Clinical Scenario 1: Frontline Treatment Selection for a Patient with EGFR-Mutated NSCLC and TP53 Co-Mutation

Dr. Riess presents a 52-year-old never-smoking woman with stage IV EGFR exon 19 deletion non-small cell lung cancer, performance status 0, full-time employment as a teacher, no significant comorbidities, and no baseline CNS metastases on brain MRI. NGS reveals a concurrent pathogenic TP53 co-mutation. Dr. Fidler approaches this case with a clear recommendation for frontline combination therapy, citing the TP53 co-mutation as a reinforcing risk factor even in a patient with otherwise favorable features (exon 19 deletion, PS0, absence of brain metastases). She notes she would recommend combination therapy regardless of TP53 status for an otherwise healthy patient, but TP53 positivity heightens urgency.

For regimen selection, the discussion weighs amivantamab-lazertinib against osimertinib plus carboplatin-pemetrexed. Dr. Fidler highlights the chemotherapy-free advantage of amivantamab-lazertinib for a working professional who values minimizing chemotherapy-related cytopenias, fatigue, and frequent infusion center visits. She emphasizes that amivantamab-lazertinib with subcutaneous administration and every-4-week dosing means significantly less time away from work compared with a chemotherapy-based regimen requiring every-3-week visits. However, the COCOON prophylactic regimen (twice-daily antibiotics, twice-daily topical applications, nail bed protection, and anticoagulation) requires a meaningful commitment to daily self-care during the initial treatment phase.

She reinforces that patients must be willing and able to adhere to the full supportive care regimen for amivantamab-lazertinib to achieve the maximum benefit; this readiness should be part of the shared decision-making conversation. Regardless of regimen, comprehensive upfront counseling about expected toxicities, dose modification strategy, and the manageable nature of these adverse events is essential to support treatment continuity in patients with EGFR-mutated NSCLC.