Results from the phase II cohort of the CodeBreaK 100 study showed that treatment with the KRAS G12C inhibitor sotorasib achieved a 37.1% objective response rate and a median overall survival of 12.5 months in previously treated patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC). The findings were presented at the 2021 ASCO Annual Meeting (Abstract 9003) and published in The New England Journal of Medicine by Ferdinandos Skoulidis, MD, PhD, and colleagues.

Trial results indicated the targeted therapy was safe and tolerable in a heavily pretreated patient population. The reported findings make sotorasib the first KRAS G12C inhibitor to demonstrate an overall survival benefit in a registrational phase II clinical trial.

Sotorasib was approved by the U.S. Food and Drug Administration on May 28, 2021, based on previously reported results from the CodeBreaK 100 trial. It is the first-ever direct KRAS inhibitor to earn regulatory approval.

This trial provides convincing evidence that mutant KRAS can be successfully and selectively targeted, resulting in meaningful prolongation of survival without compromising quality of life.

— Ferdinandos Skoulidis, MD, PhD

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“KRAS has been an elusive therapeutic target for more than 30 years and was deemed ‘undruggable.’ This trial provides convincing evidence that mutant KRAS can be successfully and selectively targeted, resulting in meaningful prolongation of survival without compromising quality of life,” said lead author Dr. Skoulidis, Assistant Professor of Thoracic/Head & Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. “These results, along with the regulatory approval of sotorasib, represent a major landmark for patients with KRAS G12C–mutated lung cancer, who now have an approved targeted therapy option.”

KRAS is the most common oncogenic driver in NSCLC, found to be mutated in 25% to 30% of patients. Sotorasib (also known as AMG 510) is an irreversible and selective small-molecule inhibitor that targets a specific type of mutant KRAS protein called KRAS G12C, which is found in approximately 13% of all lung adenocarcinomas.

Responses and Toxicities

The single-arm, multicenter trial enrolled 126 patients with locally advanced or metastatic KRAS G12C–mutated NSCLC that had progressed after receiving immune checkpoint inhibitors and/or platinum-based chemotherapy. Sotorasib is a once-daily oral drug. The primary endpoint was objective response, assessed by independent central review.

The study found an objective response in 46 patients (37.1%), including 4 complete responses (3.2%) and 42 partial responses (33.9%). A total of 100 patients (80.6%) had disease control, with tumors shrinking or remaining stable. The median overall survival was 12.5 months, median duration of response was 11.1 months, and median progression-free survival was 6.8 months.

Toxicities were reported to be manageable and primarily low-grade, with only nine patients (7.1%) discontinuing therapy due to treatment-related adverse events. Of the 88 patients (69.8%) who had treatment-related adverse events, 25 (19.8%) were grade 3 and 1 (0.8%) was grade 4.

The median age of study participants was 63.5 years; 50% were men and 50% were women. The majority of patients (81.7%) were White, followed by Asian (15.1%), Black (1.6%), and other races (1.6%). Patients had received up to three previous lines of therapy, and 96.8% had metastatic disease. A total of 81% of patients had previously received both platinum-based chemotherapy and immune checkpoint inhibitors.

“In 8 of 10 patients, the tumor either shrank or remained stable, and these patients frequently saw improvement in their symptoms,” said Dr. Skoulidis. “They’re able to lead longer, active lives, because this targeted therapy is not associated with any major toxicities that would adversely affect the patient's quality of life.”

Molecular Subgroup Analyses

The study also analyzed responses among molecular subgroups and found particularly encouraging results among patients with STK11 comutations, without concurrent mutations in KEAP1. The 50% objective response rate and 11-month median progression-free survival in this group are notable, because STK11-mutated tumors tend to respond poorly to standard-of-care therapies, including immunotherapy and chemotherapy.

Responses were also observed in subgroups defined according to PD-L1 expression and tumor mutational burden.

The drug showed broad and consistent activity across patients with a wide range of baseline characteristics related to age, previous lines of therapy, and other demographics.

“These study results are practice-changing, but our work isn’t done,” said Dr. Skoulidis. “Extensive efforts are underway to understand the determinants of response to sotorasib and to characterize the full spectrum of possible mechanisms of resistance. These results represent a foundational step in our progress against KRAS-mutant tumors and will likely be a stepping stone for even more effective combination regimens. The future looks promising.”

Disclosure: For full disclosures of the study authors, visit coi.asco.org.