731MO - A phase I trial of the bifunctional EGFR/TGFβ fusion protein BCA101 alone and in combination with pembrolizumab in patients with advanced solid tumors

Background

BCA101 is a first-in-class bifunctional fusion protein consisting of an anti-EGFR mAb and TGFβ receptor 2 extracellular domain. Herein, we report the safety, PK/PD, and preliminary efficacy data of BCA101 as monotherapy and in combination with pembrolizumab among pts with advanced solid tumors refractory to standard therapies.

Methods

Pts received BCA101 as a single agent (SA) or in combination with pembrolizumab at escalating doses in a parallel 3+3 design starting at 64 mg IV qw; and at 240 mg IV qw with pembrolizumab 200 mg IV q3w. Primary endpoint: safety and tolerability; DLT period: 21 days. Secondary: ORR, PK/PD, PFS, and changes in plasma and intra-tumoral TGFβ signaling assessed by SMAD2 phosphorylation.

Results

As of 07-Apr-2022, 60 pts received BCA101. Forty-five pts (colorectal, n=14; pancreatic, n=7; head and neck squamous cell carcinoma [HNSCC], n=6) received SA BCA101 at doses up to 1500 mg IV weekly. Fifteen pts (SCC of the anal canal [SCAC], n=8; HNSCC, n=7) received BCA101 doses from 240 to 1500 mg IV qw in combination with pembrolizumab. MTD has not been reached. Most common AEs attributed to BCA101 include rash (72%), fatigue (30%), pruritis (20%), and epistaxis (17%); all G2 or less. One DLT observed at the 1250 mg SA dose (G3 anemia, hematuria). No drug-related G4 AEs or deaths observed. One partial response (PR) and 13 (33%) stable disease (SD) observed in 40 evaluable SA pts. In combination, PR observed in 4/13 (31%) evaluable pts (2 in SCAC, 2 in HNSCC) and a DCR of 9/13 (69%). All 4 responders have been on study >4 months; including 1 confirmed PR in a HNSCC pt refractory to anti-PD-1 therapy and cetuximab. Saturation of the EGFR target was observed at BCA101 doses ≥750 mg. Dose proportional increase in Cmax and AUC observed in doses of BCA101 750-1500 mg. Prolonged neutralization of plasma TGFb1 achieved at all doses ≥500 mg. Among paired tumor biopsies (n=23), pSMAD2 reduction up to 62% was observed at doses ≥500 mg.

Conclusions

BCA101 is well tolerated and clinically active as a SA and in combination with PD-1 blockade with a predictable PK/PD profile. Expansion cohorts for HNSCC, SCAC and cutaneous SCC are currently ongoing and results will be updated and further presented at the congress.

Clinical trial identification

NCT04429542.

Editorial acknowledgement

Legal entity responsible for the study

Bicara Therapeutics, Inc.

Funding

Bicara Therapeutics, Inc.

Disclosure

G.J. Hanna: Financial Interests, Personal, Advisory Board: Bicara, Bio-Rad, Boxer Capital, Bristol Myers Squibb, Exicure, General Catalyst, Kura Oncology, Maverick, Merck, Naveris, Prelude, Rain Therapeutics, Regeneron, Remix, Sanofi Genzyme, SIRPant; Financial Interests, Personal, Invited Speaker: Coherus; Financial Interests, Personal, Expert Testimony: Aaronson Rappaport Feinstein & Deutsch, LLP, Ahmuty, Demers, & McManus, Esqs, Wilson Elser Moskowitz Edelman & Dicker, LLP; Financial Interests, Personal, Full or part-time Employment: Dana-Farber Cancer Institute; Financial Interests, Institutional, Research Grant: ACCRF, Repertoire, V Foundation; Financial Interests, Institutional, Funding: Actuate Therapeutics, ASCO Conquer Cancer Foundation, Bicara, Bristol Myers Squibb, Elevar, Exicire, Gateway for Cancer Reserach, Genentech, GSK, Kartos, Kite Pharma, KSQ Therapeutics, Kura Oncology, NantKewst/Altor Bioscience, Regeneron, Sanofi Genzyme, Secura Bio. A. Hernando Calvo: Award: Novartis. V. Morris: Financial Interests, Personal, Invited Speaker: Imedex LLC; Financial Interests, Personal, Advisory Board: Bicara; Financial Interests, Personal, DMC member: Incyte; Financial Interests, Institutional, Invited Speaker: Bicara; Financial Interests, Institutional, Funding: Pfizer, Bristol Myers Squibb, BioNTech, Novartis, EMD Serono. R.D. Carvajal: Financial Interests, Personal, Advisory Role: Merck, Aura Biosciences, Castle Biosciences, Immunocore, PureTech, Sorrento Therapeutics, Chimeron Bio, Rgenix, InxMed, Pierre Fabre, TriSalus Life Sciences, Iovance Biotherapeutics, Oncosec, Regeneron, Genzyme, Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb /Medarex, Corvus Pharmaceuticals, IDEAYA Biosciences, Mirati Therapeutics, Novartis, Pfizer, Plexxikon, Roche/genentech; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb /Medarex; Financial Interests, Institutional, Funding: Amgen, Astellas Pharma, AstraZeneca, Bayer, Bellicum Pharmaceuticals, Bristol Myers Squibb, Corvus Pharmaceuticals, Lilly, Immunocore, Incyte, Macrogenics, Mirati, Novartis, Pfizer, Plexxikon, Roche/genentech, Array BioPharma, IDEAYA Biosciences, Regeneron. P.K. Paik: Financial Interests, Personal, Advisory Board: Xencor, Mirati, EMD Serono; Financial Interests, Personal, DSMC: Takeda; Financial Interests, Personal, Consulting: Novartis; Financial Interests, Invited Speaker: EMD Serono, Bicara. D.P. Zandberg: Financial Interests, Personal, Advisory Board: Blueprint Medicines, Prelude Therapeutics; Financial Interests, Personal, Advisory Role: Macrogenics; Financial Interests, Institutional, Principal Investigator: Merck, BMS, AstraZeneca, GlaxoSmithKline, Aduro, Astellas, Macrogenics, Lilly, Bicara Therapeutics, Checkmate Pharma, Novasenta. J. Kaczmar: Financial Interests, Personal, Advisory Role: Bicara Therapeutics, Inc, Rakuten Medical, Coherus Biosciences; Financial Interests, Personal: Triangle Insights Group. L. Niculescu: Financial Interests, Personal, Full or part-time Employment: Bicara Therapeutics. R. Reiners: Financial Interests, Personal, Full or part-time Employment: Bicara Therapeutics. D. Bohr: Financial Interests, Personal, Full or part-time Employment: Bicara Therapeutics, Inc. E. Gharakhani: Financial Interests, Personal, Full or part-time Employment: Bicara Therapeutics, Inc. . R. Salazar: Financial Interests, Personal, Full or part-time Employment: Bicara Therapeutics, Inc. . P.L. Bedard: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Bicara, BMS, Amgen, Novartis, Genentech/Roche, Sanofi, Merck, Pfizer, Zymeworks, Nektar Therapeutics, Lilly, SeaGen; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Funding: Servier; Non-Financial Interests, Invited Speaker, Executive Board Member: Breast International Group; Non-Financial Interests, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Leadership Role, Past Chair IND CommitteeMember, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Advisory Role: SeaGen, Lilly, Amgen, Merck, BMS, Pfizer, Gilead. All other authors have declared no conflicts of interest.