Treatment strategies in metastatic NSCLC after progression to immuno-chemotherapy: A random-effects network meta-analysis of phase III trials.

Abstract

e20509 Background: Patients with metastatic non-small cell lung cancer (mNSCLC) progressing after immunotherapy (IO) plus chemotherapy have limited options, and the relative survival benefit of 2L+ strategies remains uncertain. A network meta-analysis (NMA) was performed to assess survival outcomes and rank experimental treatments versus standard of care in biomarker-unselected 2L+ mNSCLC. Methods: We leveraged LARVOL CLIN, an oncology outcomes database with 130k+ trials, 100k+ digitized Kaplan-Meier (KM) curves and 17k+ Hazard Ratios (HRs); to conduct a random-effects frequentist NMA. Pseudo-individual patient data (IPD) were reconstructed from published KM curves and at-risk tables using the Guyot algorithm. Trials were pooled by treatment arm and overall survival (OS) HR was estimated using Cox proportional hazards model. Results: Six phase III trials in biomarker-unselected 2L+ mNSCLC with progression after IO + chemotherapy were identified (Table 1). LEAP-008, SAPPHIRE, and CONTACT-01 evaluated IO-tyrosine kinase inhibitors (TKI); EVOKE-01 and TROPION-Lung01 TROP-2 antibody-drug conjugates (ADC); and LATIFY IO plus ATR inhibitor; all versus chemotherapy. LATIFY reported no OS benefit without published HR and was excluded from quantitative analyses. Across the remaining 5 trials, HR consistently favored experimental arms (OS 0.90 [0.82-0.99]; progression free survival (PFS) 0.87 [0.76-1.00]), with significant PFS benefit in CONTACT-01 and TROPION-Lung01. In the OS NMA, chemotherapy served as anchor. Treatments were ranked using p-scores, reflecting relative effectiveness with nivolumab- and atezolizumab-TKI ranking highest, followed by TROP-2 ADCs. Pembrolizumab-TKI and chemotherapy (0.2) ranked the lowest. No between-study heterogeneity or global inconsistency was observed (τ² = 0, Q = 0). In a pooled analysis of TROP-2 ADC trials, mOS was 12.03 and 10.48 months for chemotherapy (HR 0.91 [0.80–1.04]). Mechanism-specific grade ≥3 toxicities were observed across the 5 trials, including hypertension with IO-TKI and hematologic and gastrointestinal events with ADCs. Conclusions: This meta-analysis showed a modest trend towards improved OS and PFS for experimental treatments relative to standard of care chemotherapy. NMA ranked IO-TKI highest among the strategies, although caution is needed for cross-trial comparisons. These findings underscore the need for more effective strategies in 2L+ mNSCLC patients. Trials summary and NMA results. SAPPHIRE CONTACT-01 EVOKE-01 TROPION-LUNG01 LEAP-008 N 577 366 603 605 422 InterventionN Nivolumab + Sitravatinib284 Atezolizumab + Cabozantinib186 Sacituzumab Govitecan299 Datopotamab Deruxtecan299 Pembrolizumab + Lenvatinib185 OS HR 0.86 0.88 0.89 0.90 0.98 PFS HR 1.08 0.74* 0.92 0.75* 0.89 AE Gr3+% 49 vs 24 48 vs 46 54 vs 60 26 vs 42 60 vs 49 OS P-score 0.72 0.64 0.63 0.46