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: 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.
CITATION STYLE
Govindan, R., Fakih, M. G., Price, T. J., Falchook, G. S., Desai, J., Kuo, J. C., … Hong, D. S. (2019). Phase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours. Annals of Oncology, 30, v163–v164. https://doi.org/10.1093/annonc/mdz244.008
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