Osimertinib versus Erlotinib Combined with an Angiogenesis Inhibitor in EGFR-Mutated Non-Small Cell Lung Cancer with Malignant Pleural Effusion: a retrospective cohort study

Background: Osimertinib is the standard first-line treatment for non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. Erlotinib combined with an anti-angiogenic agent (erlotinib+A) has demonstrated efficacy in controlling malignant pleural effusion (MPE) through reduction of vascular permeability; however, no clinical trials have directly compared its MPE control efficacy with that of osimertinib. This study aimed to compare the efficacy of osimertinib versus erlotinib+A in controlling MPE in patients with EGFR-mutant NSCLC.

Methods: This multicenter retrospective cohort study analyzed longitudinal medical records of patients with advanced or recurrent EGFR-mutant NSCLC presenting with MPE at treatment initiation who received osimertinib or erlotinib+A at 14 institutions in Japan between November 2009 and October 2023. Patients with squamous cell carcinoma were excluded. The primary endpoint was time to MPE recurrence (MPE-progression-free survival [PFS]). Secondary endpoints included PFS, overall survival (OS), and adverse events graded according to the CTCAE. Multivariable Cox proportional hazards regression served as the primary analysis, with propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) utilized for sensitivity analyses.

Results: Among 421 patients (median age, 73 years; 65% female; 66% never-smokers; 99% adenocarcinoma), 373 received osimertinib and 48 received erlotinib+A. In the multivariable Cox regression analysis, no significant differences were observed between the osimertinib and erlotinib+A groups in MPE-PFS (adjusted HR: 0.79; 95% CI: 0.54–1.15; P = 0.22), PFS (adjusted HR: 0.87; 95% CI: 0.60–1.25; P = 0.45), or OS (adjusted HR: 0.95; 95% CI: 0.63–1.44; P = 0.82). However, a significant interaction between the treatment regimen and EGFR mutation type was identified (P = 0.004 for MPE-PFS). Subgroup analysis demonstrated that osimertinib was significantly superior to erlotinib+A in patients with EGFR exon 19 deletions (MPE-PFS: adjusted HR: 0.38; 95% CI: 0.21–0.67; P < 0.001), whereas no difference was observed in those with L858R mutations. Grade ≥3 adverse events were more frequent in the erlotinib+A group (38% vs. 21%; P = 0.016), whereas osimertinib was associated with a higher incidence of all-grade interstitial pneumonia (21% vs. 6%; P = 0.012).

Conclusion: Osimertinib showed comparable efficacy to erlotinib+A in MPE control with a more favorable safety profile. Subgroup analysis suggested a particular benefit in patients harboring EGFR exon 19 deletions, highlighting the potential importance of mutation subtype–based treatment selection. Given the retrospective design and potential for residual confounding, prospective validation is warranted.