2937 - Phase 1 Study of AMG 510, a Novel Molecule Targeting KRAS G12C Mutant Solid Tumors

Background

The KRAS^G12C mutation occurs in ∼13% of lung cancers (11% of non-small cell lung cancer [NSCLC]), 3% of colorectal cancer (CRC) and appendix cancers, and 1–3% of other solid tumors. KRAS^G12C is a driver of tumorigenesis, but there are no approved therapies targeting this mutation. AMG 510, a novel, orally administered small molecule, specifically and irreversibly inhibits KRAS^G12C by locking it in an inactive GDP-bound state. A phase 1, first-in-human, open-label, multicenter study is underway to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510 in adult patients (pts) with locally-advanced/metastatic KRAS^G12C solid tumors (NCT03600883).

Methods

Key eligibility: measurable/evaluable disease with identified KRAS^G12C mutation, refractory to standard therapy; ECOG PS ≤ 2; life expectancy >3 months; no active brain metastases; no myocardial infarction <6 months of enrollment. In dose exploration, 4 pt cohorts enroll sequentially to identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). After MTD or RP2D identification, ∼60 pts will enroll into dose-expansion cohorts. Primary endpoints are incidence of dose-limiting toxicities (DLTs) and adverse events (AEs); secondary endpoints include response (eg, best response, objective response rate, progression-free survival; assessed every 6 weeks) and PK.

Results

As of 4 April 2019, 35 (19 CRC, 14 NSCLC, 2 other [appendix]; 21 women; median age 55 [range: 33-77] years) pts have been enrolled; all had ≥2 prior lines of therapy. No DLTs have been reported. 16 pts reported AMG 510-related AEs, 2 with grade 3 related AEs (anemia, diarrhea). Best tumor responses are tabulated. 26 pts remain on study.Table:

446PD

Six pts (4 NSCLC; 2 CRC/Other) did not have a post-baseline radiographic scan as of the data cutoff date (4 April 2019).

Duration of response as of the data cutoff date. All 5 pts with partial response are still on treatment as of the data cutoff date.

Two of these pts (1 NSCLC; 1 CRC) had early (prior to week 6) clinical progressive disease.

Conclusions

AMG 510 is well tolerated with no DLTs at studied doses. Early results suggest antitumor activity of single-agent AMG 510 in pts with KRAS^G12C mutant solid tumors. Updated results will be presented.

Clinical trial identification

NCT03600883 (ClinicalTrials.gov).

Editorial acknowledgement

Dianne Tomita, MPH, a consultant to Amgen Inc.

Legal entity responsible for the study

Amgen Inc.

Funding

Amgen Inc.

Disclosure

R. Govindan: Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self): Millennium; Honoraria (self): F Hoffman La-Roche; Honoraria (self): Janssen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: EMD Sereno; Advisory / Consultancy: BMS; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: Nektar; Advisory / Consultancy: Merck; Advisory / Consultancy: Celgene; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Phillips Gilmore; Advisory / Consultancy: GSK; Advisory / Consultancy: Jounce; Advisory / Consultancy: Inivata. M.G. Fakih: Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Array; Research grant / Funding (self): Novartis; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Amgen. T.J. Price: Research grant / Funding (self): Amgen. G.S. Falchook: Licensing / Royalties: Wolters Kluwer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Fujifilm; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (institution), Travel / Accommodation / Expenses: Millennium; Speaker Bureau / Expert testimony: Total Health Conferencing; Research grant / Funding (institution): 3-V Biosciences; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): Aileron; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): ARMO; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bioatla; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Ciclomed; Research grant / Funding (institution): Curegenix; Research grant / Funding (institution): Curis; Research grant / Funding (institution): DelMar; Research grant / Funding (institution): eFFECTOR; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Hutchison MediPharma; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Jacobio; Research grant / Funding (institution): Jounce; Research grant / Funding (institution): Kolltan; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): miRNA Therapeutics; Research grant / Funding (institution): National Institutes of Health; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Oncothyreon; Research grant / Funding (institution): Precision Oncology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Regenix; Research grant / Funding (institution): Strategia; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): University of Texas MD Anderson Cancer Center; Research grant / Funding (institution): Vegenics; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): American Society of Clinical Oncology. J. Desai: Advisory / Consultancy, Research grant / Funding (self): Roche; Research grant / Funding (self): GSK; Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Beigene; Research grant / Funding (self): Bristol-Myers Squibbb; Advisory / Consultancy, Research grant / Funding (self): Eli Lilly.J.C. Kuo: Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Zucero Therapeutics; Travel / Accommodation / Expenses: MSD. J.H. Strickler: Research grant / Funding (self): AbbVie; Advisory / Consultancy, Research grant / Funding (self): Amgen; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self): Seattle Genetics; Advisory / Consultancy: Chengdu Kanghong Biotechnology; Advisory / Consultancy: Chugai; Advisory / Consultancy, Research grant / Funding (self): OncoMed; Research grant / Funding (self): Exelixis; Research grant / Funding (self): Gilead Sciences; Research grant / Funding (self): Macrogenics; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Nektar Therapeutics. J.C. Krauss: Research grant / Funding (self): Amgen; Research grant / Funding (self): NSABP Foundation; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Oncomed Pharmaceuticals; Research grant / Funding (self): Ignyta/Roche; Research grant / Funding (self): Baxalta; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Isofol. B.T. Li: Research grant / Funding (self): Amgen; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Hengrui Therapeutics. C.S. Denlinger: Research grant / Funding (self): Amgen; Advisory / Consultancy, Research grant / Funding (self): Bristol Myer Squibb; Research grant / Funding (self): Sanofi; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Array BioPharma; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): BeiGene; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Macrogenics; Research grant / Funding (self): Agios Pharmaceuticals; Research grant / Funding (self): Lycera; Research grant / Funding (self): Merrimack Pharmaceuticals; Advisory / Consultancy: Merck. G. Durm: Research grant / Funding (self): Merck; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): AstraZeneca. J. Ngang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. H. Henary: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. G. Ngarmchamnanrith: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. E. Rasmussen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. P.K. Morrow: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. D.S. Hong: Research grant / Funding (self): AbbVie; Advisory / Consultancy, Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Amgen; Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Research grant / Funding (self): BMS; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Eisai; Research grant / Funding (self): Fate Therapeutics; Advisory / Consultancy, Research grant / Funding (self): Genentech; Research grant / Funding (self), Travel / Accommodation / Expenses: Genmab; Research grant / Funding (self): Ignyta; Advisory / Consultancy, Research grant / Funding (self): Infinity; Research grant / Funding (self): Kite; Research grant / Funding (self): Kyowa; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self), Travel / Accommodation / Expenses: LOXO; Research grant / Funding (self): Merck; Research grant / Funding (self): Medimmune; Research grant / Funding (self): Mirati; Research grant / Funding (self), Travel / Accommodation / Expenses: miRNA; Research grant / Funding (self): Molecular Template; Research grant / Funding (self): Mologen; Research grant / Funding (self): NCI-CTEP; Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Seattle Genetics; Advisory / Consultancy, Research grant / Funding (self): Takeda; Travel / Accommodation / Expenses: AACR; Travel / Accommodation / Expenses: ASCO; Travel / Accommodation / Expenses: SITC; Advisory / Consultancy: Alpha Insights; Advisory / Consultancy: Axiom; Advisory / Consultancy: Baxter; Advisory / Consultancy: GLG; Advisory / Consultancy: Group H; Advisory / Consultancy: Guidepoint Global; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Medscape; Advisory / Consultancy: Numab; Advisory / Consultancy: Tieza Therapeutics; Advisory / Consultancy: Web MD; Advisory / Consultancy: Molecular Match; Officer / Board of Directors: OncoResponse; Advisory / Consultancy: Presagia Inc.