Front-line intensification strategies improve outcomes in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) but increase toxicity. We aimed to identify baseline predictors of early progression (EP) versus durable long response (LR) to osimertinib monotherapy to guide clinical decision-making.

We analyzed 408 patients with advanced or recurrent EGFR-mutant NSCLC. Predictors for EP (progression-free survival [PFS] < 12 months, n = 370) and LR (PFS ≥ 30 months among 12-month landmark survivors, n = 251) were identified using multivariable logistic and Cox models, adjusting for clinical factors, PD-L1 status, and metastatic organ count (Meta-N).

Median PFS and overall survival were 22.9 and 58.0 months. In the overall cohort, postoperative recurrence was independently favorable (adjusted hazard ratio [aHR], 0.52; 95 % confidence interval [CI], 0.38-0.71). Notably, higher PD-L1 expression and de novo Stage IV status at the time of osimertinib initiation (compared with postoperative recurrence) significantly increased EP risk (adjusted odds ratio [aOR] 2.98; 95 % CI, 1.36-6.51 for PD-L1 ≥ 50 %; P = 0.006). Beyond 12 months, the PD-L1 impact was no longer evident, whereas bone metastasis emerged as a persistent barrier, significantly reducing the likelihood of achieving LR (aOR, 0.46; 95 % CI 0.23-0.93; P = 0.032). Higher Meta-N demonstrated stepwise prognostic worsening.

High PD-L1 expression primarily signals early risk, whereas bone metastasis and high Meta-N are persistent barriers to long-term response durability. Postoperative recurrence is a consistently favorable factor for survival. These findings support risk-adapted therapy; these high-risk subgroups may represent rational candidates for evaluating front-line intensification strategies in prospective clinical trials, whereas osimertinib monotherapy remains appropriate for lower-burden disease, such as postoperative recurrence.