Management of NSCLC Harboring the KRAS G12C Mutation

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Advanced non–small-cell lung cancer (NSCLC) treatment has undergone a revolution in the past 15 years due to improvements in tumor gene sequencing and the development of therapies targeting tumor genetic drivers. In patients with NSCLC without targetable mutations, PD-1/PD-L1 immune checkpoint inhibitors (ICIs), either as monotherapy or in combination with chemotherapy and/or cytotoxic T-lymphocyte–associated protein 4 inhibitors, have resulted in significant improvements in clinical outcomes and survival benefits. The most common mutation in NSCLC is KRAS, with up to 30% of lung adenocarcinomas harboring this mutation. The KRAS glycine to cysteine substitution at codon 12 (G12C) is the most frequent subtype. Lung cancer with the KRAS mutation is associated with high tumor mutation burden, a history of smoking, and distinct co-mutation and transcriptomic patterns. Historically, this mutation has been considered undruggable, but results of early-phase clinical trials have found that direct KRAS G12C inhibitor use has demonstrated responses in up to 40% of patients with KRAS G12C NSCLC, presenting the option for personalized cancer management in these patients.

Ricciuti and colleagues recently reviewed the treatment landscape for advanced NSCLC with the KRAS G12C mutation. NSCLC with this mutation has an increased sensitivity to ICIs partly due to the tendency to upregulate PD-L1 and PD-L2. The use of PD-L1 inhibitors with or without platinum-based chemotherapy in patients with metastatic NSCLC has been found to improve clinical outcomes and survival and is the first-line treatment of choice for patients with NSCLC who have no actionable tumor drivers. The decision to use a PD-L1 inhibitor as monotherapy or with chemotherapy will depend upon tumor PD-L1 expression, patient performance status, patient age, co-mutation status, and tumor mutational burden.

For patients with KRAS G12C–mutated NSCLC and negative or low PD-L1 (<1%) tumor proportion score (TPS), the combination of a PD-L1 inhibitor (pembrolizumab) plus chemotherapy is preferred. The KEYNOTE-042 study found that the use of pembrolizumab as monotherapy in patients with NSCLC with PD-L1 TPS ≥1% is an approved alternative therapy for this patient group. In patients with NSCLC with KRAS G12C with PD-L1 TPS ≥1% (1%-49%), the preferred treatment is platinum doublet chemotherapy plus pembrolizumab. In patients with NSCLC KRAS G12C and PD-L1 expression ≥50%, pembrolizumab, atezolizumab, or cemiplimab are all preferred monotherapies. However, for patients with high levels of PD-L1 expression on immune cells but not on tumor cells, combination therapy of chemotherapy plus a PD-L1 inhibitor is preferred. For second-line therapy, sotorasib (a small-molecule inhibitor of KRAS G12C) is preferred, with platinum doublet chemotherapy (if not given first line), single-agent chemotherapy, or a clinical trial with a G12C inhibitor as alternatives. Third-line options and beyond include single-agent chemotherapy or enrollment in a clinical trial.

Source: Ricciuti B, Mira A, Andrini E, et al. How to manage KRAS G12C-mutated advanced non-small-cell lung cancer. Drugs Context. 2022;11:2022-7-4.

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