Abstract CT212: A phase I, open-label, dose escalation, confirmation, and expansion trial of BI 1810631 as monotherapy in patients with advanced or metastatic solid tumors with HER2 aberrations
Authors: Heymach John , Opdam Frans , Barve Minal , Gibson Neil , Sadrolhefazi Behbood , Serra Josep , Yamamoto Noboru 
Published: June 2022

Abstract
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, EGFR-targeted agents that inhibit mutant HER2 are associated with off-target wild type-related toxicities. 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 combinations 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: It is planned that ~96 pts from 3 sites in the US, Netherlands, and Japan will be recruited. In 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 (guided by Bayesian Logistic Regression Model) until MTD and/or RP2D for each schedule is determined, as well as a preferred Phase Ib schedule. In 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 and/or metastatic solid tumors refractory/not suitable for standard therapy; exhausted treatment options; measurable or evaluable lesions (according to 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 the 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, PFS, disease control, and duration of disease control (Phase Ib). The trial is actively recruiting; 5 pts have been enrolled to date and 2 dose levels have been completed.
Citation Format: John Heymach, Frans Opdam, Minal Barve, Neil Gibson, Behbood Sadrolhefazi, Josep Serra, Noboru Yamamoto. A phase I, open-label, dose escalation, confirmation, and expansion trial of BI 1810631 as monotherapy in patients with advanced or metastatic solid tumors with HER2 aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT212.