LY3537982 Demonstrates Tolerability and Preliminary Efficacy in KRAS G12C–mutated Advanced Solid Tumors

The favorable safety and preliminary efficacy demonstrated by the LY3537982 at multiple dose levels in patients with KRAS G12C–mutated advanced solid tumors indicate its potential to overcome common toxicity challenges associated with the use of KRAS G12C inhibitor and immunotherapy combinations, according to Joshua K. Sabari, MD.

The first-in-human, phase 1 LOXO-RAS-20001 study (NCT04956640)is evaluating oral LY3537982 in patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic cancer, and other solid tumors.

Data presented at the 2023 AACR Annual Meeting showed that in the dose-escalation portion, single-agent LY3537982 produced an overall response rate (ORR) of 38% in patients with KRAS G12C inhibitor–naive NSCLC (n = 8) and an ORR of 7% in patients with NSCLC who had prior exposure to KRAS G12C inhibitors (n = 14). ORR rates were 10%, 42%, and 52% in patients with KRAS G12C–mutated CRC (n = 20), pancreatic cancer (n = 12), and other tumor types (n = 21), respectively. LY3537982 monotherapy was notably well tolerated in patients with intolerance to other KRAS G12C inhibitors.

Moreover, the addition of LY3537982 to pembrolizumab (Keytruda) in the dose-expansion phase produced an ORR of 78% in patients with KRAS G12C inhibitor–naïve NSCLC (n = 9) and an ORR of 25% in patients with NSCLC who received prior treatment with a KRAS G12C inhibitor (n = 4). The combination regimen did not produce any dose-limiting toxicities, and 1 patient discontinued treatment because of treatment-related adverse effects (AEs).

“This is an early study, but preclinically and now clinically, [we saw] some exciting data [for LY3537982] in combination with a PD-1 inhibitor,” said Sabari, an assistant professor in the Department of Medicine, at NYU Grossman School of Medicine, and thoracic medical oncologist at NYU Langone Health’s Perlmutter Cancer Center, in New York. “I look forward to potentially moving [LY3537982 plus pembrolizumab] to the frontline setting in [future] investigations.”

In an interview with OncLive^®, Sabari explained how the unique pharmacokinetics and mechanism of action for LY3537982 supported its investigation in the LOXO-RAS- 20001 study, expanded on the key findings presented at AACR, and discussed how this research could address unmet needs in patients with KRAS G12C–mutant advanced solid tumors.

OncLive: What has previously been demonstrated with LY3537982 in preclinical studies, and how did these data support the first-in-human study?

Sabari: LY3537982 is a novel KRAS G12C inhibitor. This space has truly exploded. KRAS is a very common alteration in NSCLC and other tumors. It makes up about 30% of the mutations in NSCLC. When we specifically look at KRAS G12C, about 13% to 14% [of patients have this mutation], and [there is] a significant unmet need for this patient population. We have 2 FDA approved [KRAS G12C inhibitors] in the second-line setting [for patients with NSCLC] after progression on platinum [chemotherapy] and immunotherapy: adagrasib [Krazati] and sotorasib [Lumakras]. It’s exciting to see new data for a novel agent in this setting.

This is an efficient molecule. It has unique pharmacologic properties. It has a very high target occupancy at a very low dose exposure. Potentially, we could have the ability to combine this agent with other agents, such as a PD-L1 inhibitor, with potentially less toxicity. We know that sotorasib in combination with immunotherapy has unfortunately been toxic. [Combinations with LY3537982] may be different.

What is unique about the mechanism of action of LY3537982?

LY3537982 inhibits the cysteine residue on KRAS G12C. This is similar to sotorasib, adagrasib, and other agents currently being developed [such as] JDQ443 and GDC-6036. [LY3537982] is a novel compound in the sense that it has the capability to target KRAS G12C. One of the unique opportunities with this agent is the efficacy and the ability to treat [patients] at low doses and get high exposure, and the ability to combine [LY3537982] with other agents.

Could you expand on the trial design of LOXO-RAS-20001 and the patient population enrolled?

This was a phase 1 trial that included a dose-escalation followed by a [phase] 1b dose-expansion phase. In phase 1 dose escalation, we treated all-comers with KRAS G12C[–mutated tumors]. [Thirty-one percent] of patients enrolled [in the dose-escalation portion] had NSCLC. It’s important to note that [17 of 84] patients were also previously treated with other KRAS G12C inhibitors, and about 53% of these [17] patients had progressed on prior KRAS G12C inhibitors. We also studied [other tumor types]. [Patients with] CRC made up [27% of] the patients. Of note, CRC and pancreas cancer have far lower rates [with KRAS G12C inhibitors] compared with NSCLC [despite having] KRAS G12C alterations.

What were the key efficacy results presented at the 2023 AACR Annual Meeting?

In dose escalation [with LY3537982 monotherapy], in patients [with] treatment-naive KRAS G12C[–mutated] NSCLC, we saw an ORR of 38%. In the pretreated KRAS G12C[–mutant NSCLC] population, the response rate was lower at 7%.

The data were exciting in the phase 1b expansion cohort. [In this portion], we looked at the KRAS G12C inhibitor LY3537982 in combination with pembrolizumab, which is an FDA-approved [agent] in the frontline setting [of NSCLC]. There, we saw a remarkable ORR of 78% [in those without prior treatment with a KRAS G12C inhibitor]. Again, a very small number of patients [were] enrolled, but [that is still] exciting early data.

What was found regarding the safety of LY3537982 alone and in combination with pembrolizumab?

What is [even] more exciting is that this combination was safe. We saw very low rates of transaminitis, [which is] a particular concern with KRAS G12C inhibitors or any targeted therapy in combination with a PD-1 inhibitor. We didn’t see any immune-mediated toxicities here. In combination with pembrolizumab, we looked at 50 mg, 100 mg, and 150 mg [doses of LY3537982].

[There were] some unique toxicity data from the 84 patients enrolled on the phase 1 escalation [and] expansion [cohorts]. We didn’t meet the maximum tolerated dose, there were no dose-limiting toxicities, and only 1 patient required a dose reduction or discontinuation in the total study [population]. Overall [this was a] remarkable safety profile.

Looking to the future, how might this research address unmet needs in this patient population?

There are 2 critical unmet needs in the KRAS G12C–mutated population. The first unmet need is post-progression on the current FDA-approved agents, sotorasib and adagrasib. We know that space is very complex. There are multiple bypass mechanisms of resistance [and] on-target resistance for KRAS.

The second unmet need is how to move these [KRAS G12C inhibitors] to the frontline setting. These agents are clearly benefiting patients in the second- and third-line setting. [For LY3537982] in combination with pembrolizumab, if we’re truly seeing response rates in that 60% range, this could potentially be practice changing for our patients in the frontline.

There are also specific subsets of patients that we know don’t respond well to immunotherapy, particularly the [patients with] KRAS and co-altered STK11/KEAP1 [mutations]. This could be a potential possibility [for them], provided that it is safe. Down the road, we may be able to use these agents in the frontline setting, particularly in that patient population [that does not respond to immunotherapy alone].

How could the further development of KRAS G12C inhibitors help improve treatment options for this subset of patients?

KRAS G12C is an actionable alteration. We have multiple therapeutics coming down the pike [targeting this alteration]. LY3537982 in the LOXO-RAS-20001 study is another drug showing clinical activity and safety in combination with a PD-1 inhibitor in the early data set. This area is exciting, and how we move these agents to the frontline setting is what will change outcomes for our patients.

Reference

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.