The KRAS inhibitor sotorasib provides some clinical benefit in patients with advanced or metastatic KRASG12C-mutant colorectal cancer, according to results of a phase II clinical trial. The objective response rate was 9.7%, the disease control rate was 82.3%, and the progression-free survival was 4 months.

The KRAS inhibitor sotorasib (Lumakras; Amgen) offers clinical improvement in about 10% of patients with advanced or metastatic colorectal cancer, according to a recent study (Lancet Oncol 2022;23:115–24). To increase the percentage of patients who benefit, researchers say, combination therapies will be necessary.

KRAS mutations occur in about 40% of colorectal cancers and 25% of tumors overall, but until recently, researchers considered KRAS undruggable. Now, however, several KRAS inhibitors are in clinical trials, and one, sotorasib, has been approved to treat KRASG12C-mutant non–small cell lung cancer (NSCLC) based on findings from the phase II portion of the CodeBreaK100 trial.

CodeBreaK100 also included patients with colorectal cancer harboring KRASG12C mutations, who account for about 3% of cases. In the phase I portion of the trial, these patients experienced an objective response rate (ORR) of 7.1% and a median progression-free survival (PFS) of 4 months with sotorasib.

In the latest article, Marwan Fakih, MD, of City of Hope in Duarte, CA, and colleagues report interim results for the 62 participants with colorectal cancer—all of whom had advanced or metastatic disease that progressed despite treatment with fluoropyrimidine, oxaliplatin, and irinotecan—in the phase II part of the trial.

The ORR for this group was 9.7%, and 82.3% achieved disease control. After a median follow-up of 11 months, median PFS was 4 months. The median overall survival was 10.6 months. “We have proof of principle that inhibiting the G12C mutation provides clinical benefit” in colorectal cancer, says Fakih.

The participants did not fare as well on the drug as patients with NSCLC, who had an ORR of 37.1% in the phase II portion of CodeBreaK100 (N Engl J Med 2021;384:2371–81). Drugs such as BRAF inhibitors are also less effective against colorectal cancer than other tumors. Researchers are not sure what causes the difference. One hypothesis is that colorectal tumors upregulate the EGFR pathway and become resistant, whereas lung tumors do not, Fakih says.

“It's promising that there's any response—this is a heavily pretreated population,” with most patients having received at least three prior therapies, says Christopher Lieu, MD, of the University of Colorado School of Medicine in Aurora, who wasn't connected to the study. “This is a step in the right direction.”

Mohamed Salem, MD, of the Levine Cancer Institute in Charlotte, NC, who wasn't connected to the research, says that the results are encouraging because of the patients’ high rate of disease control. “Sotorasib works. Now the question is how to improve the response rate and achieve durable responses,” he says.

The answer, researchers say, lies in combining KRAS inhibitors with other drugs, such as the EGFR inhibitors cetuximab (Erbitux; Lilly) and panitumumab (Vectibix; Amgen).

“If sotorasib monotherapy existed in a vacuum, there would be reason to think it should move down a regulatory pathway for late-line use,” comments Jared Weiss, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, who wasn't involved in the study. But promising early results from pairing the KRASG12C inhibitor adagrasib (Mirati Therapeutics) with cetuximab, as well as preliminary data for the sotorasib–panitumumab combination, mean that “sotorasib monotherapy should not move forward toward FDA approval,” he says. –Mitch Leslie