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CodeBreaK 300: Promising survival trends in KRAS G12C-mutated mCRC

Presented by
Prof. Marwan Fakih, City of Hope Comprehensive Cancer Center, CA, USA
Conference
ASCO 2024
Trial
Phase 3, CodeBreaK 300
Doi
https://doi.org/10.55788/6be1a55b
The randomised phase 3 CodeBreaK 300 trial evaluated 2 doses of the KRAS G12C inhibitor sotorasib in combination with the EGFR inhibitor panitumumab in patients with pretreated KRAS G12C-mutated metastatic colorectal cancer (mCRC). Both doses led to longer overall survival (OS) compared with standard treatment, although the study was underpowered to reach significance. The toxic effects observed were consistent with those expected from each agent individually and led to few treatment discontinuations.

Earlier, the primary analysis of CodeBreaK 300 (NCT05198934) indicated that the combination of sotorasib and panitumumab was superior to the investigator’s choice of treatment (including trifluridine/tipiracil and regorafenib) to meet the primary endpoint of  progression-free survival (PFS) [1]. At the time, OS data, a secondary endpoint of the trial, was still immature. Prof. Marwan Fakih (City of Hope Comprehensive Cancer Center, CA, USA) presented the results of the final OS analysis, which was conducted when the data reached 50% maturity [2].

With a median follow-up of 13.6 months, median OS was not reached for the higher 960 mg sotorasib dose in combination with 6 mg/kg panitumumab group (n=53), and for the lower dose sotorasib 240 mg + 6 mg/kg panitumumab group (n=53) it was 11.9 months. Prof. Fakih pointed out that “the investigator’s choice group (n=54) performed better than expected, with a median OS of 10.3 months.”

The calculated hazard ratio for OS was 0.70 (95% CI 0.41–1.18; P=0.20) for the higher 960 mg sotorasib dose in combination with panitumumab compared with the investigator’s choice, and HR 0.83 (95% CI 0.49–1.39; P=0.50) for the lower dose sotorasib 240 mg + panitumumab compared with the investigator’s choice. Although the study was not powered to show a statistically significant difference in OS, these results indicate a trend toward improved OS with the higher 960 mg sotorasib dose in combination with panitumumab.

Prof. Fakih concluded: “Although the OS improvement for 960 mg sotorasib per day plus panitumumab did not reach statistical significance –the study was vastly underpowered– the improvement was clinically meaningful and did point to a trend in improved OS in the experimental arms. The data for 960 mg of sotorasib support its consideration as a standard-of-care in patients with pretreated KRAS G12C-mutated mCRC.”

  1. Fakih MG, et al. N Engl J Med 2023;389(23):2125-2139.
  2. Fakih MG et al, Overall survival (OS) of phase 3 CodeBreaK 300 study of sotorasib plus panitumumab (soto+pani) versus investigator’s choice of therapy for KRASG12C-mutated metastatic colorectal cancer (mCRC). Abstract LBA3510, ASCO Annual Meeting 2024, 31 May–4 June, Chicago, IL, USA.

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