Sotorasib Shows Modest Anti-Tumor Activity in Colorectal Cancer, More Research Needed


Sotorasib produced an objective response rate of 9.7% in patients with colorectal cancer.

Once-daily sotorasib showed modest anti-tumor activity and a manageable safety profile in patients with heavily pretreated chemorefractory patients with colorectal cancer with KRASG12C mutations. However, only an overall response rate of 9.7%, according to an analysis of the CodeBreaK100 trial published in The Lancet Oncology.

Sotorasib is a specific, irreversible KRASG12C protein inhibitor. In the CodeBreaK100 (NCT03600883) phase 1 trial, the agent showed clinical activity as a monotherapy in mutated solid tumors, such as colorectal cancer. In phase 2 of the trial was further planned to investigate clinical activity and safety.

The colorectal cohort of the basket trial enrolled patients from 33 medical centers across 9 countries. In order to be included, they must be 18 years of age or older, have at least one measurable lesion, and have an ECOG performance status of 1 or less. In order to meet enrollment criteria, patients must have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment.

In total, 86 patients were screened to be enrolled in the colorectal cohort. Ultimately, 62 patients were enrolled and treated, and all 62 patients were evaluated for efficacy and safety. At the data cutoff of March 1, 2021, 5 patients remained on treatment. Reasons for discontinuation included progressive disease (52), patient request (3), adverse events (1), and requirement for alternative therapy (1).

The median age of patients was 56 (range, 49-61), 55% were female, 68% were white, and 90% were not Hispanic or Latino. Fifty-six percent of patients had an ECOG performance status of 0, and none had brain metastasis at baseline. The number of previous lines of anti-cancer systemic therapy included 1 (5%), 2 (23%), 3 (31%), and 4 or more (42%). Previous anticancer therapies include oxaliplatin (100%), irinotecan (100%), fluoropyrimidine (100%), bevacizumab (Avastin) (90%), trifluridine-tipiracil (Lonsurf) (31%), regorafenib (Stivarga) (31%), and anti-PD-1/PD-L1. Seventy-seven percent had a diagnosis of colon cancer while 23% had a diagnosis of rectal cancer.

An objective response rate of 9.7% (95% CI, 3.6-19.9) was observed, not meeting the baseline. The disease control rate was 82.3% (95% CI, 70.5-90.8). No complete responses were seen, with partial responses seen in 10% of patients. Stable disease was observed in 73% of patients and progressive disease in 18%of patients. The median time to response was 2 months (range, 1.4-2.8) and the median duration of response was 4.2 months (range, 2.9-8.5).

Common grade 1/2 adverse events occurred in 44% of patients and included diarrhea (18%) and nausea (16%). Common grade 3 adverse events, which occurred in 10% of patients, included diarrhea (3%), back pain (2%), and acute kidney injury (2%). One incident of grade 4 blood creatine phosphokinase increase was observed.

“Although the 9.7% objective response rate for patients treated with sotorasib monotherapy did not reach the benchmark objective response rate 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 KRASG12C- mutated colorectal cancer,” wrote study authors.


Fakih M, 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: 115–24. S1470-2045(21)00605-7

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