Toshiyuki Sumi, Yutaro Nagano, Osamu Honjo, Tatsuru Ishikawa, Sayaka Kudo, Shun Kondoh, Masami Yamazoe, Keiki Yokoo, Yuta Koshino, Makoto Shioya, Yuta Sudo, Kanami Nagano, Hayato Yabe, Yuichiro Asai, Hirotaka Nishikiori, Mamoru Takahashi, Hirofumi Chiba
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.
BACKGROUND: 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.
METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.