Abstract C026: Initial safety, pharmacokinetics, and recommended Phase 2 dose from RAMP 203: A Phase 1/2 study of Avutometinib + Sotorasib in KRAS G12C Mutant Non-Small Cell Lung Cancer
Authors: Awad Mark M , Goldschmidt Jerome , Spira Alexander I , Malhotra Rajat , Yorio Jeffrey T , Bhambhani Vijeta , Cheng Yaofeng , Lee Pablo S , Govindan Ramaswamy 
Published: December 2023

Abstract
Background: KRAS mutations occur in ~30% of non-small cell lung cancer (NSCLC), KRAS G12C mutations being the most common (40%). KRAS G12C inhibitors (G12Ci) are FDA approved for KRAS G12C mutant (mt) NSCLC. Acquired mutations and amplifications occurring upon clinical progression may limit the benefit of G12Ci. Simultaneous targeting of multiple nodes in the RAS/MAPK pathway may improve response depth and durability. Avutometinib is a first-in-class oral RAF/MEK clamp that potently inhibits MEK kinase activity while also blocking the compensatory reactivation of MEK by upstream RAF. In preclinical G12Ci-naïve NSCLC models, addition of avutometinib improved depth of MAPK pathway inhibition and substantially enhanced tumor regression relative to sotorasib alone. Initial clinical efficacy of avutometinib in KRAS G12C NSCLC was observed in the FRAME study [NCT03875820]: 4/6 patients (pts) demonstrated tumor reduction including 1 PR.
Methods: RAMP 203 is a phase 1/2, multicenter, open label, dose evaluation/expansion study evaluating the efficacy and safety of avutometinib + sotorasib in pts with KRAS G12C NSCLC [NCT05074810]. Pts with unresectable stage 3B-C and stage 4 KRAS G12C NSCLC and 1-3 prior systemic regimens were enrolled. Previous treatment with MEK inhibitors was excluded, but prior G12Ci treatment was allowed. Up to 3 dose levels (DL) of avutometinib (DL1, 3.2 mg PO BIW 21/28 days; DL2, 4.0 mg PO BIW 21/28 days; DL-1, 2.4 mg PO BIW 21/28 days) + sotorasib (960 mg PO QD 28/28 days) were evaluated in the Part A (dose evaluation, standard 3+3 design) to determine the Recommended Phase 2 Dose (RP2D, based on dose limiting toxicities [DLTs], other safety data, and pharmacokinetics) for Part B (dose expansion).
Results: At the time of data cut, 10 pts (9 DLT evaluable) with KRAS G12C NSCLC (all stage 4) were enrolled to DL1 (n=3) and DL2 (n=7). Pts received a median of 3 prior systemic regimens (5 pts with previous G12Ci). No DLTs were observed in DL1 or DL2, leading to the selection of DL2 as RP2D. The majority of DL2 TRAEs observed were grades 1-2. The most common TRAEs of any grade with a frequency of ≥20% of pts included nausea, AAT increase, diarrhea, fatigue, and pruritus. The mean exposures (AUC) of avutometinib and sotorasib in DL1 and DL2 were within range of past single agent studies, indicative of minimal drug-drug interactions (DDIs). Preliminary efficacy data will be available at the time of presentation.
Conclusions: The combinability of avutometinib and sotorasib was demonstrated in heavily-pretreated, advanced KRAS G12C NSCLC. Avutometinib 4.0 mg PO BIW 21/28 days + sotorasib PO 960 mg QD 28/28 days was established as the RP2D with no indications of DDIs. No new safety signals were observed and most TRAEs were mild to moderate. Enrollment in RAMP 203 Part B is ongoing.
Citation Format: Mark M Awad, Jerome Goldschmidt, Alexander I Spira, Rajat Malhotra, Jeffrey T Yorio, Vijeta Bhambhani, Yaofeng Cheng, Pablo S Lee, Ramaswamy Govindan. Initial safety, pharmacokinetics, and recommended Phase 2 dose from RAMP 203: A Phase 1/2 study of Avutometinib + Sotorasib in KRAS G12C Mutant Non-Small Cell Lung Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C026.