2374P - A phase Ib single-arm trial of bintrafusp alfa (BA) for pretreated, locally advanced/unresectable or metastatic (advanced) urothelial cancer (aUC)

Background

Patients (pts) with aUC have poor prognosis after progression on platinum-based chemotherapy (PCT). Immune checkpoint inhibitors (ICI) post-PCT provide overall response rate (ORR) ≤ 21%. TGF-β pathway can mediate resistance to ICI in aUC. BA is a first-in-class bifunctional fusion protein composed of extracellular domain of TGF-βRII receptor (“trap”) fused to a human IgG1 mAb blocking PD-L1. We conducted a phase 1b trial evaluating the safety/efficacy of BA in PCT-refractory aUC.

Methods

This open-label multicenter trial enrolled pts with PCT-refractory aUC (ECOG PS ≤ 1) with ≤2 lines of systemic therapy for aUC (no prior therapy targeting T-cell co-stimulation, ICI, or TGF-β pathway). Pts received BA 1200mg every 2 weeks until progression, unacceptable toxicity, death, withdrawal, or for ≤2 years. Primary endpoint: investigator-assessed confirmed ORR (RECIST 1.1); secondary endpoints: duration of response (DOR), PFS, OS. A Bayesian predictive probability design for the primary endpoint had 5.7% alpha (type I error) and 85.4% power to rule out ORR ≤21% (target ORR ≥40%; target accrual 40 pts).

Results

Accrual was stopped based on available trial data indicating that BA was unlikely to show meaningful benefit beyond current available therapies, also considering the evolving therapy landscape. Between Oct 15, 2020, and Aug 31, 2021, 25 pts (21 men, median age 67) were enrolled. At data cutoff (DOC), confirmed ORR 20% (5 pts; 95%CI 6.8-40.7; 2 CR, 3PR), median DOR N/E; median PFS 1.8 mo (95% CI 1.2-3.4), median OS not reached. Median number of BA doses 4; 24 pts discontinued BA [14 for progression; 8 for treatment-emergent adverse event (TEAE); 1 completed therapy; 1 death]; 1 receiving BA at DOC. All pts experienced TEAE; 7 pts experienced G≥3 treatment-related adverse events (TRAEs). Most common G≥3 TEAEs (≥10% of pts): anemia (32%), urinary tract infection (16%); most common G≥3 TRAEs: colitis (4%), pneumonitis (4%).

Conclusions

Accrual was feasible but further development of BA in this therapy setting was halted. Limitations: relatively small sample size and no randomization. Future studies can assess the role of TGF-β pathway inhibition in UC.

Clinical trial identification

NCT04349280.

Editorial acknowledgement

Legal entity responsible for the study

GSK and Merck KGaA.

Funding

GSK and Merck KGaA.

Disclosure

P. Grivas: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Bristol Myers Squibb, Asieris Pharmaceuticals, Merck KGaA, Seattle Genetics, Aadi Bioscience, Pfizer, Janssen, Boston Gene, Mirati Therapeutics, Exelixis, Genentech/Roche, Gilead Sciences, CG Oncology, Dyania Health, Infinity Pharmaceuticals, QED Therapeutics, 4D Pharma PLC, ImmunityBio, Lucence Health, G1 Therapeutics, Fresenius Kabi, Guardant Health, PureTech, Regeneron Pharmaceuticals, Strata Oncology, Urogen, Silverback Therapeutics, Astellas Pharma; Financial Interests, Institutional, Invited Speaker: Pfizer, Clovis Oncology, Bavarian Nordic, Gilead Sciences, Bristol Myers Squibb, Debiopharm Group, MSD, QED Therapeutics, GSK, Mirati Therapeutics, G1 Therapeutics, Merck KGaA. S. Sridhar: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Bayer, BMS, Eisai, EMD Serono, Hoffmann La Roche, Pfizer; Financial Interests, Institutional, Research Grant, Unrestricted Research grant to institution for developing a database: Seagen; Financial Interests, Institutional, Research Grant: Bayer, Janssen. B. Perez Valderrama: Financial Interests, Personal, Advisory Board: Pfizer, Astellas Pharma, Bristol Myers Squibb, Ipsen, EUSA Pharma, Sanofi-Aventis, Merck, MSD, AstraZeneca; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Roche, Bayer, EUSA Pharma, MSD, Merck, Pfizer, Janssen, Astellas Pharma. D.E. Castellano Gauna: Financial Interests, Personal, Advisory Board: Pfizer, Roche, BMS, Janssen, Astellas, MSD, Ipsen, AstraZeneca, Novartis, GSK; Financial Interests, Institutional, Invited Speaker: 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. Y. Loriot: Financial Interests, Personal, Advisory Board: Merck Kga, Pfizer, Gilead, seattle genetics, Taiho; Financial Interests, Personal, Other, lectures, advisory boards: MSD, AstraZeneca, Astellas, Janssen; Financial Interests, Personal, Other, lectures, advisroy boards: Roche, BMS; Financial Interests, Institutional, Research Grant: Janssen, Sanofi, MSD, Roche, Celsius; Financial Interests, Institutional, Invited Speaker: Janssen, Pfizer, Janssen, MSD, Janssen, Exelexis, AstraZeneca, Pfizer, Merck Kga, BMS, Astellas, Gilead, Incyte; Financial Interests, Invited Speaker: MSD, Astellas, Gilead/immunomedics, Taiho; Financial Interests, Personal, Invited Speaker: Basilea; Non-Financial Interests, Member: ESMO, ASCO, AACR; Non-Financial Interests, Other, Scientific Committee: ARC. D. Pouessel: Financial Interests, Personal, Invited Speaker: Ipsen, Bristol Myers Squibb, AstraZeneca, Astellas Pharma, MSD Oncology, Pfizer / Astellas; Financial Interests, Personal, Advisory Board: Astellas Pharma, Pfizer, MSD Oncology, Bristol Myers Squibb, Merck; Financial Interests, Institutional, Invited Speaker: Merck Sharp & Dohme, Roche, Bristol Myers Squibb, AstraZeneca, Seagen. 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, Invited Speaker, Local PI + SSC member: BMS, AstraZeneca, MSD, Seagen; Financial Interests, Institutional, Invited Speaker, Local PI + study co-PI: Janssen; Financial Interests, Institutional, Invited Speaker: GSK. 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; Financial Interests, Personal, Other, Consultant: Rappta Therapeutics; Financial Interests, Institutional, Invited Speaker: Merck, AstraZeneca, Genentech, Bristol Myers Squibb, Seagen, Jazz. S. Gulati: Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Invited Speaker, RCC advantage program (ASCO): ASCO; Financial Interests, Institutional, Invited Speaker, Funding to institution to conduct investigator inititated clinical trial: AstraZeneca; Financial Interests, Institutional, Invited Speaker: IsoRay. A. Ravaud: Financial Interests, Personal, Advisory Board: Pfizer, Merck GA, Ipsen, BMS, Esai. E. Fontana: Financial Interests, Personal, Invited Speaker: CARIS Life Science, Repair Therapeutics; Financial Interests, Personal, Other, Conference attendance: Sapience Pharma; Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International; Financial Interests, Personal, Officer: EORTC; Financial Interests, Institutional, Invited Speaker: Repair Therapeutics, Bicycle Therapeutics, Artios Pharma, Seagen, Amgen, Nurix Therapeutics, BioNTech SE, Relay Therapeutics, Taiho Pharmaceutical, Pfizer, Roche, Daiichi Sankyo, Gilead Science, Basilea Pharmaceutica, Jiangsu Hengrui Medicine, Mereo Biopharma, Hutchmed, Merus, Crescendo Biologics, GSK plc, BeiGene, Turning Point Therapeutics, Sapience Pharma; Non-Financial Interests, Advisory Role: Vivan Therapeutics. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Invited Speaker: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines. A. Mortazavi: Financial Interests, Personal, Other, Consultant: Targeted Oncology - Intellisphere, Llc; Financial Interests, Personal, Advisory Board: Pfizer, Seattle Genetics; Financial Interests, Institutional, Invited Speaker, My institution (not me) has received research funding for conducting clinical trials: Seattle Genetics, Acerta Pharma, Genentech, Roche, Merck, Novartis, Astellas Pharma, Mirati Therapeutics, Bristol Myers Squibb, Debiopharm Group, GSK plc. N. Isambert: Financial Interests, Personal, Advisory Board: Novartis, Transgene, Pfizer, GSK; Financial Interests, Personal, Invited Speaker: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Novartis, Roche, Daiichi Sankyo, MSD, Deciphera, Anaveon, Dizal Pharmaceutical, Exelisis, iTeos Therapeutics, Amgen, Janssen, Pyramid Biosciences. 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. A.H. Khaled: Financial Interests, Personal, Other, Employee: GSK; Financial Interests, Personal, Other, Own stocks: GSK. R. Morales Barrera: Financial Interests, Personal, Advisory Board: AstraZeneca, Astellas, Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer, Astellas; Non-Financial Interests, Principal Investigator: AstraZeneca, Gilead, Roche, BMS, AstraZeneca. All other authors have declared no conflicts of interest.