CodeBreak 100: Phase I study of AMG 510, a novel KRAS^G12C inhibitor, in patients (pts) with advanced solid tumors other than non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).

3511 Background: Kirsten rat sarcoma viral oncogene homolog ( KRAS) p.G12C mutation occurs in approximately 13% of NSCLC and 1%–3% of CRC and other solid tumors. AMG 510 is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. Previously, AMG 510 showed preliminary antitumor activity and favorable tolerability in pts with KRAS p.G12C mutant NSCLC or CRC in the phase 1, first-in-human trial. Here, we report results in pts with other tumor types from the same trial. Methods: This study evaluates AMG 510 in pts with locally-advanced or metastatic KRAS p.G12C mutant solid tumors. Key inclusion criteria: KRAS p.G12C mutation via local testing and prior systemic anticancer treatment (tx). Oral daily doses of 180, 360, 720, and 960 mg were tested in the dose escalation, and 960 mg was selected for expansion. Primary endpoint is safety; key secondary endpoints include pharmacokinetics and objective response rate as assessed per RECIST 1.1. Response is assessed every 6 weeks (wks) for 24 wks then every 12 wks thereafter. Results: As of January 8, 2020, 25 pts (9 female, median age 60 years [range: 40–75]) with tumor types categorized by investigators as histology other than NSCLC and CRC were enrolled and dosed (10 pancreatic cancer, 4 appendiceal cancer, 2 endometrial cancer, 2 unknown primary cancer, 1 bile duct cancer, 1 sinonasal cancer, 1 ampullary cancer, 1 small bowel cancer, 1 melanoma, 1 small cell lung cancer, and 1 esophageal cancer). 23 pts received 960 mg dose. 20 pts (80.0%) had ≥2 prior lines of tx. At data cutoff, 13 pts (52.0%) remained on tx; 9 (36.0%) and 3 (12.0%) pts remained on tx for ≥3 and ≥6 months, respectively. Median follow up was 4.3 months (range: 0.1–12.6). Tx-related adverse events (TRAEs) occurred in 9 pts (36.0%). 2 pts (8.0%) had grade 3 TRAEs, including diarrhea (1/25) and pneumonia (1/25, serious AE). No dose-limiting toxicities, grade ≥4, or fatal TRAEs were reported. No TRAEs led to tx discontinuation. 3 pts had not been followed up for ≥7 wks by the data cutoff. 22 pts were followed up for ≥7 wks, and their best overall responses were: 3 confirmed partial response (1 appendiceal, 1 melanoma, and 1 endometrial), 13 stable disease (6 pancreatic, 2 appendiceal, 1 ampullary, 1 bile duct, 1 endometrial, 1 sinonasal, and 1 unknown primary), and 6 progressive disease. Conclusions: AMG 510 was well tolerated and demonstrated clinical activity in pts with advanced KRAS p.G12C mutant solid tumors other than NSCLC and CRC. Clinical trial information: NCT03600883 .

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