Abstract CT202: A first-in-human phase 1 study of LY3537982, a novel, highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C mutant advanced solid tumors (trial in progress)
Authors: Ammakkanavar Natraj Reddy , Call Justin , Shimizu Toshio , Kuboki Yasutoshi , Liu Shiyao , Willard Melinda D. , Axelson Michael , Heist Rebecca S. , Patnaik Amita 
Published: June 2022

Background: KRAS G12C mutations are recurrent oncogenic events in patients (pts) with NSCLC, CRC, and other tumors, and are found in ~14% of NSCLC and 5% of CRC. While KRAS G12C inhibitors have demonstrated activity in pts, overall efficacy may be limited by incomplete target occupancy. LY3537982 is a novel, orally bioavailable, highly selective, and potent inhibitor of the KRAS G12C protein with the potential to deliver &gt;90% target occupancy in pts. In preclinical studies, LY3537982 demonstrated dose-dependent tumor growth inhibition in vivo as a single agent in a KRAS G12C NSCLC PDX model, and robust tumor regression in combination with other agents in vivo in a KRAS G12C sensitive NSCLC model.1

Methods: LOXO-RAS-20001 is an open-label, multi-center, first-in-human Phase 1 study of oral LY3537982 in pts with KRAS G12C-mutant advanced solid tumors. This study consists of 2 parts: Phase 1a dose escalation to evaluate LY3537982 monotherapy and Phase 1b dose expansion to evaluate both LY3537982 monotherapy and in combination. Dose escalation will follow a modified toxicity probability interval-2 (mTPI-2) method, allowing for backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. DLT evaluation period will be 21 days. The primary objective of Phase 1a is to determine the LY3537982 recommended phase 2 dose (RP2D). Part 1b will enroll pts into dose expansion cohorts based on tumor type (NSCLC, CRC, other solid tumors) and prior treatment including KRAS G12C inhibitor refractory NSCLC. Key objectives of Phase 1b are to determine the safety and tolerability of LY3537982 monotherapy, and in combination with various agents: abemaciclib, erlotinib, cetuximab, an investigational ERK inhibitor (LY3214996), an investigational Aurora A kinase inhibitor (LY3295668), and an anti-PD1 antibody. Key secondary objectives include determining the pharmacokinetic properties, and antitumor activity of LY3537982 based on overall response rate (ORR), progression-free survival (PFS), time to response (TTR), and duration of response (DOR) per RECIST v1.1. Eligible pts must have measurable disease per RECIST v1.1, have a KRAS G12C mutation in tumor tissue or ctDNA, have locally advanced, unresectable and/or metastatic cancer per disease specific criteria, and be appropriate candidates for experimental therapy or refused available therapy. Additionally, pts must be ≥18 years old, have ECOG PS of 0-1, and have adequate organ function. Key exclusion criteria include presence of serious cardiac conditions, interstitial lung disease, symptomatic CNS malignancy, symptomatic CNS metastasis, or carcinomatous meningitis. The trial is currently enrolling patients (NCT04956640).

References: 1. Peng S-B, et al. 2021 Cancer Res 81(13 Suppl):1259.

Citation Format: Natraj Reddy Ammakkanavar, Justin Call, Toshio Shimizu, Yasutoshi Kuboki, Shiyao Liu, Melinda D. Willard, Michael Axelson, Rebecca S. Heist, Amita Patnaik. A first-in-human phase 1 study of LY3537982, a novel, highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C mutant advanced solid tumors (trial in progress) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT202.