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

Date

28 Sep 2019

Session

Poster Discussion – Developmental therapeutics

Presenters

Ramaswamy Govindan

Citation

Annals of Oncology (2019) 30 (suppl_5): v159-v193. 10.1093/annonc/mdz244

Authors

R. Govindan1, M.G. Fakih2, T.J. Price3, G.S. Falchook4, J. Desai5, J.C. Kuo6, J.H. Strickler7, J.C. Krauss8, B.T. Li9, C.S. Denlinger10, G. Durm11, J. Ngang12, H. Henary12, G. Ngarmchamnanrith12, E. Rasmussen13, P.K. Morrow12, D.S. Hong14

Author affiliations

  • 1 Dept Of Medical Oncology, Alvin J Siteman Cancer Center at Washington University School of Medicine, 63110 - St Louis/US
  • 2 Dept Of Gi Medical Oncology, City of Hope National Medical Center, 91010 - Duarte/US
  • 3 Dept Of Medical Oncology, The Queen Elizabeth Hospital, 5022 - Woodville South/AU
  • 4 Sarah Cannon Research Institute, HealthONE, 80218 - Denver/US
  • 5 Dept Of Medical Oncology, Peter MacCallum Cancer Centre, 3000 - Melbourne/AU
  • 6 Dept Of Medical Oncology, Scientia Clinical Research Ltd, NSW 2031 - Randwick/AU
  • 7 Dept Of Medicine, Division Of Medical Oncology, Duke University Medical Center, 27710 - Durham/US
  • 8 Division Of Hematology/oncology, Internal Medicine, University of Michigan, 48105 - Ann Arbor/US
  • 9 Dept Of Medicine, Memorial Sloan Kettering Cancer Center, 10017 - New York/US
  • 10 Dept Of Hematology/oncology, Fox Chase Cancer Center, 19111 - Philadelphia/US
  • 11 Dept Of Hematology/oncology, Indiana University, Simon Cancer Center, 46202 - Indianapolis/US
  • 12 Global Development, Amgen Inc., 91320 - Thousand Oaks/US
  • 13 Global Biostatistics, Amgen Inc., 91320 - Thousand Oaks/US
  • 14 Dept Of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, 77030 - Houston/US
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Background

The KRASG12C 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. KRASG12C 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 KRASG12C 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 KRASG12C solid tumors (NCT03600883).

Methods

Key eligibility: measurable/evaluable disease with identified KRASG12C 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

Best Tumor Response in 29* Patients
FrequencyDuration of Response or Stable Disease**
NSCLC (n = 10)
Partial Response5 (2 confirmed)7.3 - 27.4 weeks
Stable Disease48.4 - 25.1 weeks
Progressive Disease1***n/a
CRC/Other (n = 19)
Stable Disease147.3 - 24.0 weeks
Progressive Disease5***n/a
*

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 KRASG12C 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.

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