LY3537982 Shows Preliminary Efficacy in KRAS G12C-Mutated Solid Tumors


In an interview with Targeted Oncology, Joshua Sabari, MD, discussed the rationale of studying LY3537982 in the LOXO-RAS-20001 trial and next steps for the evaluation of the agent.

LY3537982, a highly selective, potent KRAS G12C inhibitor, demonstrated preliminary efficacy and tolerability in patients with KRAS G12C-mutated solid tumors in the phase 1 LOXO-RAS-20001 (NCT04956640) study, according to Joshua K. Sabari, MD.1,2

In the first-in-human, open-label, multicenter LOXO-RAS-20001 trial, investigators are evaluating LY3537982 as a monotherapy or in combination regimens for the treatment of patients with KRAS G12C-mutated non–small cell lung cancer (NSCLC), colorectal cancer, pancreatic cancer, as well as other solid tumors.2

The first part of the study, part 1a, is the dose-escalation portion which will establish the recommended phase 2 dose to be evaluated further in the second part of the trial. Part 1b is the dose-expansion portion which will consist of multiple arms where patients will be given either LY3537982 alone or LY3537982 with other drugs.1

In phase 1b, the expansion portion of the study, 2 cohorts were enrolled, including cohort part B4 which was specifically a NSCLC patient population. Here, LY3537982 was assessed in combination with pembrolizumab (Keytruda). In part C2, LY3537982 was studied in combination with cetuximab (Erbitux) for patients with colorectal cancer.

Findings from the dose-escalation portion revealed that among the 8 patients with treatment-naive KRAS G12C-mutated NSCLC, the overall response rate (ORR) was 38% with LY3537982 alone. The ORR was 7% (n = 1) in evaluable patients with NSCLC who had been previously treated with a KRAS G12C inhibitor (n = 14), and among the evaluable patients with KRAS G12C-mutated CRC (n = 20) and pancreatic cancer (n = 12), the ORRs were 10% (n = 2) and 42% (n = 5), respectively.

In the dose-expansion portion of the study, patients with treatment-naive KRAS G12C-mutated NSCLC given LY3537982 with pembrolizumab (n = 9) had an ORR of 78% (n = 7). Though this portion of the study was done using a small patient population, Sabari, assistant professor, Department of Medicine at NYU Grossman School of Medicine, and director of High Reliability Organization Initiatives at the Perlmutter Cancer Center, notes that these preliminary efficacy findings are encouraging.

Additionally, Sabari explained that LY3537982 was well-tolerated. There were very low rates of toxicity and no significant grade 3 toxicities observed among patients treated at the 50 mg or 100 mg dose level when given twice daily (BID).

In an interview with Targeted OncologyTM, Sabari discussed the rationale of studying LY3537982 in the LOXO-RAS-20001 trial and next steps for the evaluation of the agent.

Targeted Oncology: Can you discuss the mechanism of action of LY3537982 in KRAS G12C-mutant advanced solid tumors?

Sabari: LY3537982 is a potent, highly selective inhibitor of GTP-bound KRAS G12C. It's one of the novel KRAS G12C inhibitors. We have seen FDA approvals of sotorasib [Lumakras] and adagrasib [Krazati]. This is a next-in-class KRAS G12C inhibitor, and I think what's unique about this agent is that it has very unique pharmacological properties that permit a very high target occupancy at low exposures, which allow us to potentially combine this agent with other agents more safely.

What other available KRAS inhibitors can you discuss? What's the importance of targeting this biomarker?

KRAS G12C is quite common. It makes up about 13% to 14% of all non–small cell lung cancer. When you take a step back and look at KRAS in general, it makes up about 30% of non–small cell lung cancer. KRAS G12C was debated whether it was actionable or not for many years. Sotorasib was the first drug to show activity in the setting. In a phase 2 study, [it showed] about a 37% response rate. Adagrasib came a little bit later and both are now FDA-approved. [Adagrasib] showed a 43% response rate. Both agents had progression-free survival in that 6 to 6-and-a-half-month range with overall survival in that 12- to 13-month range. Clearly, we've established that KRAS G12C is a driver alteration and is actionable.

If we compare this to the EGFR space where we see responses in 80%, [progression-free survival] of 18 to 20 months, and overall survival of 38 to 39 months, we're nowhere near where we are in the EGFR space compared with KRAS at the moment. We need to do better and we need to think about either combination strategies or how to move these agents to the frontline setting to better benefit our patients.

What can you tell us about the phase 1a study assessing LY3537982?

This was a classically designed phase 1a monotherapy escalation followed by a phase 1b expansion in patients with KRAS G12C mutation-positive lung cancer. Patients were enrolled who had good performance status, who had a KRAS G12C mutation, and in the monotherapy escalation, we enrolled 84 patients starting at 50 milligrams BID, escalated all the way to 200 milligrams BID, and we included all patients with solid tumors. In the phase 1b expansion, we enrolled 2 different cohorts, including cohort part B4 which was specifically a non–small cell lung cancer population looking at LY3537982 in combination with pembrolizumab and in part C2, we looked at a colorectal cancer population. This was LY3537982 in combination with cetuximab.

What are the main findings and takeaways from this study?

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 [were] treatment naïve [and had received] prior G12C inhibitors, and that's across all histologies. Just to put this into perspective, if you look at adagrasib 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, about 37.1%. This is really in line, but this is a much heavier treated patient population.

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 [gastrointestinal (GI)] toxicity, so diarrhea, nausea, and particularly, [aspartate aminotransferase (AST)] and [alanine transaminase (ALT)] elevations were quite low, with no significant grade 3 toxicities experienced at the 50 or 100 mg BID in the combination cohort. These are the expansion cohorts, particularly cohort B4, which LY3537982 in 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.

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.

Are there any next steps in assessing LY3537982?

First off, this phase 1 study is ongoing, and I think it is important that we solidify the dose, whether it be 100 mg 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 plus LY3537982 [is what] we hope to move into the frontline setting.

Then in the colorectal cohort of LY3537982 plus cetuximab, 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.

1. Murciano-Goroff YR, Heist RS, Kuboki Y, et al. A first-in-human phase 1 study of LY3537982, a highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C-mutant advanced solid tumors. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT028.
2. Study of LY3537982 in cancer patients with a specific genetic mutation (KRAS G12C). Updated September 28, 2023. Accessed November 8, 2023.

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