Phase 1 Data Support Further Investigation of RMC-6236 in KRAS-Mutant NSCLC

The pan-RAS inhibitor RMC-6236 generated preliminary signals of durable clinical efficacy and displayed a manageable safety profile in patients with KRAS-mutant non–small cell lung cancer (NSCLC), and additional research will further define this agent’s potential for the treatment of patient population and those with other KRAS-mutated solid tumors, according to Kathryn C. Arbour, MD.

The phase 1 RMC-6236-001 trial (NCT05379985) is investigating RMC-6236 in patients with advanced solid tumors with KRAS G12X mutations—excluding those with KRAS G12C mutations—who previously received standard therapy that was appropriate for their tumor type and stage. At the 2023 ESMO Congress, Arbour presented preliminary findings from this study in patients with NSCLC and pancreatic ductal adenocarcinoma (PDAC) harboring KRAS mutations. In evaluable patients (n = 40) in the NSCLC cohort who were administered RMC-6236 at doses of at least 80 mg per day and received their first dose at least 8 weeks prior to the data extract date, the overall response rate (ORR) was 38%, including complete response (CR), partial response (PR), and stable disease (SD) rates of 3%, 35%, and 48%, respectively.¹

“This is an early look at responses, and we look forward to further data for these patients, as some have had deepening of response over time,” Arbour said in an interview with OncLive^®.

In the interview, Arbour, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, discussed the unique mechanism of action of RMC-6236, the preliminary efficacy and safety findings for this agent in patients with KRAS-mutant NSCLC, and future directions for the RMC-6236-001 trial.

OncLive: What differentiates RMC-6236 from other agents being developed for the treatment of patients with KRAS-mutant cancers, particularly NSCLC and PDAC?

Arbour: RMC-6236 is a KRAS inhibitor, but it’s unique in 2 ways. One, it falls into the category of RAS^MULTI or pan-RAS inhibitors. Inhibitors that have been developed so far for KRAS include mutant-specific inhibitors, for example, those for just KRAS G12C alterations. Increasingly, [inhibitors that are] for just KRAS G12D alterations are entering clinic. However, [RMC-6236] is a multi-RAS^MULTI inhibitor, meaning it can inhibit KRAS in its mutant form, [covering] multiple different mutations. Preclinical models indicate that this [mechanism of action] is especially effective in patients with KRAS G12 mutations, [including] KRAS G12D, KRAS G12V, and other similar mutations.

The other unique property of RMC-6236 is that it is a RAS(ON) inhibitor. Other RAS-targeted therapies, specifically sotorasib [Lumakras], adagrasib [Krazati], and divarasib [GDC-6036], [which are] KRAS G12C inhibitors, bind to RAS in its inactive [OFF] conformation. RMC-6236 binds to RAS in its activated state, hence the name KRAS(ON) inhibitor. This inhibition of RAS in the active state may lead to deeper responses and potentially more sustained responses in controlling tumors. In both targeting multiple isoforms of RAS and being a RAS(ON) inhibitor, RMC-6236 has unique properties.

What were the methods and design of the RMS-6236-001 trial, and how were patients with previously treated, KRAS-mutant, advanced solid tumors selected for enrollment?

RMC-6236-001 is a phase 1 dose-escalation study of RMC-6236 in patients with all advanced solid tumors. Patients were specifically enrolled if they had KRAS G12 alterations. One population of interest in this trial has been patients with NSCLC. Additional patients were enrolled during dose escalation at doses that cleared dose-limiting toxicity evaluation for the purposes of dose optimization. We have good experience with several patients with NSCLC who have been treated across many dose levels.

Patients were selected for enrollment based on their mutational status. This was based off next-generation sequencing testing that we routinely collect for patients. As of now, we haven’t had any targeted therapies that we’ve been able to use for patients in this setting, and that is a clinical unmet need. Patients with lung cancer were required to have been previously treated with systemic therapy, typically with both platinum-based chemotherapy and an immune checkpoint inhibitor. In this setting requiring both of these standard therapies, this is a patient population in which limited [subsequent] treatment options are available, and [current options] mostly include second-line and third-line chemotherapy options that are toxic for patients and have limited clinical activity. Patients were eligible for this study if they had an ECOG performance status of 0 to 1. Patients with brain metastases were required to have those definitively treated and stable prior to study enrollment.

Dose escalation started at 10 mg daily. At the 2023 ESMO Congress, we presented data in patients treated at 80 mg and above, the dose at which we think is the minimum threshold needed to drive tumor regression in humans, and that was predicted based on preclinical models.

What results were observed in the NSCLC population?

At the 2023 ESMO Congress, we presented the safety and tolerability [of RMC-6236] in patients with NSCLC and pancreas cancer treated at 80 mg and above. It’s crucial to investigate the safety and tolerability because there has been a question of how tolerable these multi-RAS or pan-RAS inhibitors would be for patients in the clinic. What we see here is that the medication is well tolerated at clinically active doses.

The most common toxicities we observed were rash, nausea, vomiting, stomatitis, fatigue, and diarrhea, [which were] typically all grade 1 and 2. These toxicities, especially rash, although frequent, were generally well managed with supportive medications that we routinely use in clinical practice, such as topical steroids and oral antibiotics. Only 14% of patients required a dose reduction due to a treatment-related adverse effect. An important pathway forward for understanding [the efficacy of pan-RAS inhibitors is understanding whether we can] maintain patients on consistent doses of the medication. The data so far show we can do that.

The other aspect of data that was presented for this patient population was the clinical activity of RMC-6236 in patients with NSCLC. We shared the data for 40 patients with NSCLC who had started dosing with RMC-6236 at least 8 weeks prior to the data cutoff. This is an early look at this activity. [Some] patients have only had 1 follow-up scan on treatment. CR was observed in 1 patient on study and PR was observed in 14 patients, [translating to] an ORR of 38%. The disease control rate in this population was 85%. In patients who did not meet the standard for a PR, SD and tumor shrinkage was observed in a number of them. In these patients with NSCLC, 28 of the 40 patients remain on treatment to date.

We see that [patients are responding] and can be maintained on treatment, and some of these responses can be durable. We’ll be looking out for their follow-up scans. The time to response was quick, typically on the first scan, which [shows that RMC-6236] provides symptom relief for patients quickly. Patients on study feel better within several weeks of starting treatment, which is clinically rewarding and [a result] we’d hope to see with targeted therapy.

What are the next steps for this trial? When could we expect additional data?

The dose-escalation portion of the study, as well as the dose-optimization portion, is ongoing. This will be crucial to select the most appropriate dose to move forward with in the phase 2 and dose-expansion portion of the clinical trial. [We are] trying to balance the clinical activity of the drug with toxicities observed so patients can remain [on study] and have consistent dosing. We’re already seeing dose levels for which that is feasible, and hopefully with more data with a larger number of patients, we’ll be able to see that both in lung cancer and pancreatic cancer moving forward.

Additional monotherapy cohorts are planned in the dose-expansion portion. This is important because earlier data indicated that responses [with RMC-6236] are perhaps not limited to lung cancer or pancreatic cancer; [they could] be seen in other diseases where KRAS mutations are frequent but not the common driver alteration, [such as] gynecologic cancers and melanoma. The study plans to enroll patients in these cohorts with RAS alterations to understand the clinical activity of the drug in those cohorts. It will be exciting to see whether we can move RAS inhibitors outside the realm of lung cancer to other malignancies.

What do these findings indicate about the potential for RMC-6236 and KRAS inhibitors as a class overall?

It’s an incredibly exciting time for RAS inhibitors in the management of lung cancer. Two drugs, sotorasib and adagrasib, have received accelerated FDA approval and are available to our patients. However, the challenge with these current agents is that though they typically offer good disease control with response rates in the 30% to 40% range, the durability of response is lacking with these agents. There’s been continued development to try to improve that durability of response and target some of the areas of acquired resistance. This new wave of RAS inhibitor studies can do that in a variety of ways. Combinations may be appropriate either in the up-front setting or in the resistant setting. We see newer, more potent drugs that may lead to more sustained RAS inhibition. Now, we see the new range of RAS(ON) inhibitors tackling the active state of RAS, which may have deeper inhibition of the RAS and MAPK pathway. It’s an exciting time for all these therapies. We look forward to translating these developments from clinical trials into everyday, routine care for patients.

Editor’s Note: Dr Arbour reports consulting roles with Amgen, Novartis, G1 Therapeutics, AstraZeneca, and Sanofi-Genzyme; and institutional research funding from Genentech (local PI), Mirati Therapeutics (local PI), and Revolution Medicines (local PI).

Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

Reference

Arbour KC, Punekar S, Garrido-Laguna I, et al. 652O Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34(suppl 2):S458. doi:10.1016/j.annonc.2023.09.1838