Efficacy and Safety of First-Line Immunotherapy Combinations for Advanced NSCLC: A Systematic Review and Network
Introduction:
A series of randomized controlled trials have investigated different first-line immunotherapy combinations, but the optimal combination strategy is yet to be established.
Methods:
We performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences. We included published and gray sources of randomized clinical trials comparing immunotherapy combinations with other treatments as first-line treatments for patients with advanced NSCLC. This study was registered in the Prospective Register of Systematic Reviews (CRD42020210501) to ensure transparency.
Results:
We analyzed a total of 16 studies involving 8278 patients and including 10 immunotherapy combinations. For patients without programmed death-ligand 1 (PD-L1) selection, pembrolizumab plus chemotherapy was found to be comparable with sintilimab plus chemotherapy in providing the best overall survival (OS) benefit (hazard ratio = 0.96, 95% confidence interval [CI]: 0.72-1.29). Furthermore, atezolizumab plus bevacizumab plus chemotherapy seemed to provide the best progression-free survival (hazard ratio = 0.45, 95% CI: 0.36-0.55) and the best objective response rate (OR = 0.23, 95% CI: 0.12-0.42). Subgroup analysis by PD-L1 suggested that nivolumab plus ipilimumab plus chemotherapy was associated with the best OS in patients with PD-L1 less than 1% and that pembrolizumab plus chemotherapy was associated with the best OS in patients with PD-L1 greater than or equal to 1%. Pembrolizumab and sintilimab were associated with relatively fewer grade greater than or equal to 3 adverse events when compared with other immunotherapies combined with chemotherapy.
Conclusions:
Our results suggest that antiprogrammed death-1 combinations are associated with potentially higher survival outcomes than anti-PD-L1 combinations with comparable safety profiles. Moreover, pem-chemo and nivo-ipi-chemo seem to be superior first-line immunotherapy combinations for patients with advanced NSCLC with positive and negative PD-L1 expression, respectively. Although atezo-beva-chemo treatment provided the best progression-free survival and objective response rate, the addition of chemotherapy to immunotherapy would increase the toxicity, especially when antiangiogenesis drugs are simultaneously added.
Insights
The optimal first-line immunotherapy for advanced non-small cell lung cancer (NSCLC) depends on PD-L1 status. Anti-PD-1 combinations offer better survival than anti-PD-L1, with manageable safety profiles.
Area of Science:
- Oncology
- Immunotherapy
- Lung Cancer Research
Background:
- Optimal first-line immunotherapy combinations for advanced non-small cell lung cancer (NSCLC) remain undetermined.
- Randomized controlled trials have explored various combinations, necessitating a comprehensive analysis.
Purpose of the Study:
- To systematically review and perform a Bayesian network meta-analysis of first-line immunotherapy combinations for advanced NSCLC.
- To compare the efficacy and safety of different immunotherapy regimens based on programmed death-ligand 1 (PD-L1) expression.
Main Methods:
- Systematic literature search of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and conference proceedings.
- Inclusion of randomized clinical trials comparing immunotherapy combinations as first-line treatment for advanced NSCLC.
- Bayesian network meta-analysis of 16 studies involving 8278 patients and 10 immunotherapy combinations.
Main Results:
- For patients without PD-L1 selection, pembrolizumab plus chemotherapy and sintilimab plus chemotherapy showed comparable overall survival (OS).
- Atezolizumab plus bevacizumab plus chemotherapy demonstrated the best progression-free survival (PFS) and objective response rate (ORR).
- Subgroup analysis by PD-L1 status indicated nivolumab plus ipilimumab plus chemotherapy for PD-L1 < 1% and pembrolizumab plus chemotherapy for PD-L1 ≥ 1% achieved the best OS. Pembrolizumab and sintilimab combinations had fewer severe adverse events.
Conclusions:
- Anti-PD-1 combinations appear superior to anti-PD-L1 combinations for advanced NSCLC, with similar safety profiles.
- Pembrolizumab plus chemotherapy and nivolumab plus ipilimumab plus chemotherapy are suggested as optimal first-line treatments for PD-L1 positive and negative NSCLC, respectively.
- While atezolizumab plus bevacizumab plus chemotherapy improved PFS and ORR, combining chemotherapy with immunotherapy and antiangiogenesis drugs increases toxicity.
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