KRAS G12C mutations are a key driver in a subset of non-small-cell lung cancers (NSCLC) and remain a clinical challenge due to limited response durability and eventual drug resistance. While monotherapy with KRAS G12C inhibitors has shown meaningful antitumour activity, preclinical studies suggest combining these agents with SHP2 inhibitors may enhance efficacy by more robustly suppressing downstream signalling pathways.
The combination of the oral KRAS G12C inhibitor glecirasib with the SHP2 inhibitor sitneprotafib has recently been investigated in an open-label, multicentre, phase 1/2a trial across China, providing the first clinical evidence for this dual-targeted approach.
Study Design and Patient Population
The trial enrolled 194 patients with locally advanced or metastatic KRAS G12C-mutated solid tumours, with 171 patients (88%) presenting with NSCLC. Participants were ≥18 years old, had an ECOG performance status of 0–1, and measurable disease per RECIST v1.1. Patients received oral glecirasib (400 mg or 800 mg daily) combined with oral sitneprotafib (2 mg or 3 mg daily) in seven dosing cohorts. Phase 1 primarily assessed safety and tolerability, while phase 2a evaluated objective response rates (ORR).
Safety Profile
Across both phases, 98% of patients experienced at least one treatment-related adverse event (TRAE), with grade 3–4 TRAEs reported in 46% of patients. Common TRAEs included anaemia (61%), hypertriglyceridaemia (60%), and elevated liver enzymes (49–56%). Only 2% discontinued therapy due to adverse events, and no grade 5 TRAEs were reported. Dose-limiting toxicity occurred in one patient at the highest dosing regimen.
Efficacy Results
The combination showed substantial antitumour activity, particularly in treatment-naïve NSCLC patients, achieving an ORR of 71%. Patients previously treated with systemic therapy but naïve to KRAS G12C inhibitors had an ORR of 49%, while those with prior KRAS G12C inhibitor exposure achieved 10%. These findings highlight the potential benefit of the combination in early lines of therapy.
Implications for Treating KRAS G12C Lung Cancer
The glecirasib and sitneprotafib combination offers a chemotherapy-free, targeted therapeutic option with manageable toxicity, demonstrating particularly strong efficacy in treatment-naïve KRAS G12C NSCLC patients. These results support the ongoing development of a phase 3 trial to compare this regimen with the current standard of care, potentially establishing a new treatment paradigm for this molecularly defined patient population.
Reference
Zhong J et al. Glecirasib plus sitneprotafib in patients with KRASG12C-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 1/2a trial. Lancet Respir Med. 2025; DOI:10.1016/S2213-2600(25)00258-9.
