Bintrafusp alfa plus paclitaxel for advanced gastric cancer as a second-line treatment: An open label, single-arm, phase Ib/II study.
Authors: Lee Choong-kun , Jung Minkyu , Park Sejung , Kwon Woo Sun , Kim Kyoo Hyun , Hong Moonki , Kim Hyunwook , Kim Hyo Song , Chung Hyun Cheol Cheol , Rha Sun Young 
Published: January 2023

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Background: Anti-PD-1 monotherapy did not improve overall survival compared with paclitaxel in second-line treatment for advanced gastric cancer (AGC) in KEYNOTE-061 trial. Recent studies suggest that inhibition of transforming growth factor beta (TGF-β) signaling reverses immunosuppressive tumor microenvironment into improved responses to cancer immunotherapy. Especially, genomically stable subtype of AGC showed the increased level of TGF-β pathway. Here, we report the results of phase Ib/II trial of bintrafusp alfa (M7824), a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII fused to a human IgG1 mAb blocking PD-L1, in combination with paclitaxel as a 2nd line treatment for AGC. Methods: This investigator-initiated, single-arm, open-label, phase Ib/II study enrolled HER2-negative, histologically confirmed AGC patients with evaluable disease who failed prior palliative 1st line treatment. Prior immune checkpoint inhibitor was not allowed. Phase 1b was planned to enroll 3 to 12 patients in a 3+3 design (bintrafusp alfa 1200mg on days 1 and 15 plus paclitaxel 80 mg/m2 (level 1) or 70 mg/m2 (level -1) on days 1, 8 and 15) every 28 days). The primary endpoints were to determine recommended phase II dose (RP2D) for phase Ib, and progression-free survival (PFS) at 6 months for phase II. Secondary endpoints included PFS, OS, ORR, DCR, and safety. Exploratory endpoints included immune-related biomarker changes from serial liquid biopsies (NCT04835896). Results: In phase 1b, dose limiting toxicities were not observed, and the RP2D was determined as dose level 1. During phase II, enrollment was stopped after 30 patients were recruited, following negative readouts from bintrafusp alfa trials in other indications. With a median follow-up duration of 10.9 months (95% CI 9.5–12.6), 7 patients remained on treatment (treatment duration range: 1.0 to 15.1 months) as of September, 2022. Median PFS was 3.8 months (95% CI, 2.6-7.8) and PFS rate at 6 months was 36.7% (95% CI, 20.1-53.4). Median OS was 9.6 months (95% CI, 4.1-not reached). In patients with measurable lesions (n=25), ORR was 28% (PR, n=7) and DCR was 68%. No patient was EBV-related. Patients with MSI-H (n=3; mPFS, 7.8 months; mOS, not reached) or PD-L1-positive (CPS≥1) (n=9; mPFS, 7.8 months; mOS, not reached) showed durable efficacy. Treatment-related AEs (≥G3) occurred in 23 pts (76.7%), including anemia (G3, n=12, 40%) and neutropenia (G3, n=9, 30%). Immune-related AE included urticaria (G3, n=2, 6.7%; G2, n=4, 13.3%), rash (G3, n=1, 3.3%), and pneumonitis (G3, n=1, 3.3%). Conclusions: Combination of bintrafusp alfa and paclitaxel was feasible with modest efficacy as 2nd line treatment for AGC. There was subset of patients with durable responses. Analyses of targeted next-generation sequencing from serial ctDNA sampling are ongoing. Clinical trial information: NCT04835896 .