Rechallenge of immune checkpoint inhibitor after local therapy for immune checkpoint inhibitor-resistant non-small cell lung cancer.

Background: The introduction of immune checkpoint inhibitors (ICIs) has enabled long-term survival for non-small cell lung cancer (NSCLC) patients. However, the proportion of patients achieving this is still low compared to patients with melanoma. Many NSCLC patients experience early progression (primary resistance) following ICI treatment, or relapse after initial responses (acquired resistance). While chemotherapy regimens, typically involving cytotoxic agents, are commonly used after ICI resistance, little evidence has been accumulated regarding the efficacy of ICI rechallenge. The aim of this study was to evaluate the efficacy of ICI rechallenge in patients who experienced failure of primary treatment with ICI-containing regimens. Additionally, we assessed whether the administration of local therapy prior to rechallenge influenced the efficacy of ICI rechallenge.

Methods: We retrospectively reviewed the records of advanced NSCLC patients for whom response was evaluated as progressive disease (PD) after receiving an ICI-containing regimen as first-line therapy and underwent rechallenge with an ICI in Funabashi Municipal Medical Center between January 2020 and March 2024. We analyzed progression-free survival (PFS) and overall survival (OS) based on whether local therapy (including beyond PD with local therapy) was performed. PFS was compared using the Kaplan-Meier method, with statistical significance set at P<0.05 using log-rank testing.

Results: The study included 20 patients, with 10 patients in the local therapy group and 10 in the no-local therapy group. No significant differences in patient characteristics were apparent between groups, although the no-local therapy group tended to show a higher number of organs with residual metastases at the time of rechallenge. When ICI rechallenge was administered after local therapy, median PFS was significantly longer in the local therapy group (9.0 months) than in the no-local therapy group (1.6 months, P=0.02), particularly in cases where radiation therapy was applied to the primary lesion just before rechallenge. However, no significant difference in OS was evident between the local treatment group (21.4 months) and the no-local treatment group (18.8 months; P=0.12).

Conclusions: Rechallenge with ICI following local therapy in NSCLC patients who developed resistance to ICIs may extend PFS, suggesting potential value as a therapeutic option.