Faculty, Staff and Student Publications

Language

English

Publication Date

3-1-2026

Journal

Clinical Lung Cancer

DOI

10.1016/j.cllc.2025.09.010

PMID

41193345

PMCID

PMC13092172

PubMedCentral® Posted Date

4-20-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: While substantial research has focused on first-line (1L) therapies for advanced-stage non-small cell lung cancer (aNSCLC), less is known about the effectiveness of second-line (2L) treatments following disease progression on 1L. The poor prognosis after 1L progression, limited guidance for 2L treatment, and constraints of clinical trials in addressing these questions underscore the need for real-world comparative effectiveness research.

Methods: We conducted a retrospective analysis to compare real-world overall survival (rwOS) associated with 2L treatments among patients with disease progression during 1L. Eligible patients were selected from Flatiron Health's nationwide electronic health record (EHR)-derived de-identified database. 1L and 2L treatments were categorized as chemotherapy-only (Chemo-alone), combination chemo- and immunotherapy (Chemo + Immuno), immunotherapy-only (IO-alone), targeted-alone therapy, or targeted-plus therapy. We used inverse probability of treatment weighting to adjust for extensive static and longitudinal patient-level confounding and compared rwOS using Kaplan-Meier curves and restricted mean survival time (RMST).

Results: Among patients previously treated with 1L Targeted therapy, those receiving 2L Targeted-alone therapy had longer life expectancies than those receiving a nontargeted (ΔRMST-36 + 2.61 months) or Targeted-plus regimen (ΔRMST-36 + 3.11 months). For patients progressing on 1L Chemo + Immuno, 2L Chemo + Immuno outperformed Chemo-alone (ΔRMST-36 + 2.98 months). Among patients progressing ≥1 year after initiating 1L IO-alone, 2L Chemo + Immuno again showed better life expectancy than Chemo-alone (ΔRMST-36 + 5.70 months).

Conclusions: Longitudinal real-world data can enhance assessment of 2L therapy effectiveness. After confounder adjustment, we found clinically meaningful survival differences by 2L choice. These findings underscore the importance of 2L treatment selection and the need for prospective validation.

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Male, Female, Retrospective Studies, Electronic Health Records, Middle Aged, Aged, Antineoplastic Combined Chemotherapy Protocols, Propensity Score, Immunotherapy, Survival Rate, Prognosis, Follow-Up Studies, Longitudinal Studies, Comparative Effectiveness Research, Aged, 80 and over

Published Open-Access

yes

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