Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors.

Authors

null

Marwan Fakih

The Judy and Bernard Briskin Center for Clinical Research, City of Hope, Duarte, CA

Marwan Fakih , Bert O'Neil , Timothy Jay Price , Gerald Steven Falchook , Jayesh Desai , James Kuo , Ramaswamy Govindan , Erik Rasmussen , Phuong Khanh H. Morrow , Jude Ngang , Haby A. Henary , David S. Hong

Organizations

The Judy and Bernard Briskin Center for Clinical Research, City of Hope, Duarte, CA, Indiana University School of Medicine, Indianapolis, IN, Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia, Sarah Cannon Research Institute at HealthONE, Denver, CO, Peter MacCallum Cancer Centre, Melbourne, Australia, Scientia Clinical Research, Randwick, Australia, Alvin J Siteman Cancer Center at Washington University School of Medicine, St. Louis, MO, Amgen Inc., Thousand Oaks, CA, The University of Texas MD Anderson Cancer Center, Houston, TX

Research Funding

Pharmaceutical/Biotech Company

Background: The KRASG12C mutation is found in approximately 13% of lung adenocarcinomas and 1–3% of other solid tumors, but there is no approved therapy that targets this mutation. AMG 510 is a novel small molecule that specifically and irreversibly inhibits KRASG12C by locking it in an inactive GDP-bound state. Methods: This phase 1, first-in-human, open-label, multicenter study (NCT03600883) is evaluating the safety, tolerability, PK, and efficacy of AMG 510 in adult patients (pts) with locally-advanced or metastatic KRASG12C mutant solid tumors. The primary endpoint is safety; key secondary endpoints include PK, ORR (assessed every 6 weeks [wks]), DOR, and PFS. Key inclusion criteria: KRASG12C mutation identified through DNA sequencing, measurable or evaluable disease, ECOG PS ≤2, life expectancy >3 months (mo). Key exclusion criteria: active brain metastases, myocardial infarction within 6 mo. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). A dose expansion will enroll pts with NSCLC, CRC, and other advanced solid tumors carrying the KRASG12C mutation. AMG 510 will be given PO until disease progression, intolerance, or withdrawal of consent. Results: 22 pts (8 men, 14 women; median age 55.5 y) were enrolled in the first 3 dose cohorts. Tumor types: 6 NSCLC, 15 CRC, 1 other. Most pts (n=17) had ≥3 prior lines of treatment (tx). Median tx duration was 28 d (range: 8–134). 5 pts reported 10 treatment-related AEs (grade 1, n=9; grade 2, n=1); there were no DLTs. Tumor response was evaluated in 9 pts (4 with ≥2 assessments); 13 pts have not reached their first assessment.1 pt had a PR (NSCLC at wks 6 and 12, tx ongoing), 6 pts had SD (4 CRC and 2 NSCLC; median tx duration 9.7 wks [range: 6.3–19.1], tx ongoing), 2 pts had PD. 20 pts are continuing to receive AMG 510. A second PR (NSCLC at wk 6, tx ongoing) was reported after data cutoff. Conclusions: AMG 510 has been well tolerated at the dose levels tested and has shown antitumor activity when administered as monotherapy to patients with advanced KRASG12C mutant solid tumors. MTD has not been determined, and enrollment into the dose exploration is ongoing. Clinical trial information: NCT03600883

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Abstract Details

Meeting

2019 ASCO Annual Meeting

Session Type

Oral Abstract Session

Session Title

Developmental Therapeutics and Tumor Biology (Nonimmuno)

Track

Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

Sub Track

New Targets and New Technologies (non-IO)

Clinical Trial Registration Number

NCT03600883

Citation

J Clin Oncol 37, 2019 (suppl; abstr 3003)

DOI

10.1200/JCO.2019.37.15_suppl.3003

Abstract #

3003

Abstract Disclosures