A Phase I trial of BI 1810631, a HER2 tyrosine kinase inhibitor (TKI), as monotherapy in patients (pts) with advanced/metastatic solid tumors with HER2 aberrations

Background: There is an unmet need for effective TKIs against HER2 mutations in solid tumors, particularly in NSCLC. BI 1810631 is a HER2 selective TKI that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertions, whilst sparing EGFR signaling; preclinical data suggest good tolerability and efficacy. This Phase Ia/Ib, open-label, non-randomized study aims to determine the safety, MTD, PK, pharmacodynamics and preliminary efficacy of BI 1810631 in pts with HER2 aberration-positive solid tumors (NCT04886804). Here, we present results of Phase 1a. Materials and Methods: In Phase Ia, pts with HER2 aberration-positive (overexpression, gene amplification, somatic mutation, or gene rearrangements) advanced/unresectable/metastatic solid tumors refractory/unsuitable for standard therapy were enrolled. Pts received escalating doses of BI 1810631 BID (starting dose: 15 mg) or BI 1810631 QD (starting dose: 60 mg). Phase Ib will initially include 30 pts with advanced HER2 tyrosine kinase domain mutation-positive, pre-treated NSCLC. Additional cohorts may be included in the future. Primary endpoints: MTD based on number of DLTs; number of pts with DLTs (Phase Ia); objective response (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire treatment period and PK parameters (Phase Ia/Ib); duration of response, disease control, duration of disease control and PFS (Phase Ib). Results: As of 14 September 2022, 26 patients have been treated in the US, The Netherlands, Japan and China. Patients had NSCLC (n = 15), colorectal cancer (n = 2), other tumors (n = 7) or unreported tumor type (n = 2). Most patients had a pathological HER2 mutation (n = 15). Patients received BI 1810631 15, 30, 60, 100, 150 mg BID (n = 3/3/4/4/3) or 60, 120 mg QD (n = 5/4). Median number of cycles was 4 (range 1–11). Treatment is ongoing in 16 patients. To date, one DLT has been observed (grade 2 edema in the 60 mg BID cohort). The MTD has not been reached with either schedule. Treatment-related adverse events (TRAEs) have been reported in 13 pts (50%). The most common TRAEs were diarrhea (n = 6), increased alkaline phosphatase (n = 2) and hypoalbuminemia (n = 2). There were no grade ≥3 TRAEs. In 19 patients evaluable for response the ORR (regardless of confirmation) was 37% (n = 7, all PRs; NSCLC: n = 5; esophagus, cholangiocarcinoma: n = 1). The DCR was 84%. In 11 NSCLC patients evaluable for response, the ORR was 45% and the DCR was 91%. Conclusions: These preliminary data indicate that BI 1810631 is well tolerated and shows encouraging anti-tumor activity in patients with HER2 aberration-positive solid tumors. Recruitment into Phase Ia is ongoing. Conflict of interest: Advisory Board: John Heymach reports participating in an advisory board for AstraZeneca, EMD Serono, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Hengrui Therapeutics, Eli Lilly, Spectrum, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, RefleXion, Chugai Pharmaceuticals. Noboru Yamamoto reports participating in an advisory board for Eisai, Takeda, Boehringer Ingelheim, Cimic, Chugai Pharma. Board of Directors: John Heymach reports participating in a board of directors for Rexanna Foundation. Corporate-sponsored Research: John Heymach reports receiving corporate-sponsored research fees from AstraZeneca, Boehringer-Ingelheim, Spectrum and Takeda. Yi-Long Wu reports receiving corporate-sponsored research fees from AstraZeneca, BMS, Pfizer. Other Substantive Relationships: Frans Opdam reports other substantive relationships with Boehringer Ingelheim, Astra Zeneca, GSK, Cytovation, InteRNA technologies, Merus, Taiho, and Pierre-Fabre. John Heymach reports receiving royalties and licensing fees from Spectrum. Minal Barve reports other substantive relationships with Texas Oncology physician Associates Mary Crowley Cancer Research. Yi-Long Wu reports receiving speaker fees from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Hengrui, MSD, Pfizer, Sonofi, Roche. Neil Gibson, Behbood Sadrolhefazi, and Josep Serra report being employed with Boehringer Ingelheim. Kiyotaka Yoh reports other substantive relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi sankyo, Janssen, Kyowa kirin, Lilly, Novartis, Taiho, Abbvie, AstraZeneca, Daiichi sankyo, Lilly, MSD, Pfizer, Taiho, Takeda. Noboru Yamamoto reports other substantive relationships with Chugai Pharma, Ono Pharmaceutical, Lilly Japan, Sysmex, Daiichi Sankyo/ UCB Japan, Eisai, Chiome Bioscience, Otsuka, Taiho pharmaceutical, Astellas Pharma, Novartis, Daiichi Sankyo, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Janssen, MSD, Abbvie, Bristol-Meyers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Carna Biosciences, Genmab/ Seattle Genetics, Shionogi, Toray Industries.