Dr Murciano-Goroff on the Evaluation of LY3537982 in KRAS G12C–Mutated NSCLC, CRC and Other Solid Tumors

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

At the 2023 AACR Annual Meeting, data were presented from the dose-escalation and -expansion portions of the phase 1a/1b LOXO-RAS-20001 trial (NCT04956640), which evaluated the KRAS G12C inhibitor LY3537982 in patients with advanced solid tumors harboring KRAS G12C mutations. In the dose-escalation portion of the trial, 75 patients with KRAS G12C-mutated tumors who received LY3537982 monotherapy.

Among patients with NSCLC who were naïve to a KRAS G12C inhibitor (n = 8), the overall response rate (ORR) was 38%. Those with NSCLC who received a prior KRAS G12C inhibitor (n = 14), the ORR was 7%. In patients with CRC (n = 20), pancreatic (n = 12), or other tumor types (n = 21), the ORRs were 10%, 42%, and 52%, respectively.

Dose escalation included patients with multiple tumor types because KRAS G12C is a known oncogenic driver in different solid tumors, Murciano-Goroff says. Disease-specific cohorts were used in the dose-expansion portion of the study, including patients with NSCLC who received LY3537982 in combination with pembrolizumab (Keytruda), and patients with CRC who were administered LY3537982 plus cetuximab (Erbitux).

In the dose-expansion NSCLC cohort, patients with NSCLC who were naïve to a KRAS G12C inhibitor (n = 9) experienced an ORR of 78%, and the disease control rate was 100%. Four patients with NSCLC who had prior treatment with a KRAS G12C inhibitor had an ORR of 25%. In the CRC expansion cohort (n = 11), LY3537982 plus cetuximab elicited an ORR of 45%.

Since KRAS G12C inhibition has historically been a difficult treatment option for patients with CRC, exploring a combination strategy aimed to address an area of need for this subgroup, Murciano-Goroff expands. Approximately 3% of patients with CRC harbor KRAS G12C mutations, and novel strategies using this target are needed, Murciano-Goroff concludes.