A phase 1, open-label, first-in-human study of TAS2940 in patients with advanced solid tumors.

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TPS3165 Background: Aberrant expression and signaling of the ERBB family of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), has a role in the pathogenesis of solid tumors such as breast cancer (BC), non–small cell lung cancer (NSCLC), and glioblastoma (GBM). Although therapies that target HER2 are effective in early and advanced HER2-overexpressing BC, many patients develop resistance despite tumor dependence on HER2 at the time of progression. Approximately 4% of patients with NSCLC have HER2 mutations, mostly presenting as exon 20 insertions (ex20ins); however, approved HER2/EGFR tyrosine kinase inhibitors (TKIs) have limited efficacy in patients with NSCLC and HER2 ex20ins. Many patients with NSCLC or BC develop brain metastases, and EGFR alterations, including EGFRvIII mutations, are common in GBM. There is therefore a need for a brain-penetrable TKI with activity against tumors harboring HER2/EGFR alterations. TAS2940 is a potent, selective, and orally bioavailable pan-ERBB inhibitor that has shown promising preclinical efficacy against cancers with a variety of HER2/EGFR mutations and amplifications. Further, TAS2940 inhibited tumor growth and induced tumor regression in a dose-dependent manner in nude mice intracranially implanted with NCI-N87, a HER2-overexpressing human gastric cancer cell line. Methods: TAS2940-101 (NCT04982926) is an open-label, phase 1, first-in-human trial to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of TAS2940 in patients with advanced solid tumors and HER2/ EGFR aberrations. Eligible patients are aged ≥18 years, have non-measurable (Part 1) or measurable (Part 1 and 2) disease per RECIST 1.1 or RANO criteria, ECOG performance status 0/1, and adequate organ function. Patients with non-stable brain metastases are excluded. Part 1 (dose escalation) will use a Bayesian optimal interval design with a starting dose of 15 mg/kg orally QD (planned dose levels: 15, 30, 60, 120, 240 and 480 mg). Once the recommended phase 2 dose is determined, Part 2 (dose expansion) will enroll patients with NSCLC (Cohort A), HER2+ BC (Cohort B), recurrent/refractory GBM (Cohort C), or other solid tumors with EGFR/ HER2 aberrations (Cohort D). The primary objectives are the maximum tolerated dose of TAS2940 in Part 1 and antitumor activity in Part 2. Secondary objectives include antitumor activity in Part 1. The safety and PK profile of TAS2940 will be assessed in both parts. Approximately 142 patients will be enrolled, comprising ~42 in Part 1 and ~100 in Part 2. As of January 24, 2023, 15 patients have been enrolled. No dose-limiting toxicities have been reported with dose escalation up to 240 mg QD. Recruitment is ongoing. Clinical trial information: NCT04982926 .