Abstract CT028: A first-in-human phase 1 study of LY3537982, a highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C-mutant advanced solid tumors

Abstract

Background: Mutations in KRAS are among the most frequent oncogenic drivers with the G12C mutation found in up to ~13% of NSCLC. LY3537982 is an oral, highly selective, and potent inhibitor of KRAS G12C, which preclinically delivers >90% sustained target occupancy. We present the initial results from LOXO-RAS-20001, a phase 1 study of LY3537982 in patients (pts) with KRAS G12C-mutant advanced solid tumors (NCT04956640). Methods: LY3537982 monotherapy dose escalation followed a mTPI-2 method. Dose expansion cohorts included combinations with pembrolizumab (NSCLC) and cetuximab (CRC). Key objectives were to determine the RP2D of LY3537982, safety, PK, and antitumor activity per RECIST v1.1. Results: As of 17 August 2022, 56 pts with NSCLC (16), CRC (17), PANC (8), and other tumor types (15) were treated with LY3537982 monotherapy on doses from 50-200 mg BID. Median number of prior systemic therapies was 2 (range, 0-8). No DLTs were observed, MTD was not reached, and RP2D determination is ongoing. Median time on treatment was 3 months (range, 0.3-13), 33 pts are ongoing, and 23 pts discontinued (none due to a related AE). TEAEs observed in ≥10% of pts were diarrhea (38%), constipation (16%), fatigue (16%), peripheral oedema (13%), and nausea (11%), mostly grade 1. The only grade ≥3 treatment related AE was neutropenia (n=1), and no pneumonitis or grade ≥2 transaminitis was observed. There were no treatment related serious AEs or deaths. Dose proportional steady-state exposures were observed through 150 mg BID. Table shows preliminary efficacy data. Conclusions: LY3537982 demonstrated a favorable safety profile, including the absence of high-grade liver toxicity, and tolerance in pts previously intolerant to other KRAS G12C inhibitors. Preliminary efficacy was observed with LY3537982 monotherapy across multiple tumor types. Updated data in more than 100 pts, including data in combination with pembrolizumab and cetuximab will be presented. Table: Preliminary LY3537982 Monotherapy Efficacy NSCLC (KRAS G12Ci naïve)(N=5) NSCLC(Prior KRAS G12Ci treated) (N=11) CRCd(N=17) PANCd(N=8) Other tumor typesd,f(N=15) Efficacy Evaluablea, n 5 9 15 8 11 ORR, n (%) 3 (60%) 0 1 (7%) 3 (38%) 4 (36%) BOR, n (%) PR, n (%) 3 (60%)c 0 1 (7%)e 3 (38%)e 4 (36%)g SD, n (%) 1 (20%) 6 (67%) 13 (87%) 4 (50%) 6 (55%) PD, n (%) 1 (20%) 3 (33%) 1 (7%) 1 (13%) 1 (9%) DCRb, n (%) 4 (80%) 6 (67%) 14 (93%) 7 (88%) 10 (91%) Abbreviations: CRC, colorectal cancer; NSCLC, non-small cell lung cancer; PANC, pancreatic cancer aEfficacy evaluable pts are those who had at least one post-baseline response assessment or had discontinued treatment bDCR includes PR+SD c3 NSCLC pts have unconfirmed PRs, ongoing and pending confirmation as of the data cut-off date dAll pts KRAS G12C inhibitor naïve, prior KRAS G12C inhibitor therapy not permitted for tumor types other than NSCLC e1 CRC pt and 1 PANC pt have unconfirmed PR, ongoing and pending confirmation as of the data cut-off date fOther tumor types include cholangiocarcinoma (n=4), chondrosarcoma (n=1), jejunal adenocarcinoma (n=1), large cell neuroendocrine of lung (n=1), nasal malignant melanoma (n=1), ovarian cancer (n=3), salivary adenoid cystic carcinoma (n=1), small intestine cancer (n=1), tracheal basaloid squamous cell carcinoma (n=1), and upper tract urothelial carcinoma (n=1) gPRs observed in pts with tracheal basaloid squamous cell carcinoma, cholangiocarcinoma, nasal malignant melanoma, and ovarian cancer (1 each) Citation Format: Yonina R. Murciano-Goroff, Rebecca S. Heist, Yasutoshi Kuboki, Takafumi Koyama, Natraj Reddy Ammakkanavar, Antoine Hollebecque, Amita Patnaik, Toshio Shimizu, Alexander I. Spira, Misako Nagasaka, Ji-Youn Han, Wade Thomas Iams, Dustin Deming, Justin Call, Philippe Cassier, Sae-Won Han, Quincy Siu-chung Chu, Rasha Cosman, Gregory Durm, Timothy Burns, Melinda D. Willard, Shiyao Liu, Sophie Callies, Arjun V. Balar, Joshua K. Sabari. A first-in-human phase 1 study of LY3537982, a highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C-mutant advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT028.