Efficacy and safety of Programmed Death Ligand 1 inhibitors versus Programmed Death 1 inhibitors in the first-line treatment of advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials
The combination of PD-1 inhibitors and chemotherapy may provide a significant OS and PFS benefit relative to PD-L1 inhibitors plus chemotherapy in NSCLC and a similar safety profile.
Abstract
Background With the increasing use of immune checkpoint inhibitors (ICIs) in the first-line treatment of driver mutation-negative non-small cell lung cancer (NSCLC), we conducted a systematic review and meta-analysis to compare efficacy and adverse effects (AEs) between PD-L1 inhibitors and PD-1 inhibitors. Methods We searched PubMed, Web of Science, Embase, and the Cochrane Library to identify randomized controlled trials (RCTs) related to the first-line treatment of NSCLC with ICIs alone or in combination with chemotherapy. The primary outcomes were overall survival (OS), progression-free survival (PFS), and AEs. Results In total, 28 RCTs involving 14,758 patients were included. Compared with Programmed Death 1 (PD-1) inhibitors plus chemotherapy, Programmed Death Ligand 1 (PD-L1) inhibitors plus chemotherapy were associated with worse OS (hazard ratio (HR) = 1.26; 95% confidence interval (CI) [1.13–1.41]; P < 0.001) and PFS (HR = 1.21; 95% CI [1.06–1.38]; P = 0.005). The objective response rate (ORR) did not differ between PD-1 inhibitors plus chemotherapy and PD-L1 inhibitors plus chemotherapy (odds ratio (OR) = 0.91; 95% CI [0.78–1.05], P = 0.205), and AE rates were similar between these groups. Regarding monotherapy, no difference in OS, PFS, or ORR was observed between PD-L1 and PD-1 inhibitors. The incidence of AEs leading to treatment termination and grade ≥3 AEs was lower for PD-L1 inhibitors than PD-1 inhibitors (risk ratio (RR) = 0.55; 95% CI [0.32–0.95]; P = 0.03; RR = 0.76; 95% CI [0.60–0.96]; P = 0.021). Conclusions The combination of PD-1 inhibitors and chemotherapy may provide a significant OS and PFS benefit relative to PD-L1 inhibitors plus chemotherapy in NSCLC and a similar safety profile. Meanwhile, PD-L1 inhibitor monotherapy appears less likely to result in treatment termination or grade ≥3 AEs than PD-1 inhibitor monotherapy.
Current evidence supports PD-L1 as the most widely implemented biomarker, but no single factor adequately captures the biological and temporal heterogeneity of treatment response, so integrated, dynamic, and context-specific biomarker models are required to improve precision immuno-oncology.
Longhua Lu, Ze-Yang Zeng, Zi-Qi Guan et al.· Journal of Clinical Question· 0 citations
Introduction This meta-analysis was designed to compare the efficacy and safety of PD-1/PD-L1 inhibitors versus chemotherapy or cetuximab in the treatment of platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Materials and Methods Four databases (PubMed, Embase, Web of Science, and Cochrane Library) were searched for RCTs comparing PD-1/PD-L1 inhibitors versus chemotherapy or cetuximab in the treatment of platinum-refractory R/M HNSCC, from the database’s establishment to 2 January 2026. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-related adverse events (trAEs) were subjected to meta-analyses. Results Five RCTs were included in the meta-analysis. The meta-analysis included a group of 1,700 patients diagnosed with platinum-refractory R/M HNSCC. Within this cohort, 926 patients were administered PD-1/PD-L1 inhibitors, while 774 patients received chemotherapy or cetuximab. Compared with chemotherapy or cetuximab, PD-1/PD-L1 inhibitors yielded superior OS (HR: 0.80, 95% CI: 0.72 to 0.89, P < 0.01), lower incidence of grade 3–5 trAEs (RR: 0.37, 95% CI: 0.30 to 0.45, P < 0.01) and any grade trAEs (RR = 0.74, 95% CI: 0.69 to 0.79, P < 0.01). There was no statistically significant difference in the ORR (RR: 1.01, 95% CI: 0.71 to 1.51, P = 0.94) or PFS (HR: 1.00, 95% CI: 0.90 to 1.11, P = 0.99) between the two groups. Conclusion The results indicated that PD-1/PD-L1 inhibitors were effective for platinum-refractory R/M HNSCC particularly in populations with high PD-L1 expression and exhibited a superior safety profile compared to chemotherapy or cetuximab. Additional well designed RCTs are required in the future to validate our conclusion. Clinical Trial Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251020053, identifier PROSPERO (CRD420251020053).
Zhong-Ji Chen, Zhong Zhong, Weiming Liang et al.· Frontiers in Pharmacology· 0 citations
Background: Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a major clinical research focus. Patients with extensive-stage small-cell lung cancer (ES-SCLC) have been treated with different first-line ICI combinations in randomized controlled trials (RCTs), but the optimal combination strategy has not yet been determined. Our aim was to evaluate this strategy through a systematic review and meta-analysis. Methods: Articles published from inception to October 20, 2024 were systematically searched in PubMed, Cochrane CENTRAL, Embase, and MEDLINE. Candidates were RCTs using ICI treatments as first-line treatment for ES-SCLC. According to PRISMA guidelines, 3 independent investigators extracted data. Hazard/odds ratios (HRs/ORs) with their 95% confidence intervals (CIs) and adverse event (AEs) were extracted. ICI combinations were compared for overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and AEs. A random-effects model and Bayesian network meta-analysis were used. PROSPERO: CRD42023388838. Results: The meta-analysis included 8 RCTs with 3910 patients. Overall, ICI-chemotherapy provided superior OS (HR, 0.78; 95% CI, 0.72 to 0.86), PFS (HR, 0.73; 95% CI, 0.64 to 0.82), ORR (OR, 1.20; 95% CI, 1.01 to 1.42) and DCR (OR, 2.64; 95% CI, 1.32 to 5.24) compared with chemotherapy alone. A higher risk of any grade irAEs (OR, 3.88; 95% CI, 2.09 to 7.18) and grade ≥ 3 irAEs (OR, 5.54; 95% CI, 2.38 to 12.88) was associated with ICI addition. ICI-chemotherapy combinations did not differ significantly in OS, PFS, ORR, DCR, or safety. In the Bayesian ranking analysis, the PD-1 inhibitor–based regimens Serplu-EP and Nivo-EP achieved the highest efficacy rankings; Serplu-EP ranked first for both OS and PFS, followed by Nivo-EP. Efficacy and safety were effectively balanced in Serplu-EP and Adebre-EP. Similar results were shown in subgroup analyses. Conclusion: First-line ICI-chemotherapy combinations improved survival outcomes but increased the risk of irAEs, with no significant differences in efficacy or safety among ICI-chemotherapy combinations. Among the evaluated regimens, the PD-1 inhibitor–based Serplu-EP and Nivo-EP achieved the highest efficacy rankings, whereas Serplu-EP and Adebre-EP appeared to provide the most favorable efficacy-safety balance. Further head-to-head trials are warranted to confirm the optimal first-line ICI strategy for ES-SCLC.
Xiao-Qi Ye, Haoru Meng, Qiuyan Guo et al.· Medicine· 0 citations
Background: The sequential use of anti-programmed cell death (ligand)-1 [PD-(L)1] immune-checkpoint inhibitors (ICIs) followed by targeted tyrosine-kinase inhibitors (TKIs) for advanced non-small cell lung cancer (NSCLC) with oncogenic alterations raises questions about tolerance and efficacy. Recent study results suggested an increased risk of adverse events (AEs) with this sequence. Methods: Multicenter retrospective study on advanced NSCLC patients treated with ICIs followed by targeted therapies between 2015 and 2021. The primary endpoint was the rate of grade 3–5 adverse events (AEs). Main secondary endpoints were progression-free survival (PFS), time-to-treatment failure and overall survival (OS). Results: The analysis included 109 patients (most with EGFR, 30.3%; BRAF, 17.4%; MET exon-14, 17.4%; ALK, 10.1%; and RET, 6.4% gene alterations); 28/109, which is 25.7% of the patients, experienced grade 3/4 AEs and 4/109 (3.7%) experienced grade 5 AEs, leading to the definitive cessation of targeted therapy treatment in 14/32 (44%) of cases; higher grade 3–5 rates were observed with the dabrafenib–trametinib combination (12/16, 75%), capmatinib (4/8, 50%) and crizotinib (8/16, 50%). A last ICI-administration-to-targeted therapy-start interval of <90 days appeared to be associated with grade ≥ 3 AEs (32/82, 39% vs. 0/27 p = 0.001). In these sequential strategies, effectiveness of targeted therapies, in this second-line or later setting, appears to be lower than that in the published historical data. Conclusion: According to this analysis, sequential ICI–targeted therapy use for advanced NSCLC appeared to be associated with more grade 3–5 AEs.
Thomas Pierret, J. Auliac, C. Ricordel et al.· Current Oncology· 0 citations
Background The meta-analysis assesses the efficacy and safety of first-line immune checkpoint inhibitors (ICIs) plus anti-angiogenic therapies versus sunitinib in advanced or metastatic renal cell carcinoma (RCC). The analysis places focus on differential benefits across International Metastatic RCC Database Consortium (IMDC) risk subgroups, ICI classes, and anti-angiogenic drug classes. Methods We systematically searched the Cochrane Library, Embase and PubMed for randomized controlled trials (RCTs) comparing ICI plus anti-angiogenic therapy with sunitinib as first-line treatment for advanced RCC. Efficacy measures included progression-free survival (PFS) and overall survival (OS), objective response rate (ORR), disease control rate (DCR). Safety measures assessed grade ≥3 treatment-related adverse events (TRAEs) and TRAEs leading to discontinuation. Results Seven RCTs involving 4,977 patients were included. Combination therapy was associated with significant improvements in PFS (0.63, [0.54–0.72]), OS (0.83, [0.77–0.89]), ORR (3.07, [2.01–4.67]), and DCR (2.04, [1.49–2.78]) (all P < 0.001). OS benefits were most marked in poor-risk (HR = 0.52) and intermediate-risk (HR = 0.88) patients, while favorable-risk patients showed no significant OS gain (0.97, [0.79–1.18]). Multi-targeted tyrosine kinase inhibitor (TKI)-based regimens provided the greatest PFS and ORR benefits but the highest toxicity, while vascular endothelial growth factor receptor (VEGFR)-selective TKIs showed a balanced efficacy-safety profile. Anti-VEGF monoclonal antibody-based combinations failed to demonstrate significant OS or ORR advantages over sunitinib. Safety analysis showed no significant difference in grade ≥3 TRAEs (1.22, [0.94–1.58]), but did reveal a significantly increased risk of treatment discontinuation (3.34, [2.77–4.03]). Additionally, elevated risks of hepatotoxicity, hypertension, and proteinuria were observed, whereas hematologic toxicities and fatigue were significantly reduced versus sunitinib. Conclusion TKI-based ICI combination therapy is superior to sunitinib as first-line treatment for advanced RCC, particularly in intermediate- and poor-risk patients. Anti-angiogenic agent class is the primary determinant of efficacy and tolerability, while ICI class does not influence regimen selection. These findings support a risk-adapted, class-informed approach to optimize therapeutic outcomes in clinical practice. Systematic Review registration Identifier CRD420251273931.
Zijing Liu, Yu Jiang, Zhi-Hao Zhang et al.· Frontiers in Pharmacology· 0 citations
Cervical cancer is a major global health challenge and requires the exploration
of novel treatment strategies. Immune checkpoint inhibitors, particularly those targeting Programmed
Death 1 (PD-1) and Programmed Death-Ligand 1 (PD-L1), have emerged as promising
therapeutic agents in oncology. This study aimed to evaluate the efficacy and safety of these inhibitors
in the treatment of cervical cancer.
A comprehensive literature search was conducted across PubMed, Embase, Web of Science,
Scopus, the Cochrane Library, and the China National Knowledge Infrastructure to identify
studies published up to November 1, 2024. A total of 26 relevant studies were included, including
21 Non-Randomized Controlled Trials (Non-RCTs) and 5 Randomized Controlled Trials (RCTs).
The analysis primarily evaluated the efficacy and safety of PD-1/PD-L1 inhibitors in patients with
advanced cervical cancer. The primary outcomes included the objective response rate, disease control
rate, progression-free survival, overall survival, and adverse events. Non-RCTs and RCTs were
evaluated using ROBINS-I and ROB 2, respectively. Data analysis and visualization were performed
using STATA 17.0 and GraphPad. This study has been registered with PROSPERO (registration
number CRD42024510357).
Therapeutic outcomes indicated that the objective response rate in patients with cervical
cancer was 44.30% (95% CI 31.06%–57.93%), and the disease control rate was 63.05% (95% CI
51.67%–73.78%). The complete response, partial response, stable disease, and progressive disease
rates were 12.58% (95% CI 6.46%–20.13%), 26.87% (95% CI 19.92%–34.40%), 17.95% (95% CI
12.50%–24.07%), and 27.61% (95% CI 17.68%–38.71%), respectively. The median PFS was 6.22
months (95% CI 3.86–8.59), with 6- and 12-month PFS rates of 58.93% (95% CI 47.78%–69.65%)
and 45.20% (95% CI 32.73%–57.96%), respectively. The median OS was 14.81 months (95% CI
8.45–21.16), with 6- and 12-month OS rates of 86.57% (95% CI 80.92%–91.42%) and 70.34%
(95% CI 61.47%–78.53%), respectively. Regarding safety, the incidence of treatment-related adverse
events was 83.24% (95% CI 73.93%–90.94%), serious adverse events was 25.71% (95% CI
15.33%–37.58%), adverse drug reactions was 71.57% (95% CI 57.61%–83.78%), and immunerelated
adverse events was 34.26% (95% CI 27.11%–41.76%). Common treatment-related adverse
events included anemia, diarrhea, nausea, and leukopenia.
The findings indicate that immune checkpoint inhibitors represent a potentially effective
treatment option for patients with cervical cancer; however, their safety profile warrants careful
consideration. Combination therapies involving PD-1 inhibitors appear to improve efficacy while
maintaining manageable safety.
Yuan-yuan Li, Song-Yi Wang, Yi-Rui Mai et al.· Current Gene Therapy· 0 citations