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CodeBreaK 300 showed that a KRAS drug needs an EGFR antibody partner to work in colorectal cancer.
CodeBreaK 300, trial NCT05198934 sponsored by Amgen and published in the New England Journal of Medicine in 2023, showed that a KRAS G12C inhibitor needs an EGFR antibody partner to work in colorectal cancer. It randomised 160 patients with previously treated KRAS G12C colorectal cancer to sotorasib at two doses with panitumumab or standard trifluridine-tipiracil or regorafenib, met its primary progression-free survival endpoint for the 960 mg dose with responses in about a quarter against none, and led to approval in January 2025. OnCo links it to colorectal cancer, KRAS and EGFR as targets, sotorasib, panitumumab, the pairing of a KRAS G12C inhibitor with an anti-EGFR antibody and the CodeBreaK 200 and 300 papers. Whether the combination can move into first-line treatment is the open question.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
160 enrolled.
| Endpoint | Arm | n | Value | HR (95% CI) | p | Source |
|---|---|---|---|---|---|---|
| Progression-free survival (BICR), sotorasib 960 mg + panitumumabprimary | Sotorasib 960 mg + panitumumab | 53 | 5.6 months | 0.49 (0.3 to 0.8) | 0.006 | link |
| Trifluridine-tipiracil or regorafenib | 54 | 2.2 months | ||||
| Objective response rate | Sotorasib 960 mg + panitumumab | - | 26.4% | - | - | link |
| Trifluridine-tipiracil or regorafenib | - | 0% |
Patients with KRAS G12C lung cancer that has progressed after chemo-immunotherapy can take an oral KRAS inhibitor instead of docetaxel and gain a somewhat longer time to progression with fewer severe side effects, but should understand that most tumours become resistant within a year and that survival is not improved. KRAS G12C testing is worthwhile, but first-generation inhibitors are a step rather than a cure; combinations and next-generation inhibitors are the active research fronts.
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.
It defines the population the G12C inhibitors address and sets the baseline against which CodeBreaK 300 and KRYSTAL-1 are read.
Shares KRAS G12C inhibitor + anti-EGFR antibody (colorectal), CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer, CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug, Sotorasib.
Shares CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug, Sotorasib, Amgen, Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall.
Shares KRAS G12C inhibitor + anti-EGFR antibody (colorectal), KRAS G12C metastatic colorectal cancer: specific features of a new emerging target population, Covalent chemistry for the RAS mutations that still have no drug, RAS wild-type (extended KRAS and NRAS testing).
Shares Panitumumab, Sotorasib, Amgen, KRAS & RAS inhibitors.
Shares Covalent chemistry for the RAS mutations that still have no drug, Off-the-shelf KRAS vaccines after pancreatic cancer surgery, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation, Colorectal cancer.
Shares KRAS G12C metastatic colorectal cancer: specific features of a new emerging target population, CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer, RAS wild-type (extended KRAS and NRAS testing), Panitumumab.
Shares RAS wild-type (extended KRAS and NRAS testing), Panitumumab, Amgen, EGFR.
Shares CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug, Sotorasib, Amgen, KRAS & RAS inhibitors.