Clinical trialPhase 3Colorectal cancer

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

N Engl J Med · 2023160 patients (53 in each sotorasib group and 54 in the standard-treatment group)

Fakih MG, Salvatore L, Esaki T, Modest DP, Lopez-Bravo DP, Taieb J, et al. N Engl J Med. 2023. 389:2125-2139

Study type: Clinical trial
Study name: CodeBreak 300
Phase: Phase 3
Design: Randomised, multicentre, open-label trial
Sample size: 160 patients (53 in each sotorasib group and 54 in the standard-treatment group)
Source: N Engl J Med · 2023
Trial registration: NCT05198934

In plain words

In this study, patients with advanced bowel (colorectal) cancer with a KRAS G12C gene mutation that had not improved with previous chemotherapy received the drug sotorasib together with panitumumab. This combination lengthened the time without the disease getting worse compared with standard treatment (trifluridine-tipiracil or regorafenib). The most common side effects of the combination were skin problems and low blood magnesium. Whether this treatment is right for each patient should be discussed with the treating doctor.

Key results

5.6 months (95% CI 4.2–6.3)

Median PFS — sotorasib 960 mg + panitumumab

Versus 2.2 months in the standard-treatment group (95% CI 1.9–3.9)

3.9 months (95% CI 3.7–5.8)

Median PFS — sotorasib 240 mg + panitumumab

Versus 2.2 months in the standard-treatment group

0.49 (95% CI 0.30–0.80)

Hazard ratio for progression or death — 960 mg vs standard treatment

P = 0.006

0.58 (95% CI 0.36–0.93)

Hazard ratio for progression or death — 240 mg vs standard treatment

P = 0.03

26.4% (960 mg) vs 5.7% (240 mg) vs 0% (standard treatment)

Objective response

95% CI 15.3–40.3; 1.2–15.7; 0.0–6.6

35.8% (960 mg) vs 30.2% (240 mg) vs 43.1% (standard treatment)

Grade 3 or higher treatment-related adverse events

Data still maturing

Overall survival

Median follow-up 7.8 months (range 0.1–13.9)

Dose and schedule cards

Sotorasib + panitumumab (CodeBreaK 300)

KRAS G12C-mutant metastatic colorectal cancer, after fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapyEach drug’s schedule in the tableOn the page “Colorectal cancer” · Metastatic colorectal cancer: later lines by biomarker (HER2-positive, KRAS G12C)

KRAS G12C-mutant metastatic colorectal cancer, after fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy

Drug	Dose	Route	Schedule
Sotorasib	960 mg once daily	Oral	Continuous (first dose before the first panitumumab infusion)
Panitumumab	6 mg/kg	IV	Day 1 (every 14 days)

Cycle schedule: Panitumumab every 14 days; sotorasib daily and continuously
Duration: Until disease progression or unacceptable toxicity

Doses from the FDA labels for sotorasib and panitumumab; evidence: CodeBreaK 300.

If sotorasib is withheld or permanently discontinued, panitumumab should also be stopped. Liver tests every 3 weeks for the first 3 months and monthly thereafter; stop sotorasib immediately if ILD is suspected; avoid proton pump inhibitors and H2 antagonists.

On the page “Colorectal cancer” · Metastatic colorectal cancer: later lines by biomarker (HER2-positive, KRAS G12C)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Sotorasib 960 mg + panitumumab

Sotorasib 960 mg orally once daily + panitumumab 6 mg/kg IV every 2 weeks (53 patients); until disease progression, loss of clinical benefit or intolerance. Stopping sotorasib required stopping panitumumab, but sotorasib could be continued if panitumumab was stopped. (The FDA-approved regimen.)

2Sotorasib 240 mg + panitumumab

Sotorasib 240 mg orally once daily + panitumumab 6 mg/kg IV every 2 weeks (53 patients).

3Standard treatment

At the investigator's choice: oral trifluridine/tipiracil or oral regorafenib (54 patients); doses are not given in the sources available (in the FDA labels: trifluridine/tipiracil 35 mg/m² twice daily, days 1 to 5 and 8 to 12 every 28 days; regorafenib 160 mg daily, days 1 to 21 every 28 days).

Source of the regimen details: FDA label for sotorasib (LUMAKRAS; Clinical Studies section, CodeBreaK 300) and ClinicalTrials.gov NCT05198934; the doses of the control-group drugs are not given in these sources

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with chemotherapy-refractory metastatic colorectal cancer with a KRAS G12C mutation (confirmed in tumour tissue by the central laboratory) who had not previously received a KRAS G12C inhibitor. According to the FDA label: at least one previous line of therapy for metastatic disease, previous receipt of a fluoropyrimidine, oxaliplatin and irinotecan (unless contraindicated), ECOG 0 to 2 and at least one measurable lesion.

Endpoints

Primary endpoint: progression-free survival (PFS) by blinded independent central review per RECIST version 1.1. Key secondary endpoints: overall survival and objective response.

Safety and side effects

Grade 3 or higher treatment-related adverse events occurred in 35.8%, 30.2% and 43.1% of patients in the sotorasib 960 mg + panitumumab, sotorasib 240 mg + panitumumab and standard-treatment groups, respectively. The most common adverse events with sotorasib plus panitumumab were skin-related events and hypomagnesaemia. According to the authors, the toxic effects were as expected for each of the two drugs alone and led to discontinuation in few cases.

Clinical significance and place in guidelines

Based on the abstract, sotorasib plus panitumumab improved progression-free survival compared with standard treatment in patients with chemotherapy-refractory metastatic colorectal cancer with a KRAS G12C mutation. This finding supports the strategy of combining a KRAS G12C inhibitor with an EGFR inhibitor in this group of patients. The abstract gives no definitive result for overall survival, and the data are still maturing. Drug approval status and the place of this combination in clinical guidelines should be checked against up-to-date sources.

Limitations

Based on the abstract, median follow-up was short (7.8 months) and overall survival data were not yet mature. The study was open-label and the sample size in each group was about 50 patients. An erratum to this paper was published in N Engl J Med 2025;392(7):728 and should be checked when citing it.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.