Study EV-103 dose escalation/cohort A (DE/A): 5y follow-up of first-line (1L) enfortumab vedotin (EV) + pembrolizumab (P) in cisplatin (CIS)-ineligible locally advanced or metastatic urothelial carcinoma (la/mUC)

BackgroundThe combination of EV+P is FDA-approved for treatment (tx) of la/mUC. EV+P showed a manageable safety profile and encouraging antitumor activity in cis-ineligible pts with previously untreated la/mUC in Study EV-103 DE/A, results which were confirmed by EV-302, with OS benefit regardless of cis-eligibility. We report updated safety and efficacy for DE/A of this ongoing phase 1/2b study after ∼5 y of follow-up.MethodsCis-ineligible pts with previously untreated la/mUC received EV 1.25 mg/kg (days 1, 8) in combination with P (day 1), Q3W. The primary endpoint was safety/tolerability. Key secondary endpoints included confirmed ORR (cORR), DCR, DOR, PFS (all per RECIST 1.1 by BICR), and OS.Results45 pts (median age 69 y [51-90]) received tx. As of Nov 20, 2023, all pts had discontinued tx and 15 (33%) remained on study. Median (m) follow-up was 62.1 mo (95% CI, 59.37-63.05). Pts received a median of 9 cycles of EV+P, 8 of EV and 8 of P. The cORR by BICR was 73.3% (95% CI, 58.1-85.4; CR 15.6%), and DCR was 84.4% (95% CI, 70.5-93.5). mDOR was 22.1 mo (95% CI, 8.38-NR), mPFS was 12.7 mo (95% CI, 6.11-NR), and mOS was 26.1 mo (95% CI, 15.5-NR). Landmark DOR, PFS, and OS rates through 60 mo are shown in the Table. Notably, 47% of pts who responded to tx maintained a response at 2-5y. PFS rate remained at 38.2% at 3-5y and 41.5% of pts were alive at 5y. No new safety concerns were seen. Table: 1968P Durable response rate, PFS, and OS rates in EV-103 DE/A % (95% CI) 12 mo 24 mo 36 mo 48 mo 60 mo Durable response rate (n=33)* 63.9 (44.19-78.17) 47.0 (27.57-64.31) 47.0 (27.57-64.31) 47.0 (27.57-64.31) 47.0 (27.57-64.31) PFS rate (N=45) 55.0 (38.84-68.58) 41.1 (25.69-55.88) 38.2 (23.10-53.08) 38.2 (23.10-53.08) 38.2 (23.10-53.08) OS rate (N=45) 83.4 (68.25-91.72) 56.4 (40.03-69.91) 49.1 (33.16-63.15) 44.1 (28.76-58.48) 41.5 (26.45-55.99) DE/A, Dose Escalation/Cohort A; mo, months; OS, overall survival; PFS, progression-free survival.∗ Number of pts that responded to tx. ConclusionsIn EV-103, pts treated with 1L EV+P continued to show durable responses and meaningful survival after 5y follow-up, with a generally manageable and stable safety profile. An unprecedented 41.5% of pts treated are alive at 5y, which dramatically exceeds historical data (EORTC 30986). These results further support tx with EV+P as 1L SoC in la/mUC.Clinical trial identificationNCT03288545.Editorial acknowledgementThe authors would like to thank Changting Meng and Linda Akanbi for their contributions to this publication. Medical writing support was provided by Kiran Verma, of Nucleus Global, an Inizio Company, and was funded by Pfizer and Astellas Pharma Inc.Legal entity responsible for the studyAstellas 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.FundingAstellas 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.DisclosureJ.E. Rosenberg: Financial Interests, Personal, Advisory Board: Aadi Biosciences, Alligator Biosciences, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, EMD-Serono, Genentech, Gilead, IMVax, Janssen, Lilly Oncology, Merck, Mirati, NCCN, Pfizer, Tyra Biosciences, Aktis, Samsung Bioepis, Century Therapeutics, Bayer, Kalivir; Financial Interests, Personal, Invited Speaker, Medical Education: Clinical Care Options, Peer Direct; Financial Interests, Personal, Invited Speaker, Medical education: MJH Associates, Physicians Education Resource, Research to Practice; Financial Interests, Personal, Invited Speaker: Pfizer, Medscape, Mashup Media; Financial Interests, Personal, Advisory Board, + travel funding to attend meeting: Seagen; Financial Interests, Personal, Royalties: Wolters Kluyer/Uptodate; Financial Interests, Institutional, Coordinating PI, Coordinating PI of rogaratinib/atezolizumab trial; consultant: Bayer; Financial Interests, Personal and Institutional, Steering Committee Member, EV-201, EV- 103; consultant, trial open at my institution: Seagen; Financial Interests, Personal and Institutional, Steering Committee Member, EV-301, consultant, trial open at my institution: Astellas; Financial Interests, Personal and Institutional, Coordinating PI, Consultant, PI of trial: AstraZeneca; Financial Interests, Institutional, Coordinating PI, PI of IMVIGOR210 (still open at my institution): Genentech; Financial Interests, Institutional, Coordinating PI, PI of trial, consultant to company: Loxo Oncology; Non-Financial Interests, Leadership Role, Genitourinary Committee Chair: Alliance for Clinical Trials in Oncology. D.P. Petrylak: Financial Interests, Personal, Other, Consultant Fees: Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Exelixis, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Ipsen, Janssen, Merck & Company Inc, Mirati, Monopteros, Pfizer, Pharmacyclics, Regeneron, Roche, Sanofi Aventis Pharmaceuticals, Seattle Genetics, Urogen; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Other, honorarium: Bioexcel; Financial Interests, Institutional, Local PI: Ada Cap (Advanced Accelerator Applications), Agensys Inc, Arvinas, Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Daiichi Sankyo Company Limited, Eisai, Eli Lilly, Endocyte, Ferring, Genentech, Gilead Sciences, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics, Replimune, Roche, Sanofi Aventis, Seattle Genetics; Non-Financial Interests, Leadership Role, Vice Chair: SWOG. T. Flaig: Financial Interests, Personal, Other, Consulting and advisory: Seattle Genetics,; Financial Interests, Personal, Stocks/Shares, A am founder and stockholder in this academic start up company. We are submitting SBIR/STTR grants for a patent on work done in our lab. There are no commercial products or current clinical trials - early stage: Aurora Oncology; Financial Interests, Personal, Other, We have a patent with the University of Colorado (from our lab) which has been licensed to Aurora Oncology (I am a cofounder of this faculty start up): Aurora Oncology; Financial Interests, Institutional, Local PI: Agensys, Astellas, astrazeneca/Medimmune, Bristol Myers Squibb, Janssen Oncology, La Roche - Posay, Lilly, Merck, Myovant Sciences, Pfizer, Roche - Genentech, Sanofi, Seagen; Financial Interests, Institutional, Other, I am working with Criterium to develop new clinical trial concepts for multi-center studies: Criterium; Non-Financial Interests, Personal, Member of Board of Directors: CPC - Clinical Research and Community Health; Financial Interests, Personal, Member of Board of Directors: Joint Venture between University of Colorado and UCHealth. C.J. Hoimes: Financial Interests, Personal, Advisory Board: Astellas, BMS, Foundation Medicine, Merck &Co, Seagen, Tempus, Adaptimmune; Financial Interests, Personal, Invited Speaker: BMS, Eisai; Financial Interests, Institutional, Advisory Board: Dynavax; Financial Interests, Institutional, Local PI: AbbVie, Alkermes, Astellas, BMS, Bayer, Bellicum, BioNTech, Dynavax, Genentech, Janssen, Mirati, NeoImmune Tech, Pfizer, Promontory, Tyra, Xencor, CRISPR; Financial Interests, Personal and Institutional, Steering Committee Member: Merck & Co, Seagen. 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. P.H. O'Donnell: Financial Interests, Institutional, Research Funding: Boehringer Ingelheim, Merck, Genentech/Roche, AstraZeneca/MedImmune, Acerta Pharma, Janssen, Seagen, Bristol Myers Squibb, Astellas Pharma; Financial Interests, Personal, Expert Testimony: Hart Wagner LLP, O’Brien and Ryan LLP; Financial Interests, Personal, Research Funding, Travel, Accommodations, Expenses: Curio Science, Astellas Pharma, Seagen; Financial Interests, Personal, Other: Janssen, NIH, Nektar, Dragonfly Therapeutics, G1 Therapeutics; Financial Interests, Personal, Financially compensated role, Honoraria: Adept Field Solutions, Advarra, Merck, Astellas, AbbVie, Pfizer, Custom Learning Designs, Axiom Healthcare Strategies, EMD Serono, IntrinsiQ, ISMIE, NAMCP, Seagen, Curio Science, FirstWord, MedLearning Group, Research to Practice, Great Debates and Updates, MJH Life Sciences, Peerview, Vaniam Group, Institute for Enquiring Minds, Pharmavision UK, Prime Education LLC, Amerisource Bergen, Health Advances, Parexel Intl Corp, Vida Ventures LLC. N. Mar: Financial Interests, Personal, Invited Speaker: Eisai, Merck; Financial Interests, Personal and Institutional, Funding, Funding for investigator initiated trial: Gilead. T. Friedlander: Financial Interests, Personal, Advisory Board, Advisory Board Participant: Seagen; Financial Interests, Personal, Invited Speaker, Invited speaker to discuss landscape of bladder cancer with MSLs and other team members: Pfizer; Financial Interests, Personal, Invited Speaker, Discussion of landscape in bladder cancer: AbbVie; Financial Interests, Personal, Advisory Board: BMS, EMD Serono, Aktis Oncology, AbbVie, Merck, Bicycle Therapeutics, Astellas; Financial Interests, Institutional, Local PI, EV 103 Clinical Trial: Seagen; Financial Interests, Institutional, Local PI, Local PI for Morpheus Bladder study: Roche Genentech. S.T. Tagawa: Financial Interests, Personal, Advisory Board: Convergent Therapeutics, AIkido Pharma; Financial Interests, Personal, Other, Consultant: EMD Serono, Telix Pharma, Blue Earth Diagnostics, POINT Biopharma, Myovant, Bayer, 4D Pharma, Gilead, Pfizer, Janssen, Astellas, AbbVie, Novartis, Seagen, Clarity, Merck, Myovant, EMD Serono; Financial Interests, Personal, Stocks/Shares: AIkido Pharma; Financial Interests, Personal, Other, Patent co-inventor: Gilead; Financial Interests, Institutional, Local PI: Medivation, Astellas, Janssen, Amgen, BMS, AstraZeneca, Bayer, Merck, Clovis, Seagen; Financial Interests, Institutional, Steering Committee Member: Gilead, Novartis, POINT Biopharma, Clarity, Ambrx, Promontory. M.A. Bilen: Financial Interests, Personal, Advisory Board: Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Nektar, EMD Serono, Seagen, Sanofi; Financial Interests, Institutional, Local PI: Merck, Xencor, Bayer, Bristol Myers Squibb, Genentech/Roche, Seagen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, Pfizer. J.R. Brown: Financial Interests, Personal, Invited Speaker, Speaker's Bureau for Avelumab: EMD Serono; Financial Interests, Personal, Invited Speaker, Speaker for MSL Training: AstraZeneca; Financial Interests, Institutional, Local PI: Jounce Pharmaceuticals, Seattle Genetics, Novita, Bicycle Therapeutics, roche. R.R. McKay: Financial Interests, Personal, Advisory Board: Aveo, AstraZeneca, Bayer, Calithera, Dendreon, Exelixis, JNJ, Merck, Pfizer, Sanofi, Tempus, BMS, Lilly, Sanofi, Seagen, Telix, Sorrento Therapeutics, Eisai, Blue Earth Diagnostics; Financial Interests, Personal, Other, Molecular tumor board: Caris; Financial Interests, Personal, Other, Consultant: Dendreon, Myovant; Financial Interests, Personal, Invited Speaker: Exelixis, Merck, Novartis, Pfizer; Financial Interests, Steering Committee Member: Aveo, Merck, Eli Lilly; Financial Interests, Local PI: JNJ, Seagen, Calibr, Poseida, Oncternal, Scholar Rock, Merck, Xencor, Genentech, Eli Lilly, BMS; Financial Interests, Trial Chair: Bayer, AstraZeneca; Financial Interests, Institutional, Local PI: Exelixis. J.R. Merchan: Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Institutional, Research Funding: Corvus Pharmaceuticals, Genentech/Roche, Tizona Therapeutics, Inc, Tocagen, Vyriad, Sillajen, Replimune, Peloton Therapeutics, Eisai, Seagen Inc/Astellas, Merck, Rubius Therapeutics, BioNTech, Trishula Therapeutic, Exelixis. S. Srinivas: Financial Interests, Personal, Advisory Board: Janssen, Novartis; Financial Interests, Local PI: Seagen; Financial Interests, Institutional, Local PI: Novartis, REGN, Merck. A. Shetty: Financial Interests, Institutional, Full or part-time Employment: Astellas. B. Homet Moreno: Financial Interests, Personal, Full or part-time Employment: Merck Sharp and Dohme; Financial Interests, Personal, Stocks/Shares: Merck Sharp and Dohme. G. Davis: Financial Interests, Personal, Full or part-time Employment, Full-time employment at Pfizer/Legacy-Seagen: Pfizer Inc.; Financial Interests, Personal, Stocks/Shares, Full-time Employment includes stock benefits from: Pfizer Inc.; Non-Financial Interests, Project Lead, Clinical Development / Clinical Scientist lead on EV-103: Pfizer Inc.; Non-Financial Interests, Personal, Proprietary Information, Full-time employee: Pfizer Inc. H. Wirtz: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks/Shares: Pfizer Inc., Amgen Inc., Teva Pharmaceuticals. Y. Zhu: Financial Interests, Personal, Stocks/Shares: Pfizer. M.I. Milowsky: Financial Interests, Personal, Other, Co-Editor-in-Chief, Clinical Genitourinary Cancer: Elsevier; Financial Interests, Personal, Invited Speaker: Medscape, Research to Practice; Financial Interests, Personal, Stocks/Shares: Pfizer, Merck, Gilead Sciences; Financial Interests, Institutional, Local PI: Merck, Roche/Genentech, Bristol Myers Squibb, Mirati Therapeutics, Seagen, G1 Therapeutics, Alliance Foundation Trials, Alliance for Clinical Trials in Oncology, Clovis Oncology, Arvinas, ALX Oncology, Hoosier Cancer Research Network, Novartis, Acrivon Therapeutics, Astellas Pharma, Genentech, Accuray, PCCTC, OncoC4, Flare Therapeutics, Loxo/Lilly; Non-Financial Interests, Advisory Role: G1 Therapeutics, Loxo/Lilly.