BI 1810631 Shows Early Antitumor Activity in NSCLC

Neil Gibson, PhD

The HER2 tyrosine kinase inhibitor (TKI) BI 1810631 has demonstrated antitumor activity in patients with non–small cell lung cancer (NSCLC). Although HER2 mutations present in many solid tumors, lung cancer is of particular interest because a significant number of mutations are found in the tyrosine kinase domain of the gene. Of those, about 90% take the form of insertions or deletions, according to findings from a phase 1a and b study, presented at the European Organization for Research and Treatment–National Cancer Institute–American Association for Cancer Research Symposium on Molecular Targets and Cancer Therapeutics.¹

“In lung cancer, approximately 50% of all mutations that occur are found in the tyrosine kinase domain of the gene,” said Neil Gibson, PhD, director, translational medicine and clinical pharmacology lead at Boehringer Ingelheim, during a presentation of the data.

The phase 1a portion of the study (NCT04886804; n =36) evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) or recommended phase 2 dose of BI 1810631 as monotherapy. The phase 1b portion investigated early effi cacy in patients with HER2 mutation–positive NSCLC.

Primary end points for phase 1a are MTD and dose-limiting toxicity (DLT). End points for the phase 1b portion of the study include objective response rate (ORR).

The dose escalation portion involved 5 doses from 15 mg up to 150 mg in patients with solid tumors who had HER2 aberrations. The drug was given twice a day in 3-week cycles. “We have reached the third dose level and we will soon be declaring our recommended phase 2 dose,” Gibson said.

Gibson said 29 patients had been treated, with 62% of those having a diagnosis of NSCLC and 69% demonstrating HER2-mutation, rather than overexpression or fusion. The majority were male (64%), the median age was 56 years (range, 38-79), and patients had a ECOG performance status of either 0 (29%) or 1 (71%).

As of October 21, 2022, 55% of patients were still undergoing treatment and had completed a median of 4 cycles (range, 1-12). “Our longest-treated patients are now reaching about 36 weeks on study,” Gibson said.

Response data for 23 patients show an ORR of 39% and a disease control rate (DCR) of 83%. Gibson noted that all responses were partial responses.

In patients with HER2-positive NSCLC (n = 14), the ORR was 50% and the DCR was 93%. Responses were reported across a wide range of dosing schedules and dose levels.

In 17 patients following the twice-a-day dosing schedule, Gibson reported encouraging safety results, with 1 patient experiencing a grade 3 or greater treatment-related adverse event (TRAE) and 1 patient having to reduce their dose because of a TRAE. There were no TRAEs leading to discontinuation.

The most common TRAE was diarrhea (n = 7) with 6 patients with grade 1 severity and 1 patient with grade 2 severity. Gibson noted that 1 patient developed grade 2 edema during cycle 4 of treatment.

Regarding AEs, 1 patient experienced a grade 3 or greater TRAE, with no cases of dose reduction, discontinuation, or DLTs reported. One patient developed grade 3 anemia and is being assessed for treatment relatedness, Gibson said.

In summary, MTD has not been reached with either twice daily or daily dosing schedule and manageable adverse events have been observed.

“We have not reached the maximum tolerated dose on either the twice a day or once daily schedule,” Gibson said. “Only 1 dose-limiting toxicity has been observed to date and this was a grade 2 edema. We believe BI 1810631 has demonstrated encouraging antitumor activity.”

Although pharmacokinetic data and biomarker analysis were not presented because of lack of time, the investigators plan to publish these findings in the near future, Gibson concluded.

_REFERENCE:

_{1. Opdam F, Heymach J, Barve M, et al. A phase I trial of BI 1810631, a HER2 tyrosine kinase inhibitor, as monotherapy in patients (pts) with advanced/metastatic solid tumors with HER2 aberrations. Presented at: EORTC-NCI-AACR Molecular Targets And Cancer Therapeutics Symposium; October 26-28, 2022; Barcelona, Spain. Accessed November 4, 2022. http://bit.ly/3WtCoW1}