Dr Sabari on Preliminary Data From a Phase 1 Study of LY3537982 in KRAS G12C–mutant Advanced Solid Tumors

Joshua K. Sabari, MD, assistant professor, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health’s Perlmutter Cancer Center, discusses key findings from the phase 1 LOXO-RAS-20001 study (NCT04956640) of the KRAS G12C inhibitor LY3537982 in KRAS G12C–mutant advanced solid tumors.

This first-in-human study was designed to evaluate the preliminary efficacy and safety of oral LY3537982 in patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC), colorectal cancer (CRC), endometrial cancer, ovarian cancer, and pancreatic cancer, Sabari begins. To enroll in the study, patients were required to have received prior treatment with the standard of care (SOC) in their designated tumor type, or be unable to tolerate the SOC. Patients with no SOC options available for their disease type were also included.

The study consisted of a phase 1a dose-escalation phase to evaluate single-agent LY3537982, and a phase 1b dose-expansion phase to evaluate the agent both as a monotherapy and in combination with other agents, including pembrolizumab (Keytruda) and cetuximab (Erbitux). During the trial, the dosage of LY3537982 was increased from 50 mg to 200 mg, Sabari says. The agent was evaluated in combination with pembrolizumab at 50 mg, 100 mg, and 150 mg doses, he adds.

Results from the dose-escalation portion showed that patients with treatment-naive KRAS G12C–mutated NSCLC (n = 8) had an overall response rate (ORR) of 38% with LY3537982 monotherapy, Sabari reports. This agent produced an ORR of 7% (n = 1) in evaluable patients with NSCLC who had been previously treated with a KRAS G12C inhibitor (n = 14), he says. Meanwhile, evaluable patients with KRAS G12C–mutated CRC (n = 20) and pancreatic cancer (n = 12) had an ORR of 10% (n = 2) and 42% (n = 5), respectively. Responses were observed at all dose levels.

In the dose-expansion portion, patients with treatment-naive KRAS G12C–mutated NSCLC who were treated with LY3537982 plus pembrolizumab (n = 9) achieved an ORR of 78% (n = 7), Sabari continues. Although this phase was conducted in a small patient population, these preliminary efficacy findings are promising, Sabari states.

Importantly, the combination was also deemed safe and tolerable for patients previously intolerant to other KRAS G12C inhibitors, Sabari notes. No high-grade drug-related hepatotoxicity, including transaminitis, was observed in these patients, Sabari expands. The latter toxicity is commonly associated with G12C inhibitors specifically, as well as most regimens consisting of a targeted therapy and PD-1 inhibitor, he explains. Additionally, no dose-limiting toxicities were observed at any dose level, although aspartate aminotransferase and alanine aminotransferase levels did increase at the 150 mg dose.

Next steps for this research may include evaluating LY3537982 plus pembrolizumab in earlier lines of therapy, Sabari concludes.