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Hematology/oncology and Stem Cell... Apr 2023Renal cell carcinoma (RCC) is the most common kidney cancer in adults (approximately 90%), and clear cell RCC (ccRCC) is the most frequent histologic subtype... (Review)
Review
Renal cell carcinoma (RCC) is the most common kidney cancer in adults (approximately 90%), and clear cell RCC (ccRCC) is the most frequent histologic subtype (approximately 75%). We reviewed the safety and efficacy of checkpoint inhibitors (CPIs) in ccRCC, identifying 5927 articles in PubMed, Embase, Cochrane, and Web of Science. Ten randomized control (N = 7765) and 10 non-randomized (N = 572) studies were included. Overall, 4819 patients treated with CPI combinations were compared with everolimus, sunitinib, or placebo. Overall response rates (ORR) were 9-25% with nivolumab (niv), 42% with niv + ipilimumab (ipi), 55.7% with niv + cabozantinib, 56% with niv + tivozanib vs. 5% with everolimus. ORR was 51.5-58% with avelumab + axitinib vs. 25.5% with sunitinib. ORR was 59.3-73% with pembrolizumab + tyrosine kinase inhibitor vs. 25.7% with sunitinib. ORR was 32-36% with atezolizumab + bevacizumab vs. 29-33% with sunitinib. In patients with PD-L1+ve and -ve ccRCC, niv, atezolizumab, ipi, and pembrolizumab were safe and effective alone and when combined with cabozantinib, tivozanib, axitinib, levantinib, and pegilodecakin. Atezolizumab + bevacizumab was safe and effective in ccRCC with high PD-L1 expression. Pembrolizumab was safe and effective in preventing recurrence in ccRCC patients with nephrectomy. Additional randomized, double-blind, multicenter clinical trials are needed to confirm these results.
Topics: Adult; Humans; Carcinoma, Renal Cell; Sunitinib; Axitinib; Everolimus; B7-H1 Antigen; Bevacizumab; Kidney Neoplasms; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 37023219
DOI: 10.56875/2589-0646.1027 -
Frontiers in Oncology 2023This Bayesian network meta-regression analysis provides a head-to-head comparison of first-line therapeutic immune checkpoint inhibitors (ICI) and tyrosine kinase...
BACKGROUND
This Bayesian network meta-regression analysis provides a head-to-head comparison of first-line therapeutic immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) combinations for metastatic renal cell carcinoma (mRCC) using median follow-up time as covariate.
METHODS
We searched Six databases for a comprehensive analysis of randomised clinical trials (RCTs). Comparing progression free survival (PFS) and overall survival (OS) of different interventions at the same time node by Bayesian network meta-analysis. Bayesian network meta-regression analysis was performed on objective response rate (ORR), adverse events (AEs) (grade ≥ 3) and the hazard ratios (HR) associated with PFS and OS, with the median follow-up time as the covariate.
RESULTS
Eventually a total of 22 RCTs reporting 11,090 patients with 19 interventions. Lenvatinib plus Pembrolizumab (LenPem) shows dominance of PFS, and Pembrolizumab plus Axitinib (PemAxi) shows superiority in OS at each time point. After meta-regression analysis, for HRs of PFS, LenPem shows advantages; for HRs of OS, PemAxi shows superiority; For ORR, LenPem provides better results. For AEs (grade ≥ 3), Atezolizumab plus Bevacizumab (AtezoBev) is better.
CONCLUSION
Considering the lower toxicity and the higher quality of life, PemAxi should be recommended as the optimal therapy in treating mRCC.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD4202236775.
PubMed: 36910649
DOI: 10.3389/fonc.2023.1072634 -
Cancer Medicine Mar 2023For patients with advanced or metastatic renal cell carcinoma (RCC), the dose of targeted agents was recommended in combination with immune checkpoint inhibitors. We... (Meta-Analysis)
Meta-Analysis
Optimizing targeted drug selection in combination therapy for patients with advanced or metastatic renal cell carcinoma: A systematic review and network meta-analysis of safety.
OBJECTIVE
For patients with advanced or metastatic renal cell carcinoma (RCC), the dose of targeted agents was recommended in combination with immune checkpoint inhibitors. We performed a network meta-analysis to describe a categorized safety ranking profile and assess the adaptability of the combination options of targeted agents.
METHODS
The targeted agents refer to vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) and mammalian target of rapamycin (mTOR) inhibitors. Randomized controlled trials comparing these drugs were enrolled in a Bayesian model network meta-analysis.
RESULTS
Nineteen clinical trials with 11 treatments and 10,615 patients were included. For grade ≥ 3 adverse events (AEs), compared with placebo, lenvatinib plus everolimus showed worse safety than all other treatments except for lenvatinib (placebo vs. OR 0.23, 95% CI 0.07-0.78). Everolimus was generally the safest agent (OR 1.23, 95% CI 0.50-3.14). Sorafenib arose the least renal AEs (placebo vs. OR 0.85, 95% CI 0.06-11.64), whereas lenvatinib plus everolimus had the highest risk of renal toxicity (placebo vs. 0.17 95% CI 0.01-1.02). For gastrointestinal symptoms, everolimus was related to much lower toxicity than other agents. In the respiratory safety analysis, tivozanib (placebo vs. OR 0.15, 95% CI 0.07-0.31) and axitinib (OR 5.43, 95% CI 3.26-9.22) were the riskiest agents. In terms of hepatobiliary (placebo vs. OR 0.44, 95% CI 0.09-2.10) and hemotoxicity (placebo vs. OR 1.03, 95% CI 0.14-7.68) related AEs, lenvatinib was found to be the safest treatment compared to placebo.
CONCLUSIONS
Everolimus, with the best safety of grade ≥ 3, gastrointestinal, and respiratory AEs, was more likely to be considered for combination therapies. Lenvatinib appears to be the safest for blood/lymphatic and hepatobiliary AEs. For patients with renal disorders, sorafenib arises the least renal toxicity AEs. This study will guide treatment options and optimize the trial design for advanced or metastatic RCC.
Topics: Humans; Carcinoma, Renal Cell; Everolimus; Sorafenib; Kidney Neoplasms; Vascular Endothelial Growth Factor A; Network Meta-Analysis; Bayes Theorem; Phenylurea Compounds; Antineoplastic Agents
PubMed: 36457303
DOI: 10.1002/cam4.5504 -
Seminars in Oncology Oct 2022Multiple systemic immune-oncology (IO) combination therapies have demonstrated overall survival (OS) benefits in metastatic renal clear cell carcinoma (mRCC). However,... (Review)
Review
Multiple systemic immune-oncology (IO) combination therapies have demonstrated overall survival (OS) benefits in metastatic renal clear cell carcinoma (mRCC). However, the magnitude of benefits over time has not been compared in a structured fashion. To assess OS and progression free survival (PFS) efficacy as reflected by hazard ratios [HR]) according to the duration of follow-up over time for each of four IO combination therapies. A systematic PubMed (MEDLINE) literature review was performed (January, 1, 2016 to February, 20, 2022). Only phase III randomized clinical trials with proven OS benefit relative to sunitinib were included. These search criteria yielded four eligible RCTs: CheckMate 214 (nivolumab plus ipilimumab), Keynote 426 (pembrolizumab plus axitinib), CheckMate 9ER (nivolumab plus cabozantinib), CLEAR (lenvatinib plus pembrolizumab). OS and PFS HRs were tabulated for all four studies including all reported timepoints. Median follow-up ranged from 25-68 months for CheckMate 214 (5 timepoints), 13-43 months for Keynote 426 (3 timepoints), 18-33 months for CheckMate 9ER (3 timepoints) and 27-34 months for CLEAR (2 timepoints). Respective OS and PFS HRs were 0.68-0.72 and 0.98-0.86, 0.53-0.73 and 0.69-0.68, 0.60-0.70 and 0.51-0.56, 0.66-0.72 and 0.39-0.47 for CheckMate 214, Keynote 426, CheckMate 9ER and CLEAR. Regarding OS HRs virtually no change was recorded over time for CheckMate 214, but a decrease in magnitude occurred in the three IO-TKI remaining studies. Regarding PFS HRs, no benefit was recorded for CheckMate 214. Statistically significant benefit was recorded in the remaining IO-TKI studies. However, it also decreased with longer follow-up. It remains to be seen, whether further 'slippage' of efficacy will persist as the data matures further for all IO-TKI combinations.
Topics: Humans; Antineoplastic Agents; Carcinoma, Renal Cell; Kidney Neoplasms; Nivolumab; Sunitinib
PubMed: 36333148
DOI: 10.1053/j.seminoncol.2022.10.001 -
Current Pharmaceutical Design 2022Immune checkpoint inhibitors (ICIs), specifically programmed cell death receptor- 1/ligand 1 (PD-1/L1) inhibitors, have shown potential pharmacological efficacy in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Immune checkpoint inhibitors (ICIs), specifically programmed cell death receptor- 1/ligand 1 (PD-1/L1) inhibitors, have shown potential pharmacological efficacy in several cancers. Nonetheless, data pertinent to their therapeutic efficacy in alveolar soft-part sarcoma (ASPS) are limited.
OBJECTIVE
The retrospective aspects of ICIs (anti-PD1/PD-L1 blockers) to target ASPS are comparatively analyzed for clinical outcomes with other targeted immunotherapy modalities.
METHODS
We have conducted a systematic review without statistical analysis or comprehensive meta-analysis by collecting the articles published between 1952 and Sep 10th, 2020, by searching the following words: alveolar soft part sarcoma and immunotherapy including immune checkpoint, immune checkpoint inhibitors, and PD-1, PD-L1. We performed a pooled analysis of case reports, conferences, clinical trials, and other research reports pertinent to the efficacy of a PD-1 or PD-L1 antagonist in patients diagnosed with metastatic ASPS.
RESULTS
The effective studies include 10 case reports, 2 conference reports, 5 clinical trials, and 2 additional research reports. A total of 110 patients were reported to be enrolled in the pooled analysis; among them, 87 (78.38%) received a PD-1/PD-L1 antagonist. For patients who received anti-PD-1/PD-L1as monotherapy, their clinical response rates (CRR) were 63.22% whereas those who received targeted therapy and immunotherapy had a CRR of 78.95% (15/19). In the patients treated with double immunotherapy, their CRR was 100% (4/4). Tumor mutational burden and mismatch repair status have significant implications for predicting the ASPS prognosis.
CONCLUSION
Alveolar soft-part sarcoma patients with distant metastases can exhibit better clinical outcomes with immunotherapy, particularly toripalimab, atezolizumab, and axitinib combinatorial regimen with pembrolizumab. In addition, this review describes the therapeutic implications to guide personalized medicine depending on the expression patterns of PD-1/PD-L1 during the immunotherapy with ASPS.
Topics: Humans; B7-H1 Antigen; Sarcoma, Alveolar Soft Part; Precision Medicine; Immune Checkpoint Inhibitors; Retrospective Studies; Immunotherapy
PubMed: 36154597
DOI: 10.2174/1381612828666220921151750 -
Therapeutic Advances in Medical Oncology 2022Renal cell carcinoma (RCC) is a common malignancy with approximately 30% of cases diagnosed at the advanced or metastatic stage. While single-agent vascular endothelial... (Review)
Review
BACKGROUND
Renal cell carcinoma (RCC) is a common malignancy with approximately 30% of cases diagnosed at the advanced or metastatic stage. While single-agent vascular endothelial growth factor-targeted therapy has been a mainstay of treatment, data from multiple phase III trials assessing first-line immune checkpoint inhibitor (ICI) combinations have demonstrated a significant survival benefit.
METHODS
A systematic search of the published and presented literature was performed to identify phase III trials assessing ICI combination regimens in RCC using search terms 'immune checkpoint inhibitors' AND 'renal cell carcinoma,' AND 'advanced'.
RESULTS
Six phase III trials showed significant benefits for ICI combinations compared with sunitinib. Nivolumab plus ipilimumab significantly improved overall survival [OS; median, 47.0 26.6 months, hazard ratio (HR) = 0.68, 95% confidence interval (CI) = 0.58-0.81, < 0.0001) and progression-free survival (PFS; median 11.6 8.3 months, HR = 0.73, 95% CI = 0.61-0.87, = 0.0004) in International Metastatic renal cell carcinoma Database Consortium intermediate and poor-risk patients. OS was also significantly improved for ICI plus tyrosine kinase inhibitor combinations regardless of risk, including pembrolizumab plus either axitinib (HR = 0.73, 95% CI = 0.60-0.88, < 0.001) or lenvatinib (HR = 0.66, 95% CI = 0.49-0.88, = 0.005) and nivolumab plus cabozantinib (HR = 0.66, 95% CI = 0.50-0.87, = 0.003). No new safety signals were identified.
CONCLUSIONS
Phase III first-line trials of ICI combinations showed survival benefits compared with a control arm of sunitinib. Global access to these combinations should be made available to patients with advanced RCC.
PubMed: 35782749
DOI: 10.1177/17588359221108685 -
World Journal of Urology Oct 2022The treatment landscape in metastatic renal cell carcinoma (mRCC) has evolved dramatically in recent years. Within the German guideline committee for RCC we evaluated...
PURPOSE
The treatment landscape in metastatic renal cell carcinoma (mRCC) has evolved dramatically in recent years. Within the German guideline committee for RCC we evaluated current medical treatments and gave recommendations.
METHODS
A systematic review of published evidence for medical treatment of mRCC was performed (July 2016-August 2019) to cover the duration from last guideline update in 2016. Evidence was graded according to SIGN ( http://www.sign.ac.uk/pdf/sign50.pdf ). Recommendations were made on the basis of a nominal group work with consensus approach and included patient advocates and shareholder of the German RCC treatment landscape. Each recommendation was graded according to its strength as strong recommendation (A) or recommendation (B). Expert statements were given, where appropriate.
RESULTS
Strong first-line recommendations (IA) exist for axitinib + pembrolizumab (all risk categories) and ipilimumab + nivolumab (intermediate or poor risk only). Axitinib + avelumab is a recommended first-line treatment across patients with any risk category (IB). In patients who are not candidates for immune check point inhibitor (ICI) combinations, targeted agents should be offered as an alternative treatment. Subsequent treatment after ICI-based combinations remain ill-defined and no standard of care can be formulated.
CONCLUSION
ICI-based combinations are the first-line standard of care and should be considered accordingly. There is an unmet medical need for pivotal studies that define novel standards in patients with failure of ICI-based combinations.
Topics: Axitinib; Carcinoma, Renal Cell; Humans; Ipilimumab; Kidney Neoplasms; Nivolumab
PubMed: 35562599
DOI: 10.1007/s00345-022-04015-1 -
Critical Reviews in Oncology/hematology Jul 2022To assess comparative effectiveness of adjuvant therapies for renal cell carcinoma and quantify the absolute benefit of adjuvant treatments by clinicopathological risk... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To assess comparative effectiveness of adjuvant therapies for renal cell carcinoma and quantify the absolute benefit of adjuvant treatments by clinicopathological risk groups.
METHODS
This 'living' review was conducted using Living Interactive Evidence (LIvE) synthesis framework.
RESULTS
The 'living' results are available on an interactive website. This network meta-analysis, including six RCTs with 7525 participants, showed that pembrolizumab (rank 1) significantly improved disease-free survival and overall survival compared with sunitinib but not when compared to pazopanib, and axitinib. The risk of treatment-related grade 3 or higher adverse events was increased with pembrolizumab as compared to placebo and axitinib but not when compared to sunitinib. The absolute benefit of adjuvant pembrolizumab increases substantially with larger tumor size, nodal positivity and higher Leibovich scores.
CONCLUSION
Current evidence suggests that pembrolizumab delays disease progression compared to sunitinib. A risk-adapted strategy should be used in patients undergoing consideration for treatment with adjuvant pembrolizumab.
Topics: Axitinib; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Network Meta-Analysis; Sunitinib
PubMed: 35537621
DOI: 10.1016/j.critrevonc.2022.103706 -
Immunotherapy Apr 2022This paper presents the reported dermatological adverse events (AEs) associated with approved combinations of immunotherapy with drugs of the same class, or in... (Review)
Review
This paper presents the reported dermatological adverse events (AEs) associated with approved combinations of immunotherapy with drugs of the same class, or in combination with targeted therapy or chemotherapy. PubMed was used as an electronic database, and a total of 29 articles were reviewed which reported dermatological AEs following combination therapies with nivolumab, ipilimumab, axitinib, pembrolizumab, lenvatinib, avelumab, atezolizumab, carboplatin, etoposide, paclitaxel, bevacizumab, pemetrexed, cisplatin and durvalumab. The dermatological AEs reported were mutually inclusive and the highest incidence of specific AEs was seen in the following combinations: rash in the nivolumab/ipilimumab and lenvatinib/pembrolizumab combinations, pruritus in the atezolizumab/nab-paclitaxel combination, dry skin and palmar-plantar erythrodysesthesia in the axitinib/pembrolizumab combination, and alopecia and severe skin reactions in the pembrolizumab/carboplatin/paclitaxel combination. Knowledge of such side effects is of benefit when choosing an optimal treatment regimen and should be integrated into the monitoring and follow-up phases of treatment.
Topics: Axitinib; Carboplatin; Humans; Immune Checkpoint Inhibitors; Ipilimumab; Nivolumab; Paclitaxel
PubMed: 35232283
DOI: 10.2217/imt-2021-0244 -
European Urology Open Science Mar 2022Considerable advances have been made in the first-line treatment of metastatic renal cell carcinoma (mRCC), with immunotherapy-based combinations including... (Review)
Review
CONTEXT
Considerable advances have been made in the first-line treatment of metastatic renal cell carcinoma (mRCC), with immunotherapy-based combinations including immunotherapy-tyrosine kinase inhibitors (IO-TKIs) and dual immunotherapy (IO-IO) favored. A lack of head-to-head clinical trials comparing these treatments means that there is uncertainty regarding their use in clinical practice.
OBJECTIVE
To compare and rank the efficacy and safety of first-line systemic treatments for mRCC with a focus on IO-based combinations.
EVIDENCE ACQUISITION
MEDLINE (Ovid), EMBASE, Cochrane Library, Web of Science, and abstracts of recent major scientific meetings were searched to identify the most up-to-date phase 3 randomized controlled trials (RCTs) of first-line IO-based combinations for mRCC up to June 2021. A systematic review and network meta-analysis were completed using the Bayesian framework. Primary endpoints included overall survival (OS) and progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), complete response (CR), grade 3-4 treatment-related adverse events (TRAEs), treatment-related drug discontinuation (TRDD), and health-related quality of life (HRQoL). The analysis was performed for the intention-to-treat (ITT) population as well as by clinical risk group.
EVIDENCE SYNTHESIS
A total of six phase 3 RCTs were included involving a total of 5121 patients. Nivolumab plus cabozantinib (NIVO-CABO) had the highest likelihood of an OS benefit in the ITT population (surface under the cumulative ranking curve 82%). Avelumab plus axitinib (AVEL-AXI) had the highest likelihood of an OS benefit for patients with favorable risk (65%). Pembrolizumab plus AXI (PEMBRO-AXI) had the highest likelihood of an OS benefit for patients with intermediate risk (78%). PEMBRO plus lenvatinib (PEMBRO-LENV) had the highest likelihood of an OS benefit for patients with poor risk (89%). PEMBRO-LENV was associated with a superior PFS benefit across all risk groups (89-98%). Maximal ORR was achieved with PEMBRO-LENV (97%). The highest likelihood for CR was attained with NIVO plus ipilimumab (NIVO-IPI; 85%) and PEMBRO-LENV (83%). The highest grade 3-4 TRAE rate occurred with PEMBRO-LENV (95%) and NIVO-CABO (83%), but the latter was associated with the lowest TRDD rate (2%). By contrast, NIVO-IPI had the lowest grade 3-4 TRAE rate (6%) and the highest likelihood of TRDD (100%). HRQoL consistently favored NIVO-CABO (66-75%), PEMBRO-LENV (44-85%), and NIVO-IPI (65-93%) in comparison to the other treatments.
CONCLUSIONS
IO-TKI drug combinations are associated with consistent improvements in clinically relevant outcomes for all mRCC risk groups. This benefit may be at the cost of higher TRAE rates; however, lower TRDD rates suggest a manageable side-effect profile. Longer follow-up is required to determine if the benefits of IO-TKIs will be sustained and if they should be favored in the first-line treatment of mRCC.
PATIENT SUMMARY
Combination treatments based on immunotherapy agents continue to show meaningful benefits in the first-line treatment of metastatic kidney cancer. Our review and network meta-analysis shows that immunotherapy combined with another class of agents called tyrosine kinase inhibitors is promising. However, longer follow-up is needed for this treatment strategy to clarify if the benefits are long-lasting.
PubMed: 35128482
DOI: 10.1016/j.euros.2021.12.007