KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors

Background: Targeted therapies for KRAS mutations remain unapproved. The KRAS p.G12C mutation is present in 13% of non-small-cell lung cancers (NSCLCs) and 1–3% of colorectal and other cancers. Sotorasib is a selective, irreversible small-molecule inhibitor of KRASG12C.

Methods: A phase 1 trial evaluated sotorasib in advanced solid tumors with the KRAS p.G12C mutation. Patients received oral sotorasib daily. The primary endpoint was safety, with secondary endpoints including pharmacokinetics and objective response per RECIST v1.1 criteria.

Results: Among 129 patients (59 with NSCLC, 42 with colorectal cancer, 28 with other tumors), the median prior treatment lines for metastatic disease was three (range 0–11). No dose-limiting toxicities or treatment-related deaths occurred. Treatment-related adverse events were reported in 56.6% (73 patients), with 11.6% (15 patients) experiencing grade 3 or 4 events.

NSCLC subgroup: 32.2% (19 patients) had a confirmed objective response (complete or partial), and 88.1% (52 patients) achieved disease control. Median progression-free survival (PFS) was 6.3 months (range 0.0+ to 14.9+).
Colorectal cancer subgroup: 7.1% (3 patients) showed a confirmed response, and 73.8% (31 patients) achieved disease control. Median PFS was 4.0 months (range 0.0+ to 11.1+).Responses were also observed in pancreatic, endometrial, appendiceal cancers, and melanoma.

Conclusions: Sotorasib demonstrated promising efficacy in advanced, heavily pretreated KRAS p.G12C-mutant tumors, with manageable safety, including 11.6% grade 3 or 4 treatment-related toxicities.