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.
Background A previous phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with heavily pretreated metastatic colorectal cancer (mCRC) showed promising activity with an acceptable toxicity profile. This retrospective study aimed to investigate the safety and efficacy of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC in clinical settings.Methods Records of patients with mCRC refractory to standard therapies who initiated trifluridine/tipiracil plus bevacizumab from January 2016 to March 2018 or trifluridine/tipiracil monotherapy from June 2014 to December 2015 were retrospectively reviewed at our institution.Results Totally, 60 patients received trifluridine/tipiracil plus bevacizumab and 66 received trifluridine/tipiracil monotherapy. All patients had previously received standard chemotherapy. Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 2.3−5.1] in the trifluridine/tipiracil plus bevacizumab group and 2.2 months (95% CI, 1.8−2.6) in the trifluridine/tipiracil monotherapy group [hazards ratio (HR) 0.69; 95% CI 0.48−0.99]. PFS rate at 16 weeks was 46.6% for the trifluridine/tipiracil plus bevacizumab group and 33.9% for the trifluridine/tipiracil monotherapy group. Although a relatively higher incidence of grade ≥3 neutropenia was observed in the trifluridine/tipiracil plus bevacizumab group than that in the other group (50.0% vs. 40.9%, p = 0.371), the incidence of febrile neutropenia was not high (3.3% vs. 7.8%, p = 0.444).Conclusions In real-world settings, trifluridine/tipiracil plus bevacizumab prolonged PFS and helped achieve higher 16-week PFS rate compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC with manageable toxicities.
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 >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.
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