Sotorasib Misses Mark But Yields Modest Anti-Tumor Activity in KRAS G12C-Mutated CRC

Patients with KRAS G12C-mutated colorectal cancer treated with sotorasib showed modest anti-tumor activity during a phase 2 trial.

Despite missing the mark in terms of overall response rate (ORR), investigators reported a manageable safety profile and modest anti-tumor activity among patients with KRAS G12C–mutated colorectal cancer (CRC) following treatment with sotorasib (Lumakras) orally once per day, according to a phase 2 study (NCT03600883) published in The Lancet Oncology.

Investigators reported an ORR of 9.7% (95% CI, 3.6%-19.9%) among patients who underwent treatment patients, all of whom were partial responders.

“Although the 9.7% [ORR] for patients treated with sotorasib monotherapy did not reach the benchmark [ORR] specified in our protocol, sotorasib treatment was associated with clinical benefits, such as a disease control rate of 82% and tumor shrinkage in 66%, in refractory colorectal cancer, and combination of sotorasib with targeted or non-targeted therapies warrants further evaluation in patients with KRAS G12C–mutated [CRC],” investigators of the study wrote.

A total of 62 patients who were previously treated for KRAS G12C–mutated CRC were enrolled on the trial. Patients had a median duration of treatment of 18 weeks, and 5 patients are receiving ongoing treatment sotorasib treatment after data cutoff.

Patients received 960 mg of sotorasib orally once daily, with treatment continuing until disease progression, development of adverse effects (AEs), withdrawal of consent, or death.

The median patient age was 56.0 years, and 55% of the population was women. Additionally, patients received a median of 3 lines of previous systemic anticancer therapy, and 45 patients had 3 lines of previous therapy. Previous treatment included oxaliplatin, irinotecan, and fluoropyrimidine (n = 62) and bevacizumab (Avastin; n = 56).

At baseline, it was established by blinded independent central review that all patients had measurable disease The sensitivity analysis indicated that 12.9% (95% CI, 5.7%-23.9%) of patients had a confirmed response, and all patients had a partial response.

At 6 weeks during the first tumor assessment, investigators reported that 3 of 6 patients responded, with 2 remaining on treatment 11 months past the cutoff data. Investigators also reported that the median percentage of best tumor shrinkage was 46.3% among responders. Eleven patients experienced progressive disease.

Treatment-related adverse effects (TRAEs) of any grade were observed in 60 patients. Grade 3 TRAEs were observed in 6 patients, with the most common being diarrhea in 2 patients. Grade 4 TRAEs were seen in 1 patient with blood phosphokinase increase, and there were no fatal events. Dose modifications due to TRAEs were necesary in 11 patients, and 1 patient required treatment discontinuation.

Events of interest included grade 3 or higher hepatotoxicity, which occurred in 5 patients. No cases were fatal, serious, or led to discontinuation. Five patients had grade 3 or worse renal toxicity, and 2 patients had serious renal toxicity. No patient needed to discontinue due to renal toxicity or experienced events that were fatal. Patients did not experience pneumonitis.


Fakih MG, Kopetz S, Kuboki Y, et al. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol. 2022;23(1):115-124. doi:10.1016/S1470-2045(21)00605-7

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