Maintenance Pemetrexed/Pembrolizumab Versus Pembrolizumab in Non–Small Cell Lung Cancer: A Propensity Score–Weighted Analysis

PURPOSE Pemetrexed remains part of guideline-recommended maintenance pemetrexed/pembrolizumab in advanced/metastatic non–oncogene-driven nonsquamous non–small cell lung cancer (NSCLC). Whether pemetrexed contributes to the combination's survival benefit is unknown. In this propensity-weighted analysis of US Veterans Affairs data, we compared real-world effectiveness and safety of maintenance pemetrexed/pembrolizumab versus maintenance pembrolizumab alone and estimated US government payer spending on maintenance pemetrexed. METHODS We identified Veterans who received four cycles of carboplatin/cisplatin, pemetrexed, and pembrolizumab followed by at least one dose of maintenance pemetrexed/pembrolizumab or pembrolizumab. A propensity-weighted Cox model was used to adjust for baseline between-group differences using inverse probability of treatment weights. The primary effectiveness outcome was overall survival (OS; time from first maintenance dose to death). The primary financial outcome was the estimated spending on maintenance pemetrexed across VA, Medicare Part B, and Medicaid (2017-2022). RESULTS The real-world outcomes cohort included 622 patients (473 pemetrexed/pembrolizumab; 149 pembrolizumab alone). After propensity weighting, pemetrexed was not associated with improved OS (adjusted hazard ratio [aHR] pemetrexed/pembrolizumab v pembrolizumab, 1.06 [95% CI, 0.83 to 1.36, P = .62]) but was associated with higher toxicity risk (grade ≥3 acute kidney injury [aHR 3.35, 95% CI, 1.08 to 10.41, P = .04]; neutropenia [aHR 2.86, 95% CI, 1.44 to 3.05; P = .004]; anemia [aHR 1.65, 95% CI, 1.11 to 2.47, P = .014]). Findings were robust to sensitivity analysis in which patients who crossed over from pembrolizumab to pemetrexed/pembrolizumab were excluded. Estimated government payer spending on maintenance pemetrexed from 2017 to 2022 totaled $1.588 billion (2024 USD). CONCLUSION Adding pemetrexed to maintenance pembrolizumab was not associated with improved survival but was associated with increased toxicity. Reassessing legacy chemotherapy components may improve the safety and cost-effectiveness of cancer care . Prospective evaluation of maintenance pemetrexed's incremental benefit in NSCLC in the immunotherapy era is needed.