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following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.
The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).
The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.
“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.
“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.
The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.
Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).
It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.
After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.
However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
Major disruptions in the treatment paradigm
The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.
Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?
Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.
Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?
Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
EV-302/KEYNOTE-059 details
Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.
They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.
Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.
Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.
Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.
Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).
The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.
Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.
Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.
The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
CheckMate 901 details
In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.
PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).
Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.
Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).
The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.
EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.
Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.
following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.
The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).
The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.
“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.
“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.
The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.
Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).
It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.
After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.
However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
Major disruptions in the treatment paradigm
The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.
Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?
Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.
Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?
Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
EV-302/KEYNOTE-059 details
Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.
They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.
Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.
Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.
Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.
Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).
The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.
Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.
Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.
The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
CheckMate 901 details
In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.
PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).
Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.
Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).
The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.
EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.
Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.
following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.
The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).
The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.
“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.
“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.
The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.
Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).
It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.
After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.
However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
Major disruptions in the treatment paradigm
The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.
Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?
Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.
Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?
Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
EV-302/KEYNOTE-059 details
Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.
They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.
Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.
Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.
Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.
Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).
The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.
Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.
Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.
The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
CheckMate 901 details
In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.
PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).
Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.
Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).
The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.
EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.
Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.
FROM ESMO 2023