Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRAS^G12C inhibitor, in advanced solid tumors.

Abstract

3003 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 KRAS G12C mutant solid tumors. MTD has not been determined, and enrollment into the dose exploration is ongoing. Clinical trial information: NCT03600883.

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

“…This discovery spurred the race to develop KRAS-G12C-targeting drugs for clinical use. AMG510 and MRTX1257 were the first ones to be developed as drugs to target KRAS G12C mutant for non-small cell lung cancer [274,[276][277][278]. The results from phase I trials were promising and showed a 50% response rate for patients with KRAS G12C mutations.…”

Targeted therapy in lung cancer—ASCO 2019 update

“…All patients had received at least two lines of prior systemic therapy. AMG 510 achieved a 50% response rate in patients with KRASG12C-positive NSCLC, according to results from a phase I study presented by Fakih et al [9].…”

Novel, provable algorithms for efficient ensemble-based computational protein design and their application to the redesign of the c-Raf-RBD:KRas protein-protein interface

“…Therefore, limiting the sequence space 61 to sequences energetically similar to or better than the wild-type sequence is reasonable. 62 A simplified workflow for fries/EWAK * is presented in Fig 1. Compared to the 63 previous state-of-the-art algorithm BBK * , fries and EWAK * improve runtimes by up 64 to 2 orders of magnitude, fries decreases the size of the sequence space by up to more 65 than 2 orders of magnitude, and EWAK * decreases the number of conformations 66 included in partition function calculations by up to almost 2 orders of magnitude. design algorithms approximate these partition functions for each state using either 104 stochastic [50][51][52][53] or provable [2, 12, 29-31, 33, 53] methods.…”