Modality-specific survival outcomes of biomarker-matched therapy in unresected non-small cell lung cancer: a clinicogenomic cohort study

Background: Biomarker-matched therapy (BMT), including targeted therapy (TT) and immune checkpoint blockade (ICB), has improved outcomes in selected patients with non-small cell lung cancer (NSCLC). However, real-world evidence separating the survival associations of TT and ICB within BMT remains limited. We evaluated BMT and modality-specific survival associations in patients with unresected NSCLC using the Memorial Sloan Kettering Clinicogenomic Harmonized Oncologic Real-World Dataset (MSK-CHORD).

Methods: In total, 1,992 patients with unresected NSCLC were analyzed. BMT was defined as receipt of either matched TT or ICB according to the recorded tumor biomarker profile. Overall survival (OS) was compared using propensity-score overlap-weighted Cox models. Modality-specific analyses separately assessed TT in the TT-actionable group and ICB in the ICB-actionable group. Specimen-source, race-exclusion, landmark, and time-dependent Cox analyses were performed as sensitivity analyses.

Results: Among 1,992 patients with unresected NSCLC, 894 received BMT. After overlap weighting, BMT was associated with longer OS than no BMT [adjusted hazard ratio (aHR): 0.68; 95% confidence interval (CI): 0.59–0.79], with a stronger association in stage IV disease (aHR: 0.58; 95% CI: 0.49–0.69). In modality-specific analyses, TT was associated with longer OS in the TT-actionable group (aHR: 0.66; 95% CI: 0.53–0.82), with the clearest association in stage IV disease (aHR: 0.51; 95% CI: 0.40–0.65). ICB was not associated with longer OS in the ICB-actionable group (aHR: 1.09; 95% CI: 0.89–1.33). Findings were consistent across specimen-source and race sensitivity analyses, whereas landmark and time-dependent analyses attenuated the BMT and overall TT estimates.

Conclusions: In unresected NSCLC, BMT was associated with longer OS in sequencing-anchored real-world analyses, particularly in stage IV disease. Separate modality-specific analyses showed that the clearest survival association was observed for TT, whereas ICB did not show a comparable association in the ICB-actionable group. These findings support reporting BMT, TT, and ICB separately when interpreting real-world outcomes of biomarker-matched systemic therapy.