Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors.
Abstract
3003 Background: The KRAS G12C 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 KRAS G12C 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 KRAS G12C 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: KRAS G12C 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 KRAS G12C 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.
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Sotorasib was approved by the FDA in May 2021 for the treatment of NSCLC patients with a KRASG12C mutation.
“Surprisingly, in 2021, after unremitting efforts, a milestone was achieved: the KRASG12C inhibitor sotorasib was approved by the FDA for a specific subgroup of patients with non-small cell lung cancer (NSCLC),10”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [52]
Sotorasib became the first targeted drug for the treatment of KRAS gene mutation in the world.
“It also became the first targeted drug for the treatment of KRAS gene mutation in the world, breaking the “undruggable” dilemma and marking a milestone in medical history.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [52]
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Small molecule combats cancer-causing KRAS protein at last
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- Authors
- Fakih, M., O'Neil, B., Price, T. J., Falchook, G. S., Desai, J., Kuo, J., Govindan, R., Rasmussen, E., Morrow, P. K. H., Ngang, J., Henary, H. A., & Hong, D. S.
- Affiliations
- City Of Hope National Medical Center (US)
- Indiana University School of Medicine, Indianapolis, IN;
- Queen Elizabeth Hospital (AU)
- HealthONE (US)
- Peter MacCallum Cancer Centre (AU)
- Scientia Clinical Research, Randwick, Australia;
- Washington University in St. Louis (US)
- Amgen (United States) (US)
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2019-05-20
- Volume
- 37
- Issue
- 15_suppl
- Pages
- 3003-3003
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2947477797
- Cited by
- 172
- References
- 0
- Citations by year
- 2025: 3 · 2024: 6 · 2023: 12 · 2022: 21 · 2021: 34 · 2020: 75 · 2019: 20
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- sotorasib, KRAS G12C inhibitors, KRAS G12C mutation, advanced solid tumors, non-small cell lung cancer, colorectal cancer, pharmacokinetics, safety and tolerability, maximum tolerated dose, objective response rate, progression-free survival, dose escalation, dose expansion, treatment-related adverse events
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