A phase I, open-label, dose escalation, confirmation, and expansion trial of BI 1810631 as monotherapy in patients with advanced/metastatic solid tumors with HER2 aberrations.

TPS9143 Background: HER2 mutations are present in 2–4% of NSCLC tumors; of these ̃50% are exon 20 insertion (ex20ins) mutations. There is an unmet need for effective targeted therapy against HER2 mutations in solid tumors, particularly in NSCLC. Historically, ex20ins mutations have responded poorly to TKIs. Moreover, TKIs that inhibit both mutant EGFR and HER2 are typically limited by toxicities associated with inhibition of wild-type EGFR. Despite the promise of trastuzumab deruxtecan and other agents in this setting, the development of orally available selective TKIs is important given the heterogeneity of HER2 aberrations, potential for combination regimens, and the risk of ILD with ADCs. BI 1810631 is a HER2 selective TKI that covalently binds to both wild-type and mutated HER2 receptors, including ex20ins, 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+ solid tumors (NCT04886804). Methods: ̃96 pts from 5–7 sites in the US, Netherlands, Japan, and China will be recruited. Phase Ia: consecutive cohorts of pts will receive BI 1810631 QD or BID at escalating doses. Starting dose level: 15 mg BID (̃36 pts); QD schedule will begin after one dose level above estimated therapeutic dose of BI 1810631 is determined safe by the Dose Escalation Committee (expected starting dose: 60 mg [̃30 pts]). BI 1810631 dose escalation will continue until MTD/RP2D for each schedule is determined, as well as a preferred Phase Ib schedule. Phase Ib: an initial 30 pts with HER2 ex20ins mutation-positive, pre-treated NSCLC will be enrolled, with possible inclusion of additional cohorts in the future. Overall pt inclusion criteria (Phase Ia): ≥18 years of age; histologically/cytologically confirmed HER2+ (defined as overexpression, gene amplification, non-synonymous somatic mutation, or gene rearrangement involving HER2 or NRG1) advanced/unresectable/metastatic solid tumor refractory/not suitable for standard therapy; exhausted treatment options; measurable/evaluable lesions (per RECIST v1.1); ECOG PS ≤1. Phase Ib criteria: HER2 ex20ins mutation-positive NSCLC; received ≥1 line of platinum-based combination chemotherapy in the advanced/metastatic setting. 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). The trial is actively recruiting with 6 pts enrolled to date. More patients may be recruited depending on whether 2 dose levels have been completed and the MTD/RP2D determined. Clinical trial information: NCT04886804.