Dr Murciano-Goroff on the Investigation of KRAS G12C Inhibitor LY3537982 in Solid Tumors

Yonina R. Murciano-Goroff, MD, MSc, DPhil, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses the investigation of the novel KRAS G12C inhibitor LY3537982 in patients with non–small cell lung cancer (NSCLC), colorectal cancer (CRC), and other solid tumors.

At the 2023 AACR Annual Meeting, findings were presented from the dose-escalation and -expansion portions of the phase 1a/1b LOXO-RAS-20001 study (NCT04956640) of LY3537982 in patients with advanced solid tumors harboring KRASG12C mutations. In the dose-escalation cohort, 75 patients with KRAS G12C mutant tumors were evaluated following treatment with LY3537982 monotherapy. Across all doses for patients with NSCLC who did not receive prior treatment with a KRAS G12C inhibitor (n = 8), the overall response rate (ORR) was 38% (n = 3). In patients with NSCLC who received prior treatment with a KRAS G12C inhibitor (n = 14), the ORR was 7% (n = 1). Moreover, the ORRs for patients with CRC (n = 20), pancreatic (n = 12), or other tumor types (n = 21) were 10%, 42%, and 52%, respectively.

In dose expansion, LY3537982 plus pembrolizumab (Keytruda) elicited an ORR of 78% in patients with NSCLC who were naïve to a KRAS G12C inhibitor (n = 9). Those who had prior treatment with a KRAS G12C inhibitor (n = 4) experienced an ORR of 25%. Eleven patients with CRC who received LY3537982 plus cetuximab (Erbitux) achieved an ORR of 45%.

Preclinical data for LY3537982 suggested that good target occupancy was achievable, even at low levels of the drug, leading investigators to hypothesize that patients can receive lower amounts of the drug that could be safely combined with other therapies, Murciano-Goroff notes.

In terms of monotherapy, investigators noted that the maximum tolerated dose was not reached. Additionally, investigators evaluated patients who had intolerance to a prior KRAS G12C inhibitors, and only low-grade adverse effects were observed in this group, Murciano-Goroff says.

The pembrolizumab combination cohort in patients with NSCLC and cetuximab combination cohort in patients with CRC showed promising preliminary safety and efficacy data, she adds. These encouraging results are propelling further enrollment for these groups of patients, Murciano-Goroff concludes.