Efficacy and toxicity of maintenance therapy with PD-1/PD-L1 inhibitors plus pemetrexed vs. immunotherapy alone for stage III/IV non-squamous non-small cell lung cancer: A real-world study

BACKGROUND: It is a common challenge in clinical decision-making to optimize and select maintenance therapy (MT) regimens that balance efficacy and toxicity. This study compares the efficacy and toxicity of immune checkpoint inhibitors (ICIs) monotherapy vs. ICIs plus pemetrexed as MT following initial immunotherapy in non-small cell lung cancer (NSCLC) patients. METHODS: We performed a multicenter retrospective real-world study that included non-squamous NSCLC (nqNSCLC) patients who received 4-6 cycles of ICIs plus pemetrexed as the first-line treatment and continued ICIs monotherapy or ICIs plus pemetrexed as MT between April 1, 2018, and June 30, 2023. Progression-free survival (PFS) and overall survival (OS) were reported using the Kaplan-Meier method. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: Out of 1060 recorded patients, 328 met the inclusion criteria for the analysis: 235 received ICIs plus pemetrexed, and 93 received ICIs monotherapy as MT. Demographic characteristics were comparable between the two groups. No significant difference was observed in median PFS (15.0 vs. 14.6 months; P = 0.756) between the two groups, regardless of programmed death-ligand 1 (PD-L1) stratification. Similarly, median OS did not differ significantly (28.3 vs. 38.9 months; P = 0.799). Anemia incidence was higher in the ICIs plus pemetrexed MT group (48.5 vs. 32.3%). Patients who were rechallenged with ICIs as second-line therapy experienced improved OS compared to those who received non-ICI therapy (not reached vs. 20.4 months; P = 0.009). CONCLUSION: The absence of statistically significant survival difference and increased toxicity in the ICIs plus pemetrexed cohort suggest that chemotherapy may not be crucial in MT. Moreover, the significant benefits of ICIs-based therapy as a second-line treatment reinforce its value, offering confidence to both patients and physicians in making informed decisions regarding MT strategies and subsequent systemic therapies.