Enfortumab Vedotin After Checkpoint Inhibition in Metastatic Urothelial Cancer
A phase II study found that treatment with the antibody-drug conjugate enfortumab vedotin achieved responses in 44% of patients with locally advanced or metastatic urothelial cancer previously treated with platinum chemotherapy and a checkpoint inhibitor. This is a noteworthy study because it addresses the new question of what to do after patients with metastatic urothelial cancer experience disease progression on second-line treatment with a checkpoint inhibitor.
Enfortumab vedotin is the first novel therapy to demonstrate substantial clinical activity in patients whose disease progressed after platinum chemotherapy and a PD-1 or PD-L1 inhibitor.— Daniel P. Petrylak, MD
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“The fact that we have a therapy to help people who don’t benefit from a checkpoint inhibitor is gratifying,” said lead author Daniel P. Petrylak, MD, Professor of Medicine and Urology at Yale Cancer Center, New Haven, Connecticut, who presented these findings at the 2019 ASCO Annual Meeting.1 “This study addresses an unmet need. Enfortumab vedotin is the first novel therapy to demonstrate substantial clinical activity in patients whose disease progressed after platinum chemotherapy and a programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitor. The response rate was 44%, the complete response rate was 12%, and the median duration of response was 7.6 months. Enfortumab vedotin may have the potential to become a new standard of care for patients who experience disease progression on platinum and a checkpoint inhibitor.”
Ongoing phase III trials are comparing enfortumab vedotin with “dealer’s choice” of chemotherapy, and phase I trials are beginning to explore this agent in combination with others. The results of the phase III trials are expected to support phase II findings.
After a diagnosis of locally advanced or metastatic urothelial cancer, patients usually receive first-line platinum-based chemotherapy; at disease progression, they often receive second-line checkpoint inhibitor therapy. Five different checkpoint inhibitors are currently approved for the treatment of urothelial cancer, but response rates are low, and about 75% to 80% of patients will experience disease progression on these agents. There is no approved standard of care for patients whose disease progresses on checkpoint inhibitor therapy.
Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, a cellular adhesion molecule with low expression in normal cells but upregulation in urothelial cancer cells and other types of solid tumors. Enfortumab vedotin binds to Nectin-4 and delivers chemotherapy to microtubules, leading to apoptosis of cancer cells. Based on phase I data, enfortumab vedotin was granted Breakthrough Therapy designation by the U.S. Food and Drug Administration. The antibody-drug conjugate is being investigated in the treatment of other cancers that express Nectin-4, including lung and breast.
EV-201 is a global trial conducted at 51 sites. Dr. Petrylak presented the results of cohort 1—128 platinum-eligible patients with locally advanced or metastatic urothelial cancer previously treated with platinum-based therapy and a checkpoint inhibitor. Cohort 2 comprises platinum-naive, cisplatin-ineligible patients, and accrual is ongoing and results are not available at this time. Patients in cohort 1 had metastatic or unresectable urothelial cancer. Exclusion criteria were sensory neuropathy, active central nervous system metastases, and uncontrolled diabetes.
- In the EV-201 trial, the antibody-drug conjugate enfortumab vedotin achieved a 44% response rate and a 12% complete response rate in patients with metastatic urothelial cancer whose disease progressed on platinum-based chemotherapy and immune checkpoint inhibition.
- Treatment of this patient population is considered an unmet need, and enfortumab vedotin holds promise as third-line therapy if phase III studies replicate these results.
Patients received enfortumab vedotin at 1.25 mg/kg on days 1, 8, and 15 of each 28-day cycle. Seventy percent were male; the median patient age was 69 years (27% were older than age 75); 34% had upper urinary tract cancers; 42% had two or more poor prognostic factors; and patients had a median of two previous systemic therapies. A total of 90% had visceral disease; 40% had liver metastases; 35% had PD-L1–positive disease; and all patients had Nectin-4–positive disease.
Of the 128 patients enrolled in the trial, 125 were treated and comprised the intent-to-treat analysis. The maximum time on treatment was 15.6 months. A total of 16% of patients were continuing on treatment at the time of the presentation.
The objective response rate was 44%, the complete response rate was 12%, and the partial response rate was 32%. A waterfall plot showed that 84% of patients had some tumor shrinkage as measured by computed tomography scans. All of the prespecified subgroups demonstrated responses, including 38% with liver metastases.
“Prior treatment with PD-L1 or PD-L1 staining was not correlated with response,” Dr. Petrylak noted.
The median time to response was 1.8 months, and most responses were observed at the first assessment. The median duration of response was 7.6 months. Most responders are still being followed, he said. Median progression-free survival was 5.8 months, and median overall survival was 11.7 months.
Treatment with enfortumab vedotin was generally well tolerated. Most adverse events were grades 1 and 2. The most common adverse events were fatigue, alopecia, decreased appetite, dysgeusia, and peripheral sensory neuropathy. A total of 12% of patients discontinued treatment due to treatment-related adverse events (5% due to neuropathy).
A total of 50% of patients had neuropathy of any grade; 3% had grade 3 or higher peripheral neuropathy. Peripheral neuropathy present at baseline worsened in 52% of patients. However, 76% had resolution of events ongoing at grade 1 at last follow-up. Rash of any grade was reported in 48%; 12% had grade 3 or higher rash; there was no case of grade 4 rash. One patient had grade 3 Stevens-Johnson syndrome.
“Metastatic urothelial cancer is common, yet we have limited therapeutic options,” said ASCO expert Robert Dreicer, MD, of the University of Virginia Cancer Center, Charlottesville, speaking at a press conference where these data were discussed. “For
Robert Dreicer, MD
decades, all we had was chemotherapy. Now, we have second-line checkpoint inhibitor therapy, but basically one in four patients responds. New therapies are badly needed, and I find these data on enfortumab vedotin compelling. The drug has activity in patients treated with prior chemotherapy and immunotherapy, as well as activity in disease sites considered difficult to treat such as the liver. Survival approaches 1 year.”
Dr. Dreicer continued: “We are seeing durable responses in heavily treated patients. The response rate in patients with liver metastases is compelling, as this is a resistant disease site. These patients today have limited therapeutic options, and there is no question that this drug will benefit some of these patients. I am hopeful the phase III studies will confirm these results.” ■
DISCLOSURE: The study was funded by Seattle Genetics and Astellas. Dr. Petrylak has stock and other ownership interests in Bellicum Pharmaceuticals and Tyme Technologies; has served as a consultant/advisor for Bayer, Exelixis, Pfizer, Roche, Astellas Pharma, AstraZeneca, Lilly, Ada Cap, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Incyte, Janssen, Pharmacyclics, Seattle Genetics, and UroGen Pharma; has received institutional research funding from Progenics, Sanofi, Endocyte, Genentech, Merck, Astellas Medivation, Novartis, AstraZeneca, Bayer, Lilly, Innocrin Pharmaceuticals, MedImmune, Pfizer, Roche, Seattle Genetics, Clovis Oncology, Ada Cap, Bristol-Myers Squibb; has given expert testimony for Celgene and Sanofi. Dr. Dreicer has served as a consultant/advisor for Astellas Pharma, AstraZeneca, Genentech/Roche, EMD Serono, Incyte, Pfizer, Eisai, Janssen Oncology, Seattle Genetics, and Modra Pharmaceuticals; and has received institutional research funding from Genentech, Seattle Genetics, BioClin Therapeutics, Janssen Oncology, and Merck.
1. Petrylak DP, Balar AV, O’Donnell PH, et al: EV-201: Results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. 2019 ASCO Annual Meeting. Abstract LBA4505. Presented, June 3, 2019.
Andrea Necchi, MD
Formal discussant of the EV-201 trial, Andrea Necchi, MD, of the Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy, found the data pending phase III studies promising: “This study explored enfortumab vedotin in a newly defined population who failed to respond to...