The 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor–based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care

Background: Metastatic clear-cell renal cell carcinoma (RCC) is largely incurable, and its treatment remains challenging. Sunitinib, a tyrosine kinase inhibitor, is one of the current standard-of-care options for treatment-naïve patients with metastatic RCC. Despite the proven efficacy of sunitinib, prolonged treatment with some tyrosine kinase inhibitors (TKIs) has been associated with significant adverse events (AEs). Therefore, we aimed to calculate the exact prevalence of all sunitinib-related AEs in a pooled analysis from all available randomized controlled trials (RCTs). Methods: A comprehensive electronic database search was conducted for all RCTs comparing the clinical outcomes and adverse events of sunitinib versus all other available treatments for treatment-naïve advanced/metastatic clear-cell renal cell carcinoma. We then calculated the pooled prevalence of the most common reported side effects of sunitinib. All statistical analyses were performed using R Statistical Software v3.4.0 (R Foundation, Vienna, Austria). Results: We included 8 RCTs, with a total of 4,106 patients. The mean age was 62, with 66.44% males. Any grade AEs were reported in 72% of patients with the following frequencies: fatigue, 44%; diarrhea, 38%; nausea, 31%; hand-foot syndrome, 30%; hypertension, 27%; dysgeusia, 25%; hypothyroidism, 25%; cconstipation, 20%; stomatitis, 20%; inflammation of the mucosa, 18%; dyspepsia, 16%; vomiting, 14%; rash, 12%; asthenia, 11%; and epistaxis, 10%. Grade 3 (severe) AEs were reported in 52% of patients with the following frequencies: hypertension, 9%; fatigue, 8%; hand-foot syndrome, 5%; asthenia, 5%; diarrhea, 4%; and inflammation of the mucosa, 2%. Laboratory abnormalities were also reported as follows: increased AST, 7%; increased lipase, 6%; neutropenia, 6%; thrombocytopenia, 6%; hypophosphatemia, 5%; lymphocytopenia, 5%; anemia, 4%; and leukopenia, 3%. Conclusion: Despite sunitinib being one of the current standard treatments for patients with metastatic/advanced clear-cell RCC, its safety profile is concerning, with a high prevalence of reported dangerous side effects. These findings underscore the importance of the emergence of newer drugs and treatment plans for patients with metastatic RCC, not only to achieve similar or better clinical outcomes but also to decrease the burden of adverse events.

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Clinical activity of PD1/PDL1 inhibitors in metastatic non-clear cell renal cell carcinoma (nccRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.482 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 482-482 ◽

Cited By ~ 7

Author(s):

Raphael Brandao Moreira ◽

Rana R. McKay ◽

Wanling Xie ◽

Daniel Yick Chin Heng ◽

Guillermo de Velasco ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Clinical Activity ◽

Significant Activity ◽

Cell Renal Cell Carcinoma ◽

Treatment Naïve ◽

Retrospective Multicenter Study

482 Background: PD1/PDL1 inhibitors have shown significant activity in the treatment of patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC), but their activity in nccRCC is poorly characterized. Methods: We conducted a retrospective multicenter study of pts with metastatic nccRCC treated with PD1/PDL1 inhibitors. Baseline clinical parameters, overall response rate (ORR) by RECIST, time-to-treatment failure (TTF), and overall survival (OS) were summarized. Results: We identified 40 pts across 8 academic institutions. Fourteen (35%) had papillary histology, 10 (25%) chromophobe, 3 (8%) translocation, and 7 (18%) unclassified. Six (16%) had ccRCC with a sarcomatoid component > 30%. 20% had International Metastatic RCC Database Consortium (IMDC) favorable-risk disease, 60% intermediate, and 20% poor-risk. Ten (25%) were treatment-naïve and the majority received PD1/PDL1 monotherapy (n=30, 75%), while the remaining received a combination of PD1/PDL1 with anti-VEGF(R) or anti-CTLA4 therapy. ORR for the total cohort was 18% and 10% for PD1/PDL1 monotherapy pts (Table). With a median follow-up of 5.6 months, the overall median TTF was 4.7 months (2.9-15.9) and six-month OS was 81% (60-91%). Conclusions: PD1/PDL1 blockade resulted in some activity in pts with various nccRCC histologies. In the absence of available clinical trials, this data may support the use of PD1/PDL1 blocking agents in pts with nccRCC. [Table: see text]

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Efficacy and safety profile of sunitinib as a first line treatment for advanced/metastatic clear-cell renal cell carcinoma: Pooled analysis of randomized controlled trials.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16067 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16067-e16067

Author(s):

Tarek Haykal ◽

Varun Samji ◽

Yazan Zayed ◽

Ragheed Al-Dulaimi ◽

Inderdeep Gakhal ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Pooled Analysis ◽

Current Standard ◽

Cell Renal Cell Carcinoma ◽

Hand Foot Syndrome ◽

Treatment Naïve ◽

Grade 3

e16067 Background: Metastatic clear-cell renal cell carcinoma (RCC) is largely incurable, and its treatment remains challenging. Sunitinib, a tyrosine kinase inhibitor, is one of the current standard-of-care options for treatment-naïve patients with metastatic RCC. Despite the proven efficacy of Sunitinib, prolonged treatment with some tyrosine kinase inhibitors (TKIs) has been associated with significant adverse events (AEs). Therefore, we aimed to calculate the exact efficacy in addition to the prevalence of all AEs of Sunitinib in a pooled analysis from all available randomized controlled trials (RCTs). Methods: A comprehensive electronic database search was conducted for all RCTs comparing the clinical outcomes and adverse events of Sunitinib versus all other available treatments for treatment-naïve advanced/metastatic clear-cell renal cell carcinoma. We then calculated the pooled outcomes and prevalence of the most common reported side effects of Sunitinib. All statistical analyses were performed using R Statistical Software v3.4.0 (R Foundation, Vienna, Austria). Results: We included 8 RCTs, with a total of 4106 patients. The mean age was62, with 66.44% males.The efficacy of Sunitinib was reported as 3 main outcomes: Median progression free survival at 10.73 [7.76, 13.7] months, median overall survival at 23.28 [16.74, 29.81] months and the estimated objective response rate at 25[13, 37] %. Any grade AEs were reported in 72% of patients with the following frequencies: fatigue 44%, diarrhea 38%, nausea 31%, hand-foot syndrome 30%, hypertension 27%, dysgeusia 25%, hypothyroidism25%, constipation 20%, stomatitis 20%, inflammation of the mucosa 18%, dyspepsia 16%, vomiting 14%, rash 12%, asthenia 11%, and epistaxis10%.Grade 3&4 (severe) AEs were reported in 52% of patients with the following frequencies: hypertension 9%, fatigue 8%, hand-foot syndrome 5%, asthenia 5%, diarrhea 4%, and inflammation of the mucosa 2%. Conclusions: Despite Sunitinib being one of the current standard treatments for patients with metastatic/advanced clear-cell RCC, with well-described efficacy, its safety profile is still concerning with a significant prevalence of reported grade 3-4 AEs of 52% of the treated patients in the included RCTs. These findings underscore the importance of the emergence of newer drugs and treatment plans for patients with metastatic RCC, not only to achieve similar or better clinical outcomes but also to decrease the percentage of grade 3-4 AEs.

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Elective Cytoreductive Nephrectomy After Checkpoint Inhibitor Immunotherapy in Patients With Initially Unresectable Metastatic Clear Cell Renal Cell Carcinoma

Clinical Genitourinary Cancer ◽

10.1016/j.clgc.2020.04.002 ◽

2020 ◽

Vol 18 (5) ◽

pp. 361-366 ◽

Cited By ~ 2

Author(s):

Melissa A. Reimers ◽

Robert S. Figenshau ◽

Eric H. Kim ◽

Julie Tucker ◽

Nicole Kasten ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Checkpoint Inhibitor ◽

Cytoreductive Nephrectomy ◽

Cell Renal Cell Carcinoma

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Obesity induces limited changes to systemic and local immune profiles in treatment-naive human clear cell renal cell carcinoma

PLoS ONE ◽

10.1371/journal.pone.0233795 ◽

2020 ◽

Vol 15 (5) ◽

pp. e0233795 ◽

Cited By ~ 1

Author(s):

Justin T. Gibson ◽

Katlyn E. Norris ◽

Gal Wald ◽

Claire M. Buchta Rosean ◽

Lewis J. Thomas ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Treatment Naïve

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PD-L1 Expression and Treatment Implications in Metastatic Clear Cell Renal Cell Carcinoma: A Systematic Review

Kidney Cancer ◽

10.3233/kca-200108 ◽

2021 ◽

Vol 5 (1) ◽

pp. 31-46

Author(s):

Albert Jang ◽

Patrick L. Sweeney ◽

Pedro C. Barata ◽

Vadim S. Koshkin

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Cell Renal Cell Carcinoma ◽

Hand Search ◽

Full Text Review ◽

Predictive And Prognostic Biomarker

BACKGROUND: Over the past decade, immune checkpoint inhibitors (ICIs) have increasingly become the standard of care for various advanced malignancies, including metastatic clear cell renal cell carcinoma (mccRCC). Most ICIs currently used in clinical practice inhibit the interaction between the programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) complex. A deeper understanding of this interaction and PD-L1 expression in tumors has led to more effective therapies in the treatment of advanced cancers, but the debate regarding the utility of PD-L1 as a biomarker continues. OBJECTIVE: We aimed to systematically evaluate the role of PD-L1 in mccRCC in terms of expression and treatment implications. METHODS: Following PRISMA guidelines, we performed a systematic literature search using PubMed and Embase through August 31, 2020. Titles and abstracts were screened to identify articles for full-text review. A hand search was also performed using Google Scholar and the bibliography to relevant studies. RESULTS: A total of 26 articles were identified, and relevant data were extracted and organized. The available information regarding PD-L1 expression in mccRCC from both prospective clinical trials and retrospective studies were summarized. We discussed the utility of PD-L1 as a predictive and prognostic biomarker in mccRCC, its association with other potential biomarkers, and the pattern and level of expression of PD-L1 in primary versus metastatic tumors. CONCLUSIONS: Although significant progress has been made, much more remains to be learned regarding the differences between PD-L1+ and PD-L1- ccRCC tumors, in terms of both the underlying biology and clinical responses to immunotherapy and other agents.

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Efficacy of VEGFR-TKI plus immune checkpoint inhibitor (ICI) in metastatic renal cell carcinoma (mRCC) patients with favorable IMDC prognosis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.318 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 318-318

Author(s):

Chiara Ciccarese ◽

Roberto Iacovelli ◽

Emilio Bria ◽

Giovanni Schinzari ◽

Ernesto Rossi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Immune Checkpoint ◽

Renal Cell ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Meta Analysis ◽

Favorable Prognosis ◽

Treatment Naïve

318 Background: Combinations of a PD-1/PD-L1 immune checkpoint inhibitor (ICI) with a VEGFR-TKI as front-line/treatment-naïve therapy significantly improve the outcome of metastatic renal cell carcinoma (mRCC) patients. The benefit of these combinations is well evident in IMDC intermediate- and poor-risk population, while it is unclear in the subgroup of mRCC patients with favorable prognosis. We performed a meta-analysis with the aim to evaluate whether the addition of ICIs to VEGFR-TKIs is able to improve the outcome compared to VEGFR-TKIs alone in mRCC patients with favorable IMDC prognosis. Methods: This meta-analysis searched MEDLINE/PubMed, the Cochrane Library and ASCO Meeting abstracts for phase II or III randomized clinical trials (RCTs) testing the combination of VEGFR-TKI+ICI in mRCC. Data extraction was conducted according to the PRISMA statement. The hazard ratios (HRs) for PFS and OS with the relative 95% CIs were extracted from each study. Summary HRs was calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies. Results: Three RCTs were selected for the final analysis, with a total of 605 patients (306 treated with VEGFR-TKI+ICI combinations and 299 who received sunitinib in the control arms). The combination of VEGFR-TKI+ICI improved PFS compared to sunitinib, with a 30% reduction of the risk of progression (fixed-effect, HR=0.70; p = 0.003). However, VEGFR-TKI+ICI combinations did not significantly prolong OS (fixed-effect; HR = 0.94; 95% CI 0.62–1.43; p = 0.77). Conclusions: Our analysis demonstrates a PFS benefit without an OS advantage for VEGFR-TKI+ICI combinations as first-line therapy for mRCC patients with favourable prognosis according to IMDC. Longer follow-up is required to definitely confirm the best therapy for treatment-naïve mRCC patients with favorable prognosis. [Table: see text]

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Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma

Journal of Kidney Cancer and VHL ◽

10.15586/jkcvhl.v7i4.156 ◽

2020 ◽

Vol 7 (4) ◽

pp. 17-26

Author(s):

Alexander T. Toth ◽

Daniel Cho

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Small Subset ◽

Front Line ◽

Cell Renal Cell Carcinoma ◽

Clear Cell Rcc

Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.

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