Selective KRASG12C inhibitor sotorasib leads to superior PFS in colorectal cancer

Patients with KRAS^G12C-mutated, metastatic colorectal cancer (CRC) benefit from the treatment with the combination of sotorasib, a KRAS^G12C mutation-selective inhibitor, and the EGFR-inhibitor panitumumab, first results from the phase 3 CodeBreak300 trial showed. Overall survival data is not yet mature.

Of all metastatic colorectal tumours, about 3% harbour a KRAS^G12C mutation, which is associated with poor prognosis [1]. Sotorasib is a selective KRAS inhibitor targeting the protein arising from the KRAS^G12C mutation. In the phase 1b CodeBreak 101 trial (NCT04185883), the combination of sotorasib with the EGFR inhibitor panitumumab, showed a promising objective response rate (ORR 30%) in participants with advanced KRAS^G12C-mutated CRC [2]. The current CodeBreak300 trial (NCT05198934) is a randomised phase 3 study that further explores the clinical efficacy and safety of the combination of sotorasib and panitumumab in participants with KRAS^G12C-mutated CRC. Dr Filippo Pietrantonio (Istituto Nazionale dei Tumori, Italy) presented the first results [3].

The study enrolled 159 participants who had been previously treated with at least 1 line of therapy for metastatic CRC. Participants were randomised into 3 arms: sotorasib 960 mg daily plus panitumumab (Arm A), sotorasib 240 mg daily plus panitumumab (Arm B) or the control arm (investigator’s choice: trifluridine/tipiracil or regorafenib). The primary endpoint of the study is progression-free survival (PFS).

After a median follow-up of 7.8 months, sotorasib (both doses) plus panitumumab significantly improved PFS. Median PFS was 5.6 months, 3.9 months and 2.2 months in Arm A, Arm B and the control arm, respectively (Arm A: HR 0.48; 95% CI 0.30–0.80; P=0.006 and Arm B: HR 0.58; 95% CI 0.36–0.93; P=0.30 vs control arm). PFS benefit was seen in all prespecified subgroups. ORR was significantly improved in Arm A: 26% versus 6% in Arm B and 0% in the control arm. Overall survival data were not mature at the data cut-off date. “Both sotorasib doses plus panitumumab were well tolerated with no new safety signals and no fatal treatment-related adverse events, supporting a dose of 960 mg daily as the sotorasib dose in CRC,” highlighted Dr Pietrantonio.

This data suggests that sotorasib plus panitumumab could be a potential new standard of care for patients with pretreated KRAS^G12C-mutated metastatic CRC. “However, overall survival data needs to be awaited,” cautioned discussant Dr Miriam Koopmans (University Medical Center Utrecht, the Netherlands).

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   1. Taieb J, et al. Ann Oncol. Aug 22, 2023. DOI: 10.1016/j.annonc.2023.08.006.
   2. Hong DS, et al. J Clin Oncol 2022;40(4_suppl):TPS214.
   3. Pietrantonio F, et al. Sotorasib plus panitumumab versus standard-of-care for chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreak 300 phase III study. Abstract LBA10, ESMO 2023, 20–24 October, Madrid, Spain.

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Posted on 18 December 202318 December 2023