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Checkmate 214: Upfront nivo/ipi bests TKI in advanced RCC
MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported
Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.
Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).
“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.
Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .
The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.
The results for the coprimary endpoints are noted above.
Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.
For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.
The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).
In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.
There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.
In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.
“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.
“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.
The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported
Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.
Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).
“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.
Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .
The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.
The results for the coprimary endpoints are noted above.
Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.
For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.
The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).
In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.
There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.
In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.
“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.
“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.
The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported
Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.
Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).
“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.
Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .
The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.
The results for the coprimary endpoints are noted above.
Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.
For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.
The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).
In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.
There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.
In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.
“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.
“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.
The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
AT ESMO 2017
Key clinical point: The combination of the PD-1 inhibitor nivolumab and CTLA-4 inhibitor ipilimumab was efficacious in frontline therapyfor advanced or metastatic renal cell carcinoma.
Major finding: The trial met its coprimary endpoints of overall response rate and progression-free survival, as well as its secondary endpoint of overall survival.
Data source: Randomized open-label study in 1096 patients with advanced/metastatic RCC, including 847 with intermediate- to poor-risk disease.
Disclosures: The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
Rituximab maintenance halves MCL death risk after ASCT
, results of a phase 3 trial show.
After 50.2 months median follow-up, the overall survival rate for patients aged 65 or younger randomized to rituximab maintenance after four cycles of induction chemotherapy with rituximab, dexamethasone, cytarabine, and a platinum derivative (R-DHAP) followed by ASCT was 89%, compared with 80% for patients randomized to observation (P = .004), reported Steven Le Gouill, MD, PhD, of University Hospital Hotel-Dieu, in Nantes, Frances, and colleagues.
In an unadjusted regression analysis, the difference translated into a hazard ratio for death within 4 years of 0.50 (P = .004) favoring rituximab, they wrote in the Sept. 28, 2017 issue of The New England Journal of Medicine.
“[A]n induction regimen with four courses of R-DHAP followed by transplantation without total-body irradiation resulted in a high rate of complete response. A 3-year course of rituximab maintenance therapy administered every 2 months prolonged overall survival among young patients with mantle cell lymphoma,” the investigators wrote (N Engl J Med. 2017;377:1250-60).
Dr. Le Gouill and his colleagues hypothesized that relapses following treatment for MCL may be caused by residual malignant cells that chemotherapy and ASCT fail to eradicate, suggesting that maintenance therapy with rituximab could help to suppress residual disease, prolong the duration of responses, and extend both progression-free and overall survival.
They cited an earlier study by members of the European Mantle Cell Lymphoma Network showing that among patients aged 60 and older who had a response to eight cycles of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), maintenance therapy with rituximab was associated with an 87% 4-year overall survival rate vs. 63% for patients maintained on interferon alfa (P = .005) (N Engl J Med. 2012;367:520-31).
For the current study, the researchers enrolled 299 patients, of whom 257 went on to ASCT, and 240 of whom were randomized and were included in an intention-to-treat (ITT) analysis.
Patients received induction with four cycles of R-DHAP. Those patients who had partial responses or tumor mass shrinkage of less than 75% on CT received a rescue induction with four cycles of R-CHOP.
Those patients with complete or partial responses could then go on to transplantation after a conditioning regimen of R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan).
Patients randomized after ASCT to rituximab received it every 2 months for 3 years in an intravenous infusion at a dose of 375 mg/m2.
After a median of 50.2 months from randomization, the rate of 4-year event-free survival (no disease progression, relapse, death, or severe infection), the primary endpoint, was 79% for patients maintained on rituximab vs. 61% for those on observation alone (P = .001).
The 4-year progression-free survival rate also favored rituximab at 83% vs. 64%, respectively (P less than .001), with respective overall survival rates of 89% and 80%.
The median event-free survival, progression-free survival, and overall survival was not reached in either study arm.
For the 59 patients who for various reasons did not undergo randomization, the median progression-free survival was 11.0 months, and the median overall survival was 30.6 months.
In all, 83 of the 120 patients randomized to rituximab completed the scheduled 3 years of therapy. Maintenance therapy was stopped for disease progression in 16 patients and because of neutropenia in 9. There were 13 deaths in the rituximab arm, including 3 deaths from second malignancies.
Of the 120 patients assigned to observation, 37 had disease progression during the study period, and 24 died, one from a second malignancy.
Four patients in each study arm had serious infections after ASCT, including one case each of spondylitis, pyelonephritis, septicemia, and varicella pneumonia in the rituximab group, and septicemia, cellulitis, meningitis, and severe pneumonia in the observation group.
Lymphoma was the cause of death in 8 patients assigned to rituximab, and in 16 assigned to observation.
The investigators noted that although some centers use total-body irradiation for conditioning prior to transplant, this modality is not available in all centers and is associated with both short- and long-term toxicities. The progression-free survival results seen in this trial, where only ablative drug regimens were used “suggest that total-body irradiation–based conditioning regimens may not be superior to chemotherapy alone when an effective regimen is used during induction,” they wrote.
The study was supported by Roche and Amgen. Dr. Le Gouill disclosed fees for consulting and honoraria from Roche, Janssen-Cilag, and Celgene. Multiple coauthors disclosed similar relationships with industry.
, results of a phase 3 trial show.
After 50.2 months median follow-up, the overall survival rate for patients aged 65 or younger randomized to rituximab maintenance after four cycles of induction chemotherapy with rituximab, dexamethasone, cytarabine, and a platinum derivative (R-DHAP) followed by ASCT was 89%, compared with 80% for patients randomized to observation (P = .004), reported Steven Le Gouill, MD, PhD, of University Hospital Hotel-Dieu, in Nantes, Frances, and colleagues.
In an unadjusted regression analysis, the difference translated into a hazard ratio for death within 4 years of 0.50 (P = .004) favoring rituximab, they wrote in the Sept. 28, 2017 issue of The New England Journal of Medicine.
“[A]n induction regimen with four courses of R-DHAP followed by transplantation without total-body irradiation resulted in a high rate of complete response. A 3-year course of rituximab maintenance therapy administered every 2 months prolonged overall survival among young patients with mantle cell lymphoma,” the investigators wrote (N Engl J Med. 2017;377:1250-60).
Dr. Le Gouill and his colleagues hypothesized that relapses following treatment for MCL may be caused by residual malignant cells that chemotherapy and ASCT fail to eradicate, suggesting that maintenance therapy with rituximab could help to suppress residual disease, prolong the duration of responses, and extend both progression-free and overall survival.
They cited an earlier study by members of the European Mantle Cell Lymphoma Network showing that among patients aged 60 and older who had a response to eight cycles of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), maintenance therapy with rituximab was associated with an 87% 4-year overall survival rate vs. 63% for patients maintained on interferon alfa (P = .005) (N Engl J Med. 2012;367:520-31).
For the current study, the researchers enrolled 299 patients, of whom 257 went on to ASCT, and 240 of whom were randomized and were included in an intention-to-treat (ITT) analysis.
Patients received induction with four cycles of R-DHAP. Those patients who had partial responses or tumor mass shrinkage of less than 75% on CT received a rescue induction with four cycles of R-CHOP.
Those patients with complete or partial responses could then go on to transplantation after a conditioning regimen of R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan).
Patients randomized after ASCT to rituximab received it every 2 months for 3 years in an intravenous infusion at a dose of 375 mg/m2.
After a median of 50.2 months from randomization, the rate of 4-year event-free survival (no disease progression, relapse, death, or severe infection), the primary endpoint, was 79% for patients maintained on rituximab vs. 61% for those on observation alone (P = .001).
The 4-year progression-free survival rate also favored rituximab at 83% vs. 64%, respectively (P less than .001), with respective overall survival rates of 89% and 80%.
The median event-free survival, progression-free survival, and overall survival was not reached in either study arm.
For the 59 patients who for various reasons did not undergo randomization, the median progression-free survival was 11.0 months, and the median overall survival was 30.6 months.
In all, 83 of the 120 patients randomized to rituximab completed the scheduled 3 years of therapy. Maintenance therapy was stopped for disease progression in 16 patients and because of neutropenia in 9. There were 13 deaths in the rituximab arm, including 3 deaths from second malignancies.
Of the 120 patients assigned to observation, 37 had disease progression during the study period, and 24 died, one from a second malignancy.
Four patients in each study arm had serious infections after ASCT, including one case each of spondylitis, pyelonephritis, septicemia, and varicella pneumonia in the rituximab group, and septicemia, cellulitis, meningitis, and severe pneumonia in the observation group.
Lymphoma was the cause of death in 8 patients assigned to rituximab, and in 16 assigned to observation.
The investigators noted that although some centers use total-body irradiation for conditioning prior to transplant, this modality is not available in all centers and is associated with both short- and long-term toxicities. The progression-free survival results seen in this trial, where only ablative drug regimens were used “suggest that total-body irradiation–based conditioning regimens may not be superior to chemotherapy alone when an effective regimen is used during induction,” they wrote.
The study was supported by Roche and Amgen. Dr. Le Gouill disclosed fees for consulting and honoraria from Roche, Janssen-Cilag, and Celgene. Multiple coauthors disclosed similar relationships with industry.
, results of a phase 3 trial show.
After 50.2 months median follow-up, the overall survival rate for patients aged 65 or younger randomized to rituximab maintenance after four cycles of induction chemotherapy with rituximab, dexamethasone, cytarabine, and a platinum derivative (R-DHAP) followed by ASCT was 89%, compared with 80% for patients randomized to observation (P = .004), reported Steven Le Gouill, MD, PhD, of University Hospital Hotel-Dieu, in Nantes, Frances, and colleagues.
In an unadjusted regression analysis, the difference translated into a hazard ratio for death within 4 years of 0.50 (P = .004) favoring rituximab, they wrote in the Sept. 28, 2017 issue of The New England Journal of Medicine.
“[A]n induction regimen with four courses of R-DHAP followed by transplantation without total-body irradiation resulted in a high rate of complete response. A 3-year course of rituximab maintenance therapy administered every 2 months prolonged overall survival among young patients with mantle cell lymphoma,” the investigators wrote (N Engl J Med. 2017;377:1250-60).
Dr. Le Gouill and his colleagues hypothesized that relapses following treatment for MCL may be caused by residual malignant cells that chemotherapy and ASCT fail to eradicate, suggesting that maintenance therapy with rituximab could help to suppress residual disease, prolong the duration of responses, and extend both progression-free and overall survival.
They cited an earlier study by members of the European Mantle Cell Lymphoma Network showing that among patients aged 60 and older who had a response to eight cycles of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), maintenance therapy with rituximab was associated with an 87% 4-year overall survival rate vs. 63% for patients maintained on interferon alfa (P = .005) (N Engl J Med. 2012;367:520-31).
For the current study, the researchers enrolled 299 patients, of whom 257 went on to ASCT, and 240 of whom were randomized and were included in an intention-to-treat (ITT) analysis.
Patients received induction with four cycles of R-DHAP. Those patients who had partial responses or tumor mass shrinkage of less than 75% on CT received a rescue induction with four cycles of R-CHOP.
Those patients with complete or partial responses could then go on to transplantation after a conditioning regimen of R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan).
Patients randomized after ASCT to rituximab received it every 2 months for 3 years in an intravenous infusion at a dose of 375 mg/m2.
After a median of 50.2 months from randomization, the rate of 4-year event-free survival (no disease progression, relapse, death, or severe infection), the primary endpoint, was 79% for patients maintained on rituximab vs. 61% for those on observation alone (P = .001).
The 4-year progression-free survival rate also favored rituximab at 83% vs. 64%, respectively (P less than .001), with respective overall survival rates of 89% and 80%.
The median event-free survival, progression-free survival, and overall survival was not reached in either study arm.
For the 59 patients who for various reasons did not undergo randomization, the median progression-free survival was 11.0 months, and the median overall survival was 30.6 months.
In all, 83 of the 120 patients randomized to rituximab completed the scheduled 3 years of therapy. Maintenance therapy was stopped for disease progression in 16 patients and because of neutropenia in 9. There were 13 deaths in the rituximab arm, including 3 deaths from second malignancies.
Of the 120 patients assigned to observation, 37 had disease progression during the study period, and 24 died, one from a second malignancy.
Four patients in each study arm had serious infections after ASCT, including one case each of spondylitis, pyelonephritis, septicemia, and varicella pneumonia in the rituximab group, and septicemia, cellulitis, meningitis, and severe pneumonia in the observation group.
Lymphoma was the cause of death in 8 patients assigned to rituximab, and in 16 assigned to observation.
The investigators noted that although some centers use total-body irradiation for conditioning prior to transplant, this modality is not available in all centers and is associated with both short- and long-term toxicities. The progression-free survival results seen in this trial, where only ablative drug regimens were used “suggest that total-body irradiation–based conditioning regimens may not be superior to chemotherapy alone when an effective regimen is used during induction,” they wrote.
The study was supported by Roche and Amgen. Dr. Le Gouill disclosed fees for consulting and honoraria from Roche, Janssen-Cilag, and Celgene. Multiple coauthors disclosed similar relationships with industry.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Following stem cell transplantation, rituximab maintenance cut in half the risk for death in patients with mantle cell lymphoma.
Major finding: Four-year overall survival was 89% with rituximab maintenance vs. 80% for observation alone.
Data source: Randomized phase 3 trial in 240 patients aged 65 and younger at diagnosis of mantle cell lymphoma.
Disclosures: The study was supported by Roche and Amgen. Dr. Le Gouill disclosed fees for consulting and honoraria from Roche, Janssen-Cilag, and Celgene. Multiple coauthors disclosed similar relationships with industry.
GEICAM/2006-10: Adjuvant fulvestrant/anastrozole role in early breast cancer uncertain
MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.
But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.
“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.
Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.
“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.
Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.
The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.
The investigators enrolled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.
As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).
After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).
The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.
“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.
The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.
MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.
But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.
“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.
Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.
“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.
Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.
The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.
The investigators enrolled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.
As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).
After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).
The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.
“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.
The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.
MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.
But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.
“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.
Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.
“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.
Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.
The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.
The investigators enrolled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.
As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).
After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).
The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.
“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.
The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.
AT ESMO 2017
Key clinical point: Adding fulvestrant to anastrozole did not improve outcomes in women with HR+/HER2– early-stage breast cancer, but the trial was hampered by early closure.
Major finding: There were no significant differences in disease-free, breast cancer–specific, or overall survival with fulvestrant/anastrozole vs. anastrozole alone.
Data source: Randomized phase 3 trial in 872 of 2,582 planned patients.
Disclosures: The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.
‘Very daring study’ of neoadjuvant AI/CDKi combo in early BC is hypothesis generating
MADRID – For women with luminal breast cancer who are not initially candidates for breast-conserving surgery, neoadjuvant therapy with an aromatase inhibitor and a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor offered a slightly higher residual cancer burden prior to surgery, but a significantly better safety profile than conventional chemotherapy with similar near-term safety outcomes, results of a phase 2 parallel group, noncomparative trial suggested.
Among 60 patients evaluable for response in an interim analysis of the UNICANCER NeoPAL trial, one patient (3.3%) treated with a combination of letrozole (Femara) and palbociclib (Ibrance) had a residual cancer burden (RCB) score of 0 (equivalent to a pathologic complete response; pCR), whereas three patients (10%) treated with FEC 100 chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide) had RCB 0 or I, reported Paul-Henri Cottu, MD, of the Institut Curie in Paris.
Following the interim analysis, the independent data monitoring committee for the NeoPAL trial recommended halting accrual; accrual was stopped in November 2016, after 106 patients had been randomized.
The IDMC also recommended that patients in the letrozole/palbociclib arm who did not have an RCB of 0 or I be offered adjuvant chemotherapy.
“Please note that 70% of those patients refused adjuvant chemotherapy,” Dr. Cottu said.
The investigators set out to test whether letrozole and palbociclib, which have been shown to have synergistic antiproliferative activity against advanced luminal breast cancer, could have similar benefits in the neoadjuvant setting.
They screened for women with luminal breast cancer who had newly diagnosed stage II or III breast cancer with biopsy-proven endocrine receptor–positive, human epidermal growth factor receptor 2–negative tumors, using the Prosigna test, based on the PAM50 gene signature assay. Women with node-positive luminal A or luminal B disease were enrolled and randomized to receive either letrozole 2.5 mg and palbociclib 125 mg daily for 3 out of every 4 weeks over 19 weeks, or three cycles of FEC 100, followed by three cycles of docetaxel 100 mg/m2 every 3 weeks, followed by surgery.
An interim analysis was planned after 30 patients were evaluable for RCB in the experimental arm, and, as prespecified, the trial was stopped for futility when fewer than five patients had an RCB of 0 or I.
The safety analysis, conducted with all 106 patients randomized, showed that letrozole/palbocilib was associated with more frequent grade 3 neutropenia (23% vs. 10% of patients with FEC), but less grade 4 neutropenia (1% vs. 11%, respectively), and no febrile neutropenia vs. 6% in the chemotherapy arm.
There were 2 serious adverse events with the AI/CDK-inhibitor combination vs. 17 with chemotherapy. Dose reductions or interruptions were less frequent with letrozole/palbociclib (10 and 16), and only two patients in the experimental arm required premature cessation of therapy vs. seven in the chemotherapy arm.
The final response analysis in 103 patients showed that the rate of RCB 0 or I was 7.7% with letrozole/palbociclib and 15.7% with chemotherapy. Respective rates of RCB II-III were 92.3% and 84.3%.
Clinical response rates were similar in each study arm, with approximately 30% complete responses and 44% partial responses.
In each arm, slightly less than one-third of patients underwent mastectomy, and a little more than two-thirds were able to have breast-conserving surgery after neoadjuvant therapy.
The patients will be followed out to at least 3 years to see whether those patients in the letrozole/palbociclib arm who turned down subsequent chemotherapy will have worse survival than patients who decided to undergo it, Dr. Cottu said.
Invited discussant Nadia Harbeck, MD, PhD, of the University of Munich called the NeoPAL trial “a very daring study.”
“This is not a practice-changing trial, but it’s a very, very interesting hypothesis-generating trial,” she said.
She said that the choice of RCB was probably not the best endpoint in a trial of endocrine-based therapy vs. chemotherapy.
“I think the challenge remains to identify those patients with luminal early breast cancer for whom an endocrine-based approach – not endocrine, but endocrine-based – will improve outcome, either replacing chemotherapy in the intermediate-risk setting or as an add-on in high-risk disease,” she said.
The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others, and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.
MADRID – For women with luminal breast cancer who are not initially candidates for breast-conserving surgery, neoadjuvant therapy with an aromatase inhibitor and a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor offered a slightly higher residual cancer burden prior to surgery, but a significantly better safety profile than conventional chemotherapy with similar near-term safety outcomes, results of a phase 2 parallel group, noncomparative trial suggested.
Among 60 patients evaluable for response in an interim analysis of the UNICANCER NeoPAL trial, one patient (3.3%) treated with a combination of letrozole (Femara) and palbociclib (Ibrance) had a residual cancer burden (RCB) score of 0 (equivalent to a pathologic complete response; pCR), whereas three patients (10%) treated with FEC 100 chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide) had RCB 0 or I, reported Paul-Henri Cottu, MD, of the Institut Curie in Paris.
Following the interim analysis, the independent data monitoring committee for the NeoPAL trial recommended halting accrual; accrual was stopped in November 2016, after 106 patients had been randomized.
The IDMC also recommended that patients in the letrozole/palbociclib arm who did not have an RCB of 0 or I be offered adjuvant chemotherapy.
“Please note that 70% of those patients refused adjuvant chemotherapy,” Dr. Cottu said.
The investigators set out to test whether letrozole and palbociclib, which have been shown to have synergistic antiproliferative activity against advanced luminal breast cancer, could have similar benefits in the neoadjuvant setting.
They screened for women with luminal breast cancer who had newly diagnosed stage II or III breast cancer with biopsy-proven endocrine receptor–positive, human epidermal growth factor receptor 2–negative tumors, using the Prosigna test, based on the PAM50 gene signature assay. Women with node-positive luminal A or luminal B disease were enrolled and randomized to receive either letrozole 2.5 mg and palbociclib 125 mg daily for 3 out of every 4 weeks over 19 weeks, or three cycles of FEC 100, followed by three cycles of docetaxel 100 mg/m2 every 3 weeks, followed by surgery.
An interim analysis was planned after 30 patients were evaluable for RCB in the experimental arm, and, as prespecified, the trial was stopped for futility when fewer than five patients had an RCB of 0 or I.
The safety analysis, conducted with all 106 patients randomized, showed that letrozole/palbocilib was associated with more frequent grade 3 neutropenia (23% vs. 10% of patients with FEC), but less grade 4 neutropenia (1% vs. 11%, respectively), and no febrile neutropenia vs. 6% in the chemotherapy arm.
There were 2 serious adverse events with the AI/CDK-inhibitor combination vs. 17 with chemotherapy. Dose reductions or interruptions were less frequent with letrozole/palbociclib (10 and 16), and only two patients in the experimental arm required premature cessation of therapy vs. seven in the chemotherapy arm.
The final response analysis in 103 patients showed that the rate of RCB 0 or I was 7.7% with letrozole/palbociclib and 15.7% with chemotherapy. Respective rates of RCB II-III were 92.3% and 84.3%.
Clinical response rates were similar in each study arm, with approximately 30% complete responses and 44% partial responses.
In each arm, slightly less than one-third of patients underwent mastectomy, and a little more than two-thirds were able to have breast-conserving surgery after neoadjuvant therapy.
The patients will be followed out to at least 3 years to see whether those patients in the letrozole/palbociclib arm who turned down subsequent chemotherapy will have worse survival than patients who decided to undergo it, Dr. Cottu said.
Invited discussant Nadia Harbeck, MD, PhD, of the University of Munich called the NeoPAL trial “a very daring study.”
“This is not a practice-changing trial, but it’s a very, very interesting hypothesis-generating trial,” she said.
She said that the choice of RCB was probably not the best endpoint in a trial of endocrine-based therapy vs. chemotherapy.
“I think the challenge remains to identify those patients with luminal early breast cancer for whom an endocrine-based approach – not endocrine, but endocrine-based – will improve outcome, either replacing chemotherapy in the intermediate-risk setting or as an add-on in high-risk disease,” she said.
The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others, and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.
MADRID – For women with luminal breast cancer who are not initially candidates for breast-conserving surgery, neoadjuvant therapy with an aromatase inhibitor and a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor offered a slightly higher residual cancer burden prior to surgery, but a significantly better safety profile than conventional chemotherapy with similar near-term safety outcomes, results of a phase 2 parallel group, noncomparative trial suggested.
Among 60 patients evaluable for response in an interim analysis of the UNICANCER NeoPAL trial, one patient (3.3%) treated with a combination of letrozole (Femara) and palbociclib (Ibrance) had a residual cancer burden (RCB) score of 0 (equivalent to a pathologic complete response; pCR), whereas three patients (10%) treated with FEC 100 chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide) had RCB 0 or I, reported Paul-Henri Cottu, MD, of the Institut Curie in Paris.
Following the interim analysis, the independent data monitoring committee for the NeoPAL trial recommended halting accrual; accrual was stopped in November 2016, after 106 patients had been randomized.
The IDMC also recommended that patients in the letrozole/palbociclib arm who did not have an RCB of 0 or I be offered adjuvant chemotherapy.
“Please note that 70% of those patients refused adjuvant chemotherapy,” Dr. Cottu said.
The investigators set out to test whether letrozole and palbociclib, which have been shown to have synergistic antiproliferative activity against advanced luminal breast cancer, could have similar benefits in the neoadjuvant setting.
They screened for women with luminal breast cancer who had newly diagnosed stage II or III breast cancer with biopsy-proven endocrine receptor–positive, human epidermal growth factor receptor 2–negative tumors, using the Prosigna test, based on the PAM50 gene signature assay. Women with node-positive luminal A or luminal B disease were enrolled and randomized to receive either letrozole 2.5 mg and palbociclib 125 mg daily for 3 out of every 4 weeks over 19 weeks, or three cycles of FEC 100, followed by three cycles of docetaxel 100 mg/m2 every 3 weeks, followed by surgery.
An interim analysis was planned after 30 patients were evaluable for RCB in the experimental arm, and, as prespecified, the trial was stopped for futility when fewer than five patients had an RCB of 0 or I.
The safety analysis, conducted with all 106 patients randomized, showed that letrozole/palbocilib was associated with more frequent grade 3 neutropenia (23% vs. 10% of patients with FEC), but less grade 4 neutropenia (1% vs. 11%, respectively), and no febrile neutropenia vs. 6% in the chemotherapy arm.
There were 2 serious adverse events with the AI/CDK-inhibitor combination vs. 17 with chemotherapy. Dose reductions or interruptions were less frequent with letrozole/palbociclib (10 and 16), and only two patients in the experimental arm required premature cessation of therapy vs. seven in the chemotherapy arm.
The final response analysis in 103 patients showed that the rate of RCB 0 or I was 7.7% with letrozole/palbociclib and 15.7% with chemotherapy. Respective rates of RCB II-III were 92.3% and 84.3%.
Clinical response rates were similar in each study arm, with approximately 30% complete responses and 44% partial responses.
In each arm, slightly less than one-third of patients underwent mastectomy, and a little more than two-thirds were able to have breast-conserving surgery after neoadjuvant therapy.
The patients will be followed out to at least 3 years to see whether those patients in the letrozole/palbociclib arm who turned down subsequent chemotherapy will have worse survival than patients who decided to undergo it, Dr. Cottu said.
Invited discussant Nadia Harbeck, MD, PhD, of the University of Munich called the NeoPAL trial “a very daring study.”
“This is not a practice-changing trial, but it’s a very, very interesting hypothesis-generating trial,” she said.
She said that the choice of RCB was probably not the best endpoint in a trial of endocrine-based therapy vs. chemotherapy.
“I think the challenge remains to identify those patients with luminal early breast cancer for whom an endocrine-based approach – not endocrine, but endocrine-based – will improve outcome, either replacing chemotherapy in the intermediate-risk setting or as an add-on in high-risk disease,” she said.
The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others, and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.
AT ESMO 2017
Key clinical point:
Major finding: One patient (3.3%) assigned to letrozole/palbociclib had a residual cancer burden score of 0 or I, compared with three patients (10%) assigned to chemotherapy.
Data source: Interim analysis of a phase 2 parallel group trial with 60 patients evaluable for response and 106 evaluable for safety.
Disclosures: The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.
No difference in survival between x-ray or CT NSCLC follow-up
Madrid – Computed tomography scans do not appear to be superior to plain old chest x-rays for follow-up of patients with completely resected non–small cell lung cancer (NSCLC), results of a randomized clinical trial suggest.
Among 1,775 patients followed out to 10 years with either a “minimal” protocol – consisting of history, physical exam, and periodic chest x-rays – or a “maximal” protocol – including CT scans of the thorax and upper abdomen, as well as bronchoscopy for squamous-cell carcinomas – there were no significant differences in overall survival at either 3, 5, or 8 years of follow-up, reported Virginie Westeel, MD, from the Centre Hospitalier Régional Universitaire of the Hôpital Jean Minjoz in Besançon, France.
In hopes of finding that answer, Dr. Westeel and colleagues in the French Cooperative Thoracic Oncology Group conducted a clinical trial comparing the standard follow-up approach recommended in most clinical guidelines, as described by Dr. Westeel, with an experimental protocol consisting of history and exam plus chest x-ray, CT scans, and fiber-optic bronchoscopy (mandatory for squamous- and large-cell carcinomas, optional for adenocarcinomas).
Patients with completely resected stage I, II, and IIIA tumors, and T4 tumors with pulmonary nodules in the same lobe, were randomly assigned to follow-up with one of the two protocols.
In each trial arm, the assigned procedures were repeated every 6 months after randomization for the first 2 years, then yearly until 5 years.
After a median follow-up of 8.7 years, there was no significant difference in the primary endpoint of overall survival. Median OS was 123.6 months in the maximal protocol group, compared with 99.7 months in the minimal protocol group (P = .037)
The 3-, 5-, and 8-year survival rates for the maximal and minimal protocols, respectively, were 76.1% vs. 77.3%, 65.8% vs. 66.7%, and 54.6% vs. 51.7%.
Because there appeared to be a separation of the survival curve beginning around 8 years, the investigators performed an exploratory 2-year landmark analysis.
They found that, among patients who had a recurrence within 24 months of randomization, there was no difference in OS between each follow-up protocol. However, among those patients with no recurrence within 24 months of resection, the median OS was not reached among patients assigned to the maximal protocol versus 129.3 months for those assigned to the minimal protocol (P = .04).
Patients without early recurrence had higher rates of secondary primary cancers, and for these patients, early detection with CT-based surveillance could explain the differences in overall survival, Dr. Westeel said.
“Our suggestion for practice is that, because there is no survival difference, both follow-up protocols are acceptable. However, a CT scan every 6 months is probably of no value in the first 2 years,” but yearly chest CTs to detect second primary cancers early may be of interest, she said.
Enriqueta Felip, MD, from Vall D’Hebron Institute of Oncology in Barcelona, who was not involved in the trial, commented that, while the study needed to be conducted, it was unlikely to change her clinical practice because of potential differences among patients with varying stages of NSCLC at the time of resection.
“I think it’s an important trial, [but] tomorrow I will follow my patients with a CT scan,” she said.
Dr. Felip was an invited expert at the briefing.
The study was supported by the French Ministry of Health, Fondation de France, and Laboratoire Lilly. Dr. Westeel and Dr. Felip reported no conflicts of interest relevant to the study.
Madrid – Computed tomography scans do not appear to be superior to plain old chest x-rays for follow-up of patients with completely resected non–small cell lung cancer (NSCLC), results of a randomized clinical trial suggest.
Among 1,775 patients followed out to 10 years with either a “minimal” protocol – consisting of history, physical exam, and periodic chest x-rays – or a “maximal” protocol – including CT scans of the thorax and upper abdomen, as well as bronchoscopy for squamous-cell carcinomas – there were no significant differences in overall survival at either 3, 5, or 8 years of follow-up, reported Virginie Westeel, MD, from the Centre Hospitalier Régional Universitaire of the Hôpital Jean Minjoz in Besançon, France.
In hopes of finding that answer, Dr. Westeel and colleagues in the French Cooperative Thoracic Oncology Group conducted a clinical trial comparing the standard follow-up approach recommended in most clinical guidelines, as described by Dr. Westeel, with an experimental protocol consisting of history and exam plus chest x-ray, CT scans, and fiber-optic bronchoscopy (mandatory for squamous- and large-cell carcinomas, optional for adenocarcinomas).
Patients with completely resected stage I, II, and IIIA tumors, and T4 tumors with pulmonary nodules in the same lobe, were randomly assigned to follow-up with one of the two protocols.
In each trial arm, the assigned procedures were repeated every 6 months after randomization for the first 2 years, then yearly until 5 years.
After a median follow-up of 8.7 years, there was no significant difference in the primary endpoint of overall survival. Median OS was 123.6 months in the maximal protocol group, compared with 99.7 months in the minimal protocol group (P = .037)
The 3-, 5-, and 8-year survival rates for the maximal and minimal protocols, respectively, were 76.1% vs. 77.3%, 65.8% vs. 66.7%, and 54.6% vs. 51.7%.
Because there appeared to be a separation of the survival curve beginning around 8 years, the investigators performed an exploratory 2-year landmark analysis.
They found that, among patients who had a recurrence within 24 months of randomization, there was no difference in OS between each follow-up protocol. However, among those patients with no recurrence within 24 months of resection, the median OS was not reached among patients assigned to the maximal protocol versus 129.3 months for those assigned to the minimal protocol (P = .04).
Patients without early recurrence had higher rates of secondary primary cancers, and for these patients, early detection with CT-based surveillance could explain the differences in overall survival, Dr. Westeel said.
“Our suggestion for practice is that, because there is no survival difference, both follow-up protocols are acceptable. However, a CT scan every 6 months is probably of no value in the first 2 years,” but yearly chest CTs to detect second primary cancers early may be of interest, she said.
Enriqueta Felip, MD, from Vall D’Hebron Institute of Oncology in Barcelona, who was not involved in the trial, commented that, while the study needed to be conducted, it was unlikely to change her clinical practice because of potential differences among patients with varying stages of NSCLC at the time of resection.
“I think it’s an important trial, [but] tomorrow I will follow my patients with a CT scan,” she said.
Dr. Felip was an invited expert at the briefing.
The study was supported by the French Ministry of Health, Fondation de France, and Laboratoire Lilly. Dr. Westeel and Dr. Felip reported no conflicts of interest relevant to the study.
Madrid – Computed tomography scans do not appear to be superior to plain old chest x-rays for follow-up of patients with completely resected non–small cell lung cancer (NSCLC), results of a randomized clinical trial suggest.
Among 1,775 patients followed out to 10 years with either a “minimal” protocol – consisting of history, physical exam, and periodic chest x-rays – or a “maximal” protocol – including CT scans of the thorax and upper abdomen, as well as bronchoscopy for squamous-cell carcinomas – there were no significant differences in overall survival at either 3, 5, or 8 years of follow-up, reported Virginie Westeel, MD, from the Centre Hospitalier Régional Universitaire of the Hôpital Jean Minjoz in Besançon, France.
In hopes of finding that answer, Dr. Westeel and colleagues in the French Cooperative Thoracic Oncology Group conducted a clinical trial comparing the standard follow-up approach recommended in most clinical guidelines, as described by Dr. Westeel, with an experimental protocol consisting of history and exam plus chest x-ray, CT scans, and fiber-optic bronchoscopy (mandatory for squamous- and large-cell carcinomas, optional for adenocarcinomas).
Patients with completely resected stage I, II, and IIIA tumors, and T4 tumors with pulmonary nodules in the same lobe, were randomly assigned to follow-up with one of the two protocols.
In each trial arm, the assigned procedures were repeated every 6 months after randomization for the first 2 years, then yearly until 5 years.
After a median follow-up of 8.7 years, there was no significant difference in the primary endpoint of overall survival. Median OS was 123.6 months in the maximal protocol group, compared with 99.7 months in the minimal protocol group (P = .037)
The 3-, 5-, and 8-year survival rates for the maximal and minimal protocols, respectively, were 76.1% vs. 77.3%, 65.8% vs. 66.7%, and 54.6% vs. 51.7%.
Because there appeared to be a separation of the survival curve beginning around 8 years, the investigators performed an exploratory 2-year landmark analysis.
They found that, among patients who had a recurrence within 24 months of randomization, there was no difference in OS between each follow-up protocol. However, among those patients with no recurrence within 24 months of resection, the median OS was not reached among patients assigned to the maximal protocol versus 129.3 months for those assigned to the minimal protocol (P = .04).
Patients without early recurrence had higher rates of secondary primary cancers, and for these patients, early detection with CT-based surveillance could explain the differences in overall survival, Dr. Westeel said.
“Our suggestion for practice is that, because there is no survival difference, both follow-up protocols are acceptable. However, a CT scan every 6 months is probably of no value in the first 2 years,” but yearly chest CTs to detect second primary cancers early may be of interest, she said.
Enriqueta Felip, MD, from Vall D’Hebron Institute of Oncology in Barcelona, who was not involved in the trial, commented that, while the study needed to be conducted, it was unlikely to change her clinical practice because of potential differences among patients with varying stages of NSCLC at the time of resection.
“I think it’s an important trial, [but] tomorrow I will follow my patients with a CT scan,” she said.
Dr. Felip was an invited expert at the briefing.
The study was supported by the French Ministry of Health, Fondation de France, and Laboratoire Lilly. Dr. Westeel and Dr. Felip reported no conflicts of interest relevant to the study.
AT ESMO 2017
Key clinical point: There were no differences in long-term overall survival among patients with resected NSCLC followed with x-rays and those followed with CT scans.
Major finding: Overall survival rates at 3, 5, and 8 years were similar among patients followed with minimal or maximal protocols.
Data source: Randomized controlled trial in 1,775 patients with completely resected non–small cell lung cancer.
Disclosures: The study was supported by the French Ministry of Health, Fondation de France, and Laboratoire Lilly. Dr. Westeel and Dr. Felip reported no conflicts of interest relevant to the study.
RANGE: Small PFS edge in urothelial cancer with VEGFR-2 inhibitor
MADRID – For patients with advanced or metastatic urothelial cancer that progressed on platinum-based chemotherapy, a combination of the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor ramucirumab and docetaxel offered a small but significant improvement in progression-free survival (PFS) compared with docetaxel alone.
Among 437 patients treated in the phase 3 RANGE trial, investigator-assessed PFS, the primary endpoint, was 4.07 months for patients randomized to ramucirumab and docetaxel, compared with 2.76 months for patients assigned to docetaxel and placebo, translating into a hazard ratio (HR) for ramucirumab of 0.757 (P = .0118).
“RANGE is the first phase 3 study to demonstrate a progression-free survival advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” lead author Daniel P. Petrylak, MD of Yale University, New Haven, Conn., said at a briefing at the European Society for Medical Oncology Congress.
But Richard Cathomas, Dr.med, of Kantonsspital Graubünden, in Chur, Switzerland, who was not involved in the study, said it “is too early for these results alone to change the standard of care second-line treatment, which is immune checkpoint inhibition.”
He noted that the magnitude of the benefit with ramucirumab was just 1.3 months, “and, while statistically significant, it raises the question of whether it is clinically relevant.”
He acknowledged that the improvement in response rates seen with ramucirumab in RANGE indicates a potential role for angiogenesis inhibitors in the treatment of urothelial cancers.
In the RANGE trial, results of which were published in The Lancet, investigators at 124 sites in 23 countries enrolled 530 patients with advanced or metastatic urothelial carcinoma who experienced progression during or after platinum-based chemotherapy.
Patients were randomly assigned to receive intravenous docetaxel 75 mg/m2 plus intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of each repeating 21-day cycle until disease progression or discontinuation of treatment for other reasons. The primary endpoint was assessed in an intention-to-treat analysis in the first 437 patients randomized.
As noted, at a median follow-up in the ITT analysis of 5.0 months, investigator-assessed PFS favored the addition of ramucirumab, as did a blinded central review of outcomes, which determined a median PFS of 4.04 months with ramucirumab plus docetaxel compared with 2.46 months for docetaxel alone (HR 0.672, P = .0005).
Ramucirumab/docetaxel was also associated with an improvement in the objective response rate, at 24.5% compared with 14.0% for placebo/docetaxel.
Treatment toxicities were similar between the study arms, although patients in the ramucirumab arm experienced slightly less anemia compared with those in the placebo arm.
In all, 209 of 263 patients assigned to ramucirumab/docetaxel, and 229 of 267 patients assigned to placebo/docetaxel had their treatments discontinued, primarily because they experienced disease progression.
There were no significant changes in quality of life measures during the trial, and there were no differences in quality of life between the treatment arms, Dr. Petrylak reported.
Ultimately, the combination of ramucirumab and docetaxel may be best suited for use as a third-line treatment for patients with platinum-resistant metastatic urothelial cancer that has progressed after second-line therapy with an immune checkpoint inhibitor, said Yohann Loriot, MD, of Gustave-Roussy Cancer Institute in Villejuif, France, the invited discussant at the presidential symposium where the RANGE data were presented.
However, for patients who have a short response to first-line platinum-based chemotherapy, have no visceral metastases, or are ineligible to receive immunotherapy, ramucirumab plus docetaxel could be a suitable second-line option, he said.
The RANGE trial was funded by Eli Lilly. Dr. Petrylak disclosed research funding from the company. Dr. Cathomas and Dr. Loriot disclosed consulting or advisory roles with companies other than Lilly.
MADRID – For patients with advanced or metastatic urothelial cancer that progressed on platinum-based chemotherapy, a combination of the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor ramucirumab and docetaxel offered a small but significant improvement in progression-free survival (PFS) compared with docetaxel alone.
Among 437 patients treated in the phase 3 RANGE trial, investigator-assessed PFS, the primary endpoint, was 4.07 months for patients randomized to ramucirumab and docetaxel, compared with 2.76 months for patients assigned to docetaxel and placebo, translating into a hazard ratio (HR) for ramucirumab of 0.757 (P = .0118).
“RANGE is the first phase 3 study to demonstrate a progression-free survival advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” lead author Daniel P. Petrylak, MD of Yale University, New Haven, Conn., said at a briefing at the European Society for Medical Oncology Congress.
But Richard Cathomas, Dr.med, of Kantonsspital Graubünden, in Chur, Switzerland, who was not involved in the study, said it “is too early for these results alone to change the standard of care second-line treatment, which is immune checkpoint inhibition.”
He noted that the magnitude of the benefit with ramucirumab was just 1.3 months, “and, while statistically significant, it raises the question of whether it is clinically relevant.”
He acknowledged that the improvement in response rates seen with ramucirumab in RANGE indicates a potential role for angiogenesis inhibitors in the treatment of urothelial cancers.
In the RANGE trial, results of which were published in The Lancet, investigators at 124 sites in 23 countries enrolled 530 patients with advanced or metastatic urothelial carcinoma who experienced progression during or after platinum-based chemotherapy.
Patients were randomly assigned to receive intravenous docetaxel 75 mg/m2 plus intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of each repeating 21-day cycle until disease progression or discontinuation of treatment for other reasons. The primary endpoint was assessed in an intention-to-treat analysis in the first 437 patients randomized.
As noted, at a median follow-up in the ITT analysis of 5.0 months, investigator-assessed PFS favored the addition of ramucirumab, as did a blinded central review of outcomes, which determined a median PFS of 4.04 months with ramucirumab plus docetaxel compared with 2.46 months for docetaxel alone (HR 0.672, P = .0005).
Ramucirumab/docetaxel was also associated with an improvement in the objective response rate, at 24.5% compared with 14.0% for placebo/docetaxel.
Treatment toxicities were similar between the study arms, although patients in the ramucirumab arm experienced slightly less anemia compared with those in the placebo arm.
In all, 209 of 263 patients assigned to ramucirumab/docetaxel, and 229 of 267 patients assigned to placebo/docetaxel had their treatments discontinued, primarily because they experienced disease progression.
There were no significant changes in quality of life measures during the trial, and there were no differences in quality of life between the treatment arms, Dr. Petrylak reported.
Ultimately, the combination of ramucirumab and docetaxel may be best suited for use as a third-line treatment for patients with platinum-resistant metastatic urothelial cancer that has progressed after second-line therapy with an immune checkpoint inhibitor, said Yohann Loriot, MD, of Gustave-Roussy Cancer Institute in Villejuif, France, the invited discussant at the presidential symposium where the RANGE data were presented.
However, for patients who have a short response to first-line platinum-based chemotherapy, have no visceral metastases, or are ineligible to receive immunotherapy, ramucirumab plus docetaxel could be a suitable second-line option, he said.
The RANGE trial was funded by Eli Lilly. Dr. Petrylak disclosed research funding from the company. Dr. Cathomas and Dr. Loriot disclosed consulting or advisory roles with companies other than Lilly.
MADRID – For patients with advanced or metastatic urothelial cancer that progressed on platinum-based chemotherapy, a combination of the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor ramucirumab and docetaxel offered a small but significant improvement in progression-free survival (PFS) compared with docetaxel alone.
Among 437 patients treated in the phase 3 RANGE trial, investigator-assessed PFS, the primary endpoint, was 4.07 months for patients randomized to ramucirumab and docetaxel, compared with 2.76 months for patients assigned to docetaxel and placebo, translating into a hazard ratio (HR) for ramucirumab of 0.757 (P = .0118).
“RANGE is the first phase 3 study to demonstrate a progression-free survival advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” lead author Daniel P. Petrylak, MD of Yale University, New Haven, Conn., said at a briefing at the European Society for Medical Oncology Congress.
But Richard Cathomas, Dr.med, of Kantonsspital Graubünden, in Chur, Switzerland, who was not involved in the study, said it “is too early for these results alone to change the standard of care second-line treatment, which is immune checkpoint inhibition.”
He noted that the magnitude of the benefit with ramucirumab was just 1.3 months, “and, while statistically significant, it raises the question of whether it is clinically relevant.”
He acknowledged that the improvement in response rates seen with ramucirumab in RANGE indicates a potential role for angiogenesis inhibitors in the treatment of urothelial cancers.
In the RANGE trial, results of which were published in The Lancet, investigators at 124 sites in 23 countries enrolled 530 patients with advanced or metastatic urothelial carcinoma who experienced progression during or after platinum-based chemotherapy.
Patients were randomly assigned to receive intravenous docetaxel 75 mg/m2 plus intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of each repeating 21-day cycle until disease progression or discontinuation of treatment for other reasons. The primary endpoint was assessed in an intention-to-treat analysis in the first 437 patients randomized.
As noted, at a median follow-up in the ITT analysis of 5.0 months, investigator-assessed PFS favored the addition of ramucirumab, as did a blinded central review of outcomes, which determined a median PFS of 4.04 months with ramucirumab plus docetaxel compared with 2.46 months for docetaxel alone (HR 0.672, P = .0005).
Ramucirumab/docetaxel was also associated with an improvement in the objective response rate, at 24.5% compared with 14.0% for placebo/docetaxel.
Treatment toxicities were similar between the study arms, although patients in the ramucirumab arm experienced slightly less anemia compared with those in the placebo arm.
In all, 209 of 263 patients assigned to ramucirumab/docetaxel, and 229 of 267 patients assigned to placebo/docetaxel had their treatments discontinued, primarily because they experienced disease progression.
There were no significant changes in quality of life measures during the trial, and there were no differences in quality of life between the treatment arms, Dr. Petrylak reported.
Ultimately, the combination of ramucirumab and docetaxel may be best suited for use as a third-line treatment for patients with platinum-resistant metastatic urothelial cancer that has progressed after second-line therapy with an immune checkpoint inhibitor, said Yohann Loriot, MD, of Gustave-Roussy Cancer Institute in Villejuif, France, the invited discussant at the presidential symposium where the RANGE data were presented.
However, for patients who have a short response to first-line platinum-based chemotherapy, have no visceral metastases, or are ineligible to receive immunotherapy, ramucirumab plus docetaxel could be a suitable second-line option, he said.
The RANGE trial was funded by Eli Lilly. Dr. Petrylak disclosed research funding from the company. Dr. Cathomas and Dr. Loriot disclosed consulting or advisory roles with companies other than Lilly.
AT ESMO 2017
Key clinical point: Adding the VEGFR-2 inhibitor ramucirumab to docetaxel slightly improved progression-free survival of advanced/metastatic urothelial carcinoma.
Major finding: Investigator-assessed PFS was 4.07 months for patients randomized to ramucirumab and docetaxel, vs. 2.76 months for docetaxel/placebo.
Data source: Randomized phase 3 trial of 530 patients with urothelial carcinoma that progressed during or after platinum-based chemotherapy.
Disclosures: The RANGE trial was funded by Eli Lilly. Dr. Petrylak disclosed research funding from the company. Dr. Cathomas and Dr. Loriot disclosed consulting or advisory roles with companies other than Lilly.
MONARCH 3: Abemaciclib plus AI boosts PFS in HR+/HER2- breast cancer
Madrid – A combination of the investigational cyclin-dependent kinase 4/6 (CDK4/6) agent abemaciclib and a nonsteroidal aromatase inhibitor (AI) was associated with a near doubling of progression-free survival in postmenopausal women with previously untreated hormone-receptor positive, human epidermal growth factor receptor 2–negative (HR+/HER2-) advanced breast cancer.
At a planned 18-month interim analysis of the MONARCH 3 trial, the median investigator-assessed progression free survival (PFS), the primary endpoint, had not been reached for 328 patients assigned to receive abemaciclib with either anastrozole (Arimidex) or letrozole (Femara). In contrast, the median PFS for 165 patients assigned to an AI and a placebo was 14.7 months, translating into a hazard ratio (HR) of 0.543 (P = .000021), reported Angelo Di Leo, MD, of Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
“Abemaciclib in combination with a nonsteroidal aromatase inhibitor is superior to a nonsteroidal aromatase inhibitor alone in terms of progression-free survival, but also in terms of the objective response rate as the initial treatment of HER2-negative, endocrine sensitive advanced breast cancer,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
The efficacy of abemaciclib was consistently seen across all subgroups.
“However, we have observed that the patients deriving the largest benefit from abemaciclib are those who have adverse prognostic factors such as, for instance, the presence of liver metastases, or the fact the disease has relapsed only after a few years from the end of adjuvant endocrine therapy,” he added.
The study was stopped for efficacy at the interim analysis.
Abemaciclib has previously been shown to be active as a monotherapy in treatment-refractory HR+/HER2- breast cancer, and in combination with fulvestrant (Faslodex) in patients who had disease progression on endocrine therapy.
Dr. Di Leo and his colleagues enrolled 493 postmenopausal women with metastatic or locally recurrent HR+/HER2- breast cancer who had not received systemic therapy in this setting. Patients who had prior neoadjuvant or adjuvant endocrine therapy were allowed if they had a disease-free interval of more than 1 year since completing endocrine therapy, The patients also had to have good performance status (Eastern Cooperative Oncology Group PS score 1 or less).
They were randomly assigned on a 2:1 basis to receive abemaciclib 150 mg b.i.d. on a continuous schedule plus either anastrozole 1 mg or letrozole 2.5 mg daily until disease progression, or to placebo plus either of the two AIs.
In addition to the superior PFS with abemaciclib added to an AI, as noted before, the CDK4/6 inhibitor was associated with a significantly better objective response rate (ORR), at 48.2% compared with 34.5% for placebo (P = .002). Among patients with measurable disease at baseline, the respective ORRs were 59.2% and 43.8% (P = .004). The clinical benefit rate in this subgroup was also better with abemaciclib, at 79.3% vs. 69.2% (P = .024).
In exploratory subgroup analyses, the investigators found that patients who had indicators of poor prognosis seemed to derive “substantial” benefit from the addition of abemaciclib. However, in an exploratory analysis in patients with disease only in bone, the investigators found that adding abemaciclib did not appear to improve PFS, suggesting that this subgroup could be treated effectively with endocrine therapy alone. Dr. Di Leo cautioned against overinterpreting this finding however, as only 109 patients had bone-only disease.
The safety analysis showed that patients were able to tolerate the combination fairly well. The incidence of grade 3 or 4 neutropenia was 21.1% with the combination compared with 1.2% with placebo, and grade 3 diarrhea occurred in 9.5% vs. 1.2% (no grade 4 diarrhea in either arm). The diarrhea tended to occur early in therapy and could be managed with dose adjustments and antidiarrheal medications, Dr. Di Leo said.
“What we would like to ask is, is this a practice-changing study? Do the results change standard first-line endocrine-based therapy, and then do these results change who we give endocrine therapy to?,” said invited discussant Nicholas Turner, PhD, of The Royal Marsden Hospital in London.
“The study stopped at the reported interim analysis, so at the moment the abemaciclib arm hasn’t reached the median PFS, but we can anticipate that with further follow-up we will see approximately a year improvement in median PFS by the addition of abemaciclib, which is really a substantial improvement in PFS for these patients. And importantly, this benefit was confirmed by a blinded independent central review of the investigator PFS,” he said.
Eli Lilly funded MONARCH 3. Dr. Di Leo and Dr. Turner reported receiving honoraria from the company.
Madrid – A combination of the investigational cyclin-dependent kinase 4/6 (CDK4/6) agent abemaciclib and a nonsteroidal aromatase inhibitor (AI) was associated with a near doubling of progression-free survival in postmenopausal women with previously untreated hormone-receptor positive, human epidermal growth factor receptor 2–negative (HR+/HER2-) advanced breast cancer.
At a planned 18-month interim analysis of the MONARCH 3 trial, the median investigator-assessed progression free survival (PFS), the primary endpoint, had not been reached for 328 patients assigned to receive abemaciclib with either anastrozole (Arimidex) or letrozole (Femara). In contrast, the median PFS for 165 patients assigned to an AI and a placebo was 14.7 months, translating into a hazard ratio (HR) of 0.543 (P = .000021), reported Angelo Di Leo, MD, of Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
“Abemaciclib in combination with a nonsteroidal aromatase inhibitor is superior to a nonsteroidal aromatase inhibitor alone in terms of progression-free survival, but also in terms of the objective response rate as the initial treatment of HER2-negative, endocrine sensitive advanced breast cancer,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
The efficacy of abemaciclib was consistently seen across all subgroups.
“However, we have observed that the patients deriving the largest benefit from abemaciclib are those who have adverse prognostic factors such as, for instance, the presence of liver metastases, or the fact the disease has relapsed only after a few years from the end of adjuvant endocrine therapy,” he added.
The study was stopped for efficacy at the interim analysis.
Abemaciclib has previously been shown to be active as a monotherapy in treatment-refractory HR+/HER2- breast cancer, and in combination with fulvestrant (Faslodex) in patients who had disease progression on endocrine therapy.
Dr. Di Leo and his colleagues enrolled 493 postmenopausal women with metastatic or locally recurrent HR+/HER2- breast cancer who had not received systemic therapy in this setting. Patients who had prior neoadjuvant or adjuvant endocrine therapy were allowed if they had a disease-free interval of more than 1 year since completing endocrine therapy, The patients also had to have good performance status (Eastern Cooperative Oncology Group PS score 1 or less).
They were randomly assigned on a 2:1 basis to receive abemaciclib 150 mg b.i.d. on a continuous schedule plus either anastrozole 1 mg or letrozole 2.5 mg daily until disease progression, or to placebo plus either of the two AIs.
In addition to the superior PFS with abemaciclib added to an AI, as noted before, the CDK4/6 inhibitor was associated with a significantly better objective response rate (ORR), at 48.2% compared with 34.5% for placebo (P = .002). Among patients with measurable disease at baseline, the respective ORRs were 59.2% and 43.8% (P = .004). The clinical benefit rate in this subgroup was also better with abemaciclib, at 79.3% vs. 69.2% (P = .024).
In exploratory subgroup analyses, the investigators found that patients who had indicators of poor prognosis seemed to derive “substantial” benefit from the addition of abemaciclib. However, in an exploratory analysis in patients with disease only in bone, the investigators found that adding abemaciclib did not appear to improve PFS, suggesting that this subgroup could be treated effectively with endocrine therapy alone. Dr. Di Leo cautioned against overinterpreting this finding however, as only 109 patients had bone-only disease.
The safety analysis showed that patients were able to tolerate the combination fairly well. The incidence of grade 3 or 4 neutropenia was 21.1% with the combination compared with 1.2% with placebo, and grade 3 diarrhea occurred in 9.5% vs. 1.2% (no grade 4 diarrhea in either arm). The diarrhea tended to occur early in therapy and could be managed with dose adjustments and antidiarrheal medications, Dr. Di Leo said.
“What we would like to ask is, is this a practice-changing study? Do the results change standard first-line endocrine-based therapy, and then do these results change who we give endocrine therapy to?,” said invited discussant Nicholas Turner, PhD, of The Royal Marsden Hospital in London.
“The study stopped at the reported interim analysis, so at the moment the abemaciclib arm hasn’t reached the median PFS, but we can anticipate that with further follow-up we will see approximately a year improvement in median PFS by the addition of abemaciclib, which is really a substantial improvement in PFS for these patients. And importantly, this benefit was confirmed by a blinded independent central review of the investigator PFS,” he said.
Eli Lilly funded MONARCH 3. Dr. Di Leo and Dr. Turner reported receiving honoraria from the company.
Madrid – A combination of the investigational cyclin-dependent kinase 4/6 (CDK4/6) agent abemaciclib and a nonsteroidal aromatase inhibitor (AI) was associated with a near doubling of progression-free survival in postmenopausal women with previously untreated hormone-receptor positive, human epidermal growth factor receptor 2–negative (HR+/HER2-) advanced breast cancer.
At a planned 18-month interim analysis of the MONARCH 3 trial, the median investigator-assessed progression free survival (PFS), the primary endpoint, had not been reached for 328 patients assigned to receive abemaciclib with either anastrozole (Arimidex) or letrozole (Femara). In contrast, the median PFS for 165 patients assigned to an AI and a placebo was 14.7 months, translating into a hazard ratio (HR) of 0.543 (P = .000021), reported Angelo Di Leo, MD, of Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
“Abemaciclib in combination with a nonsteroidal aromatase inhibitor is superior to a nonsteroidal aromatase inhibitor alone in terms of progression-free survival, but also in terms of the objective response rate as the initial treatment of HER2-negative, endocrine sensitive advanced breast cancer,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
The efficacy of abemaciclib was consistently seen across all subgroups.
“However, we have observed that the patients deriving the largest benefit from abemaciclib are those who have adverse prognostic factors such as, for instance, the presence of liver metastases, or the fact the disease has relapsed only after a few years from the end of adjuvant endocrine therapy,” he added.
The study was stopped for efficacy at the interim analysis.
Abemaciclib has previously been shown to be active as a monotherapy in treatment-refractory HR+/HER2- breast cancer, and in combination with fulvestrant (Faslodex) in patients who had disease progression on endocrine therapy.
Dr. Di Leo and his colleagues enrolled 493 postmenopausal women with metastatic or locally recurrent HR+/HER2- breast cancer who had not received systemic therapy in this setting. Patients who had prior neoadjuvant or adjuvant endocrine therapy were allowed if they had a disease-free interval of more than 1 year since completing endocrine therapy, The patients also had to have good performance status (Eastern Cooperative Oncology Group PS score 1 or less).
They were randomly assigned on a 2:1 basis to receive abemaciclib 150 mg b.i.d. on a continuous schedule plus either anastrozole 1 mg or letrozole 2.5 mg daily until disease progression, or to placebo plus either of the two AIs.
In addition to the superior PFS with abemaciclib added to an AI, as noted before, the CDK4/6 inhibitor was associated with a significantly better objective response rate (ORR), at 48.2% compared with 34.5% for placebo (P = .002). Among patients with measurable disease at baseline, the respective ORRs were 59.2% and 43.8% (P = .004). The clinical benefit rate in this subgroup was also better with abemaciclib, at 79.3% vs. 69.2% (P = .024).
In exploratory subgroup analyses, the investigators found that patients who had indicators of poor prognosis seemed to derive “substantial” benefit from the addition of abemaciclib. However, in an exploratory analysis in patients with disease only in bone, the investigators found that adding abemaciclib did not appear to improve PFS, suggesting that this subgroup could be treated effectively with endocrine therapy alone. Dr. Di Leo cautioned against overinterpreting this finding however, as only 109 patients had bone-only disease.
The safety analysis showed that patients were able to tolerate the combination fairly well. The incidence of grade 3 or 4 neutropenia was 21.1% with the combination compared with 1.2% with placebo, and grade 3 diarrhea occurred in 9.5% vs. 1.2% (no grade 4 diarrhea in either arm). The diarrhea tended to occur early in therapy and could be managed with dose adjustments and antidiarrheal medications, Dr. Di Leo said.
“What we would like to ask is, is this a practice-changing study? Do the results change standard first-line endocrine-based therapy, and then do these results change who we give endocrine therapy to?,” said invited discussant Nicholas Turner, PhD, of The Royal Marsden Hospital in London.
“The study stopped at the reported interim analysis, so at the moment the abemaciclib arm hasn’t reached the median PFS, but we can anticipate that with further follow-up we will see approximately a year improvement in median PFS by the addition of abemaciclib, which is really a substantial improvement in PFS for these patients. And importantly, this benefit was confirmed by a blinded independent central review of the investigator PFS,” he said.
Eli Lilly funded MONARCH 3. Dr. Di Leo and Dr. Turner reported receiving honoraria from the company.
AT ESMO 2017
Key clinical point: Adding the CDK4/6 inhibitor abemaciclib to an aromatase inhibitor significantly improved progression-free survival in the frontline for postmenopausal women with HR+/HER2- breast cancer.
Major finding: Median PFS was not reached with abemaciclib and letrozole or anastrozole, vs. 14.7 months for a placebo plus aromatase inhibitor.
Data source: Randomized phase 3 trial of 493 postmenopausal women with metastatic or locally recurrent HR+/HER2- breast cancer.
Disclosures: Eli Lilly funded MONARCH 3. Dr. Di Leo and Dr. Turner reported receiving honoraria from the company.
LORELEI sings praises of neoadjuvant taselisib/letrozole in ER+/HER2– breast cancer
MADRID – Adding the investigational PI3K inhibitor taselisib to letrozole (Femara) significantly improved overall response rates, compared with neoadjuvant letrozole alone, in postmenopausal women with early estrogen receptor–positive, human epidermal growth factor receptor 2–negative (ER+/HER2–) breast cancer, results of the LORELEI trial show.
In this phase 2 trial, the overall response rate (ORR), the primary endpoint, was 50% for 166 patients assigned to letrozole plus taselisib, compared with 39.3% for 168 patients assigned to letrozole plus placebo, reported Cristina Saura, MD, of Vall d’Hebron University Hospital in Barcelona.
Although the pathologic complete rate (pCR) was low in each study arm, this was not unexpected, due to the short course (4 months) of endocrine-based therapy, she said.
Taselisib is a selective inhibitor of phosphatidylinositol 3-kinase (PI3K), with enhanced activity against the mutation isoform of the protein, labeled p110a. The PI3K alpha isoform, Taselisib degrades p110a by a mechanism of action that is different from other PI3K inhibitors, Dr. Saura said.
As monotherapy and in combination with endocrine therapy agents in phase 1 trials, taselisib elicited partial responses in patients with PIK3CA-mutated metastatic breast cancer, she noted.
In LORELEI, 334 postmenopausal women with previously untreated ER+/HER2– stage I-III operable breast cancer with tumors of 2 cm or greater on MRI were enrolled. The patients were stratified by tumor size and nodal status and then randomly assigned to letrozole 2.5 mg daily plus taselisib 4 mg taken in 2 mg doses twice daily for 5 days each week for 16 weeks, or letrozole plus placebo. Patients then went on to surgery, were followed for safety for 30 days, and then had adjuvant therapy consisting of endocrine therapy and/or chemotherapy and/or radiation therapy.
As noted, the ORR for patients assigned to the combination was 50%, consisting of 4.8% CR, and 45.2% partial responses (PR). Additionally, 40.4% of patients assigned to the taselisib arm had stable disease. The corresponding response rates for patients assigned to the letrozole/placebo arm were 1.8%, 37.5%, and 51.2%.
The odds ratio favoring the combination was 1.55 (P = .049).
For the subset of patients with PIK3CA-mutated tumors, the ORR was 56.2% for 73 patients in the taselisib arm, vs. 38% for 79 patients in the placebo arm (OR, 2.03; P = .033).
The pCRs in the overall population were 1.8% with taselisib vs. 0.6% with placebo. The corresponding pCRs in the PIK3CA-mutated population were 1.4% and 0%. None of the differences were statistically significant.
In all, 11.4% of patients assigned to taselisib required dose reductions, and 10.8% had to discontinue the drug.
The incidence of adverse events of any grade was 91% with letrozole/taselisib, and 83.2% with letrozole placebo.
Taselisib was associated with higher rates of gastrointestinal side effects, skin and subcutaneous disorders, metabolic and nutritional side effects and respiratory, thoracic, and mediastinal disorders. Patients in the taselisib arm had a lower incidence of musculoskeletal/connective tissue problems, vascular disorders, and psychiatric complaints.
The toxicities were generally manageable and consistent with that of other PI3K inhibitors, Dr. Saura said.
She said that although taselisib is more selective than other PI3K inhibitors and has a somewhat lower incidence of GI toxicities, “it’s still difficult to manage as a drug in the clinic, but I think if we can tell a patient there is a selection criterion which is a PIK3CA mutation, then patients are more willing and we as therapists are more willing to give those drugs.”
LORELEI provides the first clinical proof of efficacy of a specific PI3K inhibitor in early breast cancer, and “results of confirmatory phase 3 trials in metastatic breast cancer are eagerly awaited,” Dr. Harbeck added.
The study was supported by Genentech/F. Hoffman–La Roche. Dr. Saura disclosed consulting fees and institutional funding from Roche. Dr. Harbeck reported no disclosures relevant to the study.
MADRID – Adding the investigational PI3K inhibitor taselisib to letrozole (Femara) significantly improved overall response rates, compared with neoadjuvant letrozole alone, in postmenopausal women with early estrogen receptor–positive, human epidermal growth factor receptor 2–negative (ER+/HER2–) breast cancer, results of the LORELEI trial show.
In this phase 2 trial, the overall response rate (ORR), the primary endpoint, was 50% for 166 patients assigned to letrozole plus taselisib, compared with 39.3% for 168 patients assigned to letrozole plus placebo, reported Cristina Saura, MD, of Vall d’Hebron University Hospital in Barcelona.
Although the pathologic complete rate (pCR) was low in each study arm, this was not unexpected, due to the short course (4 months) of endocrine-based therapy, she said.
Taselisib is a selective inhibitor of phosphatidylinositol 3-kinase (PI3K), with enhanced activity against the mutation isoform of the protein, labeled p110a. The PI3K alpha isoform, Taselisib degrades p110a by a mechanism of action that is different from other PI3K inhibitors, Dr. Saura said.
As monotherapy and in combination with endocrine therapy agents in phase 1 trials, taselisib elicited partial responses in patients with PIK3CA-mutated metastatic breast cancer, she noted.
In LORELEI, 334 postmenopausal women with previously untreated ER+/HER2– stage I-III operable breast cancer with tumors of 2 cm or greater on MRI were enrolled. The patients were stratified by tumor size and nodal status and then randomly assigned to letrozole 2.5 mg daily plus taselisib 4 mg taken in 2 mg doses twice daily for 5 days each week for 16 weeks, or letrozole plus placebo. Patients then went on to surgery, were followed for safety for 30 days, and then had adjuvant therapy consisting of endocrine therapy and/or chemotherapy and/or radiation therapy.
As noted, the ORR for patients assigned to the combination was 50%, consisting of 4.8% CR, and 45.2% partial responses (PR). Additionally, 40.4% of patients assigned to the taselisib arm had stable disease. The corresponding response rates for patients assigned to the letrozole/placebo arm were 1.8%, 37.5%, and 51.2%.
The odds ratio favoring the combination was 1.55 (P = .049).
For the subset of patients with PIK3CA-mutated tumors, the ORR was 56.2% for 73 patients in the taselisib arm, vs. 38% for 79 patients in the placebo arm (OR, 2.03; P = .033).
The pCRs in the overall population were 1.8% with taselisib vs. 0.6% with placebo. The corresponding pCRs in the PIK3CA-mutated population were 1.4% and 0%. None of the differences were statistically significant.
In all, 11.4% of patients assigned to taselisib required dose reductions, and 10.8% had to discontinue the drug.
The incidence of adverse events of any grade was 91% with letrozole/taselisib, and 83.2% with letrozole placebo.
Taselisib was associated with higher rates of gastrointestinal side effects, skin and subcutaneous disorders, metabolic and nutritional side effects and respiratory, thoracic, and mediastinal disorders. Patients in the taselisib arm had a lower incidence of musculoskeletal/connective tissue problems, vascular disorders, and psychiatric complaints.
The toxicities were generally manageable and consistent with that of other PI3K inhibitors, Dr. Saura said.
She said that although taselisib is more selective than other PI3K inhibitors and has a somewhat lower incidence of GI toxicities, “it’s still difficult to manage as a drug in the clinic, but I think if we can tell a patient there is a selection criterion which is a PIK3CA mutation, then patients are more willing and we as therapists are more willing to give those drugs.”
LORELEI provides the first clinical proof of efficacy of a specific PI3K inhibitor in early breast cancer, and “results of confirmatory phase 3 trials in metastatic breast cancer are eagerly awaited,” Dr. Harbeck added.
The study was supported by Genentech/F. Hoffman–La Roche. Dr. Saura disclosed consulting fees and institutional funding from Roche. Dr. Harbeck reported no disclosures relevant to the study.
MADRID – Adding the investigational PI3K inhibitor taselisib to letrozole (Femara) significantly improved overall response rates, compared with neoadjuvant letrozole alone, in postmenopausal women with early estrogen receptor–positive, human epidermal growth factor receptor 2–negative (ER+/HER2–) breast cancer, results of the LORELEI trial show.
In this phase 2 trial, the overall response rate (ORR), the primary endpoint, was 50% for 166 patients assigned to letrozole plus taselisib, compared with 39.3% for 168 patients assigned to letrozole plus placebo, reported Cristina Saura, MD, of Vall d’Hebron University Hospital in Barcelona.
Although the pathologic complete rate (pCR) was low in each study arm, this was not unexpected, due to the short course (4 months) of endocrine-based therapy, she said.
Taselisib is a selective inhibitor of phosphatidylinositol 3-kinase (PI3K), with enhanced activity against the mutation isoform of the protein, labeled p110a. The PI3K alpha isoform, Taselisib degrades p110a by a mechanism of action that is different from other PI3K inhibitors, Dr. Saura said.
As monotherapy and in combination with endocrine therapy agents in phase 1 trials, taselisib elicited partial responses in patients with PIK3CA-mutated metastatic breast cancer, she noted.
In LORELEI, 334 postmenopausal women with previously untreated ER+/HER2– stage I-III operable breast cancer with tumors of 2 cm or greater on MRI were enrolled. The patients were stratified by tumor size and nodal status and then randomly assigned to letrozole 2.5 mg daily plus taselisib 4 mg taken in 2 mg doses twice daily for 5 days each week for 16 weeks, or letrozole plus placebo. Patients then went on to surgery, were followed for safety for 30 days, and then had adjuvant therapy consisting of endocrine therapy and/or chemotherapy and/or radiation therapy.
As noted, the ORR for patients assigned to the combination was 50%, consisting of 4.8% CR, and 45.2% partial responses (PR). Additionally, 40.4% of patients assigned to the taselisib arm had stable disease. The corresponding response rates for patients assigned to the letrozole/placebo arm were 1.8%, 37.5%, and 51.2%.
The odds ratio favoring the combination was 1.55 (P = .049).
For the subset of patients with PIK3CA-mutated tumors, the ORR was 56.2% for 73 patients in the taselisib arm, vs. 38% for 79 patients in the placebo arm (OR, 2.03; P = .033).
The pCRs in the overall population were 1.8% with taselisib vs. 0.6% with placebo. The corresponding pCRs in the PIK3CA-mutated population were 1.4% and 0%. None of the differences were statistically significant.
In all, 11.4% of patients assigned to taselisib required dose reductions, and 10.8% had to discontinue the drug.
The incidence of adverse events of any grade was 91% with letrozole/taselisib, and 83.2% with letrozole placebo.
Taselisib was associated with higher rates of gastrointestinal side effects, skin and subcutaneous disorders, metabolic and nutritional side effects and respiratory, thoracic, and mediastinal disorders. Patients in the taselisib arm had a lower incidence of musculoskeletal/connective tissue problems, vascular disorders, and psychiatric complaints.
The toxicities were generally manageable and consistent with that of other PI3K inhibitors, Dr. Saura said.
She said that although taselisib is more selective than other PI3K inhibitors and has a somewhat lower incidence of GI toxicities, “it’s still difficult to manage as a drug in the clinic, but I think if we can tell a patient there is a selection criterion which is a PIK3CA mutation, then patients are more willing and we as therapists are more willing to give those drugs.”
LORELEI provides the first clinical proof of efficacy of a specific PI3K inhibitor in early breast cancer, and “results of confirmatory phase 3 trials in metastatic breast cancer are eagerly awaited,” Dr. Harbeck added.
The study was supported by Genentech/F. Hoffman–La Roche. Dr. Saura disclosed consulting fees and institutional funding from Roche. Dr. Harbeck reported no disclosures relevant to the study.
AT ESMO 2017
Key clinical point: Adding the PI3K inhibitor taselisib to letrozole improved response rates over letrozole alone in postmenopausal women with ER+/HER2– early breast cancer.
Major finding: The ORR was 50% for letrozole/taselisib, vs. 39.3% for letrozole/placebo (P = .049).
Data source: Randomized, double-blind phase 2 trial in 334 postmenopausal women.
Disclosures: The study was supported by Genentech/F. Hoffman–La Roche. Dr. Saura disclosed consulting fees and institutional funding from Roche. Dr. Harbeck reported no disclosures relevant to the study.
COMBI-AD: Adjuvant combo halves relapses in BRAF V600-mutated melanoma
MADRID – A combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) delivered in the adjuvant setting was associated with a halving of the risk for relapse compared with placebo among patients with advanced melanoma with BRAF V600 mutations, late-breaking results from a phase 3 trial show.
Among 438 patients with stage III BRAF V600-mutated melanoma randomly assigned after complete surgical resection to dabrafenib/trametinib in the COMBI-AD trial, the estimated rate of 3-year relapse-free survival (RFS) was 58%, compared with 39% for 432 patients assigned to double placebos. This difference translated into a hazard ratio for relapse with the dabrafenib/trametinib combination of 0.47 (P less than .001).
“The relapse-free survival benefits were observed across all 12 subgroups which have been evaluated, so there’s not a single subgroup that is an outlier,” he said in a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
Results of the study were published online concurrently in the New England Journal of Medicine.
In previous phase 3 trials in patients with BRAF V600 mutated metastatic or unresectable melanoma, the combination of dabrafenib and trametinib improved survival. Because treatment options for patients with resectable stage III melanomas are limited and less than optimal, the COMBI-AD investigators sought to explore whether the combination could improve outcomes when used in the adjuvant setting.
In the study reported by Dr. Hauschild, patients with completely resected, high-risk stage IIIA, IIIB, or IIIC cutaneous melanoma with the BRAF V600EK mutation who were surgically free of disease within 12 weeks of randomization were stratified by BRAF mutation status and disease stage, and then randomly assigned to receive either dabrafenib 150 mg twice daily plus trametinib 2 mg once daily, or two matched placebos.
The RFS curves separated early in the study, and at 1 year the rate of RFS was 88% among patients treated with the combinations, compared with 56% for patients who got placebo. The respective rates at 2 and 3 years of follow-up were 67% vs. 44%, and, as noted before, 58% vs. 39%.
At this first interim analysis, the 1-year OS rate with dabrafenib/trametinib was 97% compared with 94% for placebo. Respective rates at 2 and 3 years of follow-up were 91% vs. 83%, and 86% vs. 77%, but as noted, the Kaplan-Meier survival curves appear to separate, but have yet to reach the prespecified boundary for significance.
As might be expected, the incidence of any grade 3 or 4 adverse events was higher in the combination group than in the placebo group, but there were no fatal adverse events related to assigned treatment. In all, 26% of patients assigned to dabrafenib/trametinib had to discontinue treatment due to adverse events, compared with 3% of patients assigned to placebo.
Dr. Hauschild said that the results of the COMBI-AD study and the Checkmate 238 study presented on the same day “will make a change in our textbooks and our current guidelines, because we have at least two new treatment options, and I think this is a new treatment option and a good day for our melanoma patients.”
His remarks were echoed by Olivier Michielin, MD, PhD, of the Swiss Institute of Bioinformatics in Lausanne. He said that “we now have, with the data, two fantastic new options. We couldn’t dream those studies to be so positive. This is really something that will open new features for our patients.”
Dr. Michielin was invited by ESMO to comment on the study.
COMBI-AD was sponsored by GlaxoSmithKline. Dabrafenib and trametinib have been owned by Novartis AG since March, 2015. Dr. Hauschild disclosed trial support, honoraria, and/or consultancy fees from Novartis and others. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK.
MADRID – A combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) delivered in the adjuvant setting was associated with a halving of the risk for relapse compared with placebo among patients with advanced melanoma with BRAF V600 mutations, late-breaking results from a phase 3 trial show.
Among 438 patients with stage III BRAF V600-mutated melanoma randomly assigned after complete surgical resection to dabrafenib/trametinib in the COMBI-AD trial, the estimated rate of 3-year relapse-free survival (RFS) was 58%, compared with 39% for 432 patients assigned to double placebos. This difference translated into a hazard ratio for relapse with the dabrafenib/trametinib combination of 0.47 (P less than .001).
“The relapse-free survival benefits were observed across all 12 subgroups which have been evaluated, so there’s not a single subgroup that is an outlier,” he said in a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
Results of the study were published online concurrently in the New England Journal of Medicine.
In previous phase 3 trials in patients with BRAF V600 mutated metastatic or unresectable melanoma, the combination of dabrafenib and trametinib improved survival. Because treatment options for patients with resectable stage III melanomas are limited and less than optimal, the COMBI-AD investigators sought to explore whether the combination could improve outcomes when used in the adjuvant setting.
In the study reported by Dr. Hauschild, patients with completely resected, high-risk stage IIIA, IIIB, or IIIC cutaneous melanoma with the BRAF V600EK mutation who were surgically free of disease within 12 weeks of randomization were stratified by BRAF mutation status and disease stage, and then randomly assigned to receive either dabrafenib 150 mg twice daily plus trametinib 2 mg once daily, or two matched placebos.
The RFS curves separated early in the study, and at 1 year the rate of RFS was 88% among patients treated with the combinations, compared with 56% for patients who got placebo. The respective rates at 2 and 3 years of follow-up were 67% vs. 44%, and, as noted before, 58% vs. 39%.
At this first interim analysis, the 1-year OS rate with dabrafenib/trametinib was 97% compared with 94% for placebo. Respective rates at 2 and 3 years of follow-up were 91% vs. 83%, and 86% vs. 77%, but as noted, the Kaplan-Meier survival curves appear to separate, but have yet to reach the prespecified boundary for significance.
As might be expected, the incidence of any grade 3 or 4 adverse events was higher in the combination group than in the placebo group, but there were no fatal adverse events related to assigned treatment. In all, 26% of patients assigned to dabrafenib/trametinib had to discontinue treatment due to adverse events, compared with 3% of patients assigned to placebo.
Dr. Hauschild said that the results of the COMBI-AD study and the Checkmate 238 study presented on the same day “will make a change in our textbooks and our current guidelines, because we have at least two new treatment options, and I think this is a new treatment option and a good day for our melanoma patients.”
His remarks were echoed by Olivier Michielin, MD, PhD, of the Swiss Institute of Bioinformatics in Lausanne. He said that “we now have, with the data, two fantastic new options. We couldn’t dream those studies to be so positive. This is really something that will open new features for our patients.”
Dr. Michielin was invited by ESMO to comment on the study.
COMBI-AD was sponsored by GlaxoSmithKline. Dabrafenib and trametinib have been owned by Novartis AG since March, 2015. Dr. Hauschild disclosed trial support, honoraria, and/or consultancy fees from Novartis and others. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK.
MADRID – A combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) delivered in the adjuvant setting was associated with a halving of the risk for relapse compared with placebo among patients with advanced melanoma with BRAF V600 mutations, late-breaking results from a phase 3 trial show.
Among 438 patients with stage III BRAF V600-mutated melanoma randomly assigned after complete surgical resection to dabrafenib/trametinib in the COMBI-AD trial, the estimated rate of 3-year relapse-free survival (RFS) was 58%, compared with 39% for 432 patients assigned to double placebos. This difference translated into a hazard ratio for relapse with the dabrafenib/trametinib combination of 0.47 (P less than .001).
“The relapse-free survival benefits were observed across all 12 subgroups which have been evaluated, so there’s not a single subgroup that is an outlier,” he said in a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
Results of the study were published online concurrently in the New England Journal of Medicine.
In previous phase 3 trials in patients with BRAF V600 mutated metastatic or unresectable melanoma, the combination of dabrafenib and trametinib improved survival. Because treatment options for patients with resectable stage III melanomas are limited and less than optimal, the COMBI-AD investigators sought to explore whether the combination could improve outcomes when used in the adjuvant setting.
In the study reported by Dr. Hauschild, patients with completely resected, high-risk stage IIIA, IIIB, or IIIC cutaneous melanoma with the BRAF V600EK mutation who were surgically free of disease within 12 weeks of randomization were stratified by BRAF mutation status and disease stage, and then randomly assigned to receive either dabrafenib 150 mg twice daily plus trametinib 2 mg once daily, or two matched placebos.
The RFS curves separated early in the study, and at 1 year the rate of RFS was 88% among patients treated with the combinations, compared with 56% for patients who got placebo. The respective rates at 2 and 3 years of follow-up were 67% vs. 44%, and, as noted before, 58% vs. 39%.
At this first interim analysis, the 1-year OS rate with dabrafenib/trametinib was 97% compared with 94% for placebo. Respective rates at 2 and 3 years of follow-up were 91% vs. 83%, and 86% vs. 77%, but as noted, the Kaplan-Meier survival curves appear to separate, but have yet to reach the prespecified boundary for significance.
As might be expected, the incidence of any grade 3 or 4 adverse events was higher in the combination group than in the placebo group, but there were no fatal adverse events related to assigned treatment. In all, 26% of patients assigned to dabrafenib/trametinib had to discontinue treatment due to adverse events, compared with 3% of patients assigned to placebo.
Dr. Hauschild said that the results of the COMBI-AD study and the Checkmate 238 study presented on the same day “will make a change in our textbooks and our current guidelines, because we have at least two new treatment options, and I think this is a new treatment option and a good day for our melanoma patients.”
His remarks were echoed by Olivier Michielin, MD, PhD, of the Swiss Institute of Bioinformatics in Lausanne. He said that “we now have, with the data, two fantastic new options. We couldn’t dream those studies to be so positive. This is really something that will open new features for our patients.”
Dr. Michielin was invited by ESMO to comment on the study.
COMBI-AD was sponsored by GlaxoSmithKline. Dabrafenib and trametinib have been owned by Novartis AG since March, 2015. Dr. Hauschild disclosed trial support, honoraria, and/or consultancy fees from Novartis and others. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK.
AT ESMO 2017
Key clinical point: Adjuvant therapy with a BRAF/MEK inhibitor combination significantly improved outcomes for patients with stage III completely resectable melanoma.
Major finding: The hazard ratio for relapse with the dabrafenib/trametinib combination vs. placebo was 0.47 (P less than .001).
Data source: Randomized, placebo-controlled phase 3 trial of 870 patients with stage III, completely resectable BRAF-mutated melanoma.
Disclosures: COMBI-AD was sponsored by GlaxoSmithKline. Dabrafenib and trametinib have been owned by Novartis AG since March, 2015. Dr. Hauschild disclosed trial support, honoraria, and/or consultancy fees from Novartis and others. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK.
Checkmate 238: Nivolumab bests ipilimumab for resectable stage III or IV melanoma
MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.
Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.
However, longer follow-up will be needed to see whether the RFS advantage of nivolumab translates into an overall survival advantage, he acknowledged.
In the trial, patients with high-risk, completely resected stage IIIB, IIIC, or IV melanoma were stratified by disease stage and PD-L1 status at baseline and randomly assigned in cohorts of 453 patients each to receive either nivolumab 3 mg/kg intravenously every 2 weeks and ipilimumab placebo every 3 weeks for four doses, or to ipilimumab 10 mg/kg IV every 3 weeks for four doses, then every 12 weeks from week 24, and nivolumab placebo IV every 2 weeks.
The maximum duration of therapy was 1 year.
For the primary RFS endpoint, the hazard ratio (HR) favoring nivolumab was 0.65 (P less than .0001).
The benefit for nivolumab was observed across the majority of prespecified subgroups tested, including PD-L1 and BRAF mutational status, Dr. Weber said.
Nivolumab also had a better safety profile, with a 14.4% incidence of grade 3 or 4 treatment-related adverse events, compared with 45.9% for ipilimumab. Grade 3 or 4 treatment-related adverse events leading to discontinuation of therapy occurred in 4.6% of patients on nivolumab, compared with 30.9% of those on ipilimumab.
Two patients in the ipilimumab arm died from toxicities related to therapy, one from marrow aplasia, and one from colitis. Both of these deaths occurred more than 100 days after the patients received their last dose of ipilimumab. There were no treatment-related deaths in the nivolumab arm.
Commenting on both the Checkmate 238 trial and a second trial reported at ESMO (COMBI-AD) looking at a combination of dabrafenib and trametinib for patients with stage III melanoma with a BRAF V600 mutation, Olivier Michielin, MD, PhD, said that “we now have, with the data, two fantastic new options. We couldn’t dream those studies to be so positive. This is really something that will open new futures for our patients.”
Dr. Michielin and Dr. Dummer were invited commentators at the briefing. Dr. Michielin was not involved in either trial. Dr. Dummer was a coinvestigator for the COMBI-AD trial.
The study was published simultaneously online by the New England Journal of Medicine.
Checkmate 238 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Weber disclosed honoraria, consulting fees, and travel accommodations/expenses from BMS and multiple other companies. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK. Dr. Dummer reported advising/consulting roles with BMS and others.
MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.
Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.
However, longer follow-up will be needed to see whether the RFS advantage of nivolumab translates into an overall survival advantage, he acknowledged.
In the trial, patients with high-risk, completely resected stage IIIB, IIIC, or IV melanoma were stratified by disease stage and PD-L1 status at baseline and randomly assigned in cohorts of 453 patients each to receive either nivolumab 3 mg/kg intravenously every 2 weeks and ipilimumab placebo every 3 weeks for four doses, or to ipilimumab 10 mg/kg IV every 3 weeks for four doses, then every 12 weeks from week 24, and nivolumab placebo IV every 2 weeks.
The maximum duration of therapy was 1 year.
For the primary RFS endpoint, the hazard ratio (HR) favoring nivolumab was 0.65 (P less than .0001).
The benefit for nivolumab was observed across the majority of prespecified subgroups tested, including PD-L1 and BRAF mutational status, Dr. Weber said.
Nivolumab also had a better safety profile, with a 14.4% incidence of grade 3 or 4 treatment-related adverse events, compared with 45.9% for ipilimumab. Grade 3 or 4 treatment-related adverse events leading to discontinuation of therapy occurred in 4.6% of patients on nivolumab, compared with 30.9% of those on ipilimumab.
Two patients in the ipilimumab arm died from toxicities related to therapy, one from marrow aplasia, and one from colitis. Both of these deaths occurred more than 100 days after the patients received their last dose of ipilimumab. There were no treatment-related deaths in the nivolumab arm.
Commenting on both the Checkmate 238 trial and a second trial reported at ESMO (COMBI-AD) looking at a combination of dabrafenib and trametinib for patients with stage III melanoma with a BRAF V600 mutation, Olivier Michielin, MD, PhD, said that “we now have, with the data, two fantastic new options. We couldn’t dream those studies to be so positive. This is really something that will open new futures for our patients.”
Dr. Michielin and Dr. Dummer were invited commentators at the briefing. Dr. Michielin was not involved in either trial. Dr. Dummer was a coinvestigator for the COMBI-AD trial.
The study was published simultaneously online by the New England Journal of Medicine.
Checkmate 238 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Weber disclosed honoraria, consulting fees, and travel accommodations/expenses from BMS and multiple other companies. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK. Dr. Dummer reported advising/consulting roles with BMS and others.
MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.
Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.
However, longer follow-up will be needed to see whether the RFS advantage of nivolumab translates into an overall survival advantage, he acknowledged.
In the trial, patients with high-risk, completely resected stage IIIB, IIIC, or IV melanoma were stratified by disease stage and PD-L1 status at baseline and randomly assigned in cohorts of 453 patients each to receive either nivolumab 3 mg/kg intravenously every 2 weeks and ipilimumab placebo every 3 weeks for four doses, or to ipilimumab 10 mg/kg IV every 3 weeks for four doses, then every 12 weeks from week 24, and nivolumab placebo IV every 2 weeks.
The maximum duration of therapy was 1 year.
For the primary RFS endpoint, the hazard ratio (HR) favoring nivolumab was 0.65 (P less than .0001).
The benefit for nivolumab was observed across the majority of prespecified subgroups tested, including PD-L1 and BRAF mutational status, Dr. Weber said.
Nivolumab also had a better safety profile, with a 14.4% incidence of grade 3 or 4 treatment-related adverse events, compared with 45.9% for ipilimumab. Grade 3 or 4 treatment-related adverse events leading to discontinuation of therapy occurred in 4.6% of patients on nivolumab, compared with 30.9% of those on ipilimumab.
Two patients in the ipilimumab arm died from toxicities related to therapy, one from marrow aplasia, and one from colitis. Both of these deaths occurred more than 100 days after the patients received their last dose of ipilimumab. There were no treatment-related deaths in the nivolumab arm.
Commenting on both the Checkmate 238 trial and a second trial reported at ESMO (COMBI-AD) looking at a combination of dabrafenib and trametinib for patients with stage III melanoma with a BRAF V600 mutation, Olivier Michielin, MD, PhD, said that “we now have, with the data, two fantastic new options. We couldn’t dream those studies to be so positive. This is really something that will open new futures for our patients.”
Dr. Michielin and Dr. Dummer were invited commentators at the briefing. Dr. Michielin was not involved in either trial. Dr. Dummer was a coinvestigator for the COMBI-AD trial.
The study was published simultaneously online by the New England Journal of Medicine.
Checkmate 238 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Weber disclosed honoraria, consulting fees, and travel accommodations/expenses from BMS and multiple other companies. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK. Dr. Dummer reported advising/consulting roles with BMS and others.
AT ESMO 2017
Key clinical point: Nivolumab improved relapse-free survival over ipilimumab in patients with stage III or IV resectable melanoma.
Major finding: The rates of relapse-free survival were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab.
Data source: Randomized clinical trial in 906 patients with completely resectable stage III melanoma.
Disclosures: Checkmate 238 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Weber disclosed honoraria, consulting fees, and travel accommodations/expenses from BMS and other companies. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK.. Dr. Dummer reported advising/consulting roles with BMS and others.