Canadian Consensus Recommendations on the Management of KRAS G12C-Mutated NSCLC

• Published in: Current oncology (Toronto) Vol. 30; no. 7; pp. 6473 - 6496
• Main Authors: Cheema, Parneet K, Banerji, Shantanu O, Blais, Normand, Chu, Quincy S-C, Juergens, Rosalyn A, Leighl, Natasha B, Sacher, Adrian, Sheffield, Brandon S, Snow, Stephanie, Vincent, Mark, Wheatley-Price, Paul F, Yip, Stephen, Melosky, Barbara L
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-07-2023; MDPI
• Subjects: Cancer; Chemotherapy; Codon; Development and progression; Evidence-based medicine; Gene mutations; Glycine; Guidelines; immune checkpoint inhibitors; KRAS G12C; Lung cancer, Non-small cell; mutation testing; NSCLC; Pemetrexed; Pharmaceutical industry; resistance; Sarcoma; targeted therapy; Canada; United Kingdom; France; United States; Germany; targeted therapy; mutation testing; KRAS G12C; immune checkpoint inhibitors; NSCLC; resistance
• ISSN: 1718-7729; 1198-0052; 1718-7729
• DOI: 10.3390/curroncol30070476

Activating mutations in
, in particular, a point mutation leading to a glycine-to-cysteine substitution at codon 12 (G12C), are among the most frequent genomic alterations in non-small cell lung cancer (NSCLC). Several agents targeting KRAS G12C have recently entered clinical development. Sotorasib, a first-in-class specific small molecule that irreversibly inhibits KRAS G12C, has since obtained Health Canada approval. The emergence of novel KRAS-targeted therapies warrants the development of evidence-based consensus recommendations to help clinicians better understand and contextualize the available data. A Canadian expert panel was convened to define the key clinical questions, review recent evidence, and discuss and agree on recommendations for the treatment of advanced
-mutated NSCLC. The panel agreed that testing for KRAS G12C should be performed as part of a comprehensive panel that includes current standard-of-care biomarkers. Sotorasib, the only approved KRAS G12C inhibitor in Canada, is recommended for patients with advanced KRAS G12C-mutated NSCLC who progressed on guideline-recommended first-line standard of care for advanced NSCLC without driver alterations (immune-checkpoint inhibitor(s) [ICIs] +/- chemotherapy). Sotorasib could also be offered as second-line therapy to patients who progressed on ICI monotherapy that are not candidates for a platinum doublet and those that received first-line chemotherapy with a contraindication to ICIs. Preliminary data indicate the activity of KRAS G12C inhibitors in brain metastases; however, the evidence is insufficient to make specific recommendations. Regular liver function monitoring is recommended when patients are prescribed KRAS G12C inhibitors due to risk of hepatotoxicity.