The first KRAS inhibitor approved for the treatment of lung cancer provided a clinically meaningful overall survival benefit in an updated analysis of a phase 2 study.
Treatment with sotorasib yielded a median overall survival (OS) of 12.5 months in patients with previously treated KRAS p.G12C-mutated non-small cell lung cancer (NSCLC), according to an analysis of the phase 2 CodeBreaK 100 trial data presented at the American Society of Clinical Oncology Annual Meeting.
Median progression-free survival (PFS) was 6.8 months in this update, which included a median follow-up of more than 15 months, according to investigator Ferdinandos Skoulidis, MD, PhD, assistant professor of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.
Efficacy responses
The confirmed objective response rate was 37.1%, including a 3.2% complete response rate and a median duration of response of 11.1 months, according to the report by Dr. Skoulidis.
In exploratory analyses, the benefit of sotorasib was consistent across patient subgroups, Dr. Skoulidis said in his presentation (Abstract 9003).
In particular, efficacy was observed in subgroups with co-occurring mutations in TP53, STK11, and KEAP1, which are molecular indicators of suboptimal outcomes on standard systemic treatments, according to Dr. Skoulidis.
This update on the registrational phase 2 CodeBreaK100 trial, published concurrently in the New England Journal of Medicine , came just one week after the U.S. Food and Drug Administration (FDA) granted accelerated approval to sotorasib.
Sotorasib was approved for the treatment of patients with previously treated KRAS G12C‑mutated locally advanced or metastatic NSCLC on the basis of previously reported results from CodeBreaK100.
This sotorasib indication represents a “historic milestone,” Dr. Skoulidis said in an interview.
No previously studied selective KRAS inhibitor has been approved despite scientific research efforts that stretch back nearly four decades, he explained.
“In a way, one can say that we have dealt KRAS-mutant lung cancer a knockdown blow, however, I should point out that the fight is not over,” he added.
“These clinical results will no doubt spearhead and galvanize further efforts to develop even more effective therapeutic combinations in the future, as well as identify and either forestall or overcome the eventual development of acquired resistance,” he said.
Only 1 out of 8 patients
The KRAS p.G12C mutation is present in about 13% of lung adenocarcinomas, or about one in every eight patients with nonsquamous NSCLC, Dr. Skoulidis said in the interview.
“We are estimating that this is in the region of 13,000 patients newly diagnosed every year in the U.S., and approximately 13,000 patients or so that are currently being treated in the second- or third-line setting,” he said.
The CodeBreaK100 trial included 126 patients with locally advanced or metastatic NSCLC and KRAS p.G12C mutation who had progressed on prior systemic therapies. About 43% had one prior line of treatment, while 35% had two lines, and 22% had three lines. A total of 81% had previously received both platinum-based chemotherapy and PD-1/PD-L1 axis inhibitors.
Most treatment-related adverse events in the study were grade 1-2 and generally manageable, according to Dr. Skoulidis. About 20% of patients experienced grade 3 treatment-related adverse events, which were mostly diarrhea or increases in aspartate aminotransferase and alanine aminotransferase levels. A grade 4 treatment-related adverse event, pneumonitis and dyspnea, was reported in one patient or approximately 1%.