Modest activity of sotorasib in KRAS G12C-mutated colorectal cancer

February 2022 Cancer trials Jolien Blokken

In the phase II CodeBreaK100 trial, sotorasib monotherapy showed modest activity and notable median progression-free survival and overall survival for patients with heavily pre-treated, refractory KRASG12C-mutated colorectal cancer who have limited effective treatment options. Furthermore, targeted treatment with sotorasib was tolerable and displayed a manageable safety profile.


“In heavily pre-treated chemorefractory colorectal cancer patients with a KRASG12C mutation, sotorasib showed modest anti-tumour activity with a response rate of 10%.”

Mutations in KRAS are found in approximately 40% of colorectal cancers (CRC), with the KRASG12C mutation occurring in approximately 3% of CRC. Patients with KRASG12C-mutated CRC have worse outcomes than patients with other KRAS mutations and novel treatment options for these patients are thus urgently needed. Sotorasib is a small molecule that specifically and irreversibly inhibits the KRASG12C protein by covalently binding the cysteine residue in the P2 pocket, trapping the protein in the inactive GDP-bound state and preventing downstream signalling. Previously reported data from the CodeBreaK100 trial showed that sotorasib has clinical activity as a monotherapy in KRASG12C-mutated solid tumours. Recently, activity and safety data for 62 patients with previously treated advanced KRASG12C-mutated CRC from the ongoing, single-arm, phase II CodeBreaK100 clinical trial were published.

CodeBreaK100 study design

This single-arm, phase II basket trial enrolled patients with KRASG12C-mutated advanced solid tumours if they were aged 18 years or older, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Only data for patients with CRC, enrolled at 33 medical centres in nine countries, are presented here. To be eligible, patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg sotorasib orally once per day until disease progression, development of unacceptable side-effects, withdrawal of consent, or death. The primary endpoint was objective response (complete or partial response) as assessed by blinded independent central review. Response was evaluated in patients who received at least one dose of sotorasib and had at least one measurable lesion at baseline; safety was evaluated in patients who received at least one dose of sotorasib. This analysis is a prespecified analysis triggered by the phase II colorectal cancer cohort.


At the data cut-off for this prespecified analysis (March 2021), the median treatment duration was 18 weeks. The trial is ongoing, with five patients with CRC continuing sotorasib treatment as of data cut-off. Patients had received a median of three previous lines of systemic anticancer therapy. All patients received previous oxaliplatin, irinotecan and fluoropyrimidine and 90% received previous bevacizumab. According to blinded independent central review, all 62 patients had measurable disease at baseline and were evaluated for response. Objective response was observed in six patients, all with partial response, resulting in an objective response rate of 9.7% (95%CI: 3.6-19.9). The 95%CI lower bound of 3.6% did not exceed the benchmark of 10%. Response was observed at the first tumour assessment, at approximately week 6, in three out of six responders. Two responders were remaining on treatment with ongoing response over 11 months as of the data cut-off date. Disease control was achieved in 82.3% of patients and tumour shrinkage of any magnitude was observed in 66% of patients. At a median follow-up of 11.0 months, median PFS was 4.0 months. Furthermore, with a median follow-up of 11.4 months, median OS was 10.6 months.

Treatment-emergent adverse events of any grade, regardless of attribution, were observed in 60 (97%) patients. Treatment-related adverse events (TRAEs) of grade 3 occurred in six (10%) patients, the most common adverse event was diarrhoea (3%). A treatment-related grade 4 adverse event was reported in one patient (blood creatine phosphokinase increase), and no fatal events occurred. Serious TRAEs occurred in two patients (back pain and acute kidney injury).


In phase II of the CodeBreaK100 trial, oral administration of sotorasib once per day showed modest monotherapy anti-tumour activity and manageable safety and tolerability in patients with advanced KRASG12C-mutated colorectal cancer. Studies are ongoing to assess the safety and efficacy of sotorasib in combination with targeted or non-targeted therapies.


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. 2022:23:115-24.