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.
Authors: Gupta Shilpa , Rosenberg Jonathan E. , McKay Rana R. , Flaig Thomas W. , Petrylak Daniel P. , Hoimes Christopher J. , Friedlander Terence W. , Bilen Mehmet Asim , Srinivas Sandy , Burgess Earle F , Merchan Jaime R. , Tagawa Scott T. , Brown Jason R , Yu Yao , Carret Anne-Sophie , Wirtz Heidi , Guseva Maria , Homet Moreno Blanca , Milowsky Matthew I. 
Published: June 2023

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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 .