Phase 1 Study Shows Potential of LY3537982 in KRAS G12C NSCLC


Joshua K. Sabari, MD, discusses LY3537982 for patients with KRAS G12C-mutant advanced 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 LY3537982 for patients with KRAS G12C-mutant advanced solid tumors.

A first-in-human phase 1 study, LOXO-RAS-20001 (NCT04956640), is assessing LY3537982, a highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C-mutated non–small cell lung cancer, colorectal cancer, pancreatic cancer, and other solid tumors.

The phase 1b expansion portion of the study enrolled 2 cohorts, including cohort part B4 which was specifically a non–small cell lung cancer population looking at LY3537982 in combination with pembrolizumab (Keytruda) and in part C2, the agent was evaluated in combination with cetuximab (Erbitux) for patients with colorectal cancer.

Findings revealed that the therapy was well-tolerated with very low rates of toxicity and no significant grade 3 toxicities experienced at the 50 mg or 100 mg doses when given to patients twice daily (BID).


0:10 | I think the key takeaways from this study is that overall, in the monotherapy escalation, we saw an objective response rate of 38%. It's important to note that these were patients who both had treatment naive, as well as prior G12C inhibitors, and that's across all histologies. Just to put this into perspective, if you look at adagrasib [Krazati] or sotorasib in non–small cell lung cancer, for an adagrasib, you're seeing response rates of 43% in the second-line setting, and for sotorasib [Lumakras], about 37.1%. This is really in line, but this is a much heavier treated patient population.

0:55 | I think what's most exciting overall, if you look at the data, is how relatively well-tolerated this therapy was with very low rates of toxicity, including GI toxicity, so diarrhea, nausea, and particularly, AST and ALT elevations were quite low, with no significant grade 3 toxicities experienced at the 50 or 100 mg of BID in the combination cohort. These are the expansion cohorts, particularly cohort B4, which LY3537982in combination with pembrolizumab, and we saw a very impressive response rate, albeit a very small patient population. So we're talking about 9 patients here, but we achieved a 78% response rate with this drug.

1:44 | I think more importantly, when we look at the toxicities of this G12C inhibitor with pembrolizumab, 0 grade 3 AST and ALT elevations at the 100 mg BID [were seen]. At the 150 BID we did see 33% grade 3 AST and ALT elevation. What I take away from it is that this is a novel G12C inhibitor that potentially could be more combinable with immunotherapeutics in the frontline setting. Again, it is a very early look at the data and I hope to sort of build upon the data we have here mostly in the frontline setting in combination with a PD-1 inhibitor to change practice for our patients with non–small cell lung cancer.

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