Next-Generation KRAS G12C Inhibitor Shows ‘Robust’ Efficacy in Advanced Lung Cancer

SAN DIEGO — Treatment with investigational elisrasib, a next-generation KRAS G12C inhibitor, showed efficacy in patients with advanced non-small cell lung cancer (NSCLC) with and without previous exposure to other KRAS G12C inhibitors, according to results from a phase I/II study.

About 60% of patients who were naive to KRAS G12C inhibitor therapy responded to elisrasib, with a median progression-free survival (PFS) ranging from 9 months to 1 year, reported Byoung Chul Cho, MD, PhD, of the Yonsei University College of Medicine in Seoul.

Moreover, about one-third of patients whose disease progressed on prior KRAS G12C inhibitors responded to elisrasib, indicating “robust and durable efficacy,” even when first-generation KRAS G12C inhibitors failed, Cho said at the American Association for Cancer Research annual meeting.

Cho explained that elisrasib is similar to first-generation KRAS inhibitors such as sotorasib (Lumakras) and adagrasib (Krazati) as it selectively binds to mutant KRAS G12C and locks it in its inactive state, or the “off ” position, thus blocking downstream cancer signaling.

However, he added, elisrasib is designed to maximize target engagement efficiency and sustain inhibition.

Discussant Adrian G. Sacher, MD, of the Princess Margaret Cancer Centre in Toronto, suggested that the utility of a new KRAS G12C inhibitor hinges upon meeting certain key performance measures, and that with elisrasib, “it’s clear [it] demonstrates a favorable response rate relative to other highly potent inhibitors in this setting.”

The study also showed the drug’s potential to overcome prior resistance to other agents, and its activity in difficult-to-treat subsets, he said.

“Thus, the early-phase data here do support elisrasib as a promising KRAS G12C ‘off’ inhibitor as monotherapy, with the potential for combination therapy in the future,” Sacher observed. “That being said, elisrasib is not emerging into the field in a vacuum. It is emerging late into an extremely crowded field.”

“The reality is that the modest clinical activity of existing KRAS G12C ‘off’ inhibitor monotherapy has led to a rapid push to develop combination strategies,” he added. “KRAS G12C and immunotherapy strategies are already well along in development, particularly in the frontline setting in metastatic non-small cell lung cancer.”

In this phase I/II study, elisrasib was administered orally once daily in 21-day cycles at 6 dose levels ranging from 50 to 900 mg, with 600 mg selected as the recommended treatment dose. The median follow-up time was 11.3 months in patients who had not been previously exposed to KRAS G12C inhibitor therapy, and 10.6 months in patients with G12C inhibitor-refractory disease.

Median age was 66 years in the KRAS G12C-naive population and 68.5 years in the refractory population. Most patients were men and former or current smokers, and about half were from China.

At all dose levels of elisrasib among patients naive to KRAS G12C inhibitor therapy, the overall response rate (ORR) was 59.5%, the median duration of response (DOR) was 14.9 months, median PFS was 9.4 months, and the 12-month overall survival (OS) rate was 68%.

At the recommended phase II dose of 600 mg, the ORR was 58.8%, median DOR was 16.5 months, median PFS was 12.2 months, and the 12-month OS rate was 72%.

Among the patients who progressed after KRAS G12C inhibitor therapy and were treated with elisrasib at 600 mg, the ORR was 32.3%, median DOR was 15.6 months, median PFS was 8.1 months, and the 12-month OS rate was 71%.

In the five patients with KRAS amplification, a known mechanism of resistance to G12C inhibitors, three responded to elisrasib.

Cho noted that the drug was effective in hard-to-treat subsets of patients, including those with STK11 and/or KEAP1 co-alterations.

The most common treatment-related adverse events (TRAEs) were gastrointestinal and low grade.

Grade ≥3 TRAEs were observed in 14% of patients in the KRAS G12C-naive population and 15.6% of those in the refractory population. One patient in each group discontinued elisrasib due to a TRAE.

In his discussion, Sacher noted that there was a signal of autoimmune hepatitis (increases in aspartate aminotransferase and alanine aminotransferase), which was consistent with the class of drugs. While the incidence was low and mostly low grade, he said that about 10% of patients had not received a previous checkpoint inhibitor, and that most who had were more than 60 days out from their previous treatment.

This “means the study may underestimate the actual risk of autoimmune hepatitis,” he suggested, adding that this “should be watched carefully, as we should watch with all KRAS G12C ‘off’ inhibitors.”