Poor Prognostic Factors and Frontline Treatment Selection

The faculty open by framing frontline decision-making in EGFR-mutated advanced non-small cell lung cancer (NSCLC), noting that the NCCN Guidelines list 3 category 1 preferred options for exon 19 deletion or L858R disease, osimertinib, osimertinib plus chemotherapy, and lazertinib plus amivantamab. They review the poor prognostic factors that determine which patients receive escalated therapy, including brain metastases, liver metastases, detectable circulating tumor DNA (ctDNA), and TP53 co-mutation,emphasizing that not all EGFR-driven disease behaves the same way. The panel describes osimertinib monotherapy based on FLAURA, intensified strategies, and the COMPEL approach of adding chemotherapy at progression. Host factors that constrain regimen choice are also addressed, including reduced renal function limiting chemotherapy eligibility, underlying skin conditions, and prior thrombotic events. The faculty note emerging evidence that escalation may benefit a broader population, setting up why prospective data are needed to define who requires intensification.