Study EV-103 dose escalation/cohort A: Long-term outcome of enfortumab vedotin + pembrolizumab in first-line (1L) cisplatin-ineligible locally advanced or metastatic urothelial carcinoma (la/mUC) with nearly 4 years of follow-up.

Shilpa Gupta Cleveland Clinic, Cleveland, OH info_outline Shilpa Gupta, Jonathan E. Rosenberg, Rana R. McKay, Thomas W. Flaig, Daniel P. Petrylak, Christopher J. Hoimes, Terence W. Friedlander, Mehmet Asim Bilen, Sandy Srinivas, Earle F Burgess, Jaime R. Merchan, Scott T. Tagawa, Jason R Brown, Yao Yu, Anne-Sophie Carret, Heidi Wirtz, Maria Guseva, Blanca Homet Moreno, Matthew I. Milowsky

Authors Shilpa Gupta Cleveland Clinic, Cleveland, OH info_outline Shilpa Gupta, Jonathan E. Rosenberg, Rana R. McKay, Thomas W. Flaig, Daniel P. Petrylak, Christopher J. Hoimes, Terence W. Friedlander, Mehmet Asim Bilen, Sandy Srinivas, Earle F Burgess, Jaime R. Merchan, Scott T. Tagawa, Jason R Brown, Yao Yu, Anne-Sophie Carret, Heidi Wirtz, Maria Guseva, Blanca Homet Moreno, Matthew I. Milowsky Organizations Cleveland Clinic, Cleveland, OH, Memorial Sloan Kettering Cancer Center, New York, NY, University of California San Diego, La Jolla, CA, University of Colorado Cancer Center Anschutz Medical Campus, Aurora, CO, Yale Cancer Center, New Haven, CT, Duke Cancer Institute, Duke University, Durham, NC, University of California, San Francisco Medical Center, San Francisco, CA, Winship Cancer Institute of Emory University, Atlanta, GA, Stanford University School of Medicine, Division of Oncology, Stanford, CA, Atrium Health Levine Cancer Institute, Charlotte, NC, University of Miami Health System, Miami, FL, Weill Cornell Medical College of Cornell University, New York, NY, University Hospitals Seidman Cancer Center, Cleveland, OH, Seagen, Inc., Bothell, WA, Astellas Pharma, Northbrook, IL, Merck & Co., Inc., Rahway, NJ, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Supported by Astellas Pharma US; Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ; and Seagen Inc., U.S. National Institutes of Health Background: Despite available therapeutic options, which include carboplatin-based chemotherapy, PD-1/PD-L1 inhibitor monotherapies, and avelumab maintenance, there is an urgent unmet need for effective and durable 1L therapies for cisplatin-ineligible patients (pts) with la/mUC. Both enfortumab vedotin (EV) and pembrolizumab (P) show survival benefits as monotherapies for pts with previously treated la/mUC. The combination of EV+P previously showed a manageable safety profile and promising antitumor activity in Study EV-103 Dose Escalation/Cohort A (DE/A) and Cohort K. Here, we report updated safety, efficacy per RECIST v1.1 by BICR, survival data, and subsequent therapies for DE/A after nearly 4 years of follow-up. Methods: In DE/A of this ongoing phase 1b/2 study, 1L cisplatin-ineligible pts with la/mUC received 3-week cycles of EV 1.25 mg/kg (Days 1, 8) in combination with P (Day 1). The primary endpoint was safety/tolerability. Key secondary endpoints included confirmed ORR (cORR), DOR, PFS (all per RECIST v1.1 by BICR and investigator), and OS. Safety and subsequent therapy results are also presented. Results: As of 16 Sep 2022, 45 pts with 1L la/mUC (median age 69 yrs [51-90]) received treatment. All pts discontinued treatment and 18 pts remain on study (median follow-up of 47 months). The cORR by BICR after a median of 9 cycles was 73.3% (95% CI: 58.1, 85.4), with a DCR of 84.4% (95% CI: 70.5, 93.5) and CR rate of 15.6%. The median DOR was 22.1 months (95% CI: 8.38, -), with a 12-month DOR of 63.9% (95% CI: 44.19, 78.17). The median PFS was 12.7 months (95% CI: 6.11, -), with a 12-month PFS of 55.0% (95% CI: 38.84, 68.58). The median OS was 26.1 months (95% CI: 15.51, -), with a 12-month OS rate of 83.4% (95% CI: 68.25, 91.72). The most common treatment-related adverse events of special interest for EV were skin reactions (66.7%), peripheral neuropathy (62.2%), and ocular disorders (40.0%). The most common treatment-emergent adverse events of special interest for P were severe skin reactions (24.4%), pneumonitis (8.9%), colitis (6.7%), and hypothyroidism (6.7%). Sixty percent of pts received subsequent cancer-related therapies, including systemic therapy (48.9%), surgery (8.9%), and palliative radiotherapy (8.9%). The most common 2L systemic anti-cancer therapies were P (17.8%), carboplatin-based therapy (11.1%), and EV (6.7%). Conclusions: EV+P, continues to demonstrate promising survival trends with rapid and durable responses in 1L cisplatin-ineligible pts with la/mUC. The safety profile of the combination is manageable and stable with a longer follow-up, and no new safety concerns have emerged. These results are concordant with previously reported DE/A data by investigator assessment and support the evaluation of EV+P in ongoing phase 3 studies in UC. Clinical trial information: NCT03288545.