RMC-6236 Shows Activity With Favorable Toxicity Profile in Previously Treated PDAC

RMC-6236 administered at doses ranging from 160 mg to 300 mg led to early antitumor activity with an acceptable safety profile in patients with previously treated pancreatic ductal adenocarcinoma (PDAC), according to updated data from the phase 1 RMS-6236-001 trial (NCT05379985).¹

In the patients with second-line metastatic PDAC, which included those who progressed on previous therapy in an earlier setting within 6 months of the last dose, the median progression-free survival (PFS) was 8.1 months (95% CI, 5.9-not evaluable [NE]) in those with KRAS G12X–mutated disease and 7.6 months (95% CI, 5.3-NE) in those with RAS-mutated disease. In those with third-line or later metastatic PDAC, RMC-6236 led to a median PFS of 4.2 months (95% CI, 4.1-6.4).

The 14+ and 20+ week objective response rates (ORRs) in those with second-line or later PDAC and KRAS G12X mutations were 20% (n = 16/79) and 27% (n = 13/48), respectively; the 14+ week disease control rate (DCR) in this subset was 87% (n = 69/79). In those with second-later or later PDAC and RAS mutations, the 14+ and 20+ week ORRs were 21% (n = 20/97) and 26% (n = 16/61), respectively; in this group, the 14+ week DCR rate was 88% (n = 85/97).

Interim data indicated that the median overall survival (OS) was NE in both subsets of patients with second-line metastatic PDAC who harbored KRAS G12X and RAS mutations.

“RMC-6236, our most advanced investigational drug, is a groundbreaking RAS(ON) multi-selective inhibitor with encouraging clinical safety profile and antitumor activity across multiple RAS[-mutated] solid tumors,” according to the drug developer, Revolution Medicines. “Updated clinical data from first-in-human study indicate promising PFS with RMC-6236 in patients with previously treated PDAC.”

The phase 1 RMC-6236-001 study enrolled patients with advanced solid tumors harboring KRAS G12X mutations and excluding KRAS G12C mutations.2 Patients must have previously received standard therapy appropriate for their tumor type and stage and had an ECOG performance status of either 0 or 1. They could not have active brain metastases.

As part of the dose escalation, RM-6236 was evaluated at 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 220 mg, 300 mg, 400 mg, and 500 mg. The agent was administered orally, once daily, as part of 21-day treatment cycles.

Previous data shared during the 2023 ESMO Congress showed that in evaluable patients with KRAS G12X–mutated non–small cell lung cancer (n = 40), the ORR was 38% and the DCR was 34%. The median time to response (TTR) was 1.4 months (range, 1.2-2.7). In those with KRAS G12X­–mutated PDAC, the ORR was 20% and the DCR was 87%. The median TTR was 3.3 months (range, 0.2-10.9).

The updated data focused on 127 patients with PDAC who received the agent at doses ranging from 160 mg to 300 mg.1 The median patient age was 64 years (range, 30-86) and 56% were male. More than half (65%) had an ECOG performance status of 1. The median number of prior anticancer therapies received was 2, with a range of 1 to 11. Seventy-five percent of patients previously received modified FOLFIRINOX and 72% had prior gemcitabine plus nab-paclitaxel (Abraxane). The median number of prior anticancer therapies received in the metastatic setting was 2 (range, 0-5); in this setting, 2% received 0 prior lines, 44% received 1 prior line, and 54% received 2 or more. Most patients (68%) had baseline liver metastases and 53% had stage IV disease at the time of diagnosis.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) occurred in 96% of patients with 22% of experiencing grade 3 or higher effects. The most common TRAEs to occur in at least 10% of patients were rash (any grade, 87%; grade ≥3, 6%), diarrhea (46%; 2%), nausea (43%; 0%), stomatitis or mucositis (38%; 2%), vomiting (28%; 0%), fatigue (17%; 1%), and paronychia (10%; 0%). Other select TRAEs included increased alanine aminotransferase (5%; 0%), increased aspartate aminotransferase (6%; 0%), prolonged electrocardiogram QT (1%; 1%), neutropenia (5%; 1%), and thrombocytopenia (11%; 2%).

TRAEs resulted in dose interruptions and reductions for 27% and 11% of patients, respectively. No patients experienced TRAEs that required discontinuation. The TRAEs that most commonly led to dose reduction in 2 or more patients were rash (6%), stomatitis/mucositis (3%), reduced appetite (2%), diarrhea (2%), and decreased platelet count (2%).

Dose intensity was 92% or higher at each dose level, with an average 94% across the dosing cohorts of 160 mg to 300 mg.

“Totality of evidence supports initiating RASolute 302, a global, randomized, phase 3 trial in second-line metastatic PDAC patients,” the company wrote.

The study will enroll patients with confirmed PDAC who received 1 previous line of therapy in the metastatic setting and who have an ECOG performance status of 0 or 1. The projected 460 patients will be randomly assigned 1:1 to receive 300 mg of RMC-6236 once daily (n = 230) or investigator’s choice of standard-of-care chemotherapy (n = 230) in the form of gemcitabine/nab-paclitaxel, modified FOLFIRINOX, NAL-IRI plus 5-fluororacil and leucovorin or FOLFOX.

PFS and OS in the subset of patients with RAS G12X mutations will serve as the trial’s primary end points, and secondary end points will include PFS, OS, ORR, duration of response, and quality of life in the total patient population.

References

1. RMC-6236: pancreatic cancer update to support pivotal phase 3 trial. Revolution Medicines. July 15, 2024. Accessed July 15, 2024. https://ir.revmed.com/static-files/eeeb0690-0ef4-44b8-b5fe-8d11d8df3c9a
2. Arbour KC, Punekar S, Garriso-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