Next Steps to Evaluate LY3537982 in KRAS G12C-Mutant Solid Tumors

Joshua K. Sabari, MD, assistant professor, Department of Medicine at NYU Grossman School of Medicine, and director of High Reliability Organization Initiatives at the Perlmutter Cancer Center, discusses where research on LY3537982 for patients with KRAS G12C-mutant advanced solid tumors is headed.

The highly selective, potent KRAS G12C inhibitor, LY3537982, is under investigation in the phase 1, first-in-human, open-label, multicenter LOXO-RAS-20001 (NCT04956640) trial where patients aged 18 years and older with KRAS G12C-mutated non–small cell lung cancer, colorectal cancer, pancreatic cancer, as well as other solid tumors, are being treated with LY3537982 orally.

This study is being conducted in 2 parts with part 1a as the dose-escalation portion of the study and part 1b is a dose-expansion portion. The recommended phase 2 dose will be established in part 1a , and then using this dose, part 1b will have multiple arms of either LY3537982 monotherapy or LY3537982 given in combination with other drugs. The goal of the study is to evaluate the safety, tolerability, and preliminary efficacy of oral LY3537982 in this patient population.

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0:10 | First off, this phase 1 study is ongoing, and I think it is important that we solidify the dose, whether it be 100 mg [twice daily] BID or 150 mg BID. Dose optimization is really going to be critical. Then in early subsets where we have seen response, particularly in lung cancer, non–small cell lung cancer, pembrolizumab [Keytruda] plus LY3537982 [is what] we hope to move into the frontline setting.

0:34 | Then in the colorectal cohort of LY3537982 plus cetuximab [Erbitux], we saw about a 45% response rate. Again, I think an exciting opportunity to potentially move this combination in the GI malignancy space as well. So clearly, we need to establish the correct dose, and then I think combinations here are the next step forward, potentially and hopefully, in the frontline setting.