Second KRAS Inhibitor Represents Another Standard in Patients with Non-Small-Cell Lung Cancer and KRASG12C Mutation

A new treatment option for patients with advanced non-small-cell lung cancer (NSCLC) harboring a KRASG12C mutation is on the horizon, on the basis of results from a registrational single-arm Phase 2 study. If approved, adagrasib would represent the second agent that specifically targets KRASG12C mutations.

The data, reported at the 2022 annual meeting of the American Society of Clinical Oncology, demonstrate a median progression-free survival (PFS) of 6.5 months with adagrasib in patients with advanced incurable KRASG12C-mutant NSCLC previously treated with platinum-based chemotherapy and immunotherapy. After a median follow-up of 12.5 months, median overall survival in the study, known as KRYSTAL-1, was 12.6 months.

“These outcomes appear to be significantly better than those achieved with docetaxel, the standard-of-care chemotherapy in the second-line setting, and are similar to those observed with the first agent in this class, sotorasib,” says Nathan A. Pennell, MD, PhD, Director of the Lung Cancer Medical Oncology Program, Cleveland Clinic Taussig Cancer Institute, and a co-investigator of KRYSTAL-1. Cleveland Clinic was one of the primary sites for enrollment into KRYSTAL1.

Sotorasib received U.S. Food and Drug Administration (FDA) approval in 2021 for patients with previously treated NSCLC with a KRASG12C mutation, as determined by an FDA-approved test, based on the results from the CodeBreaK 100 clinical trial. Cleveland Clinic also participated in an expanded access protocol for sotorasib before its full approval by the FDA.

KRASG12C mutations act as oncogenic drivers. “KRAS mutations are the most common mutations in lung cancer,” says Dr. Pennell. “About 25 to 30% of people with adenocarcinoma of the lung, the most common type of NSCLC, have KRAS mutations. Almost half of those have a mutation in KRASG12C, so they occur in approximately 14% of patients with NSCLC”. Adagrasib irreversibly and selectively binds KRASG12C, locking it in its inactive state.

KRYSTAL-1 is a multicohort Phase 1/2 study evaluating adagrasib as monotherapy or in combination regimens in patients with advanced solid tumors harboring a KRASG12C mutation. Some 21% of patients enrolled had active central nervous system (CNS) metastases. Patients were treated with a median of two prior lines of systemic therapy, and 22% received three or more prior lines.

In the Phase 1/1b portion, the investigator-assessed overall response rate (ORR) was 53%, the median PFS was 11.1 months, and the median overall survival was not reached after a median follow-up of 17.3 months.

The Phase 2 cohort evaluated adagrasib in 116 patients. Almost all (98.3%) patients received adagrasib following treatment with immunotherapy and chemotherapy. As of the data cutoff of October 15, 2021, 48 responses were recorded in 112 patients evaluable for response, for an ORR of 42.9%. The complete response rate was 1%, the partial response rate was 42% and the disease control rate was 79.5%. “Historically, the response rate to second-line docetaxel is about 9%. Based purely on response rates, adagrasib appears much more effective than chemotherapy in the second line,” says Dr. Pennell. “Importantly, only about 6% of patients progressed as their best response, which means that more than 90% at least had their cancer stabilized or improved on adagrasib. That’s a hallmark of effective targeted therapies.” 

“The median duration of response with adagrasib was 8.5 months, which is much longer than we expect with chemotherapy, which tends to be less than 6 months,” he adds. “One third of patients were still on the study with their cancer under control at the final analysis, so some people get a quite long duration of response.”

Up to 42% of patients with KRASG12C–mutated NSCLC have CNS metastases at diagnosis. “Adagrasib has demonstrated CNS penetration and CNS tumor regression in preclinical models,” says Dr. Pennell. Patients with treated, stable CNS metastases had an ORR of 33% (95% CI, 18-52%) and an intracranial disease control rate of 85% (95%, CI 68-95%), with a duration of response of 11.2 months (95% CI, 3-NE).

The most commonly reported (≥25%) treatment-related adverse events (TREAs) of any grade were diarrhea, nausea, vomiting, fatigue, an increase in levels of alanine transaminase/aspartate transaminase and an increase in the level of blood creatinine. The most commonly reported grade ≥3 TRAEs were an increase in lipase level and anemia.

A Phase 3 trial comparing adagrasib monotherapy with docetaxel in previously treated patients with KRASG12C-mutant NSCLC is ongoing, as well as a first-line combination trial with pembrolizumab, and the use of adagrasib in other tumor types.

“Testing every patient with NSCLC for KRASG12C is now standard,” says Dr. Pennell. “These drugs [sotorasib and adagrasib] are absolutely the best available treatment for patients who have had initial chemotherapy immunotherapy.”