1966MO - EV-302: Exploratory analysis of nectin-4 expression and response to 1L enfortumab vedotin (EV) + pembrolizumab (P) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC)

Background

In the phase 3 EV-302 study (NCT04223856), the Nectin-4-directed antibody (Ab)–drug conjugate EV + the PD-1 inhibitor P significantly improved progression-free survival (PFS) and overall survival (OS) vs platinum-based chemotherapy (chemo) in patients (pts) with la/mUC, regardless of PD-L1 expression. We report the impact of Nectin-4 expression on outcomes with 1L EV+P and chemo.

Methods

Pts with previously untreated la/mUC were randomized 1:1 to EV (1.25 mg/kg IV; days 1 and 8 Q3W) and P (200 mg IV; day 1 Q3W) or chemo (gemcitabine + cisplatin/carboplatin). Baseline Nectin-4 expression was retrospectively assessed by immunohistochemistry in tumor tissue. H-scores of 150 and 225 represent 50% and 75% of the H-score range (0-300) and were used for subgroup analyses (<150, ≥150–<225 and ≥225). PFS and OS were assessed in Nectin-4 expression subgroups. Nectin-4 expression was assessed in responders and non-responders.

Results

Nectin-4 expression was evaluable in 800 of 886 randomized pts (EV+P: n=394; chemo: n=406); Nectin-4 H-scores skewed towards high expression, consistent with previous reports in the la/mUC population. Median H-score was 280 and 270 in the EV+P and chemo arms, respectively; 38 and 50 pts, respectively, had H-score

Conclusions

EV+P showed consistent PFS and OS benefit across subgroups regardless of Nectin-4 expression. Furthermore, Nectin-4 does not predict for benefit from EV+P.

Clinical trial identification

NCT04223856.

Editorial acknowledgement

The authors would like to thank Keith Earley of Pfizer for his contribution to data analysis strategy and interpretation. Medical writing support was provided by Ed Carter, MSc, of Nucleus Global, an Inizio Company, and was funded by Pfizer and Astellas Pharma Inc.

Legal entity responsible for the study

The EV-302 study was funded by Astellas Pharma Inc., Northbrook, IL, USA; Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; and Seagen Inc., Bothell, WA, USA, which was acquired by Pfizer in December 2023.

Funding

The EV-302 study was funded by Astellas Pharma Inc., Northbrook, IL, USA; Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; and Seagen Inc., Bothell, WA, USA, which was acquired by Pfizer in December 2023.

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, Other, honoraria: Gilead; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck, MSD, Seattle Genetics, Novartis, Pfizer, Merck Serono, Astellas, Johnson & Johnson, Eisai; Financial Interests, Institutional, Other, Honoraria: Gilead. M.S. van der Heijden: Financial Interests, Institutional, Advisory Board: AstraZeneca, BMS, Janssen, MSD, Seagen, Pfizer, Astellas; Financial Interests, Institutional, Funding, Investigator-initiated trial: BMS, Roche, AstraZeneca, 4SC, MSD; 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. 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 Sorono; 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 Sorono, Gilead, Roche, QED, Exelixis, Moderna, Pfizer. B. Perez Valderrama: Financial Interests, Personal, Advisory Board: Pfizer, Astellas Pharma, Bristol Myers Squibb, Ipsen, Eusa Pharma, Merck, MSD, AstraZeneca, AAA, Recordati; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Bayer, MSD, Merck, Pfizer, Astellas Pharma, AAA, Almirall pharma; Other, Travel/accommodations: Bristol Myers Squibb, Pfizer. M.D. Galsky: Financial Interests, Personal, Advisory Board: Janssen, Merck, GSK, Eli Lilly, Astellas, Genentech, Bristol Myers Squibb, Pfizer, EMD Serono, AstraZeneca, Seagen, Incyte, Alligator, AbbVie, Asieris, Bicycle, Gilead, Curis, Fujifilm; Financial Interests, Personal, Other, Consultant: Rappta Therapeutics; Financial Interests, Personal, Invited Speaker: Veracyte; Financial Interests, Institutional, Steering Committee Member: Merck, Genentech, Bristol Myers Squibb; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Jazz; Financial Interests, Institutional, Local PI: Seagen. J. Bedke: Financial Interests, Personal, Speaker, Consultant, Advisor: Apogepha, Astellas Pharma, Bristol Myers Squibb, Eisai, F. Hoffmann LaRoche, Ipsen Innovation, Janssen Pharmaceuticals, Merck KGaA, Merck, Sharp and Dohme, Pfizer Pharma GMBH, Seagen; Financial Interests, Personal, Advisory Board: Astellas Pharma, Bristol Myers Squibb, Eisai, F. Hoffmann LaRoche, Gilead Sciences Inc, Ipsen Innovation, Janssen Pharmaceuticals, Merck KGaA, Merck, Sharp and Dohme, Pfizer. E. Kikuchi: Financial Interests, Personal, Speaker, Consultant, Advisor: Astellas Pharma, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Janssen Biotech, Inc., Kissei, Merck, MSD, Pfizer; Financial Interests, Personal, Speaker’s Bureau: Astellas Pharma, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Janssen Biotech, Inc., Kissei, Merck, MSD, Nippon Kayaku, Pfizer, Taiho Pharmaceutical. 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. J.P. Maroto Rey: Financial Interests, Personal, Advisory Board, Participation in Ad boards: Bayer; Financial Interests, Personal, Advisory Board, Participation in ad boards: Astellas, Merck, Pfizer, MSD; Financial Interests, Personal, Invited Speaker: Janssen; Non-Financial Interests, Principal Investigator, Collaboration as PI in trials: AstraZeneca. C. Vulsteke: Financial Interests, Personal, Advisory Board: MSD, Janssens-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. G. Iyer: Financial Interests, Personal, Advisory Board: Flare Therapeutics, EMD Serono, Loxo @ Lilly, Aadi Biosciences, AstraZeneca; Financial Interests, Personal, Invited Speaker: Pfizer, Curio Science, Janssen; Financial Interests, Institutional, Local PI: Aadi Biosciences, AstraZeneca, Flare Therapeutics, Pfizer, Loxo @ Lilly, Tyra. U. Swami: Financial Interests, Personal, Writing Engagement: Astellas; Financial Interests, Personal, Advisory Board: Seagen, Exelixis, AstraZeneca, Adaptimmune, Gilead, Imvax, Pfizer, Sanofi; Financial Interests, Institutional, Research Grant: Janssen, Exelixis; Financial Interests, Institutional, Local PI: Astellas/Seattle Genetics. A. Rodriguez-Vida: Financial Interests, Personal, Invited Speaker: roche, BMS, Janssen, AstraZeneca, Ipsen; Financial Interests, Personal, Advisory Board: MSD, Pfizer, Astellas, Bayer, Merck. M. Wozniak: Financial Interests, Personal, Full or part-time Employment, Employee: Astellas. B. Homet Moreno: Financial Interests, Personal, Full or part-time Employment: Merck Sharp and Dohme. J. Lu: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. C. Yu: Financial Interests, Personal, Full or part-time Employment: Seagen (Pfizer). L. Hogdal: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. Y. Loriot: Financial Interests, Personal, Advisory Board: Merck Kga, Pfizer, Gilead, Seattle Genetics, Tahio; Financial Interests, Personal, Other, lectures, advisory boards: MSD, AstraZeneca, Astellas, Janssen; Financial Interests, Personal, Other, lectures, advisory boards: Roche, BMS; Financial Interests, Institutional, Research Grant: Janssen, Sanofi, MSD, Roche, Celsius; Financial Interests, Institutional, Steering Committee Member: Janssen; Financial Interests, Steering Committee Member: MSD, Astellas, Gilead/Immunomedics, Tahio; Financial Interests, Personal, Steering Committee Member: Basilea; Financial Interests, Institutional, Local PI: Pfizer, MSD, Janssen, Exelixis, AstraZeneca, Pfizer, Merck Kga, BMS, Astellas, Gilead, Incyte; Financial Interests, Institutional, Coordinating PI: Janssen; Non-Financial Interests, Member: ESMO, ASCO, AACR; Non-Financial Interests, scientific committee: ARC. All other authors have declared no conflicts of interest.