M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with pretreated biliary tract cancer: Preliminary results from a phase I trial

Background: Biliary tract cancers (BTCs) are a group of aggressive cancers with limited treatment options. Overall response rates (ORRs) with 2L chemotherapy in BTC are <10%, and no standard of care exists. M7824 is an innovative first-in-class bifunctional fusion protein composed of a human anti–PD-L1 IgG1 monoclonal antibody fused with 2 extracellular domains of the transforming growth factor β (TGF-β) receptor II (a TGF-β “trap”). We report on the safety and efficacy of M7824 in patients (pts) with pretreated BTC. Methods: In this expansion cohort of the ongoing phase 1, open-label trial NCT02699515, Asian pts who progressed after platinum-based 1L treatment received M7824 1200 mg q2w until confirmed progressive disease, unacceptable toxicity or trial withdrawal. The primary objective is safety/tolerability; secondary objectives include assessment of best overall response per RECIST v1.1. Tumor cell PD-L1 expression was evaluated (antibody clone 73-10). Results: As of March 20, 2018, 30 pts with pretreated BTC received M7824 for a median duration of 8.9 (range, 2-57.6) wk; 5 pts remained on treatment. The most common treatment-related adverse events (TRAEs) were pyrexia, maculopapular rash (both 13.3%) rash and lipase increase (both 10%); 10 pts (33.3%) experienced grade ≥3 TRAEs. 3 deaths due to AEs were reported; 1 death was due to septic shock (bacteremia, etiology unknown) after 14 doses, and 2 deaths due to interstitial lung disease (ILD), 1 on treatment after 3 doses and 1 with grade 3 ILD after 3 doses that recovered, initiated chemotherapy due to PD, and worsened with death 6 months after initial ILD diagnosis and last M7824 dose. 7 pts had an objective response (ORR, 23.3%, including one late PR pending confirmation), with 4 of 6 PRs ongoing (0.7+, 2.8, 3.9+, 5.5+, 5.6, and 6.9+ mo) and 1 CR ongoing for 5.6+ mo. 1 additional pt had ongoing PR for 7.6+ mo after initial pseudoprogression. Confirmed ORR by PD-L1 expression was 25% and 15.4% in pts with PD-L1 + (≥1%) and PD-L1− tumors, respectively. Conclusions: M7824 monotherapy has promising efficacy in Asian pts with pretreated BTC, including long-lasting responses in 8 of 30 pts (27%). Clinical trial identification: NCT02699515. Editorial acknowledgement: Medical writing support was provided by ClinicalThinking, and was funded by Merck KGaA, Darmstadt, Germany. Legal entity responsible for the study: Merck KGaA, Darmstadt, Germany. Funding: Merck KGaA, Darmstadt, Germany. Disclosure: C. Yoo: Research funding: CKD pharm, Shire; Honoraria: Bayer, Ipsen. D-Y. Oh: Research funding: AstraZeneca. M. Ueno: Research Funding: Taiho Pharmaceutical, Shire, Daiichi Sankyo, Eisai, AstraZeneca, Ono Pharmaceutical, MSD, Merck Serono, NanoCarrier, Dainippon Sumitomo Pharma, Incyte; Honoraria: Taiho Pharmaceutical, Yakult Honsha, AstraZeneca, Novartis, Lilly, Teijin Pharma, Shire, Ono Pharmaceutical. S. Kondo: Research Funding: MSD, Bayer, Aslan, Pfizer, AstraZeneca, Lilly. M. Osada: Employee: Merck Serono, Tokyo, Japan. C. Helwig: Employee: Merck KGaA, Germany; Equity ownership: Merck KGaA, Germany. I. Dussault: Employee: EMD Serono. M. Ikeda: Research Funding: Bayer Yakuhin, Kyowa Hakko Kirin, Yakult, Taiho Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, Eisai, AstraZeneca, Zeria Pharmaceutical, Baxter, Chugai Pharmaceutical, Bristol Myers Squibb, Merck Serono, Kowa, Nano Carrier, ASLAN Pharmaceuticals; Honoraria: Novartis Pharma, Bayer Yakuhin, Bristol-Myers Squibb, Abbott Japan, Eisai, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi-Sankyo, Yakult, Otsuka Pharmaceutical, Nobelpharma; Membership board of directors or advisory committees: Nano Carrier, Bayer Yakuhin, Eisai, Kyowa Hakko Kirin, Novartis Pharma, Shire, MSD. All other authors have declared no conflicts of interest.