PD-1/PD-L1 inhibitor plus chemotherapy versus standard of care in the first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitor plus chemotherapy vs standard of care (SoC) treatment in the first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M-SCCHN). METHODS: Randomized controlled trials (RCTs) that investigated PD-1/PD-L1 inhibitor plus chemotherapy vs SoC as first-line treatment for R/M-SCCHN were searched from electronic databases (PubMed, Embase and Cochrane Library). The primary outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). RESULTS: In total, three phase 3 RCTs (KEYNOTE-048, CAPTAIN-1st, and JUPITER-02; n = 1120) with three PD-1 inhibitors (pembrolizumab, camrelizumab and toripalimab) were included in the analysis. Compared with SoC, PD-1 inhibitor plus chemotherapy significantly prolonged PFS (hazard ratio [HR] 0.66, 95% CI 0.40-0.93, p < 0.001) and OS (HR 0.73, 95% CI 0.60-0.86, p < 0.001) of patients. There was no statistical differences in ORR (odds ratio [OR] 1.26; 95% CI 0.97-1.64, p = 0.086), grade 3 or higher AEs (OR 0.77, 95% CI 0.50-1.17, p = 0.221), and treatment-related deaths (OR 1.34, 95% CI 0.60-2.98, p = 0.470) between the two groups. CONCLUSION: PD-1 inhibitor plus chemotherapy showed more survival benefit than SoC in the first-line treatment for R/M-SCCHN, with a similar safety profile.

The efficacy and safety of immune checkpoint inhibitor plus chemotherapy in patients with advanced non-small-cell lung cancer: a meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of immune checkpoint inhibitor (ICI) and chemotherapy (CT) versus CT alone in advanced non-small-cell lung cancer (NSCLC). METHODS: Databases (PubMed, Embase and Cochrane Library) were searched for relevant randomized controlled trials (RCTs). Clinical outcome measures including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade 3-5 treatment-related adverse events (AEs) were analyzed by Stata 15.0 software; significance level was 0.05. RESULTS: Eight RCTs involving 4227 patients were included. The results showed ICI + CT significantly improved OS (hazard ratio [HR] = 0.74, 95% CI: 0.62-0.85, p < 0.001), PFS (HR = 0.66, 95% CI: 0.57 - 0.75, p < 0.001) and ORR (odds ratio [OR] = 1.89; 95% CI, 1.43-2.49, p < 0.001) compared with CT alone. Subgroup analysis indicated that significantly longer OS was also observed in subgroups including combination regimens (pembrolizumab + CT, atezolizumab + CT, ipilimumab + CT, and nivolumab + ipilimumab + CT) and PD-L1 status [negative (< 1%), positive (≥ 1%), low (1-49%) and high (≥ 50%)]. However, ICI + CT showed signifcantly higher grade 3-5 treatment-related AEs than CT (OR = 1.46, 95% CI: 1.19 - 1.79, p < 0.001). CONCLUSIONS: ICI + CT showed better clinical efficacy than CT alone in patients with advanced NSCLC, with increased treatment-related AEs.

Combination therapy with immune checkpoint inhibitors in advanced renal cell carcinoma: A meta-analysis of randomized controlled trials.

PURPOSE: To evaluate the efficacy and safety of immune checkpoint inhibitor combination therapy in advanced renal cell carcinoma (RCC). METHODS: We searched PubMed/Embase/Cochrane Library for relevant randomized controlled trials (RCTs). Clinical outcome measures including overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), and adverse events (AEs) were analyzed by Stata 15.1 software. RESULTS: Seven RCTs involving 3461 patients were included. The pooled hazard ratios of OS and PFS for combination therapy were 0.67 (0.53-0.82, p < 0.001) and 0.68 (0.52-0.83, p < 0.001), respectively. Longer OS and PFS for combination therapy was also observed in the PD-L1 expression leve ≥1% group. The pooled odds ratios of ORRs and grade 3 or higher AEs were 2.31 (1.61-3.32, p < 0.001) and 0.94 (0.65-1.37, p = 0.753), respectively. CONCLUSIONS: Immune checkpoint inhibitor combination therapy showed more clinical benefit in the first-line treatment for advanced RCC, with a safety profile.

Severe and fatal adverse events of immune checkpoint inhibitor combination therapy in patients with metastatic renal cell carcinoma: a systematic review and meta-analysis.

Introduction: Immune checkpoint inhibitor (ICI) combination therapy has changed the treatment landscape for metastatic renal cell carcinoma (mRCC). However, little evidence exists on the treatment-related severe adverse events (SAEs) and fatal adverse events (FAEs) of ICI combination therapy in mRCC. Method: We searched PubMed, Embase, and Cochrane Library databases to evaluate randomized controlled trials (RCTs) of ICI combination therapy versus conventional tyrosine kinase inhibitor (TKI)-targeted therapy in mRCC. Data on SAEs and FAEs were analyzed using revman5.4 software. Results: Eight RCTs (n=5380) were identified. The analysis showed no differences in SAEs (60.5% vs. 64.5%) and FAEs (1.2% vs. 0.8%) between the ICI and TKI groups (odds ratio [OR], 0.83; 95%CI 0.58-1.19, p=0.300 and OR, 1.54; 95%CI 0.89-2.69, p=0.120, respectively). ICI-combination therapy was associated with less risk of hematotoxicities, including anemia (OR, 0.24, 95%CI 0.15-0.38, p<0.001), neutropenia (OR, 0.07, 95%CI 0.03-0.14, p<0.001), and thrombocytopenia (OR, 0.05, 95%CI 0.02-0.12, p<0.001), but with increased risks of hepatotoxicities (ALT increase [OR, 3.39, 95%CI 2.39-4.81, p<0.001] and AST increase [OR, 2.71, 95%CI 1.81-4.07, p<0.001]), gastrointestinal toxicities (amylase level increase [OR, 2.32, 95%CI 1.33-4.05, p=0.003] and decreased appetite [OR, 1.77, 95%CI 1.08-2.92, p=0.020]), endocrine toxicity (adrenal insufficiency [OR, 11.27, 95%CI 1.55-81.87, p=0.020]) and nephrotoxicity of proteinuria (OR, 2.21, 95%CI 1.06-4.61, p=0.030). Conclusions: Compared with TKI, ICI combination therapy has less hematotoxicity in mRCC but more specific hepatotoxicity, gastrointestinal toxicity, endocrine toxicity, and nephrotoxicity, with a similar severe toxicity profile. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023412669.

Efficacy of immune checkpoint inhibitor as maintenance therapy for advanced or metastatic cancers: A meta-analysis of randomized controlled trials.

BACKGROUND: This study aimed to evaluate the efficacy of immune checkpoint inhibitors (ICIs) as maintenance therapy for advanced or metastatic cancers. METHODS: The PubMed, Embase, and Cochrane Library databases were searched for eligible randomized controlled trials. A meta-analysis of eligible studies investigating the outcomes including progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) with a significance level set to 0.05 was performed. RESULTS: Five RCTs (n = 2828) were identified in this analysis. The pooled hazard ratios (HRs) of PFS and OS for ICI maintenance therapy were 0.88 (95% CI: 0.68-1.13, P = .31) and 0.82 (95% confidence interval [CI]: 0.74-0.92, P = .0005), respectively; the pooled odds ratio (OR) of ORR was 2.24 (95% CI: 1.23-4.09, P = .0008). Subgroup analysis indicated that anti-PD-L1 antibody significantly improved the OS (P = .0008), while anti-PD-1 and anti-PD-1 plus anti-cytotoxic T lymphocyte antigen 4 antibodies significantly prolonged the PFS of patients. CONCLUSION: ICI maintenance therapy enhanced the survival of patients with advanced or metastatic cancers.

Efficacy and safety of adjuvant therapy with PD­1/PD­L1 inhibitors in cancer.

Anti-programmed cell death protein-1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) antibodies have been widely used in cancers. The present study aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors in human cancers. Studies were searched from Cochrane Library, PubMed and Embase databases. Randomized controlled trials (RCTs) that investigated adjuvant therapy with anti-PD-1/PD-L1 agents in solid cancers were eligible for inclusion. As the primary focus of the meta-analysis, clinical outcome measures including overall survival (OS), disease-free survival (DFS), and adverse events (AEs) were analyzed by Stata 15.0 software. A total of six RCTs (n=4,436) met the inclusion criteria. The DFS [hazard ratio (HR)=0.71; 95% confidence interval (CI): 0.63-0.78; P<0.001] and OS (HR=0.66, 95% CI: 0.46-0.86, P<0.001) of patients were significantly prolonged by adjuvant immunotherapy. Subgroup analysis indicated that significantly improved DFS was observed in patients treated with different anti-PD-1/PD-L1 drugs (nivolumab, pembrolizumab, or atezolizumab), as well as in those with different tumors (melanoma, urothelial carcinoma, esophageal or gastroesophageal junction cancer, or renal cell carcinoma), and PD-L1 status [negative (<1%) or positive (≥1%)]. However, PD-1/PD-L1 inhibitors was associated with increased ≥ grade 3 treatment-related AEs (odds ratio=1.63; 95% CI: 1.20-2.21; P=0.002). The available evidence suggests that adjuvant therapy with PD-1/PD-L1 inhibitors provided more survival benefit than placebo for patients with cancer, with increased grade 3 or higher AEs. Prospero registration no. CRD42021290654.

The efficacy and safety of combination therapy with immune checkpoint inhibitors in non-small cell lung cancer: A meta-analysis.

PURPOSE: Combination therapies with immune checkpoint blockade demonstrate promising antitumor activity and safety in Non-small Cell Lung Cancer (NSCLC). However, whether the combination therapy is superior to their monotherapies, and which combination regimen is most efficacious remain unknown. This meta-analysis aims to synthesize the current available evidences on the efficacy and safety of combination immunotherapy in patients with NSCLC. METHODS: PubMed, Embase and Cochrane Library were searched. Randomized controlled trials (RCTs) investigating combination therapy with immune checkpoint inhibitors in NSCLC were included. RESULTS: We identified nine RCTs including a total of 5,142 patients. The study showed that the pooled hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) for combination therapy were 0.74 (95% CI: 0.63-0.86, p = 0.001) and 0.65 (95% CI: 0.56-0.73, p = 0.004); the pooled odds ratios (ORs) of objective response rates (ORRs) and grade 3 or higher adverse events (AEs) were 1.51 (95% CI: 1.02-1.99, p < 0.001) and 1.30 (95% CI: 1.03-1.57, p = 0.007). Subgroup analysis showed that the OR of grade 3 or higher AEs for immunotherapy plus chemotherapy was higher than that of chemotherapy alone, but did not reach statistical significance (p = 0.061) , and there was PFS and OS benefit for either immunotherapy plus chemotherapy, double agent immunotherapy or immunotherapy plus targeted plus chemotherapy combination regimens. CONCLUSIONS: Combination therapy with immune checkpoint inhibitors showed more clinical benefit for patients with NSCLC, with increased grade 3 or higher AEs, but toxicities were manageable.

Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review.

OBJECTIVE: Both pembrolizumab and lenvatinib demonstrate antitumor activity and safety in cancers. However, whether their combination is safer and more effective than monotherapies remains unknown. A systematic review was performed to assess the safety and efficacy of pembrolizumab plus lenvatinib versus their respective monotherapies in solid cancers. METHODS: PubMed, Embase, and Cochrane Library were searched. Forty-two clinical trials with 8155 patients were included. RESULTS: The total ≥grade 3 adverse events (AEs) and objective response rates (ORRs) among pembrolizumab plus lenvatinib and pembrolizumab or lenvatinib monotherapies in solid cancers were 68.0% vs 17.7% vs 68.5% and 40.6% vs 20.8% vs 43.3%, respectively. The most common AEs of pembrolizumab plus lenvatinib were hypertension (20-61.1%), fatigue (12-59.1%), diarrhea (9-51.9%), hypothyroidism (25-47%), and proteinuria (8-17%). Good ORRs for combination therapy were observed in renal cell carcinoma (70%), gastric cancer (69%), melanoma (48%), head and neck squamous cell carcinoma (46%), and endometrial cancer (38-53%), while these rates were reported as 27%, 11.6-22%, 26-37%, 14.6-23%, and 11-14.3% for monotherapies, respectively. Longer median progression-free survival (mPFS) and median overall survival (mOS) were observed for hepatocellular carcinoma (mPFS 9.3 months, mOS 22.0 months), renal cell carcinoma (mPFS 19.8 months), gastric cancer (mPFS 7.1 months, mOS not reached), and endometrial cancer (mPFS 7.4 months, mOS 16.7 months). CONCLUSIONS: Compared with their monotherapies, pembrolizumab plus lenvatinib showed more promising antitumor activity and resulted in higher ORRs and significant survival benefits in the above cancers. Toxicities were manageable, with no unexpected safety issues.

Prenatal diagnosis of pulmonary atresia with ventricular septal defect.

Pulmonary atresia with ventricular septal defect (PA-VSD) is a rare complex congenital heart defect. Major artery-pulmonary collateral arteries (MAPCAs) are characteristic of PA-VSD. Prenatal diagnosis can be achieved in most cases of PA-VSD with recent advances in echocardiography. However, it is extremely rare that all MAPCAs can be observed on the echocardiograph. Here, we report a case of prenatally diagnosed type C PA-VSD in which all the MAPCAs could be seen on the echocardiograph, with the diagnosis supported by autopsy evidence.