The SOS1 Inhibitor BI 1701963 as Monotherapy or in Combination with Trametinib in Patients with KRAS Mutation-Positive Solid Tumors.

purposeBI 1701963 is a small-molecule son of sevenless 1 (SOS1) inhibitor that selectively binds to SOS1, blocking the protein-protein interaction of SOS1 with guanosine diphosphate-bound rat sarcoma virus (RAS) proteins [Kirsten RAS (KRAS), Harvey RAS, and neuroblastoma RAS], thereby inhibiting the growth of RAS-dependent cancer cells. PATIENTS AND

methodsThree phase I dose-escalation studies evaluated BI 1701963 as monotherapy (starting dose of 50 mg) or in combination with trametinib (starting dose of 100 mg/1 mg) in patients with KRAS mutation-positive solid tumors (NCT04111458, USA and Europe; NCT04835714, Japan; and NCT04627142, China). Primary endpoints were maximum tolerated dose (MTD) based on dose-limiting toxicities (DLT; part A NCT04111458) and the number of patients with DLT in the MTD evaluation period (part A NCT04111458 and NCT04835714) or the on-treatment period (Part B NCT04835714).

resultsNinety-four patients were treated: 75 with monotherapy (50-800 mg) and 19 in combination (100 mg/1 mg; 100 mg/1.5 mg; and 200 mg/1 mg). Six monotherapy patients (8%) and six combination patients (31.6%) experienced DLT 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, which was considered drug-related by the investigator. In the monotherapy group, one patient (1.8%) experienced a 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.

conclusionsBI 1701963 treatment demonstrated limited efficacy as monotherapy. MTD was determined to be 800-mg monotherapy (NCT04111458) and 100 mg/1 mg in combination with trametinib (NCT04111458).