Pembrolizumab alone or combined with chemotherapy versus chemotherapy for the treatment of metastatic cancer: A meta-analysis of randomized clinical trials.

Whether pembrolizumab alone or in combination with chemotherapy is superior to chemotherapy in metastatic cancer remains controversial. The study aims to give the effectiveness and safety of pembrolizumab-related interventions compared to chemotherapy in metastatic cancer. Electronic databases were systematically searched until November 20, 2023, for all randomized controlled trials comparing Pembrolizumab alone or in combination with chemotherapy versus chemotherapy for metastatic cancer. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) and odds ratios with 95% confidence intervals (CI) were calculated for OS, PFS, overall response rate, and overall adverse events (AEs) by random effects models. 16 Randomized controlled trials with 9148 patients were included. Compared with chemotherapy, pembrolizumab was associated with longer OS (HR 0.82; 95% CI 0.73-0.91, P = .0004), more immune-mediated AEs, fewer overall AEs, and grade 3 or 4 AEs, however, no significant difference was found in PFS, overall response rate, and events leading to death. Pembrolizumab with chemotherapy was associated with longer OS (HR 0.74; 95% CI 0.61-0.90, P = .002) and PFS (HR 0.63; 95% CI 0.50-0.79, P < .0001), higher overall response rate, and more immune-mediated AEs comparing to chemotherapy alone, however, no significant advantages were observed in disease control rates, overall AEs, grade 3 or 4 AEs and events leading to death. The patients with programmed cell death ligand 1 tumor proportion scores of at least 50% or combined positive scores (CPS) of at least 10 could derive significantly better OS and PFS benefits from pembrolizumab alone or combined with chemotherapy. Similar OS results were found for first-line treatment and lung cancer subgroup analysis. Pembrolizumab alone or combined with chemotherapy indicates an effective and safe treatment for metastatic cancer. Pembrolizumab alone or combined with chemotherapy provides a better survival advantage under first-line treatment or programmed cell death ligand 1 combined positive scores of at least 10 or programmed cell death ligand 1 tumor proportion scores of at least 50%. However, we found that the specific efficacy of pembrolizumab in unused tumor types could not be effectively evaluated.

Yue Y ，Wang Q ，Wei M ，Ding F ，Li J ，Zheng B ... -  《-》

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 ... -  《-》

Anti-angiogenic therapy for high-grade glioma.

Ameratunga M ，Pavlakis N ，Wheeler H ，Grant R ，Simes J ，Khasraw M ... -  《Cochrane Database of Systematic Reviews》

Biosimilar monoclonal antibodies for cancer treatment in adults.

Biosimilars are products containing an approved biological medicine. They are similar, but not identical, to an originator medicine. In cancer, biosimilars have been developed from the monoclonal antibodies, bevacizumab, rituximab, and trastuzumab. They have become available for the treatment of lung, colorectal, non-Hodkin's lymphoma, and breast cancers. As these biological products are not identical, synthesis of evidence of the clinical effects of biosimilars compared to their originators is needed to understand their comparative effectiveness and harms. To evaluate the benefits and harms of biosimilar monoclonal antibodies versus their originator drugs for adults with cancer. We searched bibliographic (CENTRAL, MEDLINE, Embase, Web of Science) and clinical trials databases to February 2024. We included head-to-head randomised controlled trials conducted in adults with cancer treated with biosimilar or originator monoclonal antibodies. We followed standard Cochrane methodology. Primary outcomes were progression-free survival, duration of response, overall survival, breast cancer's pathological complete response, serious adverse events, and health-related quality of life. If survival estimates were adjusted or provided as rates, we did not combine them. We used Cochrane's RoB 1 tool to assess the risk of bias and GRADE to evaluate the certainty of evidence of critical and important outcomes according to the relevance determined by consumers. We included 55 studies with 22,046 adults (23 of bevacizumab, 10,639 participants with colorectal or lung cancer; 17 of rituximab, 4412 participants with non-Hodgkin's lymphoma; and 15 of trastuzumab, 6995 participants with breast cancer). Studies were conducted in all continents, most were multicentre, and all were funded by the drug manufacturer. Participants' ages ranged from 47 (mean) to 62 (median) years and the proportion of women from 18% to 100%. Fifteen studies were conducted as non-inferiority and 40 as equivalence. The overall risk of bias was low; main biases were in the incomplete outcome data and selective reporting domains. Bevacizumab biosimilar versus bevacizumab originator in lung or colorectal cancer Progression-free survival is likely similar between bevacizumab biosimilar and the originator (per 1000: 380 in both groups at 12 months, hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.91 to 1.09; 5 studies, 2660 participants; moderate-certainty evidence). There were no differences in lung or colorectal cancer subgroups. Bevacizumab biosimilar is likely similar to the originator in duration of response (per 1000: 219 participants who achieved response progressed with biosimilar versus 210 with originator at 12 months; HR 1.05, 95% CI 0.81 to 1.37; 1 study, 762 participants; moderate-certainty evidence) and overall survival (per 1000: 592 with biosimilar versus 610 with originator at 12 months; HR 1.06, 95% CI 0.94 to 1.19; 5 studies, 2783 participants; moderate-certainty evidence). There were no differences in cancer type subgroups. Bevacizumab biosimilar is likely similar to the originator in serious adverse events (per 1000: 303 with biosimilar versus 309 with originator; risk ratio (RR) 0.98, 95% CI 0.93 to 1.03; 23 studies, 10,619 participants; moderate-certainty evidence). Bevacizumab biosimilar may be similar to originator in health-related quality of life as scores were comparable in the one study that assessed this outcome in metastatic colorectal cancer (low-certainty evidence). This critical outcome was not assessed in other biosimilars comparisons. Bevacizumab biosimilar is likely similar to originator in objective response (per 1000: 481 with biosimilar versus 501 with originator; RR 0.96, 95% CI 0.93 to 1.00; 23 studies, 10,054 participants; moderate-certainty evidence) and mortality (per 1000: 287 with biosimilar versus 279 with originator; RR 1.03, 95% CI 0.97 to 1.09; 19 studies, 9231 participants; moderate-certainty evidence). There were no differences in lung or colorectal cancers. Rituximab biosimilar versus rituximab originator in non-Hodgkin's lymphoma Rituximab biosimilar is likely similar to originator in progression-free survival (7 studies, 2456 participants), duration of response (2 studies, 522 participants), and overall survival (7 studies, 2353 participants; data not pooled as survival estimates were adjusted for different factors or reported as rates) (all moderate-certainty evidence). Rituximab biosimilar is likely similar to originator in the risk of serious adverse events (per 1000: 210 with biosimilar versus 204 with originator; RR 1.03, 95% CI 0.94 to 1.14; 15 studies, 4197 participants; moderate-certainty evidence) and objective response (per 1000: 807 with biosimilar versus 799 with originator; RR 1.01, 95% CI 0.98 to 1.04; 16 studies, 3922 participants; moderate-certainty evidence). No study reported quality of life. Rituximab biosimilar is similar to originator in mortality (per 1000: 52 with biosimilar versus 53 with originator; RR 0.97, 95% CI 0.70 to 1.35; 8 studies, 2557 participants; high-certainty evidence). Trastuzumab biosimilar versus trastuzumab originator in breast cancer Trastuzumab biosimilar is likely similar to originator in progression-free survival (4 studies, 2221 participants), duration of response (3 studies, 1488 participants), and overall survival (6 studies, 2221 participants), which were not pooled due to adjustment for different factors or provided as rates. No study reported quality of life. Trastuzumab biosimilar may be similar to originator in pathological complete response (per 1000: 459 with biosimilar versus 433 with originator; RR 1.06, 95% CI 0.95 to 1.17; 7 studies, 3403 participants; low-certainty evidence), is likely similar in serious adverse events (per 1000: 129 in both groups; RR 1.00, 95% CI 0.85 to 1.17; 13 studies, 6183 participants; moderate-certainty evidence), and slightly increases objective response (per 1000: 801 with biosimilar versus 777 with originator; RR 1.03, 95% CI 1.01 to 1.05; 13 studies, 5509 participants; moderate-certainty evidence). Treatment with bevacizumab, rituximab, and trastuzumab biosimilars are likely similar to their originator drugs in terms of their impact on progression-free survival, duration of response, overall survival, serious adverse events, objective response, and mortality. Limited evidence showed similarity in pathological complete response for trastuzumab and quality of life for bevacizumab compared with originators, which was not assessed in the other comparisons. The overall certainty of evidence was moderate and imprecision was the main reason for downgrading our certainty in the findings.

Galvao TF ，Livinalli A ，Lopes LC ，Zimmermann IR ，Silva MT ... -  《Cochrane Database of Systematic Reviews》

Maintenance therapy for chronic lymphocytic leukaemia.

Lee CH ，Wu YY ，Huang TC ，Lin C ，Zou YF ，Cheng JC ，Chen PH ，Jhou HJ ，Ho CL ... -  《Cochrane Database of Systematic Reviews》