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).

Abstract

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 .

Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer

“…in vitro and in vivo, these KRAS G12C mutations are more sensitive to combined pan-HER and MEK inhibition [5,6]. An ongoing phase I study with the specific KRAS G12C inhibitor AMG510 shows a partial response in three out of 225 patients and stable disease in 13 patients with KRAS G12C mutant solid tumors [7].…”

Evaluation of Somatic Mutations in Solid Metastatic Pan-Cancer Patients

“…Our results suggest a similar frequency to other NGS-guided studies that match targeted therapy based on the identification of at least one actionable alteration [ 62 , 63 ]. The advent of novel therapeutics, including new NTRK, RAS, RET, and MET inhibitors has transformed the clinical trial landscape and presented more therapeutic options to patients than ever before [ 64 , 65 , 66 , 67 ]. These advancements in genomic sequencing and trial accrual validate precision medicine to deliver improved outcomes in all solid tumors.…”

“…Combinatory targeted therapeutic options are a potential non-toxic avenue for combatting this resistance, and several early and late-stage clinical trials, including NCI #10327, NCI #9466, and NCT03944772, are currently underway to understand their efficacy. The promise of precision medicine is quickly transforming into the reality of precision therapeutics with the discovery of effective KRAS-inhibitors and other drug targets that were previously thought to be undruggable [ 65 , 71 ]. Therefore, the outcomes of patients with solid tumors rely on the successful inhibition of oncogenic mutational signatures that drive disease progression by utilizing informed targeted therapy.…”

6th Molecular Oncology Society Conference: Improving patient survival by molecularly targeted therapies

“…[12] Dr. Deepak Shukla discussed the results of the Phase II CodeBreak 100 trial, which showed that sotorasib provided durable clinical benefit with a favorable safety profile in pre-treated NSCLC patients with KRAS p.G12C mutations. [13] In the LIBRETTO-001 study, selpercatinib resulted in 64% objective response rate in RET fusion-positive NSCLC patients previously treated with platinum-based chemotherapy as presented by Dr. Pushpak Chirmade. [14] In the ARROW study, pralsetinib produced robust clinical responses in RET fusion-positive NSCLC patients.…”