings from the phase 3 MONARCH 2 trial.

At a median follow-up of 47.7 months, overall survival – a secondary study endpoint – was 46.7 months in 446 patients randomized to receive abemaciclib and fulvestrant, compared with 37.3 months in 223 patients who received placebo and fulvestrant (hazard ratio, 0.757), George W. Sledge, MD, reported at the European Society for Medical Oncology Congress.

The overall survival benefit was consistent across stratification factors, which included site of metastasis (visceral, bone, or other) and resistance to prior endocrine therapy (primary versus secondary), but it was most pronounced in patients with visceral disease (HR, 0.675) and primary resistance to prior endocrine therapy (HR, 0.686), said Dr. Sledge, a professor of medicine at Stanford (Calif.) Medical Center.

Progression-free survival, the primary study endpoint, was 16.4 and 9.3 months at the previously reported 2-year follow-up in the treatment and placebo groups, respectively, and the current analysis showed progression-free survival to be “highly consistent” with those findings (16.9 vs. 9.3 months; HR, 0.563), he said.

“Of note, and of interest for further follow-up, a landmark analysis at 3 years shows that approximately three times as many patients on the abemaciclib arm remained progression free, compared to the control arm,” he added, also noting that time from randomization to postdiscontinuation chemotherapy was prolonged with abemaciclib, compared with placebo (50.2 vs. 22.1 months; HR, 0.625).

“A highly significant result,” he said.

At the 47.7 month follow-up, 17% and 4% of patients in the treatment and placebo groups, respectively, remained on treatment.

An additional exploratory analysis showed that 5.8% of patients receiving abemaciclib crossed over to another CDK4/6 inhibitor after discontinuation of therapy, compared with 17.0% of those in the placebo group.

“CDK4/6 inhibitors have emerged as standard-of-care treatment for patients with HR+, HER2– breast cancer,” he said, noting that abemaciclib is a selective CDK4/6 inhibitor with continuous, twice-daily oral administration. “It is approved for monotherapy after progression on endocrine therapy and prior chemotherapy in the metastatic setting, and ... in combination with endocrine therapy in the front-line setting and after progression.”

The global, randomized, double-blind MONARCH 2 trial assessed abemaciclib + fulvestrant in women with advanced endocrine therapy–resistant HR+, HER2– advanced breast cancer, including pre- or perimenopausal women with ovarian suppression and postmenopausal women.

Study participants were randomized 2:1 to receive 500 mg of fulvestrant per label instructions plus 150 mg of abemaciclib every 12 hours or placebo.

Treatment-emergent adverse events in MONARCH 2 were consistent with those previously reported in the primary analysis, Dr. Sledge said.

“Continued follow-up of MONARCH 2 is ongoing to further characterize the overall survival benefit and to look at exploratory efficacy and correlative endpoints,” he noted.

Speaking about the findings during a press conference at the meeting, Nadia Harbeck, MD, a professor at Ludwig Maximilians University, Munich, Germany, said they have important practice-changing implications.

“We were always struggling with whether to give these drugs first or second line, and I think now if we consider the first-line survival benefit ... [first-line use] should be standard of care,” she said, referring to CDK4/6 inhibitors and to findings from MONARCH 2 and prior studies of the inhibitors, including the MONALEESA-3 trial presented at the ESMO Congress.

MONALEESA-3 showed similar overall survival results with the CDK4/6 inhibitor ribociclib in postmenopausal women with HR+, HER2– advanced breast cancer.

“The data are highly clinically meaningful; I think they are going to make a huge impact on how we treat breast cancer,” Dr. Harbeck said.

Dr. Sledge has received trial support, research grants, and travel accommodations from Eli Lilly and Company; is a board member for Tessa Therapeutics; and is a consultant for Syndax, Symphogen, and Verseau Therapeutics. Dr. Harbeck disclosed financial relationships with Agendia, Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Nanostring, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. She is also director of the West German Study Group and a member of the German AGO Breast Committee.

SOURCE: Sledge G et al., ESMO 2019, Abstract LBA6-PR.

BARCELONA – Adding the CDK4/6 inhibitor abemaciclib to fulvestrant significantly improves overall survival in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer patients who progressed on prior endocrine therapy, according to findings from the phase 3 MONARCH 2 trial.

At a median follow-up of 47.7 months, overall survival – a secondary study endpoint – was 46.7 months in 446 patients randomized to receive abemaciclib and fulvestrant, compared with 37.3 months in 223 patients who received placebo and fulvestrant (hazard ratio, 0.757), George W. Sledge, MD, reported at the European Society for Medical Oncology Congress.

The overall survival benefit was consistent across stratification factors, which included site of metastasis (visceral, bone, or other) and resistance to prior endocrine therapy (primary versus secondary), but it was most pronounced in patients with visceral disease (HR, 0.675) and primary resistance to prior endocrine therapy (HR, 0.686), said Dr. Sledge, a professor of medicine at Stanford (Calif.) Medical Center.

Progression-free survival, the primary study endpoint, was 16.4 and 9.3 months at the previously reported 2-year follow-up in the treatment and placebo groups, respectively, and the current analysis showed progression-free survival to be “highly consistent” with those findings (16.9 vs. 9.3 months; HR, 0.563), he said.

“Of note, and of interest for further follow-up, a landmark analysis at 3 years shows that approximately three times as many patients on the abemaciclib arm remained progression free, compared to the control arm,” he added, also noting that time from randomization to postdiscontinuation chemotherapy was prolonged with abemaciclib, compared with placebo (50.2 vs. 22.1 months; HR, 0.625).

“A highly significant result,” he said.

At the 47.7 month follow-up, 17% and 4% of patients in the treatment and placebo groups, respectively, remained on treatment.

An additional exploratory analysis showed that 5.8% of patients receiving abemaciclib crossed over to another CDK4/6 inhibitor after discontinuation of therapy, compared with 17.0% of those in the placebo group.

“CDK4/6 inhibitors have emerged as standard-of-care treatment for patients with HR+, HER2– breast cancer,” he said, noting that abemaciclib is a selective CDK4/6 inhibitor with continuous, twice-daily oral administration. “It is approved for monotherapy after progression on endocrine therapy and prior chemotherapy in the metastatic setting, and ... in combination with endocrine therapy in the front-line setting and after progression.”

The global, randomized, double-blind MONARCH 2 trial assessed abemaciclib + fulvestrant in women with advanced endocrine therapy–resistant HR+, HER2– advanced breast cancer, including pre- or perimenopausal women with ovarian suppression and postmenopausal women.

Study participants were randomized 2:1 to receive 500 mg of fulvestrant per label instructions plus 150 mg of abemaciclib every 12 hours or placebo.

Treatment-emergent adverse events in MONARCH 2 were consistent with those previously reported in the primary analysis, Dr. Sledge said.

“Continued follow-up of MONARCH 2 is ongoing to further characterize the overall survival benefit and to look at exploratory efficacy and correlative endpoints,” he noted.

Speaking about the findings during a press conference at the meeting, Nadia Harbeck, MD, a professor at Ludwig Maximilians University, Munich, Germany, said they have important practice-changing implications.

“We were always struggling with whether to give these drugs first or second line, and I think now if we consider the first-line survival benefit ... [first-line use] should be standard of care,” she said, referring to CDK4/6 inhibitors and to findings from MONARCH 2 and prior studies of the inhibitors, including the MONALEESA-3 trial presented at the ESMO Congress.

MONALEESA-3 showed similar overall survival results with the CDK4/6 inhibitor ribociclib in postmenopausal women with HR+, HER2– advanced breast cancer.

“The data are highly clinically meaningful; I think they are going to make a huge impact on how we treat breast cancer,” Dr. Harbeck said.

Dr. Sledge has received trial support, research grants, and travel accommodations from Eli Lilly and Company; is a board member for Tessa Therapeutics; and is a consultant for Syndax, Symphogen, and Verseau Therapeutics. Dr. Harbeck disclosed financial relationships with Agendia, Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Nanostring, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. She is also director of the West German Study Group and a member of the German AGO Breast Committee.

SOURCE: Sledge G et al., ESMO 2019, Abstract LBA6-PR.

BARCELONA – Adding the CDK4/6 inhibitor abemaciclib to fulvestrant significantly improves overall survival in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer patients who progressed on prior endocrine therapy, according to findings from the phase 3 MONARCH 2 trial.

At a median follow-up of 47.7 months, overall survival – a secondary study endpoint – was 46.7 months in 446 patients randomized to receive abemaciclib and fulvestrant, compared with 37.3 months in 223 patients who received placebo and fulvestrant (hazard ratio, 0.757), George W. Sledge, MD, reported at the European Society for Medical Oncology Congress.

The overall survival benefit was consistent across stratification factors, which included site of metastasis (visceral, bone, or other) and resistance to prior endocrine therapy (primary versus secondary), but it was most pronounced in patients with visceral disease (HR, 0.675) and primary resistance to prior endocrine therapy (HR, 0.686), said Dr. Sledge, a professor of medicine at Stanford (Calif.) Medical Center.

Progression-free survival, the primary study endpoint, was 16.4 and 9.3 months at the previously reported 2-year follow-up in the treatment and placebo groups, respectively, and the current analysis showed progression-free survival to be “highly consistent” with those findings (16.9 vs. 9.3 months; HR, 0.563), he said.

“Of note, and of interest for further follow-up, a landmark analysis at 3 years shows that approximately three times as many patients on the abemaciclib arm remained progression free, compared to the control arm,” he added, also noting that time from randomization to postdiscontinuation chemotherapy was prolonged with abemaciclib, compared with placebo (50.2 vs. 22.1 months; HR, 0.625).

“A highly significant result,” he said.

At the 47.7 month follow-up, 17% and 4% of patients in the treatment and placebo groups, respectively, remained on treatment.

An additional exploratory analysis showed that 5.8% of patients receiving abemaciclib crossed over to another CDK4/6 inhibitor after discontinuation of therapy, compared with 17.0% of those in the placebo group.

“CDK4/6 inhibitors have emerged as standard-of-care treatment for patients with HR+, HER2– breast cancer,” he said, noting that abemaciclib is a selective CDK4/6 inhibitor with continuous, twice-daily oral administration. “It is approved for monotherapy after progression on endocrine therapy and prior chemotherapy in the metastatic setting, and ... in combination with endocrine therapy in the front-line setting and after progression.”

The global, randomized, double-blind MONARCH 2 trial assessed abemaciclib + fulvestrant in women with advanced endocrine therapy–resistant HR+, HER2– advanced breast cancer, including pre- or perimenopausal women with ovarian suppression and postmenopausal women.

Study participants were randomized 2:1 to receive 500 mg of fulvestrant per label instructions plus 150 mg of abemaciclib every 12 hours or placebo.

Treatment-emergent adverse events in MONARCH 2 were consistent with those previously reported in the primary analysis, Dr. Sledge said.

“Continued follow-up of MONARCH 2 is ongoing to further characterize the overall survival benefit and to look at exploratory efficacy and correlative endpoints,” he noted.

Speaking about the findings during a press conference at the meeting, Nadia Harbeck, MD, a professor at Ludwig Maximilians University, Munich, Germany, said they have important practice-changing implications.

“We were always struggling with whether to give these drugs first or second line, and I think now if we consider the first-line survival benefit ... [first-line use] should be standard of care,” she said, referring to CDK4/6 inhibitors and to findings from MONARCH 2 and prior studies of the inhibitors, including the MONALEESA-3 trial presented at the ESMO Congress.

MONALEESA-3 showed similar overall survival results with the CDK4/6 inhibitor ribociclib in postmenopausal women with HR+, HER2– advanced breast cancer.

“The data are highly clinically meaningful; I think they are going to make a huge impact on how we treat breast cancer,” Dr. Harbeck said.

Dr. Sledge has received trial support, research grants, and travel accommodations from Eli Lilly and Company; is a board member for Tessa Therapeutics; and is a consultant for Syndax, Symphogen, and Verseau Therapeutics. Dr. Harbeck disclosed financial relationships with Agendia, Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Nanostring, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. She is also director of the West German Study Group and a member of the German AGO Breast Committee.

SOURCE: Sledge G et al., ESMO 2019, Abstract LBA6-PR.

BARCELONA – Patients with newly diagnosed metastatic non–small cell lung cancer (NSCLC) had better overall survival with a first-line therapy combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.

Neil Osterweil/MDedge News

Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.

The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.

Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.

CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.

The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.

Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).

In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.

The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.

Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.

Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.

Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.

“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.

“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.

He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).

Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.

Neil Osterweil/MDedge News

“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.

“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.

The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.

SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.

BARCELONA – Patients with newly diagnosed metastatic non–small cell lung cancer (NSCLC) had better overall survival with a first-line therapy combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.

Neil Osterweil/MDedge News

Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.

The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.

Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.

CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.

The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.

Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).

In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.

The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.

Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.

Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.

Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.

“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.

“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.

He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).

Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.

Neil Osterweil/MDedge News

“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.

“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.

The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.

SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.

BARCELONA – Patients with newly diagnosed metastatic non–small cell lung cancer (NSCLC) had better overall survival with a first-line therapy combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.

Neil Osterweil/MDedge News

Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.

The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.

Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.

CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.

The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.

Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).

In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.

The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.

Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.

Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.

Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.

“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.

“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.

He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).

Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.

Neil Osterweil/MDedge News

“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.

“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.

The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.

SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.

BARCELONA – Adding olaparib to bevacizumab as maintenance after first-line platinum-based chemotherapy for advanced ovarian cancer provided a significant and clinically meaningful progression-free survival (PFS) benefit in the phase 3 PAOLA-1/ENGOT-ov25 trial.

The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.

Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.

The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.

In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.

“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”

The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.

“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.

Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.

Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.

The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.

Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.

The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.

During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.

“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.

Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.

“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”

In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”

Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”

In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”

As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.

The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.

sworcester@mdedge.com

SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
 

BARCELONA – Adding olaparib to bevacizumab as maintenance after first-line platinum-based chemotherapy for advanced ovarian cancer provided a significant and clinically meaningful progression-free survival (PFS) benefit in the phase 3 PAOLA-1/ENGOT-ov25 trial.

The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.

Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.

The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.

In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.

“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”

The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.

“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.

Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.

Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.

The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.

Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.

The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.

During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.

“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.

Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.

“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”

In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”

Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”

In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”

As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.

The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.

sworcester@mdedge.com

SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
 

BARCELONA – Adding olaparib to bevacizumab as maintenance after first-line platinum-based chemotherapy for advanced ovarian cancer provided a significant and clinically meaningful progression-free survival (PFS) benefit in the phase 3 PAOLA-1/ENGOT-ov25 trial.

The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.

Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.

The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.

In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.

“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”

The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.

“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.

Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.

Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.

The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.

Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.

The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.

During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.

“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.

Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.

“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”

In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”

Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”

In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”

As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.

The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.

sworcester@mdedge.com

SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
 

BARCELONA – In patients with advanced, treatment-naive non–small cell lung cancer (NSCLC), therapy with osimertinib (Tagrisso) is associated with a significant and clinically meaningful improvement in overall survival, compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.

Neil Osterweil/MDedge News

After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).

The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.

“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.

Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.

Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.

Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).

The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.

The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.

The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.

“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
 

FLAURA details

In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).

Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.

The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.

Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.

PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).

Neil Osterweil/MDedge News

“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.

“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.

He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.

FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.

SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.

BARCELONA – In patients with advanced, treatment-naive non–small cell lung cancer (NSCLC), therapy with osimertinib (Tagrisso) is associated with a significant and clinically meaningful improvement in overall survival, compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.

Neil Osterweil/MDedge News

After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).

The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.

“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.

Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.

Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.

Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).

The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.

The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.

The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.

“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
 

FLAURA details

In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).

Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.

The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.

Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.

PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).

Neil Osterweil/MDedge News

“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.

“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.

He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.

FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.

SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.

BARCELONA – In patients with advanced, treatment-naive non–small cell lung cancer (NSCLC), therapy with osimertinib (Tagrisso) is associated with a significant and clinically meaningful improvement in overall survival, compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.

Neil Osterweil/MDedge News

After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).

The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.

“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.

Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.

Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.

Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).

The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.

The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.

The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.

“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
 

FLAURA details

In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).

Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.

The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.

Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.

PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).

Neil Osterweil/MDedge News

“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.

“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.

He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.

FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.

SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.

BARCELONA – A continuous schedule of combination cediranib and olaparib demonstrated clinical benefit in 85% of patients with platinum-resistant ovarian cancer (PROC) in the randomized, phase 2 BAROCCO (Best Approach in Recurrent Ovarian Cancer With Cediranib-Olaparib) study.

Sharon Worcester/MDedge News

The continuous treatment approach was also associated with a trend toward improved progression-free survival (PFS) versus weekly paclitaxel in heavily pretreated patients with PROC, and this was particularly true in patients with germline BRCA wild-type (gBRCAwt), with a hazard ratio for PFS of 0.63, Nicolleta Colombo, MD, reported at the European Society of Medical Oncology Congress.

Median investigator-assessed PFS was 3.1, 5.7, and 3.8 months, respectively, in 123 patients with PROC and any gBRCA status who were enrolled from multiple centers in Italy and randomized 1:1:1 to receive 80 mg/m² of weekly paclitaxel for up to 24 weeks, continuous combination therapy with 20 mg of cediranib daily and 300 mg of olaparib twice daily, or intermittent dosing with 20 mg of cediranib given 5 days per week until progression, said Dr. Colombo, director of gynecologic cancer medical treatments at Istituto Europeo di Oncologia, Milan.

The hazard ratios for PFS with continuous therapy and intermittent therapy versus paclitaxel were 0.76 and 1.08, respectively, but the former comparison was not proportional and the difference in the area under the PFS curves was assessed and found to be 1.25 months in favor of continuous therapy with cediranib and olaparib, she explained.

“Surprisingly, the intermittent regimen did not perform as well,” she noted.

Subgroup analyses showed that in patients with gBRCAwt or unknown BRCA status, median PFS was 2.1, 5.8, and 3.8 months in the paclitaxel, continuous, and intermittent groups, respectively, demonstrating a trend toward greater benefit with continuous combination therapy versus the other arms (HR, 0.63; P = .13). The area under the PFS curves showed a difference of 1.32 months in favor of continuous therapy, she said.

Similarly, a trend toward greater benefit was seen in patients who had received up to two prior lines of therapy (HR, 0.47; P = .28).

As for the secondary study endpoint of response rates, complete responses occurred in 2 of 24 evaluable paclitaxel patients, and none of 39 and 35 patients in the continuous and intermittent groups. Partial responses occurred in 6, 7, and 4 patients in the groups, respectively; stable disease occurred in 5, 26, and 18, respectively; and progressive disease occurred in 11, 6, and 13 patients, respectively.

“The [rate of] progression was much higher with paclitaxel than in the continuous and intermittent arms,” Dr. Colombo said. “So the clinical benefit was very good; it was 84.6% for the continuous arm, and 62.8% for the intermittent arm.”

Clinical benefit in the paclitaxel arm was 54.1%, and duration of response was 4.4, 6.2, and 2.7 months in the arms, respectively.

The findings are of note, as the BAROCCO study includes a difficult-to-treat population with a high unmet need, she said, explaining that 59% of patients had received three or more prior lines of therapy, and the median platinum-free interval was only 1.8 months.

“Median progression-free survival for these patients is only about 3-4 months, even after weekly paclitaxel, which is recognized as the most effective chemotherapy regimen in this patient population,” she said, noting that new therapeutic options in this setting are of great clinical interest.

Additionally, BAROCCO is the first trial of combined cediranib-olaparib in PROC to include a control arm, she noted.

Single-agent olaparib was approved by the Food and Drug Administration in 2017 for the treatment of patients with germline BRCA mutated (gBRCAm) relapsed ovarian cancer after 3 or more lines of chemotherapy, but the efficacy of the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor in gBRCAwt PROC is limited.

Findings from the CLIO trial presented in June at American Society of Clinical Oncology annual meeting showed an overall response rate (ORR) of 13% and PFS of 2.9 months in gBRCAwt patients with PROC treated with olaparib, and in the QUADRA study, the ORR in gBRCAwt PROC was just 3%

“On the other hand, olaparib activity was observed beyond BRCA-mutated tumors in the platinum-sensitive relapsed ovarian cancer patients, and was increased when combined with an antiangiogenic agent,” Dr. Colombo said. “In fact, both the trials with cediranib and olaparib, and with bevacizumab and niraparib, showed an improvement in progression-free survival, compared with a single agent.

“So there is a strong rationale for the combination and the synergistic effect of cediranib and olaparib, because molecular pharmacologic studies suggest that cediranib induces downregulation of some genes that are involved in homologous recombination, thus producing a sort of functional ‘BRCAness’ that favors the selective activity of the PARP inhibitors,” she explained.

Preclinical evidence suggests this may be related to the antiangiogenic effect of cediranib, or possibly to the inhibition of the platinum-derived growth factor signaling by cediranib.

BAROCCO was designed to assess whether the combination would provide superior PFS, compared with weekly paclitaxel, in the platinum-resistant population, and if an intermittent schedule might improve gastrointestinal tolerability, as treatment has been associated with severe diarrhea in previous trials, she said.

However, the toxicity profile of the study arms was as expected, and similar between experimental arms, with 11%, 18%, and 7% of patients in the paclitaxel, continuous, and intermittent arms discontinuing treatment because of adverse events, she noted.

Five serious adverse drug reactions occurred and two were fatal, including one in the control arm and one in the continuous arm.

Although not statistically significant, the continuous administration regimen was well tolerated, and showed “a promising trend for improved PFS,” particularly in gBRCAwt patients.

Notably, only 5% of patients in that arm experienced severe diarrhea, Dr. Colombo said, adding that “the continuous administration of cediranib and olaparib is active in PROC patients, with clinical benefit observed in 85% of cases.”

“We believe that [this combination] represents an active, feasible oral regimen, which deserves further investigation, and these results support ongoing trials investigating the same combination in platinum-resistant ovarian cancer,” she concluded.

Invited discussant Antonio Gonzalez Martin, MD, said that some of the drug-related adverse events reported in the study – which occurred in 70%-78% of patients in the three arms and included diarrhea, nausea, fatigue, and others – could have an impact on quality of life.

“It’s something that we need to study; patient-reported outcomes should be integrated in these types of trials for this very important population,” said Dr. Gonzalez-Martin, head of medical oncology at Clinica Universidad de Navarra, Madrid.

He added that the future of antiangiogenic and PARP inhibitor combinations remains to be defined in the first-line, platinum-sensitive, and platinum-resistant ovarian cancer settings.

The BAROCCO Trial was funded by AstraZeneca. Dr. Colombo has received honoraria from or been an advisor or consultant to Roche/Genentech, PharmaMar; AstraZeneca, Tesaro, Clovis Oncology, Pfizer, MSD Oncology, BioCad, and Takeda. Dr. Gonzalez-Martin has received fees, honoraria, and/or grants from Roche, AstraZeneca, Tesaro, GSK, Clovis, MSD, Pfizer, Novartis, PharmaMar, and Imugene.

sworcester@mdedge.com

SOURCE: Colombo N et al. ESMO 2019, Abstract LBA58. Ann Oncol. 2019;30:suppl 5.

BARCELONA – A continuous schedule of combination cediranib and olaparib demonstrated clinical benefit in 85% of patients with platinum-resistant ovarian cancer (PROC) in the randomized, phase 2 BAROCCO (Best Approach in Recurrent Ovarian Cancer With Cediranib-Olaparib) study.

Sharon Worcester/MDedge News

The continuous treatment approach was also associated with a trend toward improved progression-free survival (PFS) versus weekly paclitaxel in heavily pretreated patients with PROC, and this was particularly true in patients with germline BRCA wild-type (gBRCAwt), with a hazard ratio for PFS of 0.63, Nicolleta Colombo, MD, reported at the European Society of Medical Oncology Congress.

Median investigator-assessed PFS was 3.1, 5.7, and 3.8 months, respectively, in 123 patients with PROC and any gBRCA status who were enrolled from multiple centers in Italy and randomized 1:1:1 to receive 80 mg/m² of weekly paclitaxel for up to 24 weeks, continuous combination therapy with 20 mg of cediranib daily and 300 mg of olaparib twice daily, or intermittent dosing with 20 mg of cediranib given 5 days per week until progression, said Dr. Colombo, director of gynecologic cancer medical treatments at Istituto Europeo di Oncologia, Milan.

The hazard ratios for PFS with continuous therapy and intermittent therapy versus paclitaxel were 0.76 and 1.08, respectively, but the former comparison was not proportional and the difference in the area under the PFS curves was assessed and found to be 1.25 months in favor of continuous therapy with cediranib and olaparib, she explained.

“Surprisingly, the intermittent regimen did not perform as well,” she noted.

Subgroup analyses showed that in patients with gBRCAwt or unknown BRCA status, median PFS was 2.1, 5.8, and 3.8 months in the paclitaxel, continuous, and intermittent groups, respectively, demonstrating a trend toward greater benefit with continuous combination therapy versus the other arms (HR, 0.63; P = .13). The area under the PFS curves showed a difference of 1.32 months in favor of continuous therapy, she said.

Similarly, a trend toward greater benefit was seen in patients who had received up to two prior lines of therapy (HR, 0.47; P = .28).

As for the secondary study endpoint of response rates, complete responses occurred in 2 of 24 evaluable paclitaxel patients, and none of 39 and 35 patients in the continuous and intermittent groups. Partial responses occurred in 6, 7, and 4 patients in the groups, respectively; stable disease occurred in 5, 26, and 18, respectively; and progressive disease occurred in 11, 6, and 13 patients, respectively.

“The [rate of] progression was much higher with paclitaxel than in the continuous and intermittent arms,” Dr. Colombo said. “So the clinical benefit was very good; it was 84.6% for the continuous arm, and 62.8% for the intermittent arm.”

Clinical benefit in the paclitaxel arm was 54.1%, and duration of response was 4.4, 6.2, and 2.7 months in the arms, respectively.

The findings are of note, as the BAROCCO study includes a difficult-to-treat population with a high unmet need, she said, explaining that 59% of patients had received three or more prior lines of therapy, and the median platinum-free interval was only 1.8 months.

“Median progression-free survival for these patients is only about 3-4 months, even after weekly paclitaxel, which is recognized as the most effective chemotherapy regimen in this patient population,” she said, noting that new therapeutic options in this setting are of great clinical interest.

Additionally, BAROCCO is the first trial of combined cediranib-olaparib in PROC to include a control arm, she noted.

Single-agent olaparib was approved by the Food and Drug Administration in 2017 for the treatment of patients with germline BRCA mutated (gBRCAm) relapsed ovarian cancer after 3 or more lines of chemotherapy, but the efficacy of the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor in gBRCAwt PROC is limited.

Findings from the CLIO trial presented in June at American Society of Clinical Oncology annual meeting showed an overall response rate (ORR) of 13% and PFS of 2.9 months in gBRCAwt patients with PROC treated with olaparib, and in the QUADRA study, the ORR in gBRCAwt PROC was just 3%

“On the other hand, olaparib activity was observed beyond BRCA-mutated tumors in the platinum-sensitive relapsed ovarian cancer patients, and was increased when combined with an antiangiogenic agent,” Dr. Colombo said. “In fact, both the trials with cediranib and olaparib, and with bevacizumab and niraparib, showed an improvement in progression-free survival, compared with a single agent.

“So there is a strong rationale for the combination and the synergistic effect of cediranib and olaparib, because molecular pharmacologic studies suggest that cediranib induces downregulation of some genes that are involved in homologous recombination, thus producing a sort of functional ‘BRCAness’ that favors the selective activity of the PARP inhibitors,” she explained.

Preclinical evidence suggests this may be related to the antiangiogenic effect of cediranib, or possibly to the inhibition of the platinum-derived growth factor signaling by cediranib.

BAROCCO was designed to assess whether the combination would provide superior PFS, compared with weekly paclitaxel, in the platinum-resistant population, and if an intermittent schedule might improve gastrointestinal tolerability, as treatment has been associated with severe diarrhea in previous trials, she said.

However, the toxicity profile of the study arms was as expected, and similar between experimental arms, with 11%, 18%, and 7% of patients in the paclitaxel, continuous, and intermittent arms discontinuing treatment because of adverse events, she noted.

Five serious adverse drug reactions occurred and two were fatal, including one in the control arm and one in the continuous arm.

Although not statistically significant, the continuous administration regimen was well tolerated, and showed “a promising trend for improved PFS,” particularly in gBRCAwt patients.

Notably, only 5% of patients in that arm experienced severe diarrhea, Dr. Colombo said, adding that “the continuous administration of cediranib and olaparib is active in PROC patients, with clinical benefit observed in 85% of cases.”

“We believe that [this combination] represents an active, feasible oral regimen, which deserves further investigation, and these results support ongoing trials investigating the same combination in platinum-resistant ovarian cancer,” she concluded.

Invited discussant Antonio Gonzalez Martin, MD, said that some of the drug-related adverse events reported in the study – which occurred in 70%-78% of patients in the three arms and included diarrhea, nausea, fatigue, and others – could have an impact on quality of life.

“It’s something that we need to study; patient-reported outcomes should be integrated in these types of trials for this very important population,” said Dr. Gonzalez-Martin, head of medical oncology at Clinica Universidad de Navarra, Madrid.

He added that the future of antiangiogenic and PARP inhibitor combinations remains to be defined in the first-line, platinum-sensitive, and platinum-resistant ovarian cancer settings.

The BAROCCO Trial was funded by AstraZeneca. Dr. Colombo has received honoraria from or been an advisor or consultant to Roche/Genentech, PharmaMar; AstraZeneca, Tesaro, Clovis Oncology, Pfizer, MSD Oncology, BioCad, and Takeda. Dr. Gonzalez-Martin has received fees, honoraria, and/or grants from Roche, AstraZeneca, Tesaro, GSK, Clovis, MSD, Pfizer, Novartis, PharmaMar, and Imugene.

sworcester@mdedge.com

SOURCE: Colombo N et al. ESMO 2019, Abstract LBA58. Ann Oncol. 2019;30:suppl 5.

BARCELONA – A continuous schedule of combination cediranib and olaparib demonstrated clinical benefit in 85% of patients with platinum-resistant ovarian cancer (PROC) in the randomized, phase 2 BAROCCO (Best Approach in Recurrent Ovarian Cancer With Cediranib-Olaparib) study.

Sharon Worcester/MDedge News

The continuous treatment approach was also associated with a trend toward improved progression-free survival (PFS) versus weekly paclitaxel in heavily pretreated patients with PROC, and this was particularly true in patients with germline BRCA wild-type (gBRCAwt), with a hazard ratio for PFS of 0.63, Nicolleta Colombo, MD, reported at the European Society of Medical Oncology Congress.

Median investigator-assessed PFS was 3.1, 5.7, and 3.8 months, respectively, in 123 patients with PROC and any gBRCA status who were enrolled from multiple centers in Italy and randomized 1:1:1 to receive 80 mg/m² of weekly paclitaxel for up to 24 weeks, continuous combination therapy with 20 mg of cediranib daily and 300 mg of olaparib twice daily, or intermittent dosing with 20 mg of cediranib given 5 days per week until progression, said Dr. Colombo, director of gynecologic cancer medical treatments at Istituto Europeo di Oncologia, Milan.

The hazard ratios for PFS with continuous therapy and intermittent therapy versus paclitaxel were 0.76 and 1.08, respectively, but the former comparison was not proportional and the difference in the area under the PFS curves was assessed and found to be 1.25 months in favor of continuous therapy with cediranib and olaparib, she explained.

“Surprisingly, the intermittent regimen did not perform as well,” she noted.

Subgroup analyses showed that in patients with gBRCAwt or unknown BRCA status, median PFS was 2.1, 5.8, and 3.8 months in the paclitaxel, continuous, and intermittent groups, respectively, demonstrating a trend toward greater benefit with continuous combination therapy versus the other arms (HR, 0.63; P = .13). The area under the PFS curves showed a difference of 1.32 months in favor of continuous therapy, she said.

Similarly, a trend toward greater benefit was seen in patients who had received up to two prior lines of therapy (HR, 0.47; P = .28).

As for the secondary study endpoint of response rates, complete responses occurred in 2 of 24 evaluable paclitaxel patients, and none of 39 and 35 patients in the continuous and intermittent groups. Partial responses occurred in 6, 7, and 4 patients in the groups, respectively; stable disease occurred in 5, 26, and 18, respectively; and progressive disease occurred in 11, 6, and 13 patients, respectively.

“The [rate of] progression was much higher with paclitaxel than in the continuous and intermittent arms,” Dr. Colombo said. “So the clinical benefit was very good; it was 84.6% for the continuous arm, and 62.8% for the intermittent arm.”

Clinical benefit in the paclitaxel arm was 54.1%, and duration of response was 4.4, 6.2, and 2.7 months in the arms, respectively.

The findings are of note, as the BAROCCO study includes a difficult-to-treat population with a high unmet need, she said, explaining that 59% of patients had received three or more prior lines of therapy, and the median platinum-free interval was only 1.8 months.

“Median progression-free survival for these patients is only about 3-4 months, even after weekly paclitaxel, which is recognized as the most effective chemotherapy regimen in this patient population,” she said, noting that new therapeutic options in this setting are of great clinical interest.

Additionally, BAROCCO is the first trial of combined cediranib-olaparib in PROC to include a control arm, she noted.

Single-agent olaparib was approved by the Food and Drug Administration in 2017 for the treatment of patients with germline BRCA mutated (gBRCAm) relapsed ovarian cancer after 3 or more lines of chemotherapy, but the efficacy of the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor in gBRCAwt PROC is limited.

Findings from the CLIO trial presented in June at American Society of Clinical Oncology annual meeting showed an overall response rate (ORR) of 13% and PFS of 2.9 months in gBRCAwt patients with PROC treated with olaparib, and in the QUADRA study, the ORR in gBRCAwt PROC was just 3%

“On the other hand, olaparib activity was observed beyond BRCA-mutated tumors in the platinum-sensitive relapsed ovarian cancer patients, and was increased when combined with an antiangiogenic agent,” Dr. Colombo said. “In fact, both the trials with cediranib and olaparib, and with bevacizumab and niraparib, showed an improvement in progression-free survival, compared with a single agent.

“So there is a strong rationale for the combination and the synergistic effect of cediranib and olaparib, because molecular pharmacologic studies suggest that cediranib induces downregulation of some genes that are involved in homologous recombination, thus producing a sort of functional ‘BRCAness’ that favors the selective activity of the PARP inhibitors,” she explained.

Preclinical evidence suggests this may be related to the antiangiogenic effect of cediranib, or possibly to the inhibition of the platinum-derived growth factor signaling by cediranib.

BAROCCO was designed to assess whether the combination would provide superior PFS, compared with weekly paclitaxel, in the platinum-resistant population, and if an intermittent schedule might improve gastrointestinal tolerability, as treatment has been associated with severe diarrhea in previous trials, she said.

However, the toxicity profile of the study arms was as expected, and similar between experimental arms, with 11%, 18%, and 7% of patients in the paclitaxel, continuous, and intermittent arms discontinuing treatment because of adverse events, she noted.

Five serious adverse drug reactions occurred and two were fatal, including one in the control arm and one in the continuous arm.

Although not statistically significant, the continuous administration regimen was well tolerated, and showed “a promising trend for improved PFS,” particularly in gBRCAwt patients.

Notably, only 5% of patients in that arm experienced severe diarrhea, Dr. Colombo said, adding that “the continuous administration of cediranib and olaparib is active in PROC patients, with clinical benefit observed in 85% of cases.”

“We believe that [this combination] represents an active, feasible oral regimen, which deserves further investigation, and these results support ongoing trials investigating the same combination in platinum-resistant ovarian cancer,” she concluded.

Invited discussant Antonio Gonzalez Martin, MD, said that some of the drug-related adverse events reported in the study – which occurred in 70%-78% of patients in the three arms and included diarrhea, nausea, fatigue, and others – could have an impact on quality of life.

“It’s something that we need to study; patient-reported outcomes should be integrated in these types of trials for this very important population,” said Dr. Gonzalez-Martin, head of medical oncology at Clinica Universidad de Navarra, Madrid.

He added that the future of antiangiogenic and PARP inhibitor combinations remains to be defined in the first-line, platinum-sensitive, and platinum-resistant ovarian cancer settings.

The BAROCCO Trial was funded by AstraZeneca. Dr. Colombo has received honoraria from or been an advisor or consultant to Roche/Genentech, PharmaMar; AstraZeneca, Tesaro, Clovis Oncology, Pfizer, MSD Oncology, BioCad, and Takeda. Dr. Gonzalez-Martin has received fees, honoraria, and/or grants from Roche, AstraZeneca, Tesaro, GSK, Clovis, MSD, Pfizer, Novartis, PharmaMar, and Imugene.

sworcester@mdedge.com

SOURCE: Colombo N et al. ESMO 2019, Abstract LBA58. Ann Oncol. 2019;30:suppl 5.

BARCELONA – Men who undergo radical prostatectomy can be spared from adjuvant radiotherapy and its associated side effects unless or until they have disease recurrence, results of a large randomized trial and separate meta-analysis indicate.

Among nearly 1,400 men with postoperative prostate-specific antigen (PSA) levels below 0.2 ng/mL and one or more risk factors, followed for a median of 5 years, there were no significant differences in any of the secondary outcomes between men randomized to radiotherapy and observation alone, reported Chris Parker, MD, from the Royal Marsden Hospital in London.

“In comparison with a policy of early salvage radiotherapy, adjuvant radiotherapy did not improve biochemical progression-free survival and did not delay the further use of hormone therapy,” he said at the European Society for Medical Oncology Congress, on behalf of colleagues in the RADICALS-RT trial.

Results of the RADICAL-RT trial were also pooled with results from two other large trials in a collaborative series of meta-analyses of long-term prostate cancer outcomes – dubbed ARTISTIC – which found no significant differences in event-free survival (EFS) for men randomized to either adjuvant or salvage radiotherapy.

“We don’t see any evidence from the ARTISTIC results that adjuvant radiotherapy improves event-free survival, compared to early salvage radiotherapy, and our best estimate is of a small, 1% difference in event-free survival at 5 years,” said Claire Vale, PhD, a research fellow at University College, London.

RADICALS RT details

Dr. Parker presented results from an early analysis of the secondary endpoint of biochemical progression-free survival (PFS), conducted in cooperation with the ARTISTIC investigators.

In RADICALS RT, investigators in the United Kingdom, Denmark, Canada, and Ireland enrolled 1,369 men following radical prostatectomy and after stratification by Gleason score, margin status, treatment center, and radiotherapy schedule (52.5 Gy delivered in 20 fractions, or 66 Gy delivered), randomly assigned them to either postoperative radiotherapy or observation with radiotherapy.

The patients enrolled had postoperative PSAs less than 2 ng/mL and one or more risk factors, either pathologic stage 3/4, Gleason score 7-10, positive surgical margins, or preoperative PSA of 10 ng/mL or greater.

The trigger for radiotherapy in men assigned to observation was PSA failure, defined as a PSA level of at least 0.1 ng/mL or 3 consecutive PSA rises.

At the median 5-year follow-up, PFS rates were 85% for patients assigned to adjuvant radiotherapy, and 88% for those assigned to observation, translating to a hazard ratio of 1.10, which was not statistically significant.

However, there were significant differences between the groups in both self-reported urinary incontinence (5.3% of patients in the radiotherapy group vs. 2.7% in the observation group, P = .008) and grade 3 or 4 urethral stricture at any time (8% vs. 5%, respectively, P = .03).

Results of the primary outcome, freedom from distant metastases will require longer follow-up, Dr. Parker said.

ARTISTIC meta-analysis

Dr. Vale presented results of the ARTISTIC collaborative meta-analysis, which included data from three randomized trials, including RADICALS, GETUG-AFU 17, and RAVES.

The meta-analysis was designed to include a consistent definition of PSA-driven EFS, prior to the unblinding of trial results.

The definition of EFS used in the trial was time from randomization until the first evidence of either PSA of 0.4 ng/mL or greater and rising after completion of radiotherapy, clinical/radiological progression, initiation on nontrial treatment, death from prostate cancer following completion of radiotherapy, or PSA level of 2.0 ng/mL or greater any time after randomization.

They analyzed data on a total of 1,074 men assigned to adjuvant radiotherapy and 1,077 assigned to salvage radiotherapy.

In each of the three trials included in the meta-analysis, there was a nonsignificant trend toward better PSA-driven EFS with salvage radiotherapy vs. adjuvant radiotherapy. The overall hazard ratio was 1.12, with the 95% confidence interval crossing 1, indicating a nonsignificant result.

Dr. Vale noted that early salvage radiotherapy spares many men from potentially unnecessary radiation and its negative consequences. Of the men included in the trials, more than 60% of those randomized to observation with salvage radiotherapy have yet to start radiotherapy.

She noted that investigators still need to assess long-term definitive outcomes such as metastases and survival, and whether some patients may derive benefit from adjuvant radiotherapy.

Invited discussant Gert De Meerleer, MD, PhD, a radiation oncologist at University Hospitals Leuven in Belgium, acknowledged that he agreed with most of the findings of the RADICALS-RT and ARTISTIC investigators.

An important take-home message, he said, is that “cure is the aim, and radiotherapy the keystone. If you have PSA relapse after prostatectomy, you can say, ‘I don’t treat the patient’ – fair enough. But if you treat the patient, only giving systemic therapy is the wrong way to go, you have to add radiotherapy,” he said.

He also agreed that “salvage is probably the modality of choice, and it is also in a lot of European countries, provided it is early.”

The RADICALS-RT trial is supported by Cancer Research UK and the Medical Research Council UK. Dr. Parker said he had no disclosures relevant to the trial. ARTISTIC is funded by the Medical Research Council. Dr. Vale reported having no disclosures. Dr. De Meerleer reported speaker fees, advisory board activities, and scientific grants not related to the studies.

SOURCE: Parker C et al. and Vale C et al. ESMO 2019. Abstracts LBA49_PR and LBA48_PR.

BARCELONA – Men who undergo radical prostatectomy can be spared from adjuvant radiotherapy and its associated side effects unless or until they have disease recurrence, results of a large randomized trial and separate meta-analysis indicate.

Among nearly 1,400 men with postoperative prostate-specific antigen (PSA) levels below 0.2 ng/mL and one or more risk factors, followed for a median of 5 years, there were no significant differences in any of the secondary outcomes between men randomized to radiotherapy and observation alone, reported Chris Parker, MD, from the Royal Marsden Hospital in London.

“In comparison with a policy of early salvage radiotherapy, adjuvant radiotherapy did not improve biochemical progression-free survival and did not delay the further use of hormone therapy,” he said at the European Society for Medical Oncology Congress, on behalf of colleagues in the RADICALS-RT trial.

Results of the RADICAL-RT trial were also pooled with results from two other large trials in a collaborative series of meta-analyses of long-term prostate cancer outcomes – dubbed ARTISTIC – which found no significant differences in event-free survival (EFS) for men randomized to either adjuvant or salvage radiotherapy.

“We don’t see any evidence from the ARTISTIC results that adjuvant radiotherapy improves event-free survival, compared to early salvage radiotherapy, and our best estimate is of a small, 1% difference in event-free survival at 5 years,” said Claire Vale, PhD, a research fellow at University College, London.

RADICALS RT details

Dr. Parker presented results from an early analysis of the secondary endpoint of biochemical progression-free survival (PFS), conducted in cooperation with the ARTISTIC investigators.

In RADICALS RT, investigators in the United Kingdom, Denmark, Canada, and Ireland enrolled 1,369 men following radical prostatectomy and after stratification by Gleason score, margin status, treatment center, and radiotherapy schedule (52.5 Gy delivered in 20 fractions, or 66 Gy delivered), randomly assigned them to either postoperative radiotherapy or observation with radiotherapy.

The patients enrolled had postoperative PSAs less than 2 ng/mL and one or more risk factors, either pathologic stage 3/4, Gleason score 7-10, positive surgical margins, or preoperative PSA of 10 ng/mL or greater.

The trigger for radiotherapy in men assigned to observation was PSA failure, defined as a PSA level of at least 0.1 ng/mL or 3 consecutive PSA rises.

At the median 5-year follow-up, PFS rates were 85% for patients assigned to adjuvant radiotherapy, and 88% for those assigned to observation, translating to a hazard ratio of 1.10, which was not statistically significant.

However, there were significant differences between the groups in both self-reported urinary incontinence (5.3% of patients in the radiotherapy group vs. 2.7% in the observation group, P = .008) and grade 3 or 4 urethral stricture at any time (8% vs. 5%, respectively, P = .03).

Results of the primary outcome, freedom from distant metastases will require longer follow-up, Dr. Parker said.

ARTISTIC meta-analysis

Dr. Vale presented results of the ARTISTIC collaborative meta-analysis, which included data from three randomized trials, including RADICALS, GETUG-AFU 17, and RAVES.

The meta-analysis was designed to include a consistent definition of PSA-driven EFS, prior to the unblinding of trial results.

The definition of EFS used in the trial was time from randomization until the first evidence of either PSA of 0.4 ng/mL or greater and rising after completion of radiotherapy, clinical/radiological progression, initiation on nontrial treatment, death from prostate cancer following completion of radiotherapy, or PSA level of 2.0 ng/mL or greater any time after randomization.

They analyzed data on a total of 1,074 men assigned to adjuvant radiotherapy and 1,077 assigned to salvage radiotherapy.

In each of the three trials included in the meta-analysis, there was a nonsignificant trend toward better PSA-driven EFS with salvage radiotherapy vs. adjuvant radiotherapy. The overall hazard ratio was 1.12, with the 95% confidence interval crossing 1, indicating a nonsignificant result.

Dr. Vale noted that early salvage radiotherapy spares many men from potentially unnecessary radiation and its negative consequences. Of the men included in the trials, more than 60% of those randomized to observation with salvage radiotherapy have yet to start radiotherapy.

She noted that investigators still need to assess long-term definitive outcomes such as metastases and survival, and whether some patients may derive benefit from adjuvant radiotherapy.

Invited discussant Gert De Meerleer, MD, PhD, a radiation oncologist at University Hospitals Leuven in Belgium, acknowledged that he agreed with most of the findings of the RADICALS-RT and ARTISTIC investigators.

An important take-home message, he said, is that “cure is the aim, and radiotherapy the keystone. If you have PSA relapse after prostatectomy, you can say, ‘I don’t treat the patient’ – fair enough. But if you treat the patient, only giving systemic therapy is the wrong way to go, you have to add radiotherapy,” he said.

He also agreed that “salvage is probably the modality of choice, and it is also in a lot of European countries, provided it is early.”

The RADICALS-RT trial is supported by Cancer Research UK and the Medical Research Council UK. Dr. Parker said he had no disclosures relevant to the trial. ARTISTIC is funded by the Medical Research Council. Dr. Vale reported having no disclosures. Dr. De Meerleer reported speaker fees, advisory board activities, and scientific grants not related to the studies.

SOURCE: Parker C et al. and Vale C et al. ESMO 2019. Abstracts LBA49_PR and LBA48_PR.

BARCELONA – Men who undergo radical prostatectomy can be spared from adjuvant radiotherapy and its associated side effects unless or until they have disease recurrence, results of a large randomized trial and separate meta-analysis indicate.

Among nearly 1,400 men with postoperative prostate-specific antigen (PSA) levels below 0.2 ng/mL and one or more risk factors, followed for a median of 5 years, there were no significant differences in any of the secondary outcomes between men randomized to radiotherapy and observation alone, reported Chris Parker, MD, from the Royal Marsden Hospital in London.

“In comparison with a policy of early salvage radiotherapy, adjuvant radiotherapy did not improve biochemical progression-free survival and did not delay the further use of hormone therapy,” he said at the European Society for Medical Oncology Congress, on behalf of colleagues in the RADICALS-RT trial.

Results of the RADICAL-RT trial were also pooled with results from two other large trials in a collaborative series of meta-analyses of long-term prostate cancer outcomes – dubbed ARTISTIC – which found no significant differences in event-free survival (EFS) for men randomized to either adjuvant or salvage radiotherapy.

“We don’t see any evidence from the ARTISTIC results that adjuvant radiotherapy improves event-free survival, compared to early salvage radiotherapy, and our best estimate is of a small, 1% difference in event-free survival at 5 years,” said Claire Vale, PhD, a research fellow at University College, London.

RADICALS RT details

Dr. Parker presented results from an early analysis of the secondary endpoint of biochemical progression-free survival (PFS), conducted in cooperation with the ARTISTIC investigators.

In RADICALS RT, investigators in the United Kingdom, Denmark, Canada, and Ireland enrolled 1,369 men following radical prostatectomy and after stratification by Gleason score, margin status, treatment center, and radiotherapy schedule (52.5 Gy delivered in 20 fractions, or 66 Gy delivered), randomly assigned them to either postoperative radiotherapy or observation with radiotherapy.

The patients enrolled had postoperative PSAs less than 2 ng/mL and one or more risk factors, either pathologic stage 3/4, Gleason score 7-10, positive surgical margins, or preoperative PSA of 10 ng/mL or greater.

The trigger for radiotherapy in men assigned to observation was PSA failure, defined as a PSA level of at least 0.1 ng/mL or 3 consecutive PSA rises.

At the median 5-year follow-up, PFS rates were 85% for patients assigned to adjuvant radiotherapy, and 88% for those assigned to observation, translating to a hazard ratio of 1.10, which was not statistically significant.

However, there were significant differences between the groups in both self-reported urinary incontinence (5.3% of patients in the radiotherapy group vs. 2.7% in the observation group, P = .008) and grade 3 or 4 urethral stricture at any time (8% vs. 5%, respectively, P = .03).

Results of the primary outcome, freedom from distant metastases will require longer follow-up, Dr. Parker said.

ARTISTIC meta-analysis

Dr. Vale presented results of the ARTISTIC collaborative meta-analysis, which included data from three randomized trials, including RADICALS, GETUG-AFU 17, and RAVES.

The meta-analysis was designed to include a consistent definition of PSA-driven EFS, prior to the unblinding of trial results.

The definition of EFS used in the trial was time from randomization until the first evidence of either PSA of 0.4 ng/mL or greater and rising after completion of radiotherapy, clinical/radiological progression, initiation on nontrial treatment, death from prostate cancer following completion of radiotherapy, or PSA level of 2.0 ng/mL or greater any time after randomization.

They analyzed data on a total of 1,074 men assigned to adjuvant radiotherapy and 1,077 assigned to salvage radiotherapy.

In each of the three trials included in the meta-analysis, there was a nonsignificant trend toward better PSA-driven EFS with salvage radiotherapy vs. adjuvant radiotherapy. The overall hazard ratio was 1.12, with the 95% confidence interval crossing 1, indicating a nonsignificant result.

Dr. Vale noted that early salvage radiotherapy spares many men from potentially unnecessary radiation and its negative consequences. Of the men included in the trials, more than 60% of those randomized to observation with salvage radiotherapy have yet to start radiotherapy.

She noted that investigators still need to assess long-term definitive outcomes such as metastases and survival, and whether some patients may derive benefit from adjuvant radiotherapy.

Invited discussant Gert De Meerleer, MD, PhD, a radiation oncologist at University Hospitals Leuven in Belgium, acknowledged that he agreed with most of the findings of the RADICALS-RT and ARTISTIC investigators.

An important take-home message, he said, is that “cure is the aim, and radiotherapy the keystone. If you have PSA relapse after prostatectomy, you can say, ‘I don’t treat the patient’ – fair enough. But if you treat the patient, only giving systemic therapy is the wrong way to go, you have to add radiotherapy,” he said.

He also agreed that “salvage is probably the modality of choice, and it is also in a lot of European countries, provided it is early.”

The RADICALS-RT trial is supported by Cancer Research UK and the Medical Research Council UK. Dr. Parker said he had no disclosures relevant to the trial. ARTISTIC is funded by the Medical Research Council. Dr. Vale reported having no disclosures. Dr. De Meerleer reported speaker fees, advisory board activities, and scientific grants not related to the studies.

SOURCE: Parker C et al. and Vale C et al. ESMO 2019. Abstracts LBA49_PR and LBA48_PR.

BARCELONA – Cancer drug prices are significantly higher in the United States than in Europe, and they don’t correlate with clinical benefit in either region, according to an analysis of drug costs and value-related scores between 2009 and 2018.

Of 63 cancer drugs approved by the Food and Drug Administration between 2009 and 2017 and by the European Medicines Agency as of December 31, 2018, 46 (73%) were approved for solid tumors, and 17 (27%) for hematologic malignancies. Median cancer drug prices in Europe were 52% lower than U.S. prices, Kerstin N. Vokinger, MD, Academic Chair For Health Policy at the Institute For Primary Care, University Hospital Zürich, and colleagues found.

The findings were released via press release at the European Society for Medical Oncology (ESMO) Congress and will be part of a poster discussion session there.

The investigators found no association between monthly treatment cost and the American Society of Clinical Oncology Value Framework (ASCO-VF) or the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) scores in any country. They also found no association between the price differential in the United States and Europe and either ASCO-VF (P = .599) or ESMO-MBCS (P = .321) scores.

For the analysis, they assessed U.S. average sales prices or, when those weren’t available, wholesale acquisition costs as of Feb. 1, 2019, and compared them with comparable currency-adjusted ex-factory drug costs in England, France, Germany, and Switzerland.

ASCO-VF and ESMO-MCBS scores were then assessed based on the highest score from pivotal trials supporting each solid tumor drug.

The median monthly cost for drugs with low-benefit scores on ESMO-MCBS ranged from $4,361-$5,273 in the European countries, compared with $12,436 in the United States, according to the release.

“Drug costs were not associated with clinical benefit score in any of the countries we looked at. For example, some of the more expensive drugs for prostate and lung cancer in Switzerland had lower ESMO-MCBS scores, while cheaper drugs had higher scores,” said Dr. Vokinger, who also is affiliated with the Program on Regulation, Therapeutics, and Law at Harvard Medical School, Boston. “It is important that drug pricing is aligned with clinical value and that our limited resources are spent on innovative medicines that offer improved outcomes.”

Barbara Kiesewetter, MD, of the Medical University of Vienna and a member of the ESMO-MCBS Working Group, said the findings underscore the importance of using the scoring systems in clinical practice to assist in treatment-related decision making.

The ESMO-MCBS, for example, is available online, easy to use, and helps explain “the factors that are used to grade the clinical benefit of medicines.

“It’s very important to have this validated score not only for daily decision making, but to influence reimbursement decisions and reduce treatment disparities,” she said, also noting in the release that “[c]ost is one of the main reasons why patients are denied access to the newer anticancer drugs.”

“By showing which drugs are most likely to be worth the higher cost, we can hopefully improve access to the drugs with greatest value so that patients receive standardized, optimal therapy wherever they live,” she said.

The study was funded by the Swiss Cancer League. The authors reported having no conflicts of interest.

SOURCE: Vokinger KN et al. ESMO 2019, Abstract 1631PD-PR.

BARCELONA – Cancer drug prices are significantly higher in the United States than in Europe, and they don’t correlate with clinical benefit in either region, according to an analysis of drug costs and value-related scores between 2009 and 2018.

Of 63 cancer drugs approved by the Food and Drug Administration between 2009 and 2017 and by the European Medicines Agency as of December 31, 2018, 46 (73%) were approved for solid tumors, and 17 (27%) for hematologic malignancies. Median cancer drug prices in Europe were 52% lower than U.S. prices, Kerstin N. Vokinger, MD, Academic Chair For Health Policy at the Institute For Primary Care, University Hospital Zürich, and colleagues found.

The findings were released via press release at the European Society for Medical Oncology (ESMO) Congress and will be part of a poster discussion session there.

The investigators found no association between monthly treatment cost and the American Society of Clinical Oncology Value Framework (ASCO-VF) or the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) scores in any country. They also found no association between the price differential in the United States and Europe and either ASCO-VF (P = .599) or ESMO-MBCS (P = .321) scores.

For the analysis, they assessed U.S. average sales prices or, when those weren’t available, wholesale acquisition costs as of Feb. 1, 2019, and compared them with comparable currency-adjusted ex-factory drug costs in England, France, Germany, and Switzerland.

ASCO-VF and ESMO-MCBS scores were then assessed based on the highest score from pivotal trials supporting each solid tumor drug.

The median monthly cost for drugs with low-benefit scores on ESMO-MCBS ranged from $4,361-$5,273 in the European countries, compared with $12,436 in the United States, according to the release.

“Drug costs were not associated with clinical benefit score in any of the countries we looked at. For example, some of the more expensive drugs for prostate and lung cancer in Switzerland had lower ESMO-MCBS scores, while cheaper drugs had higher scores,” said Dr. Vokinger, who also is affiliated with the Program on Regulation, Therapeutics, and Law at Harvard Medical School, Boston. “It is important that drug pricing is aligned with clinical value and that our limited resources are spent on innovative medicines that offer improved outcomes.”

Barbara Kiesewetter, MD, of the Medical University of Vienna and a member of the ESMO-MCBS Working Group, said the findings underscore the importance of using the scoring systems in clinical practice to assist in treatment-related decision making.

The ESMO-MCBS, for example, is available online, easy to use, and helps explain “the factors that are used to grade the clinical benefit of medicines.

“It’s very important to have this validated score not only for daily decision making, but to influence reimbursement decisions and reduce treatment disparities,” she said, also noting in the release that “[c]ost is one of the main reasons why patients are denied access to the newer anticancer drugs.”

“By showing which drugs are most likely to be worth the higher cost, we can hopefully improve access to the drugs with greatest value so that patients receive standardized, optimal therapy wherever they live,” she said.

The study was funded by the Swiss Cancer League. The authors reported having no conflicts of interest.

SOURCE: Vokinger KN et al. ESMO 2019, Abstract 1631PD-PR.

BARCELONA – Cancer drug prices are significantly higher in the United States than in Europe, and they don’t correlate with clinical benefit in either region, according to an analysis of drug costs and value-related scores between 2009 and 2018.

Of 63 cancer drugs approved by the Food and Drug Administration between 2009 and 2017 and by the European Medicines Agency as of December 31, 2018, 46 (73%) were approved for solid tumors, and 17 (27%) for hematologic malignancies. Median cancer drug prices in Europe were 52% lower than U.S. prices, Kerstin N. Vokinger, MD, Academic Chair For Health Policy at the Institute For Primary Care, University Hospital Zürich, and colleagues found.

The findings were released via press release at the European Society for Medical Oncology (ESMO) Congress and will be part of a poster discussion session there.

The investigators found no association between monthly treatment cost and the American Society of Clinical Oncology Value Framework (ASCO-VF) or the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) scores in any country. They also found no association between the price differential in the United States and Europe and either ASCO-VF (P = .599) or ESMO-MBCS (P = .321) scores.

For the analysis, they assessed U.S. average sales prices or, when those weren’t available, wholesale acquisition costs as of Feb. 1, 2019, and compared them with comparable currency-adjusted ex-factory drug costs in England, France, Germany, and Switzerland.

ASCO-VF and ESMO-MCBS scores were then assessed based on the highest score from pivotal trials supporting each solid tumor drug.

The median monthly cost for drugs with low-benefit scores on ESMO-MCBS ranged from $4,361-$5,273 in the European countries, compared with $12,436 in the United States, according to the release.

“Drug costs were not associated with clinical benefit score in any of the countries we looked at. For example, some of the more expensive drugs for prostate and lung cancer in Switzerland had lower ESMO-MCBS scores, while cheaper drugs had higher scores,” said Dr. Vokinger, who also is affiliated with the Program on Regulation, Therapeutics, and Law at Harvard Medical School, Boston. “It is important that drug pricing is aligned with clinical value and that our limited resources are spent on innovative medicines that offer improved outcomes.”

Barbara Kiesewetter, MD, of the Medical University of Vienna and a member of the ESMO-MCBS Working Group, said the findings underscore the importance of using the scoring systems in clinical practice to assist in treatment-related decision making.

The ESMO-MCBS, for example, is available online, easy to use, and helps explain “the factors that are used to grade the clinical benefit of medicines.

“It’s very important to have this validated score not only for daily decision making, but to influence reimbursement decisions and reduce treatment disparities,” she said, also noting in the release that “[c]ost is one of the main reasons why patients are denied access to the newer anticancer drugs.”

“By showing which drugs are most likely to be worth the higher cost, we can hopefully improve access to the drugs with greatest value so that patients receive standardized, optimal therapy wherever they live,” she said.

The study was funded by the Swiss Cancer League. The authors reported having no conflicts of interest.

SOURCE: Vokinger KN et al. ESMO 2019, Abstract 1631PD-PR.