211MO - EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC)

Background

Platinum-based chemo is the standard of care (SOC) for la/mUC. An unmet need remains as long-term outcomes are poor. Here we present EV-302, a global, phase 3, open-label, randomized study evaluating EV+P in patients (pts) with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemo.

Methods

Pts with previously untreated la/mUC (regardless of PD-L1 expression) were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg; IV) on Days 1 and 8 and P (200 mg; IV) on Day 1 or gemcitabine with cisplatin or carboplatin. Dual primary endpoints were PFS per RECIST v1.1 by BICR and OS. Select secondary endpoints included overall response rate (ORR) and safety.

Results

886 pts (EV+P: 442; chemo: 444) were randomized; pt characteristics were balanced between arms. At data cutoff, median follow-up was 17.2 mo. PFS was significantly prolonged with EV+P vs chemo, reducing the risk of progression or death by 55% (median PFS, 12.5 mo vs 6.3 mo, respectively; HR 0.45 [95% CI: 0.38-0.54]; P<0.00001). OS was significantly prolonged with EV+P vs chemo, reducing the risk of death by 53% (median OS, 31.5 mo vs 16.1 mo, respectively; HR 0.47 [95% CI: 0.38-0.58]; P<0.00001). Confirmed ORR was 67.7% and 44.4% in the EV+P and chemo arms, respectively (P<0.00001). Grade ≥3 TRAEs occurred in 55.9% with EV+P and 69.5% with chemo; most common were maculopapular rash (7.7%), hyperglycemia (5.0%), and neutropenia (4.8%) for EV+P and anemia (31.4%), neutropenia (30.0%), and thrombocytopenia (19.4%) for chemo. Most common (≥5% ) grade ≥3 TRAEs of special interest for EV included skin reactions (15.5%), peripheral neuropathy (6.8%), and hyperglycemia (6.1%). Most common (≥5% ) grade ≥3 treatment-emergent AEs of special interest for P included severe skin reactions (11.8%).

Conclusions

EV+P significantly improved outcomes in pts with previously untreated la/mUC, nearly doubling the median PFS and OS vs chemo. The safety profile was generally manageable with no new safety signals. These results support EV+P as a new SOC for 1L la/mUC.

Clinical trial identification

NCT-04223856.

Editorial acknowledgement

Medical writing and editorial support were provided by Philip Ruane of Envision.

Legal entity responsible for the study

Astellas Pharma, Inc. and Seagen Inc.

Funding

Astellas Pharma, Inc. and Seagen Inc.

Disclosure

T.B. Powles: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Merck, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, MSD; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Roche, Pfizer, MSD, AstraZeneca, Ipsen; Financial Interests, Personal, Other, Sponsorship for Uromigos Podcast: Mashup Ltd; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck, MSD, Seattle Genetics, Novartis, Pfizer, Merck Serono, Astellas, Johnson & Johnson, Eisai. B. Perez Valderrama: Financial Interests, Personal, Advisory Board: Pfizer, Astellas Pharma, Bristol Myers Squibb, Ipsen, EUSA Pharma, Merck, MSD, AstraZeneca, AAA; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Roche, Bayer, EUSA Pharma, MSD, Merck, Pfizer, Janssen, Astellas Pharma, AAA. S. Gupta: Financial Interests, Personal, Advisory Board: Seattle Genetics, BMS, Pfizer, Bayer, Merck, Gilead, Loxo Oncology, Guardant, Foundation one; Financial Interests, Personal, Other, Speaker's Bureau: Janssen; Financial Interests, Personal, Other, Consultant: EMD Serono; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Stocks/Shares: BioNTech, Moderna; Financial Interests, Personal, Steering Committee Member: BMS, Merck, Seattle Genetics, Acrivon; Financial Interests, Institutional, Local PI: EMD Serono, Gilead, Roche, QED, Exelixis, Moderna, Pfizer. E. Kikuchi: Financial Interests, Personal, Invited Speaker: MSD, Bristol, Janssen, Astellas, Merck Biopham, Nippon Kayaku, Pfizer; Financial Interests, Personal, Advisory Board: Astellas, MSD, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Takeda, Nippon Kayaku, Kyorin, Taiho, Nippon Shinyaku. J. Hoffman-Censits: Financial Interests, Personal, Other, Consultant: Gilead Sciences, Inc; Financial Interests, Institutional, Research Grant, Providing dug and funding for investigator initiated trial: Genentech; Financial Interests, Institutional, Local PI, Local PI for global Phase III trial: Seagen; Financial Interests, Institutional, Local PI, local PI for national trial: Ikena Oncology; Financial Interests, Institutional, Local PI, Local PI for national trial: Daiichi Sankyo, Inc.; Financial Interests, Institutional, Coordinating PI, Coordinating PI for JAVELIN Medley study: Merck. C. Vulsteke: Financial Interests, Personal, Advisory Board: MSD, Janssen Cilag, GSK, Astellas Pharma, BMS, Leo Pharma, Bayer, AstraZeneca, Pfizer, Merck; Financial Interests, Institutional, Research Grant, Funding for research project on immune related toxicities: MSD. D.E. Castellano Gauna: Financial Interests, Personal, Advisory Board: Pfizer, Roche, BMS, Janssen, Astellas, MSD, Ipsen, AstraZeneca, Novartis, GSK; Financial Interests, Institutional, Local PI: Pfizer, Roche, MSD, BMS, AstraZeneca, Janssen, Astellas, Ipsen, Exelisis, Eisai, Lilly, Bayer, GSK, CLOVIS, QED Therapeutics; Non-Financial Interests, Personal, Other, Executive member: SOGUG (Spanish Oncology Genito-Urinary Group) Foundation. G. Fornarini: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Bristol Myers Squibb, Janssen, Eisai, Ipsen, Pfizer, Bayer; Financial Interests, Personal, Other, ESMO meeting - travel accomodation: Ipsen. J. Li: Financial Interests, Personal, Invited Speaker: Astellas, Janssen Pharma, Bayer Pharmaceuticals, AstraZeneca, Ono Pharmaceutical, Merck, MSD, Roche, Synmosa, Pfizer, COOK. M. Gumus: Financial Interests, Institutional, Invited Speaker: Pfizer, Gen Pharmaceuticals, Novartis, Bayer; Financial Interests, Institutional, Advisory Board: Amgen, Roche, BMS, AstraZeneca; Financial Interests, Institutional, Coordinating PI: Amgen; Financial Interests, Institutional, Local PI: Jounce Therapeutics. N. Mar: Financial Interests, Personal, Invited Speaker: Eisai, Aveo, Tempus, Seattle Genetics; Financial Interests, Personal and Institutional, Funding, Funding for investigator initiated trial: Gilead. S. Narayanan: Financial Interests, Institutional, Full or part-time Employment: Seagen Inc; Financial Interests, Institutional, Stocks/Shares: Seagen Inc. S. Gorla: Financial Interests, Personal, Other, I have been a full time employee of Astellas since 2012 and part of my role involves review of publications and other documents regarding the clinical trials we have conducted involving our products.: Astellas; Financial Interests, Personal, Full or part-time Employment, I have been a full time employee of Astellas since 2012: Astellas; Non-Financial Interests, Personal, Project Lead, I have been a full time employee of Astellas since 2012 and have a leadership role in the projects that I lead.: Astellas; Non-Financial Interests, Personal, Proprietary Information, I have been a full time employee of Astellas since 2012 and therefore have access to company confidential information about our products.: Astellas. M.S. van der Heijden: Financial Interests, Institutional, Advisory Board: AstraZeneca, BMS, Janssen, MSD, Seagen, Pfizer; Financial Interests, Institutional, Funding, Investigator-initiated trial: BMS, Roche, AstraZeneca, 4SC; Financial Interests, Institutional, Steering Committee Member, Local PI + SSC member: BMS, AstraZeneca, MSD, Seagen; Financial Interests, Institutional, Steering Committee Member, Local PI + study co-PI: Janssen; Financial Interests, Institutional, Local PI: GSK. All other authors have declared no conflicts of interest.