CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer
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.
- Median PFS 5.6 months (sotorasib 960 mg plus panitumumab) vs 2.2 months (standard care); HR 0.49 (95% CI 0.30-0.80).
- Median PFS 3.9 months with sotorasib 240 mg plus panitumumab; HR 0.58.
- Objective response 26.4% (960 mg), 5.7% (240 mg) and 0% (standard care).
- Skin toxicity (from panitumumab) and hypomagnesaemia were the main adverse events; grade 3 or higher treatment-related events about 36% (960 mg), 30% (240 mg) and 43% (standard care).
- Overall survival showed a trend favouring the 960 mg arm but was not powered to detect a difference.
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 barely works in bowel cancer. Responses are still modest and short-lived compared with EGFR or ALK inhibitors in lung cancer.
- Small trial with a PFS primary endpoint; OS benefit not established.
- The comparator drugs are of very limited efficacy, so the bar was low.
- Median PFS of 5.6 months underlines that resistance develops quickly.
- Only KRAS G12C is covered; the far more common G12D and G12V mutations await other inhibitors.
Pages like this
not linked directly; found by shared links- Key paperCodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug
Shares CodeBreaK 300, Amgen, Sotorasib, KRAS & RAS inhibitors.
- PairingKRAS G12C inhibitor + anti-EGFR antibody (colorectal)
Shares CodeBreaK 300, Sotorasib, KRAS & RAS inhibitors, EGFR.
- ProductPanitumumab
Shares CodeBreaK 300, Amgen, Monoclonal antibodies, EGFR.
- Key paperOstrem and Shokat: the hidden pocket that made KRAS G12C druggable
Shares Sotorasib, KRAS & RAS inhibitors, KRAS, The undruggable drivers.
- InstitutionIstituto di Candiolo IRCCS – FPO
Shares Drug resistance (primary and acquired), Monoclonal antibodies, KRAS, Acquired resistance to every therapy.
- IdeaAdd the second drug on day one when the escape route is predictable
Shares Sotorasib, Wrong doses, KRAS, Acquired resistance to every therapy.
- Key paperBREAKWATER: encorafenib plus cetuximab with chemotherapy as first treatment for BRAF V600E-mutated colorectal cancer
Shares Tae Won Kim, Objective response rate (ORR), Monoclonal antibodies, Progression-free survival (PFS).
- IdeaCovalent chemistry for the RAS mutations that still have no drug
Shares Sotorasib, KRAS & RAS inhibitors, KRAS, The undruggable drivers.