STK11 and KEAP1 co-mutations in KRAS-mutated NSCLC are biomarkers for aggressive disease. For these patients, a more intensive upfront treatment strategy, such as adding chemotherapy to a targeted therapy and immunotherapy combination, should be considered to combat the poor prognosis.
Shifting from clinician-ordered to pathologist-initiated reflex testing for NSCLC biomarkers combines diagnosis and molecular analysis into one workflow. This operational change minimizes delays, increases testing rates, and optimizes the use of small biopsy samples, getting actionable results to oncologists faster.
A new class of drugs, "RAS on" inhibitors (e.g., daxorarasib), targets the active, GTP-bound state of KRAS. This mechanism is distinct from first-generation "RAS off" inhibitors (e.g., sotorasib) and is designed to treat patients who develop resistance, offering a subsequent line of targeted therapy.
DNA-based NGS can fail to detect clinically actionable fusions in NSCLC due to assay design limitations (low sensitivity). It can also report fusions of unclear significance (low specificity). Integrating RNA-based NGS is critical to reliably identify true driver fusions and clarify ambiguous DNA findings.
In frontline clinical trials for KRAS G12C NSCLC, combining olomorasib with pembrolizumab alone yielded a 90% response rate in patients with >50% PD-L1 expression. This surpassed the 78% rate seen when chemotherapy was added, suggesting a more targeted approach may be superior for this specific biomarker-defined subgroup.
To integrate RNA sequencing, labs can use a sequential workflow (DNA-NGS first, then RNA-NGS on driver-negative cases), which is cost-effective but slower. Alternatively, upfront co-testing is faster and decision-free but more expensive and may be unnecessary for patients with common DNA-level drivers.