Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC).
Authors: Garrido-Laguna Ignacio , Wolpin Brian M. , Park Wungki , Azad Nilofer Saba , Spira Alexander I. , Starodub Alexander , Sommerhalder David , Punekar Salman Rafi , Herzberg Benjamin , Barve Minal A. , Pelster Meredith , Valerin Jennifer Brooke , Hecht Joel R , Vora Rashmi , Hegde Aparna Madhukeshwar , Gustafson Clay , Tao Lin , Kar Sumit , Lin Kevin K. , Hong David S. 
Published: January 2025

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Background:
PDAC is the third leading cause of cancer mortality, with limited treatment options. Even with multi-agent chemotherapy, patients with second-line (2L) PDAC have a median progression-free survival (PFS) of ≈2–3.5 months and median overall survival (OS) of ≈6–7 months. RAS mutations occur in >90% of patients with PDAC, mainly KRAS G12X (G12X = non-synonymous mutations in KRAS codon 12 [G12]). RMC-6236 is an oral, RAS(ON), multi-selective, tri-complex inhibitor of the active GTP-bound state of both mutant and wild-type RAS. In a Phase 1 study, RMC-6236 demonstrated efficacy and manageable safety in patients with PDAC harboring KRAS G12X or other RAS mutations (NCT05379985). Data on ctDNA reduction with targeted therapy in PDAC are sparse. We report safety, updated efficacy, and exploratory analyses of early ctDNA reduction with clinically active doses of RMC-6236 in patients with RAS mutant PDAC.
Methods:
Escalating doses of RMC-6236 were administered orally to patients with previously treated RAS mutant PDAC. Additional patients were enrolled for dose optimization and expansion. Patients receiving clinically active doses (160–300 mg QD) of RMC-6236 ≥14 weeks before the July 23, 2024 data cutoff were included. Plasma samples were collected for ctDNA analysis of change in RAS mutant variant allele fraction at baseline (BL; cycle 1, day 1 [C1D1]), and on treatment (C2D1 or C3D1).
Results:
As of July 23, 2024, 127 patients with RAS mutant PDAC had received RMC-6236 160–300 mg QD. The most common (≥10% of patients) any-grade treatment-related adverse events were rash (91%), diarrhea (48%), nausea (43%), vomiting (31%), stomatitis (31%), fatigue (20%), paronychia (13%), mucosal inflammation (13%), decreased appetite (11%), and peripheral edema (10%). The Table shows objective response rate (ORR), PFS, and OS with 2L RMC-6236. Paired plasma samples were tested in 106/127 patients. Of these, 68 patients with RAS mutant allele ctDNA at BL were evaluable for ctDNA response (Table).
Conclusions:
RMC-6236 showed a manageable safety profile and encouraging efficacy in patients with previously treated RAS mutant PDAC, and early and deep reductions in RAS mutant ctDNA. RASolute 302, a global, randomized, Phase 3 trial evaluating RMC-6236 as 2L treatment vs chemotherapy in patients with metastatic PDAC, is ongoing.
Clinical trial information: NCT05379985
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KRAS G12X
RAS mutant

Efficacy with 2L RMC-6236

(n=42)

(n=57)

ORR, % (95% CI)[confirmed + pending confirmation]
29 (16–45)
25 (14–38)

Median PFS, months (95% CI)
8.5 (5.3–11.7)
7.6 (5.9–11.1)

Median OS, months (95% CI)
14.5 (8.8–not evaluable)
14.5 (8.8–not evaluable)

ctDNA Response with 2L+ RMC-6236

(n=56)

(n=68)

>50% decrease from BL, n (%)
53 (95)
63 (93)

100% decrease from BL, n (%)
28 (50)
32 (47)