Nephrotoxicity of immune checkpoint inhibitor combination therapy in patients with advanced renal cell carcinoma: a meta-analysis.

PURPOSE: Few data are available regarding the nephrotoxicity of immune checkpoint inhibitor (ICI) combination therapy in advanced renal cell carcinoma (RCC). This study aimed to investigate the nephrotoxicity of ICI-based combination therapy versus standard of care sunitinib in patients with advanced RCC. METHODS: We searched Embase/PubMed/Cochrane Library for relevant randomized controlled trials (RCTs). Treatment-related nephrotoxicities including increase of creatinine and proteinuria were analyzed by Review Manager 5.4 software. RESULTS: Seven RCTs involving 5239 patients were included. The analysis showed that ICI combination therapy had similar risks of any grade (RR = 1.03, 95% CI: 0.77-1.37, P = 0.87) and grade 3-5 (RR = 1.48, 95% CI: 0.19-11.66, P = 0.71) increased creatinine compared with sunitinib monotherapy. However, ICI combination therapy was associated with significantly higher risks of any grade (RR = 2.33, 95% CI: 1.54-3.51, P < 0.0001) and grade 3-5 proteinuria (RR = 2.25, 95% CI: 1.21-4.17, P = 0.01). CONCLUSIONS: This meta-analysis suggests that ICI combination therapy shows more nephrotoxicity of proteinuria than sunitinib in advanced RCC, which deserves a high attention in the clinic.

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.

LINC01806 mediated by STAT1 promotes cell proliferation, migration, invasion, and stemness in non-small cell lung cancer through Notch signaling by miR-4428/NOTCH2 axis.

BACKGROUND: Non-small cell lung cancer (NSCLC), the most primary lung cancer subtype, threatens human health globally. Long non-coding RNAs (lncRNAs) have been uncovered to affect multiple cancers progression. Nevertheless, the specific function of long intergenic non-protein coding RNA 1806 (LINC01806) in NSCLC remains elusive. METHODS: RT-qPCR and western blot were involved in this study. The influence of LINC01806 on NSCLC was assessed by in vitro and in vivo assays. Via ChIP, RNA pull down, RIP, and luciferase reporter assays, the in-depth cellular mechanisms of LINC01806 in NSCLC were explored. RESULTS: LINC01806 expression was high in NSCLC cell lines. Functionally, LINC01806 knockdown impeded cell proliferation, migration, invasion, and stemness, along with tumor growth. As for its mechanism, signal transducer and activator of transcription 1 (STAT1) activated LINC01806 transcription in NSCLC. Furthermore, LINC01806 sequestered microRNA-4428 (miR-4428) to enhance notch receptor 2 (NOTCH2) expression, thus activating Notch signaling pathway. Finally, in vitro and in vivo assays jointly validated that LINC01806 exerted its function in NSCLC development via miR-4428/NOTCH2 pathway. CONCLUSION: LINC01806 enhanced NOTCH2 expression to stimulate Notch signaling via sponging miR-4428, thereby facilitating NSCLC progression, which provided a novel mechanism for NSCLC therapeutic approaches.

PD-1/PD-L1 inhibitor monotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck: a meta-analysis.

PURPOSE: To evaluate the efficacy and safety of programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy compared to the standard of care in the first-line setting for recurrent or metastatic head and neck squamous cell carcinoma. MATERIALS AND METHODS: The PubMed, Embase, and Cochrane Library databases were searched for relevant randomized controlled trials. The clinical outcomes of overall survival, progression-free survival, objective response rates, and grade 3 or higher adverse events were analyzed using Stata SE 15 software with a significance level set to 0.05. RESULTS: We identified four randomized controlled trials (1 nivolumab, 2 pembrolizumab, and 1 durvalumab), including a total of 2474 patients. The results of the meta-analysis showed pooled hazard ratios of overall and progression-free survival for programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy of 0.82 (95% CI: 0.73-0.91, p < 0.001) and 0.96 (95%CI: 0.84-1.07, p < 0.001) and pooled odds ratios of objective response rates and grade 3 or higher adverse events of 1.04 (95%CI: 0.46-2.37; p = 0.926) and 0.28 (95%CI: 0.22-0.35, p < 0.001), respectively. Subgroup analysis showed that inhibitors for both programmed cell death-1 (nivolumab and pembrolizumab) and programmed cell death-ligand 1 (durvalumab) were associated with significantly longer overall survival (HR = 0.80, 95% CI: 0.70-0.90, p < 0.001 and HR = 0.88, 95%CI: 0.70-1.06, p < 0.001, respectively). CONCLUSIONS: Programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy showed more clinical benefit versus the standard of care in patients with recurrent or metastatic head and neck squamous cell carcinoma, with an acceptable safety profile.

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.

LncRNA FEZF1-AS1 promotes non-small lung cancer cell migration and invasion through the up-regulation of NOTCH1 by serving as a sponge of miR-34a.

BACKGROUND: The involvement of lncRNA FEZF1-AS1 has been analyzed in many types of cancers, while its roles in non-small cell lung cancer (NSCLC) remains unclear. We then explored the role of FEZF1-AS1 in NSCLC. METHODS: qPCR and western blot were performed to measure gene expression. FEZF1-AS1, miR-34a, and NOTCH-1 were overexpressed to analyze the relationship between them. Transwell assays were performed to analyze the effects of transfections on cell invasion and migration. RESULTS: FEZF1-AS1 was up-regulated in NSCLC patients. Increased expression levels of FEZF1-AS1 were observed with the increase in clinical stages. Bioinformatics analysis showed that miR-34a can bind with FEZF1-AS1. In NSCLC tissues, NOTCH-1 and FEZF1-AS1 were positively correlated. In NSCLC cells, over-expression of FEZF1-AS1 resulted in up-regulated expressions of NOTCH-1, while miR-34a over-expression mediated down-regulated expressions of NOTCH-1. In addition, FEZF1-AS1 and miR-34a did not alter each other, while bioinformatics analysis showed that miR-34a can bind FEZF1-AS1. Analysis of cell migration and invasion showed increased cell invasion and migration rates after FEZF1-AS1 and NOTCH-1 over-expression. MiR-34a played the opposite role and reduced the effects of FEZF1-AS1 over-expression. CONCLUSIONS: FEZF1-AS1 promoted NSCLC cell migration and invasion through the up-regulation of NOTCH1 by serving as a sponge of miR-34a.

Combination therapy with immune checkpoint inhibitors in recurrent or metastatic squamous cell carcinoma of the head and neck: A meta-analysis.

OBJECTIVES: To evaluate the efficacy and safety of immune checkpoint inhibitor (ICI) combination therapy in the first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). METHODS: We conducted a meta-analysis between ICI combination therapy and standard of care (SOC) treatment (chemotherapy with or without cetuximab) in R/M-SCCHN based on randomized controlled trials (RCTs). The outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). RESULTS: Five RCTs involving 2576 patients were included in the analysis. Compared with SOC, PD-1 inhibitor plus chemotherapy significantly improved OS (hazard ratio [HR], 0.73, 95 % CI 0.62-0.87, p = 0.0004), PFS (HR, 0.65, 95 % CI 0.43-0.99, p = 0.04) and ORR (risk ratio [RR], 1.10; 95 % CI 1.01-1.19, p = 0.02) of patients, while double-agent immunotherapy could not improve either the outcome of OS, PFS, or ORR (all p > 0.05). In safety analyses, combination immunotherapy showed similar risks of grade 3 or higher treatment-related AEs (RR, 0.79, 95 % CI 0.56-1.11, P = 0.17) and treatment-related deaths (RR, 1.16, 95 % CI 0.65-2.07, P = 0.63) compared to SOC. CONCLUSIONS: Compared with SOC, PD-1 inhibitor plus chemotherapy enhanced OS, PFS, and ORR in the first-line treatment for patients with R/M-SCCHN, but double-agent immunotherapy showed no more benefit for these patients.

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 angiotensin receptor and neprilysin inhibitor, LCZ696, in heart failure: A meta-analysis of randomized controlled trials.

BACKGROUND: LCZ696 is a novel neuroendocrine inhibitor that has been widely used in heart failure (HF). However, its advantage over other neuroendocrine inhibitors, such as angiotensin-converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) has not been fully elucidated. This study aimed to provide the latest evidence regarding the efficacy and safety of LCZ696 as compared to other ACEis and ARBs with regards to the treatment of HF. METHODS: We systematically searched databases, including PubMed, Embase, and the Cochrane Library, for relevant randomized controlled trials (RCTs). The outcome measures included all-cause mortality, rate of hospitalizations for HF, rate of death from cardiovascular causes, change in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and decline of renal function. RESULTS: Five RCTs involving 19,078 patients were identified. The meta-analysis indicated that LCZ696 was associated with a significant reduction in all-cause mortality (hazard ratio [HR] = 0.84; 95% confidence interval [CI], 0.76-0.93; P = .0005), rate of hospitalizations for HF (HR = 0.80; 95% CI, 0.73-0.87; P < .00001), reduction in NT-proBNP levels (rate ratio = 0.78; 95% CI, 0.70-0.88; P < .0001), and decline in renal function (odds ratio = 0.77; 95% CI, 0.68-0.88; P < .0001) compared with ACEis and ARBs. However, there was no statistical difference in the rate of death from cardiovascular causes (HR = 0.86; 95% CI, 0.72-1.03; P = .09) between LCZ696 and ACEis and ARBs. CONCLUSION: LCZ696 is superior to ACEis and ARBs in the treatment of HF. Hence, it should be more widely used clinically.

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.