A meta-analysis of phase III trials suggests that chemoimmunotherapy may provide superior overall survival and progression-free survival compared with PD-(L)1 inhibitor monotherapy in patients with previously untreated advanced non-small cell lung cancer (NSCLC) and high PD-L1 expression.
The findings, published in JAMA Oncology, address a longstanding clinical question regarding the optimal first-line treatment approach for patients with advanced NSCLC whose tumours express PD-L1 in at least 50% of cells.
PD-(L)1 inhibitor monotherapy is widely used in this setting and has demonstrated durable responses in a subset of patients. However, whether the addition of chemotherapy confers additional benefit has remained uncertain due to the lack of prospective head-to-head randomised trials.
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To investigate this question, Alessandro Di Federico and colleagues conducted a systematic review and meta-analysis of 24 phase III randomised clinical trials involving 5,546 patients with advanced NSCLC and PD-L1 expression of 50% or higher. Sixteen trials evaluated chemoimmunotherapy and eight evaluated PD-(L)1 inhibitor monotherapy, with all studies comparing treatment against chemotherapy alone.
Across the included studies, both treatment approaches improved outcomes compared with chemotherapy. However, indirect comparisons consistently favoured chemoimmunotherapy.
In pooled analyses, chemoimmunotherapy was associated with greater improvements in both overall survival and progression-free survival than PD-(L)1 inhibitor monotherapy. The findings were consistent across subgroup analyses, meta-regression, network meta-analysis and reconstructed individual patient data analyses.
The investigators also reconstructed individual patient data from published Kaplan-Meier curves to enable longer-term comparisons. In this analysis, median overall survival was 29.2 months with chemoimmunotherapy compared with 19.8 months with PD-(L)1 inhibitor monotherapy. Median progression-free survival was 11.3 months and 6.8 months, respectively.
According to the authors, the findings suggest that chemoimmunotherapy may provide greater clinical benefit than PD-(L)1 inhibitor monotherapy in patients with high PD-L1-expressing tumours.
However, the authors cautioned that the analysis was based on indirect comparisons across separate clinical trials rather than prospective randomised comparisons between treatment strategies. Differences in trial populations, study designs and treatment regimens may therefore have influenced the results.
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The authors concluded that chemoimmunotherapy was associated with significantly improved overall survival and progression-free survival compared with PD-(L)1 inhibitor monotherapy in patients with advanced NSCLC and high PD-L1 expression. However, they emphasised that prospective trials directly comparing the two approaches are required to confirm these findings.
If confirmed in prospective comparative studies, the findings could help inform treatment selection in patients with advanced NSCLC and high PD-L1 expression, a population for whom both approaches are currently widely used.
Paper: Di Federico A, Compagno S, Mantuano F, et al. PD-(L)1 Inhibitor Monotherapy vs Chemoimmunotherapy for Advanced NSCLC With High PD-L1 Expression: A Systematic Review and Meta-Analysis. JAMA Oncol. Published online June 04, 2026. Access online here.
