Outcome differences between PD-1/PD-L1 inhibitors-based monotherapy and combination treatments in NSCLC with brain
Haowei Wang1, Fangfang Liu2, Xiaoxia Chen1
1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Zhengmin Road 507, Shanghai, 200433, China.
Introduction:
Without the clear immunophenotyping of brain metastases (BrMs), the optimal treatment strategy based on PD-1/PD-L1 inhibitor for patients with non-small-cell lung cancer (NSCLC) and BrMs remains unknown.
Methods:
308 patients with NSCLC received PD-1/PD-L1 inhibitor-based monotherapy or combination therapy were retrospectively identified. Kaplan-Meier curves with log-rank tests were used to determine the treatment outcomes differences. Transcriptomic analysis of paired primary lung lesions and BrMs were performed to dissect the specific tumor immune microenvironment (TIME) of BrMs.
Results:
The presence of BrMs was associated with significantly inferior PFS (2.5 vs. 3.7 months; P = 0.0053) and OS (8.3 vs. 15.4 months; P = 0.0122) in monotherapy group, while it was only associated with poorer PFS (4.6 vs. 7.0 months; P = 0.0009) but similar OS (22.8 vs. 21.0 months; P = 0.9808) in combination treatment group. Of patients with BrMs, PD-1/PD-L1 inhibitor plus antiangiogenic therapy was associated with longest PFS (7.7 vs. 3.2 vs. 2.5 months; P = 0.0251) and OS (29.2 vs. 15.8 vs. 8.3 months; P = 0.0001) when compared with PD-1/PD-L1 inhibitor plus chemotherapy or anti-PD-1/PD-L1 monotherapy. Multivariate analyses suggested that combination treatment was independently correlated with significantly longer PFS (P = 0.028) and OS (P < 0.001) in patients with BrMs. Transcriptomic analysis showed a suppressive TIME in BrMs with decreased CD4+ T cells and M1 macrophages but increased M2 macrophages infiltration.
Conclusion:
NSCLC with BrMs obtained barely satisfactory overall benefit from anti-PD-1/PD-L1 monotherapy, partly due to its immunosuppressive TIME. PD-1/PD-L1 inhibitor-based combination treatment, especially anti-PD-1/PD-L1 plus anti-angiogenic treatment, could significantly improve the clinical outcomes of patients with NSCLC and BrMs.
Insights
For non-small-cell lung cancer patients with brain metastases, PD-1/PD-L1 inhibitor monotherapy offers limited benefit due to an immunosuppressive tumor microenvironment. Combination therapies, particularly with anti-angiogenic agents, significantly improve outcomes.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Metastasis
Background:
- Optimal treatment for non-small-cell lung cancer (NSCLC) with brain metastases (BrMs) using PD-1/PD-L1 inhibitors is unclear.
- Immunophenotyping of BrMs is crucial for guiding treatment strategies.
Purpose of the Study:
- To evaluate the efficacy of PD-1/PD-L1 inhibitor-based therapies in NSCLC patients with BrMs.
- To investigate the tumor immune microenvironment (TIME) of BrMs.
Main Methods:
- Retrospective analysis of 308 NSCLC patients treated with PD-1/PD-L1 inhibitors (monotherapy or combination).
- Kaplan-Meier curves and log-rank tests for outcome assessment.
- Transcriptomic analysis of primary tumors and BrMs to characterize TIME.
Main Results:
- PD-1/PD-L1 inhibitor monotherapy showed inferior progression-free survival (PFS) and overall survival (OS) in patients with BrMs.
- Combination therapy, especially with anti-angiogenic agents, significantly improved PFS and OS in patients with BrMs.
- BrMs exhibit a suppressive TIME with reduced CD4+ T cells and M1 macrophages, and increased M2 macrophages.
Conclusions:
- PD-1/PD-L1 inhibitor monotherapy provides limited benefit for NSCLC with BrMs due to an immunosuppressive TIME.
- Combination treatments, particularly PD-1/PD-L1 inhibitors plus anti-angiogenic therapy, enhance clinical outcomes for NSCLC patients with BrMs.
