BACKGROUND: BI 1701963 is a small molecule son of sevenless 1 (SOS1) inhibitor which selectively binds to SOS1, blocking the protein-protein interaction of SOS1 with guanosine diphosphate-bound RAS (rat sarcoma virus) proteins (KRAS, HRAS and NRAS), thus inhibiting the growth of RAS-dependent cancer cells. STUDY DESIGN: Three Phase I dose-escalation studies evaluated BI 1701963 as monotherapy (starting dose: 50 mg) or in combination with trametinib (starting dose: 100 mg/1 mg), in patients with KRAS mutation-positive solid tumors (NCT04111458, USA and Europe; NCT04835714, Japan; NCT04627142, China). Primary endpoints were maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs; Part A NCT04111458), and number of patients with DLTs in the MTD evaluation period (Part A NCT04111458 and NCT04835714) or the on-treatment period (Part B NCT04835714). RESULTS: Ninety-four patients were treated; 75 with monotherapy (50-800 mg), 19 in combination (100 mg/1 mg; 100 mg/1.5 mg; 200 mg/1 mg). Six monotherapy patients (8.0%) and 6 combination patients (31.6%) experienced DLTs in the MTD evaluation period. All patients experienced adverse events; of note, three monotherapy patients had interstitial lung disease during the first treatment cycle leading to death, considered drug-related by the investigator. In the monotherapy group, one patient (1.8%) experienced partial response, and 12 patients (21.8%) had stable disease. In the combination group, four patients (33.3%) had stable disease, carrying different KRAS alleles. CONCLUSIONS: BI 1701963 treatment demonstrated limited efficacy as monotherapy. MTD was determined as 800 mg monotherapy (NCT04111458) and 100 mg/1 mg in combination with trametinib (NCT04111458).
Jänne et al. (Tue,) studied this question.