83MO - AMG 510, a novel small molecule inhibitor of KRAS(G12C), for patients (pts) with advanced gastrointestinal (GI) cancers: Results from the CodeBreaK100 phase I trial

Background

KRAS p.G12C mutation occurs in 1-3% of GI cancers. AMG 510 is a first-in-class small molecule inhibitor of KRAS^G12C. Previously, AMG 510 demonstrated a favorable safety profile and preliminary efficacy in the phase I, first-in-human trial involving pts with advanced solid tumors harboring KRAS p.G12C. Here, we present updated data in a subset of pts with advanced colorectal cancer (CRC) or other GI cancers.

Methods

Key inclusion criteria: KRAS p.G12C identified by molecular testing and prior systemic anticancer therapy. Primary endpoint was safety. Key secondary endpoints: objective response rate (ORR) and disease control rate (DCR), as per RECIST 1.1. Oral daily doses of 180, 360, 720, and 960mg were tested in dose escalation, and 960mg was selected for expansion.

Results

As of Jan 8, 2020, 59 pts (25 [42.4%] female, median age 58 [range: 33–82]), including 42 with CRC and 17 with other GI cancers, were enrolled. Pts received a median of 3 (range: 1–4) prior lines of therapy, with 24 (40.7%) receiving > 3 prior lines. Median follow-up was 7.7 (range: 1.2–15.9) months. 17 (28.8%) died, and 16 (27.1%) remained on treatment (tx). 28 (47.5%) and 10 (16.9%) pts had remained on tx for ≥ 3 and 6 months, respectively. Tx-related adverse events (TRAEs) occurred in 27 pts (45.8%); most were grade 1/2. 3 (5.1%) had grade 3 TRAEs, including diarrhea (3.4%) and anemia (1.7%). No dose-limiting toxicities, fatal / grade >3 TRAEs, or TRAEs leading to discontinuation were reported. All 42 pts with CRC had been followed up by ≥ 7 weeks and were evaluable for response. ORR and DCR were 7.1% (all confirmed) and 76.2%, respectively. At 960mg, ORR and DCR were 12.0% (3/25) and 80.0% (20/25). 15 of 17 pts with other GI cancers were evaluable: 1 confirmed partial response (appendiceal), 9 stable disease (6 pancreatic, 2 appendiceal, and 1 bile duct), and 5 progressive disease. 3 pts with pancreatic cancer achieving stable disease had the best tumor burden reduction of 28.0%, 28.9%, and 31.6% from baseline, respectively.

Conclusions

In pts with heavily pretreated KRAS p.G12C mutant GI cancers, AMG 510 was well tolerated, with the majority of pts achieving disease control. Study is ongoing (NCT03600883).

Clinical trial identification

NCT03600883.

Editorial acknowledgement

Yang Li, PhD (Amgen Inc.) provided medical writing assistance.

Legal entity responsible for the study

Amgen Inc.

Funding

Amgen Inc.

Disclosure

J.H. Strickler: Advisory/Consultancy, Research grant/Funding (institution): Amgen; Bayer; Seattle Genetics; OncoMed; Genentech/Roche; Research grant/Funding (institution): AbbVie; Exelixis; Gilead Sciences; Macrogenics; MedImmune; Nektar Therapeutics; Advisory/Consultancy: Celgene; Chengdu Kanghong Biotechnology; Chugai. M. Fakih: Research grant/Funding (institution): AstraZeneca; Amgen; Novartis; Advisory/Consultancy: Array; Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Advisory/Consultancy: Seattle Genetics. T.J. Price: Research grant/Funding (institution): Amgen. J. Desai: Advisory/Consultancy: Amgen; Advisory/Consultancy: BeiGene; Advisory/Consultancy, Research grant/Funding (institution): Bionomics; Advisory/Consultancy: Eisai; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Roche. G. Durm: Research grant/Funding (institution): Merck; BMS; AstraZeneca. J.C. Krauss: Research grant/Funding (institution): Amgen; NSABP Foundation; AbbVie; Boehringer Ingelheim; Boston Biomedical; Oncomed Pharmaceuticals; Ignyta/Roche; Baxalta; Pfizer; Isofol. Y. Kuboki: Research grant/Funding (institution): Amgen; Takeda; AstraZeneca; Ono Pharmaceutical Company Limited; Taiho Pharmaceutical Company Limited; Daiichi-sankyo Company Limited; Boehringer Ingelheim GmbH; Honoraria (self): Takeda; Taiho; MSD; Sanofi; Bayer Yakuhin; Eli Lilly Japan. A. Sacher: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca/MedImmune; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: Kisoji; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: Amgen; Travel/Accommodation/Expenses: Gritstone Oncology; Travel/Accommodation/Expenses: GSK; Honoraria (self): Tesaro. H. Henary; J. Kim: Shareholder/Stockholder/Stock options, Full/Part-time employment: Amgen. D.S. Hong: Shareholder/Stockholder/Stock options: MolecularMatch; Oncorena; Presagia; Honoraria (self), Advisory/Consultancy: Adaptimmune; Baxter; Bayer; Merrimack; Advisory/Consultancy: Alpha Insights; Axiom Biotechnologies; Eisai; Genentech; GLG; GroupH; Guidepoint Global; Janssen; Medscape; Numab; Pfizer; Seattle Genetics; Advisory/Consultancy, Additional disclosures: advisory - Trieza Therapeutics. Research Funding: AbbVie; Adaptimmune; Amgen; Amgen; AstraZeneca; Bayer; Bristol-Myers Squibb; Daiichi Sankyo; Eisai; Fate Therapeutics; Genentech; Genmab; Ignyta; Infinity Pharmaceuticals; Kite Pharma; Kyowa Hakko Kirin; Lilly; Loxo; MedImmune; Merck; Mirati Therapeutics; miRNA Therapeutics; Molecular Templates; Mologen; NCI-CTEP; Novartis; Pfizer; Seattle Genetics; Takeda Travel, Accommodations, Expenses: Genmab; Loxo; miRNA Therapeutics: Takeda. All other authors have declared no conflicts of interest.