Paper recently published in The Lancet Oncology demonstrates that sotorasib may be a therapeutic strategy for heavily pretreated patients with KRAS p.G12C mutated metastatic CRC, whose current treatment options are quite limited
Patients with advanced colorectal cancer (CRC) have a poor prognosis, with 5-year survival rates around 14%. For patients who have progressed or relapsed after fluoropyrimidine, oxaliplatin, and irinotecan, the addition of a 3rd-line or higher therapeutic agent (regorafenib or trifluridine-tipiracil, for example) are options whose response rates are between 1-4%, progression-free survival between 2-3 months and overall survival around 6-9 months, highlighting the great unmet need for safer and more effective treatment options.
KRAS mutations are present in approximately 40% of CRCs. The KRAS p.G12C mutation is found in 3% of CRCs, conferring worse outcomes compared to patients with CRC that harbor other KRAS mutations. Although targeted therapy with EGFR inhibitors is indicated for a selected subgroup of patients with metastatic CRC, the strategy is not effective for mutated RAS CRC.
On this point, data was published, in The Lancet, from CodeBreaK100 (NCT03600883), an ongoing, single-arm, international, phase 2 study evaluating the efficacy and safety of sotorasib monotherapy, a small molecule that inhibits the KRASG12C protein specifically and irreversibly in previously treated patients with advanced CRC (mean of 3 previous systemic lines) who had a mutation in KRAS p.G12C.
Adults ≥ 18 years with advanced solid tumors KRAS p.G12C mutated from August 2019 to May 2020 were included. Patients received 960 mg of sotorasib orally once daily. The primary endpoint was the objective response rate (complete or partial response) according to the central blinded independent review. Major secondary outcomes included: duration of response, rate of disease control (complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. The data cut took place on March 1st, 2021.
In all, 62 patients with KRAS p.G12C mutated CRC were enrolled and received at least 1 dose of sotorasib; 72.5% of patients were exposed to ≥ 3 previous systemic lines. An objective response was observed in 6 individuals (9.7%, 95% CI: 3.63-19.88), all with partial response. The duration of response ranged from 1.4+ to 9.7+ months; 2 responders (33.3%) remained on treatment due to sustained response. Disease control was achieved in 51 patients (82.3%, 95% CI: 70.47-90.80).
The median progression-free survival was 4.0 months (95% CI: 2.8-4.2) and the median overall survival was 10.6 months (95% CI: 7.7-15.6), with a mean follow-up time of 11.0 and 11.4 months, respectively.
Treatment-emergent adverse events of any degree, regardless of attribution, were observed in 60 patients (96.8%). The most common treatment-related grade 3 adverse event was diarrhea (2 of 62 patients [3.2%]). In addition, a grade 4 event in 1 patient (1.6%) was also reported, and no fatal events.
The authors conclude that sotorasib demonstrated modest activity in monotherapy, but notable median progression-free and overall survival for patients with KRAS p.G12C mutated, heavily pretreated, and refractory metastatic CRC whose current treatment options are quite limited. In view of the manageable toxicity profile, sotorasib has the potential to offer greater efficacy if evaluated in combination with other anticancer therapies.
1. Marwan G. Fakih, MD et al., Sotorasib for previously treated colorectal cancers with KRAS p.G12C mutation: results from a single-arm phase 2 clinical trial. Lancet Oncol 2021. Published Online December 14, 2021 https://doi.org/10.1016/ S1470-2045(21)00605-7