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The antibody-drug conjugate enfortumab vedotin is superior to chemotherapy in patients with previously treated advanced urothelial carcinoma, primary results of the EV-301 trial show.
Findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 393).
“Treatment after platinum-based chemotherapy and immune checkpoint inhibitors is challenging. Overall survival is short, and therapeutic options are also limited,” noted first author Thomas Powles, MD, a professor of genitourinary oncology and director of the Barts Cancer Centre, Queen Mary University of London. “Chemotherapy is being used as the global standard of care, but randomized trials supporting these treatment choices are actually lacking. In this setting, new therapeutic agents supported by randomized trials are needed.”
Patients enrolled in EV-301 (NCT03474107), an international open-label, phase 3 trial, had locally advanced or metastatic urothelial carcinoma, had received platinum-based chemotherapy, and had experienced progression during or after immune checkpoint inhibitor therapy (anti–PD1/PD-L1 therapy).
The trial met its primary endpoint, showing that, relative to chemotherapy, enfortumab vedotin reduced the risk of death by 30%, giving patients nearly 4 additional months of life. The toxicity profile was similar to that seen in earlier trials and was manageable.
“Enfortumab vedotin is the first drug, beyond chemotherapy and immunotherapy, to show a significant survival advantage in previously treated urothelial cancer. This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited,” Dr. Powles maintained.
The drug is also showing promising activity when used in the immunotherapy-treated but cisplatin-ineligible patients in the second cohort of the predecessor EV-201 trial, reported at the symposium as well (Abstract 394), he noted. “I hope that, as we move it earlier, we will show better efficacy.”
The Food and Drug Administration granted enfortumab vedotin accelerated approval as third-line therapy in 2019 on the basis of data from the EV-201 trial’s first cohort. With these new data from both trials, the manufacturers have submitted applications to convert the accelerated approval to regular approval, and to expand the current label to include cisplatin-ineligible patients.
Trial details
In EV-301, a total of 608 patients were randomized evenly to enfortumab vedotin (an antibody-drug conjugate that targets nectin-4, a cell-adhesion molecule highly expressed in urothelial carcinoma) or the physician’s choice among three standard chemotherapy options having similar efficacy (docetaxel, paclitaxel, or vinflunine).
“None of these chemotherapy drugs have spectacular response rates, and the overall survival is best described as modest,” Dr. Powles said.
He reported results of the trial’s planned interim analysis, which became the primary analysis because the primary endpoint was positive. Specifically, median overall survival was 12.9 months with enfortumab vedotin and 9.0 months with chemotherapy (hazard ratio, 0.70; P = .00142). Benefit was similar across most patient subgroups.
The enfortumab vedotin group also had a better median progression-free survival (5.6 vs. 3.7 months; HR, 0.62; P < .00001) and investigator-assessed overall response rate (40.6% vs. 17.9%; P < .001).
The rate of grade 3 or worse treatment-related adverse events was 51% with enfortumab vedotin and 50% with chemotherapy. The former was associated with a higher rate of grade 3 or worse maculopapular rash (7% vs. 0%), whereas the latter was associated with higher rates of grade 3 or worse decreased neutrophil count (13% vs. 6%), decreased white blood cell count (7% vs. 1%), and febrile neutropenia (6% vs. 1%).
Regarding events of special interest, enfortumab vedotin led to more grade 3 or worse skin reactions of any type (15% vs. 1%), peripheral neuropathy (5% vs. 2%), and hyperglycemia (4% vs. 0%). However, the majority of all treatment-related adverse events of special interest were mild to moderate in severity and consistent with those previously reported.
“There is a skill associated with the management of toxicity, and there is going to be a learning curve for people who haven’t used the drug before,” Dr. Powles acknowledged. “But my experience is, it’s a manageable drug, and delays and dose interruptions actually make it a relatively straightforward drug to give in the context of the profile that we’ve seen today.”
Level 1 evidence
“We now know that enfortumab vedotin is here to stay in the armamentarium for the treatment of urothelial cancer, adding its name to the ranks of others which have shown level 1 evidence, proof of a survival benefit in metastatic urothelial carcinoma,” commented invited discussant Arlene O. Siefker-Radtke, MD, a professor in the department of genitourinary medical oncology, University of Texas MD Anderson Cancer Center, Houston.
“I’ve been impressed not only by the activity of enfortumab vedotin in visceral and liver metastases, but also by the impact in patients with bone metastases as this appears very helpful in controlling bone pain in many patients,” she noted.
Preventing and managing toxicity requires appropriate patient selection, careful monitoring, and dose modifications, with knowledge of the agent’s adverse event profile and of factors conferring elevated risk for events, Dr. Siefker-Radtke said.
“The early evidence for enfortumab vedotin in the postimmunotherapy, platinum-ineligible group suggests that this can help treat patients with an unmet need due to their inability to receive platinum-based therapy,” she concluded. “And while it’s currently approved in the third-line setting, we are all eagerly awaiting the outcomes of the frontline studies of enfortumab vedotin combined with pembrolizumab, which showed such a promising objective response rate, as has been presented at earlier meetings.”
The trial was sponsored by Astellas Pharma and Seagen. Dr. Powles disclosed relationships with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, and numerous other pharmaceutical and biotechnology companies. Dr. Siefker-Radtke disclosed relationships with AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, and a variety of other pharmaceutical and biotechnology companies, as well as patents, royalties, and/or other intellectual property pertaining to methods of characterizing and treating molecular subsets of muscle-invasive bladder cancer.
The antibody-drug conjugate enfortumab vedotin is superior to chemotherapy in patients with previously treated advanced urothelial carcinoma, primary results of the EV-301 trial show.
Findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 393).
“Treatment after platinum-based chemotherapy and immune checkpoint inhibitors is challenging. Overall survival is short, and therapeutic options are also limited,” noted first author Thomas Powles, MD, a professor of genitourinary oncology and director of the Barts Cancer Centre, Queen Mary University of London. “Chemotherapy is being used as the global standard of care, but randomized trials supporting these treatment choices are actually lacking. In this setting, new therapeutic agents supported by randomized trials are needed.”
Patients enrolled in EV-301 (NCT03474107), an international open-label, phase 3 trial, had locally advanced or metastatic urothelial carcinoma, had received platinum-based chemotherapy, and had experienced progression during or after immune checkpoint inhibitor therapy (anti–PD1/PD-L1 therapy).
The trial met its primary endpoint, showing that, relative to chemotherapy, enfortumab vedotin reduced the risk of death by 30%, giving patients nearly 4 additional months of life. The toxicity profile was similar to that seen in earlier trials and was manageable.
“Enfortumab vedotin is the first drug, beyond chemotherapy and immunotherapy, to show a significant survival advantage in previously treated urothelial cancer. This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited,” Dr. Powles maintained.
The drug is also showing promising activity when used in the immunotherapy-treated but cisplatin-ineligible patients in the second cohort of the predecessor EV-201 trial, reported at the symposium as well (Abstract 394), he noted. “I hope that, as we move it earlier, we will show better efficacy.”
The Food and Drug Administration granted enfortumab vedotin accelerated approval as third-line therapy in 2019 on the basis of data from the EV-201 trial’s first cohort. With these new data from both trials, the manufacturers have submitted applications to convert the accelerated approval to regular approval, and to expand the current label to include cisplatin-ineligible patients.
Trial details
In EV-301, a total of 608 patients were randomized evenly to enfortumab vedotin (an antibody-drug conjugate that targets nectin-4, a cell-adhesion molecule highly expressed in urothelial carcinoma) or the physician’s choice among three standard chemotherapy options having similar efficacy (docetaxel, paclitaxel, or vinflunine).
“None of these chemotherapy drugs have spectacular response rates, and the overall survival is best described as modest,” Dr. Powles said.
He reported results of the trial’s planned interim analysis, which became the primary analysis because the primary endpoint was positive. Specifically, median overall survival was 12.9 months with enfortumab vedotin and 9.0 months with chemotherapy (hazard ratio, 0.70; P = .00142). Benefit was similar across most patient subgroups.
The enfortumab vedotin group also had a better median progression-free survival (5.6 vs. 3.7 months; HR, 0.62; P < .00001) and investigator-assessed overall response rate (40.6% vs. 17.9%; P < .001).
The rate of grade 3 or worse treatment-related adverse events was 51% with enfortumab vedotin and 50% with chemotherapy. The former was associated with a higher rate of grade 3 or worse maculopapular rash (7% vs. 0%), whereas the latter was associated with higher rates of grade 3 or worse decreased neutrophil count (13% vs. 6%), decreased white blood cell count (7% vs. 1%), and febrile neutropenia (6% vs. 1%).
Regarding events of special interest, enfortumab vedotin led to more grade 3 or worse skin reactions of any type (15% vs. 1%), peripheral neuropathy (5% vs. 2%), and hyperglycemia (4% vs. 0%). However, the majority of all treatment-related adverse events of special interest were mild to moderate in severity and consistent with those previously reported.
“There is a skill associated with the management of toxicity, and there is going to be a learning curve for people who haven’t used the drug before,” Dr. Powles acknowledged. “But my experience is, it’s a manageable drug, and delays and dose interruptions actually make it a relatively straightforward drug to give in the context of the profile that we’ve seen today.”
Level 1 evidence
“We now know that enfortumab vedotin is here to stay in the armamentarium for the treatment of urothelial cancer, adding its name to the ranks of others which have shown level 1 evidence, proof of a survival benefit in metastatic urothelial carcinoma,” commented invited discussant Arlene O. Siefker-Radtke, MD, a professor in the department of genitourinary medical oncology, University of Texas MD Anderson Cancer Center, Houston.
“I’ve been impressed not only by the activity of enfortumab vedotin in visceral and liver metastases, but also by the impact in patients with bone metastases as this appears very helpful in controlling bone pain in many patients,” she noted.
Preventing and managing toxicity requires appropriate patient selection, careful monitoring, and dose modifications, with knowledge of the agent’s adverse event profile and of factors conferring elevated risk for events, Dr. Siefker-Radtke said.
“The early evidence for enfortumab vedotin in the postimmunotherapy, platinum-ineligible group suggests that this can help treat patients with an unmet need due to their inability to receive platinum-based therapy,” she concluded. “And while it’s currently approved in the third-line setting, we are all eagerly awaiting the outcomes of the frontline studies of enfortumab vedotin combined with pembrolizumab, which showed such a promising objective response rate, as has been presented at earlier meetings.”
The trial was sponsored by Astellas Pharma and Seagen. Dr. Powles disclosed relationships with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, and numerous other pharmaceutical and biotechnology companies. Dr. Siefker-Radtke disclosed relationships with AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, and a variety of other pharmaceutical and biotechnology companies, as well as patents, royalties, and/or other intellectual property pertaining to methods of characterizing and treating molecular subsets of muscle-invasive bladder cancer.
The antibody-drug conjugate enfortumab vedotin is superior to chemotherapy in patients with previously treated advanced urothelial carcinoma, primary results of the EV-301 trial show.
Findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 393).
“Treatment after platinum-based chemotherapy and immune checkpoint inhibitors is challenging. Overall survival is short, and therapeutic options are also limited,” noted first author Thomas Powles, MD, a professor of genitourinary oncology and director of the Barts Cancer Centre, Queen Mary University of London. “Chemotherapy is being used as the global standard of care, but randomized trials supporting these treatment choices are actually lacking. In this setting, new therapeutic agents supported by randomized trials are needed.”
Patients enrolled in EV-301 (NCT03474107), an international open-label, phase 3 trial, had locally advanced or metastatic urothelial carcinoma, had received platinum-based chemotherapy, and had experienced progression during or after immune checkpoint inhibitor therapy (anti–PD1/PD-L1 therapy).
The trial met its primary endpoint, showing that, relative to chemotherapy, enfortumab vedotin reduced the risk of death by 30%, giving patients nearly 4 additional months of life. The toxicity profile was similar to that seen in earlier trials and was manageable.
“Enfortumab vedotin is the first drug, beyond chemotherapy and immunotherapy, to show a significant survival advantage in previously treated urothelial cancer. This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited,” Dr. Powles maintained.
The drug is also showing promising activity when used in the immunotherapy-treated but cisplatin-ineligible patients in the second cohort of the predecessor EV-201 trial, reported at the symposium as well (Abstract 394), he noted. “I hope that, as we move it earlier, we will show better efficacy.”
The Food and Drug Administration granted enfortumab vedotin accelerated approval as third-line therapy in 2019 on the basis of data from the EV-201 trial’s first cohort. With these new data from both trials, the manufacturers have submitted applications to convert the accelerated approval to regular approval, and to expand the current label to include cisplatin-ineligible patients.
Trial details
In EV-301, a total of 608 patients were randomized evenly to enfortumab vedotin (an antibody-drug conjugate that targets nectin-4, a cell-adhesion molecule highly expressed in urothelial carcinoma) or the physician’s choice among three standard chemotherapy options having similar efficacy (docetaxel, paclitaxel, or vinflunine).
“None of these chemotherapy drugs have spectacular response rates, and the overall survival is best described as modest,” Dr. Powles said.
He reported results of the trial’s planned interim analysis, which became the primary analysis because the primary endpoint was positive. Specifically, median overall survival was 12.9 months with enfortumab vedotin and 9.0 months with chemotherapy (hazard ratio, 0.70; P = .00142). Benefit was similar across most patient subgroups.
The enfortumab vedotin group also had a better median progression-free survival (5.6 vs. 3.7 months; HR, 0.62; P < .00001) and investigator-assessed overall response rate (40.6% vs. 17.9%; P < .001).
The rate of grade 3 or worse treatment-related adverse events was 51% with enfortumab vedotin and 50% with chemotherapy. The former was associated with a higher rate of grade 3 or worse maculopapular rash (7% vs. 0%), whereas the latter was associated with higher rates of grade 3 or worse decreased neutrophil count (13% vs. 6%), decreased white blood cell count (7% vs. 1%), and febrile neutropenia (6% vs. 1%).
Regarding events of special interest, enfortumab vedotin led to more grade 3 or worse skin reactions of any type (15% vs. 1%), peripheral neuropathy (5% vs. 2%), and hyperglycemia (4% vs. 0%). However, the majority of all treatment-related adverse events of special interest were mild to moderate in severity and consistent with those previously reported.
“There is a skill associated with the management of toxicity, and there is going to be a learning curve for people who haven’t used the drug before,” Dr. Powles acknowledged. “But my experience is, it’s a manageable drug, and delays and dose interruptions actually make it a relatively straightforward drug to give in the context of the profile that we’ve seen today.”
Level 1 evidence
“We now know that enfortumab vedotin is here to stay in the armamentarium for the treatment of urothelial cancer, adding its name to the ranks of others which have shown level 1 evidence, proof of a survival benefit in metastatic urothelial carcinoma,” commented invited discussant Arlene O. Siefker-Radtke, MD, a professor in the department of genitourinary medical oncology, University of Texas MD Anderson Cancer Center, Houston.
“I’ve been impressed not only by the activity of enfortumab vedotin in visceral and liver metastases, but also by the impact in patients with bone metastases as this appears very helpful in controlling bone pain in many patients,” she noted.
Preventing and managing toxicity requires appropriate patient selection, careful monitoring, and dose modifications, with knowledge of the agent’s adverse event profile and of factors conferring elevated risk for events, Dr. Siefker-Radtke said.
“The early evidence for enfortumab vedotin in the postimmunotherapy, platinum-ineligible group suggests that this can help treat patients with an unmet need due to their inability to receive platinum-based therapy,” she concluded. “And while it’s currently approved in the third-line setting, we are all eagerly awaiting the outcomes of the frontline studies of enfortumab vedotin combined with pembrolizumab, which showed such a promising objective response rate, as has been presented at earlier meetings.”
The trial was sponsored by Astellas Pharma and Seagen. Dr. Powles disclosed relationships with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, and numerous other pharmaceutical and biotechnology companies. Dr. Siefker-Radtke disclosed relationships with AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, and a variety of other pharmaceutical and biotechnology companies, as well as patents, royalties, and/or other intellectual property pertaining to methods of characterizing and treating molecular subsets of muscle-invasive bladder cancer.
FROM GUCS 2021