Comprehensive molecular testing (PD-L1, EGFR, ALK) is no longer reserved for advanced disease. It is now critical for all patients with stage 1B or higher resectable NSCLC *before* starting any treatment to guide neoadjuvant and adjuvant therapy decisions.
Emerging data from major trials shows that ctDNA clearance during neoadjuvant therapy and negative post-surgical MRD status are strong predictors of improved survival. MRD positivity, in contrast, is associated with worse biology and rapid progression.
For patients with actionable mutations like EGFR or ALK, targeted therapy is the priority, regardless of PD-L1 score. Starting immunotherapy first in these patients can significantly increase the risk of developing severe pneumonitis (ILD) when they later switch to targeted therapy like osimertinib.
Data from trials like CheckMate 816 shows that achieving a Pathologic Complete Response (PCR) after neoadjuvant chemo-immunotherapy is a powerful early surrogate endpoint. Patients with PCR demonstrate markedly improved overall and event-free survival.
The NeoADURA trial demonstrates that adding osimertinib in the neoadjuvant setting for EGFR-mutated NSCLC results in a 'humongous benefit' in major pathological response and nodal downstaging compared to chemotherapy alone, significantly improving surgical outcomes.
While neoadjuvant-only immunotherapy has a strong rationale, a patient-level cross-trial comparison of CheckMate 816 (neoadjuvant) and 770T (perioperative) suggests the addition of adjuvant therapy improves event-free survival, favoring a full perioperative approach.