Efficacy and safety evaluation of frontline immunotherapy combinations in advanced esophageal squamous cell carcinoma: a network meta-analysis highlighting the value of PD-L1 expression positivity scores.

The systematic review and network meta-analysis (NMA) consolidate all relevant randomized controlled trials (RCTs) related to initial immunotherapy treatments for advanced esophageal squamous cell carcinoma (ESCC). Our goal is to thoroughly assess the effectiveness and safety of various immunotherapy methods, focusing on overall survival (OS) and progression-free survival (PFS) among patients with advanced ESCC positive for PD-L1. We conducted a systematic search of the PubMed, Embase, Cochrane Library, and Web of Science databases, covering all records from their inception until January 22, 2024. The inclusion criteria targeted patients with advanced ESCC undergoing first-line immunotherapy or chemotherapy, limiting the study selection to randomized controlled trials (RCTs) exclusively. The study upholds the values of openness, originality, and dependability, as evidenced by its enrollment in the Prospective Register of Systematic Reviews (CRD42024504992). Our analysis encompasses 7 RCTs, totaling 4688 patients, and evaluates 8 distinct immunotherapy combinations. In advanced ESCC patients irrespective of PD-L1 expression, both sintilimab-chemotherapy and toripalimab-chemotherapy regimens demonstrated comparable OS benefits (HR=0.92, 95% CI: 0.64-1.33). The most pronounced PFS advantages were seen with sintilimab-chemotherapy and camrelizumab-chemotherapy as compared to standard chemotherapy (HR=0.56, 95% CI: 0.46-0.58). Notably, camrelizumab-chemotherapy (HR=0.83, 95% CI: 0.59-1.16) and nivolumab-ipilimumab (HR=0.84, 95% CI: 0.60-1.17) demonstrated significant safety profiles over chemotherapy alone. Subgroup analysis based on PD-L1 expression revealed nivolumab-chemotherapy to yield the highest OS benefit (HR=0.54, 95% CI: 0.37-0.79) in ESCC patients with PD-L1 expression ≥1%. Furthermore, camrelizumab-chemotherapy (HR=0.51, 95% CI: 0.39-0.67) exhibited superior PFS benefits. Among patients with PD-L1 expression ≥10%, camrelizumab-chemotherapy (HR=0.52, 95% CI: 0.35-0.78) emerged as the most efficacious in improving OS, while serplulimab-chemotherapy (HR=0.48, 95% CI: 0.34-0.68) was associated with the longest PFS benefit. The integration of immune checkpoint inhibitors (ICIs) with chemotherapy appears to significantly enhance survival outcomes in patients with advanced ESCC compared to chemotherapy alone. Sintilimab-chemotherapy is potentially the optimal regimen for patients without PD-L1 expression. In contrast, nivolumab-chemotherapy and camrelizumab-chemotherapy are likely to offer the best OS and PFS benefits, respectively, in patients with PD-L1 expression ≥1%. Among those with PD-L1 expression ≥10%, camrelizumab-chemotherapy is projected to provide the greatest OS advantage, whereas serplulimab-chemotherapy is anticipated to offer the most prolonged PFS benefit. Since most of the patients in this study originated from Asia, the above findings are more applicable to the Asian population. https://www.crd.york.ac.uk/prospero/, identifier CRD42024504992.

Chen W ，Cao K ，Zhang L ，Zhao X ，Chen B ，Li W ，Shang R ，Sun L ，Jiang Z ，Wang J ，Xue W ... -  《Frontiers in Immunology》

Comparison of efficacy and safety of PD-1/PD-L1 combination therapy in first-line treatment of advanced NSCLC: an updated systematic review and network meta-analysis.

The use of immune checkpoint inhibitors has led to an increase in randomized controlled trials exploring various first-line combination treatment regimens. With the introduction of new PD-1/PD-L1 inhibitors, there are now more clinical options available. For the first time, the AK105 monoclonal antibody Penpulimab, developed in China, was included. The AK105-302 Phase III trial studied the efficacy and safety of Penpulimab combined with chemotherapy in patients with advanced or metastatic squamous NSCLC. To determine the optimal treatment options, we conducted an updated network meta-analysis to compare the effectiveness and safety of these regimens. The system retrieves data from Chinese and English electronic databases, Clinical Trials, and the gov Clinical Trial Registration website up to September 6, 2023. The study indirectly compared the efficacy and safety of PD-1/PD-L1 combination regimens, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), all-grade adverse events, and above-grade III adverse events. Subgroup analyses were conducted based on programmed death ligand 1 (PD-L1) level, histological type, ECOG score, sex, and smoking history. Nineteen RCTS were included, with a total of ten thousand eight hundred patients. Penpulimab plus chemotherapy (Pen + CT) provided the best OS (HR = 0.55, 95% CI 0.38-0.81) for PD-L1 patients with non-selective advanced NSCLC. Except Nivolumab plus Ipilimumab (Niv + Ipi), other PD-1/PD-L1 combination therapies significantly extended PFS compared with CT, and Nivolumab plus Bevacizumab combined with chemotherapy (Niv + Bev + CT) (HR = 0.43, 95% CI 0.26-0.74) provided the best PFS benefit and was comparable to Pen + CT (HR = 1.0) for PFS prolongation. For ORR, except Niv + Ipi, all the other regimens significantly improved ORR compared with CT. In terms of safety, except Tor + CT, the incidence of any-grade AEs or grade ≥ 3 adverse events may be higher than those of chemotherapy. The subgroup analysis revealed that for patients with PD-L1 levels below 1%, treatment with Tor + CT resulted in the best progression-free survival (HR = 0.47, 95% CI 0.25-0.86). For patients with PD-L1 levels of 1% or higher, Sintilimab plus chemotherapy (Sin + CT) (HR = 0.56, 95% CI 0.31-0.99) and Camrelizumab plus chemotherapy (Cam + CT) (HR = 0.43, 95% CI 0.28-0.64) were associated with the best overall survival and progression-free survival, respectively. For patients with SqNSCLC, combined immunotherapy may provide greater survival benefits. For patients with Non-sqNSCLC, Niv + Bev + CT and Tor + CT were associated with optimal PFS and OS, respectively. Cam + CT provided the best PFS in male patients with a history of smoking and an ECOG score of 0. In both female and non-smoking patient subgroups, Pem + CT was associated with the best PFS and OS benefits. For patients with advanced non-selective PD-L1 NSCLC, two effective regimens are Pen + CT and Niv + Bev + CT, which rank first in OS and PFS among all patients. Cam + CT and Tor + CT have advantages for OS in patients with SqNSCLC and Non-sqNSCLC, respectively. Niv + Ipi + CT provided the best OS benefit for patients with an ECOG score of 0, while Pem + CT may be the most effective treatment for patients with an ECOG score of 1. Pem + CT has a better effect on female patients and non-smokers. Sin + CT was found to be the most effective treatment for male patients and the smoking subgroup, while Cam + CT was found to be the most effective for PFS. In addition, Tor + CT was associated with the best PFS for patients with negative PD-L1 expression. Pem + CT was found to significantly improve both PFS and OS compared to CT alone. For patients with positive PD-L1 expression, Sin + CT and Cam + CT were found to be optimal for OS and PFS, respectively. It is important to note that, with the exception of Tor + CT, the toxicity of the other combinations was higher than that of CT alone.

Yang Y ，Chen W ，Dong L ，Duan L ，Gao P ... -  《-》

Immune checkpoint inhibitors plus platinum-based chemotherapy compared to platinum-based chemotherapy with or without bevacizumab for first-line treatment of older people with advanced non-small cell lung cancer.

Lung cancer is a cancer of the elderly, with a median age at diagnosis of 71. More than one-third of people diagnosed with lung cancer are over 75 years old. Immune checkpoint inhibitors (ICIs) are special antibodies that target a pathway in the immune system called the programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway. These antibodies help the immune system fight cancer cells by blocking signals that cancer cells use to avoid being attacked by the immune system. ICIs have changed the treatment of people with lung cancer. In particular, for people with previously-untreated advanced non-small cell lung cancer (NSCLC), current first-line treatment now comprises ICIs plus platinum-based chemotherapy, rather than platinum-based chemotherapy alone, regardless of their PD-L1 expression status. However, as people age, their immune system changes, becoming less effective in its T cell responses. This raises questions about how well ICIs work in older adults. To assess the effects of immune checkpoint inhibitors (ICIs) in combination with platinum-based chemotherapy compared to platinum-based chemotherapy (with or without bevacizumab) in treatment-naïve adults aged 65 years and older with advanced NSCLC. We searched the Cochrane Lung Cancer Group Trial Register, CENTRAL, MEDLINE, Embase, two other trial registers, and the websites of drug regulators. The latest search date was 23 August 2023. We also checked references and searched abstracts from the meetings of seven cancer organisations from 2019 to August 2023. We included randomised controlled trials (RCTs) that reported on the efficacy and safety of adding ICIs to platinum-based chemotherapy compared to platinum-based chemotherapy alone for people 65 years and older who had not previously been treated. All data emanated from international multicentre studies involving adults with histologically-confirmed advanced NSCLC who had not received any previous systemic anticancer therapy for their advanced disease. We used standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival and treatment-related adverse events (grade 3 or higher). Our secondary outcomes were progression-free survival, objective response rate, time to response, duration of response, and health-related quality of life (HRQoL). We included 17 primary studies, with a total of 4276 participants, in the review synthesis. We identified nine ongoing studies, and listed one study as 'awaiting classification'. Twelve of the 17 studies included people older than 75 years, accounting for 9% to 13% of their participants. We rated some studies as having 'some concerns' for risk of bias arising from the randomisation process, deviations from the intended interventions, or measurement of the outcome. The overall GRADE rating for the certainty of the evidence ranged from moderate to low because of the risk of bias, imprecision, or inconsistency. People aged 65 years and older The addition of ICIs to platinum-based chemotherapy probably increased overall survival compared to platinum-based chemotherapy alone (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.70 to 0.88; 8 studies, 2093 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events may not differ between the two treatment groups (risk ratio (RR) 1.09, 95% CI 0.89 to 1.32; 1 study, 127 participants; low-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improves progression-free survival (HR 0.61, 95% CI 0.54 to 0.68; 7 studies, 1885 participants; moderate-certainty evidence). People aged 65 to 75 years, inclusive The addition of ICIs to platinum-based chemotherapy probably improved overall survival compared to platinum-based chemotherapy alone (HR 0.75, 95% CI 0.65 to 0.87; 6 studies, 1406 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events probably increased in people treated with ICIs plus platinum-based chemotherapy compared to those treated with platinum-based chemotherapy alone (RR 1.47, 95% CI 1.02 to 2.13; 1 study, 97 participants; moderate-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improved progression-free survival (HR 0.64, 95% CI 0.57 to 0.73; 8 studies, 1466 participants; moderate-certainty evidence). People aged 75 years and older There may be no difference in overall survival in people treated with ICIs combined with platinum-based chemotherapy compared to platinum-based chemotherapy alone (HR 0.90, 95% CI 0.70 to 1.16; 4 studies, 297 participants; low-certainty evidence). No data on treatment-related adverse events were available in this age group. The effect of combination ICI and platinum-based chemotherapy on progression-free survival is uncertain (HR 0.83, 95% CI 0.51 to 1.36; 3 studies, 226 participants; very low-certainty evidence). Only three studies assessed the objective response rate. For time to response, duration of response, and health-related quality of life, we do not have any evidence yet. Compared to platinum-based chemotherapy alone, adding ICIs to platinum-based chemotherapy probably leads to higher overall survival and progression-free survival, without an increase in treatment-related adverse events (grade 3 or higher), in people 65 years and older with advanced NSCLC. These data are based on results from studies dominated by participants between 65 and 75 years old. However, the analysis also suggests that the improvements reported in overall survival and progression-free survival may not be seen in people older than 75 years.

Orillard E ，Adhikari A ，Malouf RS ，Calais F ，Marchal C ，Westeel V ... -  《Cochrane Database of Systematic Reviews》

Anti-PD-1 and anti-PD-L1 antibodies for glioma.

Glioblastoma multiforme (GBM) is the most common and aggressive adult glioma (16-month median survival). Its immunosuppressive microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). To assess the effects of the ICIs antibodies anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) in treating adults with diffuse glioma. We searched CENTRAL, MEDLINE, Embase, and clinical trials registers on 8 March 2024. We included randomised controlled trials (RCTs) evaluating adults with diffuse glioma treated with anti-PD-1/PD-L1 compared to placebo or other therapies used alone or with other ICIs. Primary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events (SAE). Secondary outcomes were overall response rate (ORR), quality of life (QoL), and less serious AEs. We followed standard Cochrane methods. We included seven RCTs evaluating anti-PD-1 treatment in recurrent (N = 4) and newly diagnosed (N = 3) grade 4 glioma participants. The analysis encompassed 1953 participants; sample sizes ranged from 35 to 716. Meta-analyses were not possible due to heterogeneity and the small number of studies. Most trials had high risk of bias. Nivolumab versus bevacizumab in people with recurrent GBM (1 trial, 369 participants) Nivolumab probably does not increase OS (hazard ratio (HR) 1.04, 95% confidence interval (CI) 0.83 to 1.30; 1.3% more, 95% CI 6.30 fewer to 7.80 more; 369 participants; moderate-certainty evidence) or PFS (HR 1.97, 95% CI 1.57 to 2.48; 16.40% more, 95% CI 12.40 more to 19.00 more; 369 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (risk ratio (RR) 1.20, 95% CI 0.74 to 1.92; 347 participants). Nivolumab probably does not increase ORR (RR 0.34, 95% CI 0.18 to 0.63; 309 participants; moderate-certainty evidence), but may not increase less serious AEs (RR 1.03, 95% CI 0.96 to 1.10; 347 participants; low-certainty evidence). Nivolumab plus bevacizumab 10 mg/kg versus nivolumab plus bevacizumab 3 mg/kg in people with recurrent GBM (1 trial, 90 participants) Nivolumab plus bevacizumab 10 mg/kg may not increase OS (HR 1.39, 95% CI 0.86 to 2.25; 9.90% more, 95% CI 5.20 fewer to 18.80 more; 90 participants; low-certainty evidence). The evidence for PFS (HR 1.23, 95% CI 0.78 to 1.93; 5.80% more, 95% CI 8.20 fewer to 14.20 more; 90 participants) and SAE (RR 1.19, 95% CI 0.79 to 1.79; 90 participants) is very uncertain. Nivolumab may not increase less serious AEs (RR 1.02, 95% CI 0.96 to 1.09; low-certainty evidence; 90 participants). Pembrolizumab plus bevacizumab versus pembrolizumab in people with recurrent GBM (1 trial, 80 participants) The evidence for OS (HR 1.03, 95% CI 0.65 to 1.63; 0.30% more, 95% CI 7.60 fewer to 2.90 more; 80 participants), PFS (HR 0.97, 95% CI 0.61 to 1.54: 0.40% fewer, 95% CI 9.20 fewer to 2.80 more; 80 participants), SAE (RR 1.32, 95% CI 0.75 to 2.42; 80 participants), and ORR (RR 12.76, 95% CI 0.77 to 210.27; 80 participants) is very uncertain. Pembrolizumab plus bevacizumab may not increase less serious AEs (RR 1.04, 95% CI 0.96 to 1.13; 80 participants; low-certainty evidence). Neoadjuvant (before surgical resection) and adjuvant (after surgical resection) pembrolizumab versus adjuvant-only pembrolizumab in people with recurrent GBM (1 trial, 35 participants) The evidence for OS (HR 0.39, 95% CI 0.17 to 0.92; 25.20% fewer, 95% CI 37.10 fewer to 2.10 fewer; 35 participants), PFS (HR 0.43, 95% CI 0.20 to 0.91; 30.10% fewer, 95% CI 52.20 fewer to 3.60 fewer; 35 participants), and SAE (RR 1.00, 95% CI 0.31 to 3.28; 32 participants) is very uncertain. Nivolumab plus radiotherapy versus temozolomide plus radiotherapy in people with newly diagnosed unmethylated GBM (1 trial, 560 participants) Nivolumab plus radiotherapy probably does not increase OS (HR 1.31, 95% CI 1.09 to 1.58 months; 8.30% more, 95% CI 2.80 more to 12.90 more; 560 participants) and PFS (HR 1.38, 95% CI 1.15 to 1.65 months; 7.50% more, 95% CI 3.60 more to 10.30 more; 560 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (RR 0.87, 95% CI 0.65 to 1.18; 553 participants). It may not increase ORR (RR 1.08, 95% CI 0.43 to 2.69; 560 participants; low-certainty evidence) and probably does not increase less serious AEs (RR 1.00, 95% CI 0.96 to 1.04; 560 participants; moderate-certainty evidence). The evidence for time to deterioration of QoL is very uncertain (HR 0.76, 95% CI 0.59 to 0.99; 560 participants). Nivolumab plus temozolomide plus radiotherapy versus placebo plus temozolomide plus radiotherapy in people with newly diagnosed methylated GBM (1 trial, 716 participants) Nivolumab plus temozolomide plus radiotherapy probably does not increase OS (HR 1.10, 95% CI 0.92 to 1.32; 3.50 more, 95% CI 3.80 fewer to 9.60 more; 716 participants) and PFS (HR 1.10, 95% CI 0.92 to 1.32; 3.00 more, 95% CI 3.50 fewer to 7.90 more; 716 participants), and probably increases SAE (RR 2.91, 95% CI 2.05 to 4.12; 709 participants; moderate-certainty evidence). It does not increase less serious AEs (RR 1.02, 95% CI 1.00 to 1.04; 709 participants; high-certainty evidence). Adjuvant nivolumab plus temozolomide versus temozolomide in older people with GBM (1 trial, 103 participants) Nivolumab plus temozolomide probably does not increase OS (HR 0.85, 95% CI 0.54 to 1.33; 3.10 fewer, 95% CI 15.80 fewer to 3.60 more; 103 participants; moderate-certainty evidence) and PFS (HR 0.77, 95% CI 0.49 to 1.19; 5.40 fewer, 95% CI 19.10 fewer to 2.40 more; 103 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (RR 1.58, 95% CI 0.88 to 2.81; 103 participants). The evidence for QoL is very uncertain (results only reported graphically; 103 participants). In recurrent GBM, nivolumab alone probably has no benefit. Anti-PD1 plus bevacizumab may also be ineffective based on low- to very low-certainty evidence. Neoadjuvant plus adjuvant pembrolizumab may improve OS and PFS, but this was based on only one small trial and very low-certainty evidence. In newly diagnosed GBM, nivolumab plus radiotherapy in unmethylated and plus radiotherapy plus temozolomide in methylated GBM probably has no benefit. In older participants, adjuvant nivolumab probably offers no benefit.

de Melo SM ，Elias Nunes da Silva ME ，Torloni MR ，Riera R ，De Cicco K ，Latorraca CO ，Pinto ACPN ... -  《Cochrane Database of Systematic Reviews》

The efficacy and safety of induction chemotherapy combined with sintilimab followed by concurrent chemoradiotherapy plus sintilimab sequencing maintaining with sintilimab for patients with unresectable locally advanced esophageal squamous cell carcinoma.

To evaluate the efficacy and safety of induction chemotherapy combined with programmed death protein 1 (PD-1) inhibitor (sintilimab) followed by concurrent chemoradiotherapy (CCRT) plus sintilimab, and subsequent maintenance with sintilimab (IC-ICCRT-IO) for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) in a retrospective study. Data from patients with histologically confirmed, locally advanced, inoperable ESCC who received IC-ICCRT-IO were retrospectively analyzed. Treatment effects were evaluated after 2 cycles of induction therapy and after CCRT by contrast-enhanced CT scans and esophagograms, followed by subsequent evaluations every 3 months post-treatment. The primary endpoints included progression-free survival (PFS) and PFS rates at 6, 12, and 18 months. Secondary endpoints involved overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The influence of the expression level of programmed death ligand-1 (PD-L1) as well as neutrophil-to-lymphocyte ratio (NLR) on efficacy of the IC-ICCRT-IO was analyzed. In total, 29 eligible patients were enrolled and analyzed. The median follow-up time was 20.5 months. The median PFS was not reached; the 6-, 12-, and 18-month PFS rates were 100.0%, 93.1%, and 82.8%, respectively. The median OS was not reached, and the 6-, 12-, and 18-month OS rates were all 100.0%. The ORR and DCR were 89.7% and 100.0%. Adverse events (AEs) were manageable, with grade 3 or higher AEs observed in 48.2% of patients, primarily nonimmune-related and clinically manageable. Hematologic toxicity was predominant. Two patients developed grade 3 immune-related rash, and two patients developed grade 3 radiation pneumonitis, all of whom were managed with appropriate symptomatic treatment. No significant differences in survival outcomes were observed with respect to PD-L1 and NLR. Our results indicated that the IC-ICCRT-IO regimen for unresectable locally advanced ESCC provided a survival benefit with manageable safety profile. More prospective clinical studies should be warranted. 2024-04-22, No. QYFY WZLL 28,684, retrospectively registered.

Wang R ，Guo T ，Wang Q ，Gao W ，Yu Y ，Zhang J ，Fu W ，Wang H ，Zhang B ... -  《BMC CANCER》