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Combining a KRAS G12C inhibitor with an EGFR antibody produced responses in about a quarter of patients with heavily pretreated KRAS G12C bowel cancer, versus none with standard chemotherapy, and more than doubled the time to progression.
Open-label phase 3 trial of 160 patients with KRAS G12C-mutated metastatic colorectal cancer that had progressed after fluoropyrimidine, oxaliplatin and irinotecan, randomised 1:1:1 to sotorasib 960 mg or 240 mg daily plus panitumumab, or investigator's choice of trifluridine-tipiracil or regorafenib. Primary endpoint was PFS by blinded review.
Median PFS was 5.6 months with sotorasib 960 mg (HR 0.49) and 3.9 months with 240 mg (HR 0.58) versus 2.2 months with standard care; response rates were 26.4%, 5.7% and 0%. It showed that KRAS G12C inhibition in colorectal cancer needs EGFR co-blockade to overcome adaptive feedback, and led to FDA approval of the combination in 2025.
Patients with metastatic colorectal cancer carrying a KRAS G12C mutation (about 3-4% of cases) who have exhausted standard chemotherapy now have a targeted option that works far better than trifluridine-tipiracil or regorafenib. The higher sotorasib dose is clearly superior, and the EGFR antibody is essential because KRAS inhibition alone has little effect in bowel cancer. Responses are still modest and short-lived compared with EGFR or ALK inhibitors in lung cancer.
Shares CodeBreaK 300, Panitumumab, Sotorasib, KRAS G12C-mutant colorectal cancer.
Shares CodeBreaK 300, Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable, KRAS roadmap: undruggable → G12C → pan-RAS, Sotorasib.
Shares CodeBreaK 300, KRAS roadmap: undruggable → G12C → pan-RAS, Sotorasib, KRAS & RAS inhibitors.
Shares CodeBreaK 300, KRAS G12C, Sotorasib, KRAS & RAS inhibitors.
Shares KRAS G12C, KRAS G12C-mutant colorectal cancer, KRAS & RAS inhibitors, RAS / RAF / MEK / ERK (MAPK).
Shares Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable, KRAS G12C, Sotorasib, KRAS & RAS inhibitors.
Shares Panitumumab, Sotorasib, Amgen, KRAS & RAS inhibitors.
Shares Tae Won Kim, Objective response rate (ORR), Progression-free survival (PFS), Acquired resistance to every therapy.