Updated ASCO Guidelines for Treating Stage IV Non–Small Cell Lung Cancer

Sponsoring Organization: American Society of Clinical Oncology (ASCO)

Background and Objective

Non–small cell lung cancer (NSCLC) comprises a multitude of biomarker-driven diseases. Two ASCO guidelines on stage IV NSCLC highlight the need for biomarker analysis in treatment decisions and show the array of treatment options.

Key Recommendations

• Start with testing. At diagnosis, order a tissue or blood-based multigene panel. At minimum, look for mutations in EGFR, HER2, BRAF, KRAS; rearrangements in ALK, ROS1, RET, NTRK, NRG1; and MET exon 14 skipping. Use immunohistochemistry to check for PD-L1 and HER2.
• If a driver is present, target the therapy. If testing identifies a driver alteration, targeted therapy is critical and often the preferred first-line treatment, depending on the alteration. At progression, retesting can uncover new resistance mechanisms to target.
• If no driver is present, use PD-L1. Here, immunotherapy — alone or combined with chemotherapy — remains the foundation of care
• Integrate palliative care early. Alongside any treatment path, early integration of palliative care improves quality of life.

The guidelines note new but not practice-changing findings:

• The RAMOSE trial added ramucirumab to osimertinib in EGFR-mutated disease, modestly improving progression-free survival, but methodological issues preclude changes in guidance for first-line EGFR treatment.
• In a phase 2 trial, zenocutuzumab showed promise in NRG1 fusion, a rare event in solid tumors, with a 29% response rate, supporting its use in this population.
• Trials of dual checkpoint blockade or ivonescimab, a novel bispecific VEGF and PD-1 antibody, showed mixed efficacy and higher toxicity, leaving standard regimens unchanged.