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Therapeutic Advances in Medical Oncology 2020Conventional cytotoxic chemotherapy offers minor benefit to patients with mucosal melanoma (MM). Although immune checkpoint inhibitors (ICIs) have become the preferred... (Review)
Review
BACKGROUND
Conventional cytotoxic chemotherapy offers minor benefit to patients with mucosal melanoma (MM). Although immune checkpoint inhibitors (ICIs) have become the preferred approach in patients with advanced or metastatic cutaneous melanoma, the evidence of their clinical use for MM is still limited. This systematic review aims to summarize the efficacy and safety of ICIs in advanced or metastatic MM.
METHODS
We searched electronic databases, conference abstracts, clinical trial registers and reference lists for relevant studies. The primary outcomes included the overall response rate (ORR), median progression-free survival (PFS), median overall survival (OS), one-year PFS rate, and one-year OS rate.
RESULTS
This review identified 13 studies assessing anti-CTLA-4 monotherapy, 22 studies assessing anti-PD-1 monotherapy, two studies assessing anti-CTLA-4 and anti-PD-1 combination therapy, one study assessing anti-PD-1 antibodies combined with axitinib, and three studies assessing anti-PD-1 antibodies combined with radiotherapy. For most patients who received ipilimumab monotherapy, the ORR ranged from 0% to 17%, the median PFS was less than 5 months, and the median OS was less than 10 months. For patients who received nivolumab or pembrolizumab monotherapy, most studies showed an ORR of more than 15% and a median OS of more than 11 months. The combined administration of anti-CTLA-4 and anti-PD-1 agents showed benefits over single-agent therapy with an ORR of more than 33.3%. In a phase Ib trial of toripalimab in combination with axitinib, approximately half of patients had complete or partial responses. Three retrospective studies that investigated anti-PD-1 antibodies combined with radiotherapy showed an ORR of more than 50%, which was higher than each single modality treatment.
CONCLUSIONS
Immune checkpoint inhibitors, especially anti-PD-1 monoclonal antibodies alone and in combination with anti-CTLA-4 monoclonal antibodies or other modalities, are promising treatment options for advanced or metastatic MM. However, high-level evidence is still needed to support the clinical application.
PubMed: 32489431
DOI: 10.1177/1758835920922028 -
Clinical Genitourinary Cancer Aug 2020Combination treatments with immuno-oncology (IO) agents and IO agents plus a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) have been... (Meta-Analysis)
Meta-Analysis
Combination treatments with immuno-oncology (IO) agents and IO agents plus a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) have been approved for first-line treatment of patients with metastatic renal cell carcinoma (mRCC). No direct comparisons have been performed among these treatment options. We performed a systematic review and network meta-analysis to compare and rank the available regimens for first-line treatment in terms of survival benefit and efficacy. In accordance with the Preferred Reporting Items for Systematic Review statement, a systematic search of reported studies was performed in MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE up to May 31, 2019. Network meta-analysis models were adjusted using the Bayesian method. Four randomized clinical trials, with a total of 3758 patients, met the inclusion criteria. Considering systemic therapy, 1880 patients had received sunitinib and 550, 432, 442, and 454 patients had received ipilimumab plus nivolumab (ipi + nivo), pembrolizumab plus axitinib (pembro + axi), avelumab plus axitinib (avelu + axi), and atezolizumab plus bevacizumab (atezo + bev). No difference was found in overall survival between ipi + nivo and pembro + axi for the intention to treat population (hazard ratio [HR], 1.34; 95% credible interval [CrI], 0.92-1.97). No difference was found in progression-free survival among the treatments. The overall response rate (ORR) was superior with pembro + axi and avelu + axi compared with the ORR with the other treatments (atezo + bev vs. pembro + axi: HR, 0.66; 95% CrI, 0.52-0.84; ipi + nivo vs. pembro + axi: HR, 0.73; 95% CrI, 0.59-0.90; atezo + bev vs. avelu + axi: HR, 0.55; 95% CrI, 0.43-0.71; avelu + axi vs. ipi + nivo: HR, 1.66; 95% CrI, 1.31-2.12), with no differences across them (HR, 1.21; 95% CrI, 0.95-1.53). In the present indirect comparison, for an intention to treat population, we found no survival differences between pembro + axi and ipi + nivo. All treatments showed better progression-free survival compared with sunitinib that was similar among them. The combination of an IO agent (pembrolizumab or avelumab) and axitinib seemed to be the most effective therapy for the ORR.
Topics: Carcinoma, Renal Cell; Humans; Immune Checkpoint Inhibitors; Kidney Neoplasms; Prognosis; Survival Rate
PubMed: 32303427
DOI: 10.1016/j.clgc.2020.02.012 -
American Journal of Clinical Oncology Jul 2020Randomized clinical trials have shown combination therapy to be superior in progression-free survival (PFS) rates when compared with sunitinib alone. However, there have... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Randomized clinical trials have shown combination therapy to be superior in progression-free survival (PFS) rates when compared with sunitinib alone. However, there have been no direct comparisons among the combination strategies making it unclear as to which may be the preferred option. We performed a network meta-analysis of the combination therapy (immune checkpoint inhibitor plus axitinib or bevacizumab) used in metastatic renal cell carcinoma (mRCC) and provided a rank order preference based on PFS, and adverse events (AEs).
MATERIALS AND METHODS
A systematic search on the treatment of mRCC using combination therapy till July 2019 was done. Studies reporting on combination therapies with immune checkpoint inhibitor plus axitinib or bevacizumab for mRCC were selected. Frequentist method was used for rank order generation.
RESULTS
A total of 3 studies consisting of 2672 patients were selected. All combination therapies demonstrated improved PFS when compared with sunitinib alone. The rank order for PFS showed combination of pembrolizumab plus axitinib had the highest probability of favorability followed by avelumab plus axitinib and atezolizumab plus bevacizumab (surface under the cumulative ranking 0.9, 0.7, and 0.4, respectively). For AEs, pembrolizumab plus axitinib had the least AEs ≥grade 3, followed by avelumab plus axitinib and atezolizumab plus bevacizumab (surface under the cumulative ranking 0, 0.5, 1.0).
CONCLUSIONS
This network meta-analysis demonstrates that combination of pembrolizumab plus axitinib may be the preferred option based on efficacy and side effect profile compared with avelumab plus axitinib or atezolizumab plus bevacizumab. However, all the 3 combination strategies were superior to sunitinib alone in improving PFS in patients with mRCC.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Network Meta-Analysis; Sunitinib
PubMed: 32251121
DOI: 10.1097/COC.0000000000000695 -
Expert Review of Clinical Pharmacology Mar 2020: We performed a meta-analysis to quantify the overall incidence and risk of proteinuria associated with five newly approved VEGFR-TKIs (regorafenib, vandetanib,... (Meta-Analysis)
Meta-Analysis
Incidence and risk of proteinuria associated with newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: an up-to-date meta-analysis of randomized controlled trials.
: We performed a meta-analysis to quantify the overall incidence and risk of proteinuria associated with five newly approved VEGFR-TKIs (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) in cancer patients.: Pubmed, Embase, ASCO abstracts, and ESMO abstracts were searched to identify relevant studies. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were estimated using random or fixed effects models according to the heterogeneity of included studies.: A total of 9,446 patients from 20 RCTs were included for the meta-analysis. The use of newly approved VEGFR-TKIs was associated with an increased risk of all-grade (RR 2.35, 95% CI 1.69-3.27, P < 0.001) and high-grade (RR 3.70, 95% CI 2.09-6.54, P < 0.001) proteinuria. On subgroup analysis, lenvatinib, axitinib, and vandetanib significantly increased the risk of all-grade proteinuria, and lenvatinib was associated with an increased risk of high-grade proteinuria. In addition, the risk of developing high-grade proteinuria events was significant for patients with hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), but not for patients with colorectal cancer (CRC) and thyroid cancer (TC).: Treatment with newly approved VEGFR-TKIs significantly increases the risk of developing proteinuria events in cancer patients, especially for patients treated with lenvatinib.
Topics: Antineoplastic Agents; Humans; Incidence; Neoplasms; Protein Kinase Inhibitors; Proteinuria; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Risk
PubMed: 32105149
DOI: 10.1080/17512433.2020.1734450 -
Kidney Cancer (Clifton, Va.) 2020There have been a number of recent advances in the management of advanced clear cell renal cell carcinoma (ccRCC). However, the majority of these studies excluded...
INTRODUCTION
There have been a number of recent advances in the management of advanced clear cell renal cell carcinoma (ccRCC). However, the majority of these studies excluded patients with non-clear cell RCC (nccRCC), and optimal management of nccRCC remains unknown.
MATERIALS AND METHODS
A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to evaluate systemic treatment options in locally advanced or metastatic nccRCC between 2000-2019. Randomized controlled trials, single-arm phase II-IV trials, and prospective analyses of medication access programs were included. The primary outcome measures were progression free survival (PFS), overall survival (OS), and objective response rate (ORR).
RESULTS
A total of 31 studies were included in the final analysis. There was the highest level of evidence to support first-line treatment of nccRCC with sunitinib. Additional single-arm trials support the use of other vascular endothelial growth factor (VEGF) inhibitors with axitinib and pazopanib, as well as mammalian target of rapamycin (mTOR) inhibition with temsirolimus or everolimus +/- bevacizumab. Immune checkpoint inhibition has an emerging role in nccRCC, but optimal sequencing of available options is not clear. Prospective data to support the use of newer immunotherapy combinations are lacking. Treatment for collecting duct carcinoma remains platinum-based chemotherapy.
CONCLUSIONS
The availability of randomized trials in nccRCC is limited, and most studies include outcomes for nccRCC as a group, making conclusions about efficacy by subtype difficult. This systematic review supports consensus guidelines recommending sunitinib or clinical trial enrollment as preferred first-line treatment options for nccRCC, but also suggests a more nuanced approach to management and new options for therapy such as immune checkpoint inhibition.
PubMed: 34435168
DOI: 10.3233/kca-190078 -
European Urology Oncology Nov 2019No head-to-head clinical trials compare contemporary first-line therapies for metastatic renal cell carcinoma (mRCC). A network meta-analysis provides an approach for... (Meta-Analysis)
Meta-Analysis
CONTEXT
No head-to-head clinical trials compare contemporary first-line therapies for metastatic renal cell carcinoma (mRCC). A network meta-analysis provides an approach for quantitative analysis.
OBJECTIVE
To indirectly compare the efficacy and safety of first-line treatments for mRCC in the intention-to-treat (ITT) population and by clinical risk group.
EVIDENCE ACQUISITION
An updated systematic review from database inception to February 17, 2019 identified all parallel-group randomized controlled trials assessing first-line therapy for mRCC. "Clinically relevant" studies were selected for a network meta-analysis. Progression-free survival (PFS) was the primary outcome. Overall survival (OS), overall response rate (ORR), and grade 3 and 4 adverse events (AEs) were secondary outcomes.
EVIDENCE SYNTHESIS
We identified 12 relevant trials: 12 reported outcomes for PFS, nine for OS, 10 for ORR, and nine for AEs. In the ITT population, cabozantinib (surface under the cumulative ranking curves [SUCRA] 84%), avelumab plus axitinib (SUCRA 68%), and pembrolizumab plus axitinib (SUCRA 82%) were superior to the other agents for PFS; pembrolizumab plus axitinib appeared superior for OS (SUCRA 95%); and atezolizumab demonstrated the lowest likelihood of AEs (SUCRA 100%). Findings were similar in the intermediate/poor-risk subgroup. Based on the limited data available, avelumab plus axitinib may be preferred in patients with favorable-risk disease.
CONCLUSIONS
The optimal first-line treatment for mRCC appears to differ by efficacy endpoint, toxicity, and clinical risk group. Direct comparative studies remain important in guiding treatment choice.
PATIENT SUMMARY
Head-to-head comparisons do not exist for the newest treatments of metastatic renal cell carcinoma (mRCC). In an indirect comparison, we found that pembrolizumab plus axitinib and cabozantinib are good options for most patients with mRCC.
Topics: Carcinoma, Renal Cell; Humans; Neoplasm Metastasis; Progression-Free Survival
PubMed: 31588018
DOI: 10.1016/j.euo.2019.09.002 -
BMC Urology Jun 2019Conflicting evidence exists regarding the effect of hypertension on the prognosis of metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Conflicting evidence exists regarding the effect of hypertension on the prognosis of metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). This study aimed to assess the predictive value of TKIs-induced hypertension in patients with mRCC.
METHODS
This study was registered in PROSPERO (CRD42019129593). PubMed, Embase, Web of Science and the Cochrane Library database were searched with terms: "renal cell carcinoma", "hypertension", "blood pressure", "tyrosine kinase inhibitor", "sunitinib", "axitinib", "sorafenib" and "pazopanib" until March 21, 2019. Hazard Ratios (HR) and 95% confidence intervals (CI) for progression-free survival (PFS) or overall survival (OS) were extracted and analyzed with Stata 15.0 software. Heterogeneity was assessed using the I value. Meta-regression, subgroup analysis and sensitivity analysis were also performed to explore heterogeneity. Publication bias was assessed with funnel plots and precisely assessed by Egger's and Begg's tests. The quality of evidence of outcomes was generated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE).
RESULTS
A total of 4661 patients from 22 studies were included in the study. The results showed that the increase of blood pressure was an effective predictor for longer PFS (HR = 0.59, 95% CI: 0.48-0.71, p < 0.001; I = 77.3%) and OS (HR = 0.57, 95% CI: 0.45-0.70, p < 0.001; I = 77.4%) of patients with mRCC. Subgroup analysis revealed that patients receiving sunitinib and pazopanib could have longer PFS and OS.
CONCLUSIONS
This study indicated that TKIs-induced hypertension may be a good predictor for better prognosis of patients with mRCC receiving TKIs treatment, especially using sunitinib or pazopanib.
Topics: Carcinoma, Renal Cell; Disease-Free Survival; Humans; Hypertension; Kidney Neoplasms; Prognosis; Protein Kinase Inhibitors; Survival Rate
PubMed: 31174518
DOI: 10.1186/s12894-019-0481-5 -
PloS One 2019In the absence of clinical trials providing direct efficacy results, this study compares different methods of indirect treatment comparison (ITC), and their respective... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
In the absence of clinical trials providing direct efficacy results, this study compares different methods of indirect treatment comparison (ITC), and their respective impacts on efficacy estimates for lenvatinib (LEN) plus everolimus (EVE) combination therapy compared to other second-line treatments for advanced/metastatic renal cell carcinoma (a/mRCC).
METHODS
Using EVE alone as the common comparator, the Bucher method for ITC compared LEN + EVE with cabozantinib (CAB), nivolumab (NIV), placebo (PBO) and axitinib (AXI). Hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) estimated the impact of applying three versions of the LEN+EVE trial data in separate ITCs. Last, to overcome exchangeability bias and potential violations to the proportional hazards assumption, a network meta-analysis using fractional polynomials was performed.
RESULTS
Bucher ITCs demonstrated LEN + EVE superiority over EVE for PFS, indirect superiority to NIV, AXI, and PBO, and no difference to CAB. For OS, LEN + EVE was superior to EVE and indirectly superior to PBO, applying original HOPE 205 data. Using European Medicines Agency data, LEN + EVE was directly superior to EVE for OS. Fractional polynomial HRs for PFS and OS substantially overlapped with Bucher estimates, demonstrating LEN+EVE superiority over EVE, alone, NIV, and CAB. However, there were no statistically significant results as the credible intervals for HR crossed 1.0.
CONCLUSIONS
Comparing three Bucher ITCs, LEN + EVE demonstrated superior PFS when indirectly compared to NIV, AXI, and PBO, and mixed results for OS. While fractional polynomial modelling for PFS and OS failed to find statistically significant differences in LEN + EVE efficacy, the overall HR trends were comparable.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Neoplasm Staging; Phenylurea Compounds; Quinolines; Treatment Outcome
PubMed: 30835737
DOI: 10.1371/journal.pone.0212899 -
BMJ Open Mar 2019To compare the effectiveness and safety of treatments for advanced or metastatic renal cell carcinoma (amRCC) after treatment with vascular endothelial growth factor...
OBJECTIVE
To compare the effectiveness and safety of treatments for advanced or metastatic renal cell carcinoma (amRCC) after treatment with vascular endothelial growth factor (VEGF)-targeted treatment.
DESIGN
Systematic review and network meta-analysis of randomised controlled trials (RCTs) and comparative observational studies. MEDLINE, EMBASE and Cochrane Library were searched up to January 2018.
PARTICIPANTS
People with amRCC requiring treatment after VEGF-targeted treatment.
INTERVENTIONS
Axitinib, cabozantinib, everolimus, lenvatinib with everolimus, nivolumab, sorafenib and best supportive care (BSC).
OUTCOMES
Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were objective response rate (ORR), adverse events, and health-related quality of life (HRQoL).
RESULTS
Twelve studies were included (n=5144): five RCTs and seven observational studies. Lenvatinib with everolimus significantly increased OS and PFS over everolimus (HR 0.61, 95% Credible Interval [95%CrI]: 0.36 to 0.96 and 0.47, 95%CrI: 0.26 to 0.77, respectively) as did cabozantinib (HR 0.66, 95%CrI: 0.53 to 0.82 and 0.51, 95%CrI: 0.41 to 0.63, respectively). This remained the case when observational evidence was included. Nivolumab also significantly improved OS versus everolimus (HR 0.74, 95%CrI: 0.57 to 0.93). OS sensitivity analysis, including observational studies, indicates everolimus being more effective than axitinib and sorafenib. However, inconsistency was identified in the OS sensitivity analysis. PFS sensitivity analysis suggests axitinib is more effective than everolimus, which may be more effective than sorafenib. The results for ORR supported the OS and PFS analyses. Nivolumab is associated with fewer grade 3 or grade 4 adverse events than lenvatinib with everolimus or cabozantinib. HRQoL could not be analysed due to differences in tools used.
CONCLUSIONS
Lenvatinib with everolimus, cabozantinib and nivolumab are effective in prolonging the survival for people with amRCC subsequent to VEGF-targeted treatment, but there is considerable uncertainty about how they compare to each other and how much better they are than axitinib and sorafenib.
PROSPERO REGISTRATION NUMBER
CRD42017071540.
Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Network Meta-Analysis; Observational Studies as Topic; Progression-Free Survival; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 30826762
DOI: 10.1136/bmjopen-2018-024691 -
Endocrine-related Cancer Sep 2018In the last few years, the therapeutic approach for neuroendocrine neoplasms (NENs) has changed dramatically following the approval of several novel targeted treatments....
In the last few years, the therapeutic approach for neuroendocrine neoplasms (NENs) has changed dramatically following the approval of several novel targeted treatments. The multitarget tyrosine kinase inhibitor (MTKI), sunitinib malate, has been approved by Regulatory Agencies in pancreatic NENs. The MTKI class, however, includes several other molecules (approved for other conditions), which are currently being studied in NENs. An in-depth review on the studies published on the MTKIs in neuroendocrine tumors such as axitinib, cabozantinib, famitinib, lenvatinib, nintedanib, pazopanib, sorafenib and sulfatinib was performed. Furthermore, we extensively searched on the Clinical Trial Registries databases worldwide, in order to collect information on the ongoing clinical trials related to this topic. Our systematic analysis on emerging MTKIs in the treatment of gastroenteropancreatic and lung NENs identifies and studies, which demonstrate anti-tumor activity of diverse MTKIs on neuroendocrine cells and tumors. Moreover, for the first time in the literature, we report an updated view concerning the upcoming clinical trials in this field: presently, phase I, II and III clinical trials are ongoing and will include, overall, a staggering 1667 patients. This fervid activity underlines the increasing interest of the scientific community in the use of emerging MTKIs in NEN treatment.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Neuroendocrine Tumors; Protein Kinase Inhibitors; Protein-Tyrosine Kinases
PubMed: 29769293
DOI: 10.1530/ERC-17-0531