Editorial Open Access
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Jan 24, 2022; 13(1): 1-8
Published online Jan 24, 2022. doi: 10.5306/wjco.v13.i1.1
Update on the treatment of metastatic renal cell carcinoma
Rafael Antonio Medina López, Ines Rivero Belenchon, Javier Mazuecos-Quirós, Carmen Belén Congregado-Ruíz, Felipe Couñago
Rafael Antonio Medina López, Javier Mazuecos-Quirós, Carmen Belén Congregado-Ruíz, Department of Urology and Nephrology, Virgen del Rocío University Hospital, Biomedical Institute of Seville/CSIC/University of Seville, Sevilla 41013, Spain
Ines Rivero Belenchon, Department of Urology and Nephrology, Virgen del Rocío University Hospital, Seville 41005, Spain
Felipe Couñago, Radiation Oncology, Hospital Universitario Quirónsalud, Hospital La Luz, Universidad Europea de Madrid, Madrid 28223, Spain
ORCID number: Rafael Antonio Medina López (0000-0002-4514-4329); Ines Rivero Belenchon (000-0002-6217-4618); Javier Mazuecos-Quirós (0000-0001-5338-7526); Carmen Belén Congregado-Ruíz (0000-0001-8801-0614); Felipe Couñago (0000-0001-7233-0234).
Author contributions: Medina López RA, Rivero Belenchon I, Mazuecos-Quirós J, Congregado-Ruíz CB, and Couñago F contributed equally to the manuscript; all authors have read and approved the final manuscript.
Conflict-of-interest statement: Dr. Rivero Belenchon has nothing to disclose.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ines Rivero Belenchon, MD, Staff Physician, Department of Urology and Nephrology, Virgen del Rocío University Hospital, Manuel Siurot s/n, Seville 41005, Spain. ines.rivero.belenchon@gmail.com
Received: December 25, 2020
Peer-review started: December 25, 2020
First decision: September 29, 2021
Revised: October 5, 2021
Accepted: January 10, 2022
Article in press: January 10, 2022
Published online: January 24, 2022


Metastatic renal cell cancer (mRCC) management has undergone a paradigm shift in recent decades. The first revolution came with the emergence of vascular endothelial growth factor inhibitors; there was a second wave with the unprecedented success of checkpoint inhibitors, and then the latest approach, which is becoming the new care standard in mRCC, of combining these two strategies in different ways. Updated results of Checkmate-214 after 42 mo of follow-up were consistent with previously published results showing the superiority of nivolumab/ipilimumab over sunitinib in progression free survival (PFS), overall survival (OS), and objective response rate (ORR) in intermediate and high-risk patients. However, several studies presented at the American Society of Clinical Oncology 2020 suggested that the best place, and so far, the only one for nivolumab/ipilimumab is the frontline setting. The update on Keynote-426 after 23 mo of follow-up showed no superiority of pembroli-zumab/axitinib over sunitinib in favorable-risk mRCC, suggesting that it should no longer be the first line of choice in low-risk patients. Finally, the phase III Checkmate 9ER trial results revealed the superiority of nivolumab/cabozantinib vs sunitinib in PFS, OS, and ORR, providing a new first-line option among all International Metastatic RCC Database Consortium risk patients. Some phase II clinical trials also presented this year showed promising results with new combination therapies such as nivolumab/sitravatinib, cabozantinib/atezolizumab, and lenvatinib/pembrolizumab, providing promising grounds upon which to start phase III studies. In addition, other works are using novel therapeutic agents with different mechanisms of action, including telaglenastat (a glutaminase inhibitor), entinostat [an inhibitor of histone deacetylases (HDACs)], and olaparib and talazoparib, poly(ADP-ribose) polymerase inhibitors widely used in other tumors. However, some questions regarding mRCC management still need to be addressed, such as head-to-head comparisons between the current options, treatment sequencing, non-clear cell mRCC, and the role of biomarkers to ascertain the best treatment choice.

Key Words: Metastatic renal cell carcinoma, Systemic treatment, Immune checkpoint inhibitors, Antiangiogenic, Update, Biomarkers

Core Tip: Kidney cancer therapeutics is a fast-changing field, and the outcome of metastatic renal cell carcinoma (mRCC) has thus improved considerably in recent years with the introduction of different combinations of immune checkpoint and vascular endothelial growth factors inhibitors. State-of-the-art systemic therapy regimens must be addressed to be in a position to offer patients the best options. The aim of this editorial is to provide an update and insight on future directions on mRCC management.


Historically, the therapeutic strategy for metastatic renal cell carcinoma (mRCC) relied on cytokines. These drugs had a moderate response rate and were associated with substantial side effects[1].

Since then, the treatment of mRCC has improved considerably with the introduction and regulatory approval of agents that block vascular endothelial growth factor (VEGF) or mechanistic target of rapamycin (mTOR) pathways and significantly improve objective response rates (ORR) and/or median progression free survival (PFS) compared to previous treatment approaches. Since 2005, the United States Food and Drug Administration and the European Medicines Agency have approved VEGF receptors; tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib; the anti-VEGF antibody bevacizumab (in combination with interferon); and mTOR inhibitors everolimus and temsirolimus to treat mRCC[2].

Despite the notable efficacy of these targeted therapies, which changed the treatment landscape, tumor resistance to TKI made it necessary to investigate different treatment mechanisms. In this context, stimulating the immune system through drugs targeting the so-called checkpoint pathways through the blockage of programmed cell death 1 (PD1), programmed cell death ligand 1 (PDL1), and the cytotoxic T-lymphocyte antigen 4 have been tested in RCC with successful results. As a result, nivolumab was the first immune checkpoint inhibitor (ICI) approved based on data from the phase III Checkmate 025 study of nivolumab vs everolimus in patients who had received prior antiangiogenic therapy for mRCC[3].

Combination therapies, based on the rationale that using drugs that work by different mechanisms may decrease the likelihood of cancer resistance, emerged in an effort to improve outcomes. The treatment landscape for first-line therapy has thus changed dramatically in recent years with the publication of a phase III clinical trial (CT) that showed three combinations’ advantage over sunitinib: (1) Nivolumab/ipili-mumab (Checkmate-214), which proved a higher overall survival (OS), PFS, and ORR in intermediate and high-risk patients[4,5]; (2) Avelumab/axitinib, which showed longer PFS (JAVELIN Renal 101)[6]; and (3) Pembrolizumab/axitinib, which proved higher in OS, PFS, and ORR among all International Metastatic RCC Database Consortium (IMDC) risk patients (KEYNOTE-426)[7]. This work has led to the current standard practice recommendations set in the European Association of Urology[8], ESMO[9], and National Comprehensive Cancer Network guidelines[10].

American Society of Clinical Oncology genitourinary 2020

Updated results of Checkmate 214 after 42 mo of follow-up have been presented[11]. These results were consistent with the superior performance of nivolumab/ipili-mumab vs sunitinib in intermediate and poor-risk patients. An OS of 52% with nivolumab/ipilimumab vs 39% with sunitinib [hazard ratio (HR): 0.66; 95% confidence interval (CI): 0.55-0.80]; ORR of 42% with nivolumab/ipilimumab vs 26% with sunitinib (P = 0.0001); and complete response (CR) of 10% with nivolumab/ipili-mumab vs 1% with sunitinib have been observed (Table 1).

Table 1 Results from clinical trials.
Checkmate 214
Nivolumab/ipilimumab (n = 425)
Sunitinib (n = 422)
Minimum follow-up42 mo42 mo
OS IP52%; 47 (35.6-NE) mo39% 26.6 (22.1-33.5) mo
ORR IP42% (37-47)26% (22-31)
CR IP10%1%
Checkmate 025Nivolumab (n = 410)Everolimus (n = 411)
Minimum follow-up5 yr5 yr
OS26% (22.2-29.8)18% (17.6-22.1)
ORR23% (19-27)4% (2-7)
mDOR18.2 (12.9-25.8) mo14 (8.3-19.2) mo
Keynote 426Pembrolizumab/axitinib (n = 432)Sunitinib (n = 429)
Minimum follow-up23 mo23 mo
HR: 0.68; 95%CI: 0.55-0.85; P < 0.001
PFS favorable risk20.8 (15.4-28.8) mo18 (12.5-20.8) mo
Checkmate 9ERNivolumab/cabozantinib (n = 323)Sunitinib (n = 328)
Minimum follow-up10.6 mo10.6 mo
PFS16.6 (12.5-24.9)8.3 (7-9.7)
OSNR (NE)NR (22.6-NE)
ORR55.7% (50.1-61.1)27% (22.4-32.3)
Adverse events grades 3-560.6%50.9%

The final analysis of Checkmate 025 after 5 years of follow-up was also presented[12]. An OS of 26% with nivolumab vs 18% with everolimus; ORR of 23% with nivolumab vs 4% with everolimus; and median duration of objective response (mDOR) of 18.2 mo with nivolumab vs 14 mo with everolimus were presented (Table 1).

The first phase II in-human study of the hypoxia-inducible factor (HIF)-2α inhibitor Midkine (MK)-6482 was also presented[13]. This is an oral agent with antiangiogenic activity. Preliminary results on 55 patients treated in the second, third, and fourth line settings revealed a disease control of 80%, ORR of 24%, and tumor reduction of 67%. The median PFS was 11 mo. After 1 year, 30% continued under treatment, which was well tolerated. These results provided promising grounds upon which to start the phase III trial (MK-6482 005 against everolimus).

Finally, another interesting approach was the combination of nivolumab/sitra-vatinib, a novel TKI that modulates the tumor microenvironment in order to render it more responsive to immunotherapy[14]. Administration in the first, second, and third line settings (n = 40) demonstrated a tumor reduction of 92%, disease control of 90%, ORR of 39%, and PFS of 10.5 mo. Again, this is promising data for the next phase III trial.

American Society of Clinical Oncology 2020

Updated data for Keynote-426 after a minimum follow-up of 23 mo were presented[15]. OS was 74% with pembrolizumab/axitinib vs 66% with sunitinib. Patients with favorable-risk disease no longer presented a significant difference in OS or PFS, with a median PFS of 20.8 mo with pembrolizumab/axitinib and 18 mo with sunitinib. However, patients with IMDC intermediate or poor-risk disease showed significant differences in OS and PFS with an HR of 0.63 for OS and 0.69 for PFS. The CR rate increased from 6% at 12 mo of follow-up[16] to 9% after 23 mo. A new post hoc analysis of the relationship between depth of response and OS showed that in patients receiving pembrolizumab/axitinib, deeper responses, as measured by percent shrinkage of target lesions, correlated to better OS (See Table 1).

Two studies, the OMNIVORE study[17] (n = 83) and the HCRN GU16-260 study[18] (n = 123), were presented to investigate whether treating mRCC patients with nivolumab initially and later adding ipilimumab in patients with either stable or progressive disease would be as effective as an upfront combination therapy. The results showed only 4% and 11% additional partial responses, respectively, suggesting that delaying treatment with ipilimumab decreased the overall efficacy of upfront combination treatment.

The results of the phase II FRACTION-RCC CT[19] to assess nivolumab/ipili-mumab after progression to an ICI (PD-1) were also presented (n = 46). The ORR was 15.2%, which suggests that this combination should ideally be administered as first-line therapy.

However, one study showed the results of a phase II bevacizumab/erlotinib study in 83 patients, of which 50% had hereditary leiomyomatosis (HLRCC) and 50% had sporadic (PSRCC) advanced papillary RCC[20]. This combination proved to be very active in papillary RCC, especially in HLRCC, with an ORR of 64%, tumor shrinkage of 95%, and PFS of 21.1 mo.

Finally, a phase III study (SAVOIR) with savolitinib vs sunitinib for papillary RCC with abnormal MET gene was presented (n = 60)[21]. The results showed a PFS of 7.0 and 5.6 mo in the savolitinib and sunitinib groups, respectively, with better tolerability in the savolitinib group. Initial data look promising, despite the small cohort study.

ESMO 2020

The results of Checkmate 9ER[22], a phase III study of nivolumab/cabozantinib vs sunitinib in previously untreated mRCC with a clear cell component, were presented. Patients were stratified by IMDC, PD-L1, and region (n = 651). At a median follow-up of 18.1 mo, nivolumab/cabozantinib led to higher rates of PFS, OS, and ORR vs sunitinib (Table 1), with consistent improvements observed across all pre-specified subgroups according to IMDC risk and PD-L1 expression. The combination was generally well tolerated, and patients had significantly better quality of life than those treated with sunitinib. These results support nivolumab/cabozantinib as a potential first-line option for patients with advanced renal cell carcinoma in every IMDC risk (Table 1).

The results of COSMIC 021, a phase II study that tested an escalation dose of cabozantinib from 40 mg to 60 mg with atezolizumab in first-line treatment, was also reported[23]. Data of 70 mRCC patients were presented, showing encouraging clinical efficacy with reasonable safety profiles. The findings suggested that PD-L1+ tumors with high CD8+ T cell infiltrates were more likely to respond to therapy. There is a phase III study (CONTACT-03) currently underway to confirm this combination’s efficacy.

A phase II trial of lenvatinib plus pembrolizumab in 104 mRCC patients that were not responding to treatment with immunotherapy was also presented[24]. The ORR was 51%, PFS 11.7 mo, and mDOR 12.2 mo. These results are currently being studied in the phase III CLEAR trial [(lenvatinib + pembrolizumab) vs (lenvatinib + everolimus) vs sunitinib].


Updates and new trials presented in conferences this year may establish new care standards for mRCC. The update of Keynote 426 presented during American Society of Clinical Oncology (ASCO) 2020[15] suggested that pembrolizumab/axitinib should no longer be offered as the first line of choice of treatment in favorable risk mRCC. Moreover, the results of Checkmate 9ER presented at ESMO[22] showed some advantages of nivolumab/cabozantinib over sunitinib in first-line treatment among all IMDC subgroups and proposed it as a potential first-line option for mRCC.

At this point, there are multiple combination options for first-line treatment and the medical community is divided over which choice is better - two immunotherapies or immunotherapy plus an antiangiogenic drug - considering that the different combinations appear to have similar rates of efficacy, and there are no clear recommendations as to which is the most appropriate for each patient. More data and longer follow-up are needed to clarify the issue and learn whether there are certain populations who would benefit more from one of these combinations, as well as head-to-head comparisons between the combination therapies approved for first-line treatment. Additionally, biomarker-based studies are advisable when several approaches are available and clinical criteria are insufficient to guide treatment strategies.

Until then, taking into account the usual caveats pertaining to this practice, some insight may be gleaned from comparing CTs. At ASCO 2020, for example, the current first-line treatments in intermediate and high-risk mRCC patients (Checkmate 214[11] and Keynote-426[15]) were compared and discussed. Regarding OS data, outcomes in KEYNOTE426 appear to be slightly better at 2 years, and the ORR appears to be slightly higher with pembrolizumab/axitinib in KEYNOTE-426 (55%) than with nivolumab/ipilimumab in Checkmate 214 (42%). However, the percentage of patients who experienced primary progression with tumor growth while on treatment is more striking: 27% for nivolumab/ipilimumab and approximately half that, 15%, for pembrolizumab/axitinib. In clinical practice, pembrolizumab/axitinib appears to be the better choice, compared with nivolumab/ipilimumab, for a patient who needs a response to a rapidly progressing disease or to ameliorate symptoms, based on this cross-study comparison. For other patients, the adverse event profile of each com-bination would likely help to choose the most appropriate treatment.

An additional consideration is that the choice of first-line treatment may impact selection of second-line therapy. Starting with a combination of immune therapy only forces an automatic choice to use an antiangiogenic drug in the second line. However, starting with a combination of immune therapy and an antiangiogenic makes the second-line choice less clear. For this reason, more data are needed on the most suitable order of therapy for the population at large and specific groups, such as high vs slow-growing disease. Indeed, some ongoing CTs are trying to find the best alternative in second and third lines: Atezolizumab/cabozantinib vs cabozantinib (CONTACT-03)[25]; MK-6482 vs everolimus[26].

Also noteworthy is the recent trend toward three-part strategies, with various ongoing CTs, which have so far provided only preliminary results, including nivolumab + ipilimumab +/- cabozantinib (COSMIC 313)[27]; and the PDIGREE study[28], which proposes the use of nivolumab and ipilimumab followed by nivolumab or nivolumab with cabozantinib.

Conversely, other trials, such as the Checkmate 209-8Y8[29] and the KEYNOTE-427, are looking at maintaining monotherapies. The former proposes the use of nivolumab alone after nivolumab/ipilimumab in intermediate to poor-risk mRCC, while the latter studies the use of pembrolizumab in the frontline setting, showing promising activity (ORR of 36.4%, and disease control of 57.3%)[30].

Another field of study pertains to neoadjuvants and adjuvants, where either nivolumab or pembrolizumab is being evaluated in treatment before surgery (NCT02595918 and NCT02212730, respectively). The PROSPER trial (NCT03055013) assesses nivolumab in neoadjuvant and adjuvant use in node-positive or stage T2-T4 patients compared to observation[31].

Generally speaking, ongoing trials are moving away from sunitinib as the control arm and focus their research on triple therapies or novel therapeutic agents. PIVOT-9, a phase III randomized study, compares NKTR-214 plus nivolumab vs sunitinib or cabozantinib in previously untreated mRCC (NCT03729245). A phase II CT (NCT03634540) is studying the combination of HIF-2α inhibitor (PT2977) and cabozantinib.

Telaglenastat, a glutaminase inhibitor, is being studied in previously treated mRCC in combination with cabozantinib and everolimus in two phase II trials (CANTATA and ENTRATA, respectively), and entinostat, an orally available inhibitor of HDACs, is being considered in several combination therapies[32].

Poly(ADP-ribose) polymerase inhibitors, widely used in other tumors, have been proposed for RCC: Olaparib for patients with DNA repair gene mutations and talazoparib with avelumab.

Finally, the great challenge in mRCC treatment remains to find predictive and prognosis biomarkers. Interesting data are emerging from mRCC patients enrolled in CTs. PD-L1 expression, for example, was associated with poor outcomes in a meta-analysis[33]; but as a predictive marker, the results have been varied[4,34]. Genes have also been studied, including BRCA1-associated protein, which correlates with a poor survival[35], and PBRM1 mutation, which was associated with a longer PFS in the sunitinib and atezolizumab/bevacizumab group in IMotion150[36]. Another attempt to find a gene expression signature tool was made in IMmotion 151[34], where tumors characterized by angiogenesis-high signatures had better PFS with sunitinib and tumors with T effector/interferon-γ-high or angiogenesis-low signatures exhibited better outcomes with atezolizumab/bevacizumab. However, to date, the only predictive biomarker likely to be validated in a phase III randomized controlled trial is the IMDC risk model.


In conclusion, we are hopeful that in the coming years, patients and oncologists will continue to move away from a “one-size-fits-all” approach to treatment sequencing and instead move toward a more personalized treatment paradigm in mRCC.


Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Oncology

Country/Territory of origin: Spain

Peer-review report’s scientific quality classification

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Grade B (Very good): B, B

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P-Reviewer: Barbosa OA, He Z S-Editor: Wang JJ L-Editor: Wang TQ P-Editor: Wang JJ

1.  Gill DM, Hahn AW, Hale P, Maughan BL. Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma. Curr Treat Options Oncol. 2018;19:6.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 31]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
2.  Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib vs interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4384]  [Cited by in F6Publishing: 4670]  [Article Influence: 274.0]  [Reference Citation Analysis (0)]
3.  Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab vs Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373:1803-1813.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3796]  [Cited by in F6Publishing: 4063]  [Article Influence: 474.5]  [Reference Citation Analysis (0)]
4.  Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus Ipilimumab vs Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378:1277-1290.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2277]  [Cited by in F6Publishing: 2441]  [Article Influence: 455.4]  [Reference Citation Analysis (0)]
5.  Soares A, Monteiro FSM, Maluf FC, Bastos DA, Jardim DL, Sasse AD, Gonçalves E Silva A, Fay AP, da Rosa DAR, Wierman E, Kater F, Schutz FA, de Oliveira FNG, Morbeck IAP, Rinck JA Jr, da Trindade KM, Maia MC, Souza VC, da Silva Neto DCV, de Almeida E Paula F, Korkes F, Carvalhal GF, Nogueira L, de Carvalho Fernandes R, Dos Reis RB, Matheus WE, Busato WFS Jr, da Costa WH, de Cássio Zequi S. Advanced renal cell carcinoma (RCC) management: an expert panel recommendation from the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG). J Cancer Res Clin Oncol. 2020;146:1829-1845.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 2]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
6.  Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus Axitinib vs Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1103-1115.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1222]  [Cited by in F6Publishing: 1302]  [Article Influence: 305.5]  [Reference Citation Analysis (0)]
7.  Gurram S, Al Harthy M, Ball MW. The changing landscape of systemic therapy in metastatic renal cell carcinoma: an update. Discov Med. 2020;29:191-199.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  EAU Guidelines  Renal Cell Carcinoma. [cited 3 January 2021]. Available from: https://uroweb.org/guideline/renal-cell-carcinoma/.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Escudier B, Porta C, Schmidinger M, Rioux-Leclercq N, Bex A, Khoo V, Grünwald V, Gillessen S, Horwich A; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019;30:706-720.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 442]  [Cited by in F6Publishing: 474]  [Article Influence: 110.5]  [Reference Citation Analysis (0)]
10.  National Comprehensive Cancer Network  NCCN Guidelines Insights, Kidney Cancer Version 2. 2020. [cited 3 January 2021]. Available from: https://jnccn.org/view/journals%24002fjnccn%24002f17%24002f11%24002farticle-p1278.xml.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5:e001079.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 179]  [Cited by in F6Publishing: 183]  [Article Influence: 89.5]  [Reference Citation Analysis (0)]
12.  Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab vs everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020;126:4156-4167.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 104]  [Cited by in F6Publishing: 109]  [Article Influence: 34.7]  [Reference Citation Analysis (0)]
13.  Choueiri TK, Plimack ER, Bauer TM, Merchan JR, Papadopoulos K, McDermott D, Michaelson MD, Appleman LJ, Thamake S, Zojwalla NJ, Jonasch E. Phase I/II study of the oral HIF-2 alfa inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma. J Clin Oncol. 2020;38:611.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 28]  [Article Influence: 9.3]  [Reference Citation Analysis (0)]
14.  Msaouel P, Thall PF, Yuan Y, Wang X, Jonasch E, Gao J, Campbell MT, Shah AY, Corn PG, Tam A, Ahrar K, Rao P, Sircar K, Der-Torossian H, Tannir NM. A phase I/II trial of Sitravatinib combined with Nivolumab in patients with advanced clear cell renal cell cancer that progressed on prior VEGF targeted therapy. J Clin Oncol. 2020;38:612.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 7]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
15.  Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. Pembrolizumab plus axitinib vs sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21:1563-1573.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 227]  [Cited by in F6Publishing: 240]  [Article Influence: 75.7]  [Reference Citation Analysis (0)]
16.  Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib vs Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1116-1127.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1565]  [Cited by in F6Publishing: 1667]  [Article Influence: 391.3]  [Reference Citation Analysis (0)]
17.  McKay RR, McGregor BA, Xie W, Braun DA, Wei X, Kyriakopoulos CE, Zakharia Y, Maughan BL, Rose TL, Stadler WM, McDermott DF, Harshman LC, Choueiri TK. Optimized Management of Nivolumab and Ipilimumab in Advanced Renal Cell Carcinoma: A Response-Based Phase II Study (OMNIVORE). J Clin Oncol. 2020;38:4240-4248.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 43]  [Article Influence: 12.3]  [Reference Citation Analysis (0)]
18.  Atkins MB, Jegede O, Haas NB, McDermott DF, Bilen MA, Drake CG, Sosman JA, Alter RS, Plimack ER, Rini BI, Hurwitz ME, Peace DJ, Signoretti S, Ru CJ, Catalano PJ, Hammers HJ. Phase II study of Nivolumab and salvage Nivolumab + Ipilimumab in treatment-näive patients with advanced renal cell carcinoma (RCC) (HCRN GU16-260). J Clin Oncol. 2020;38:5006.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 40]  [Article Influence: 12.7]  [Reference Citation Analysis (0)]
19.  Choueiri TK, Kluger HM, George S, Tykodi SS, Kuzel TM, Perets R, Nair S, Procopio G, Carducci MA, Castonguay V, Folefac E, Lee CH, Hotte SJ, Miller WH, Saggi SS, Gold D, Motzer RJ, Escudier B. FRACTION-RCC: Innovative, high-throughput assesment of Nivolumab + Ipilimumab for treatment-refractory advanced renal cell carcinoma (aRCC). J Clin Oncol. 2020;38:5007.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 23]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
20.  Srinivarsan R, Gurram S, AL Harthy M, Singer EA, Sidana A, Shuch BM, Ball MW, Friend JC, Mac L, Purcell E, Vcoker C, Kong HH, Cowen EW, Choyke PL, Malayeri AA, Long L, Shih JH, Merino MJ, Linenhan WM. Results from a phase II study of Bevacizumab and Erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or Sporadic Papillary Renal Cell Cancer. J Clin Oncol. 2020;38:5004.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 36]  [Article Influence: 12.0]  [Reference Citation Analysis (0)]
21.  Mollica V, Rizzo A, Massari F. Re: Toni K. Choueiri, Daniel Y.C. Heng, Jae Lyun Lee, et al Efficacy of Savolitinib vs Sunitinib in Patients With MET-Driven Papillary Renal Cell Carcinoma: The SAVOIR Phase 3 Randomized Clinical Trial. JAMA Oncol. In press. https://doi.org/10.1001/jamaoncol.2020.2218: SAVOIR: From Own Goal to Winning Goal? Eur Urol Oncol. 2020;3:561-562.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 3]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
22.  Choueiri TK, Powles T, Burotto M, Bourlon MT, Zurawski B, Juárez VM, Hsieh JJ, Basso U, Shah AY, Suarez C, Hamzaj A, Barrios CH, Richardet M, Pook D, Tomita Y, Escudier B, Zhang J, Simsek B, Apolo AB, Motzer RJ. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2020;31:S1142-S1215.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Pal S, Tsao CK, Suarez C, Kelly W, Pagliaro L, Vaishampayan UN, Loriot Y, Srinivas S, McGregor BA, Panneerselvam A, Curran D, Choueiri TK, Agarwal N. Cabozantinib in combination with Atezolizumab as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from the COSMIC-021 study. Ann Oncol. 2020;31:S550.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Lee CH, Shah AY, Hsieh JJ, Rao A, Pinto A; Bilen MA;  Cohn AL, Simone CD, Shaffer DR, Sarrio RG, Ribe SG, Wu J, Schmidt E, Kubiak P, Okpara CE, Smith AD, Motzer RJ. Phase II trial of lenvatinib (LEN) + pembrolizumab (PEMBRO) for progressive disease after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell (mcc) renal cell carcinoma (RCC): Results by independent imaging review and subgroup analyses. Ann Oncol. 2020;31:S558-S559.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 3]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
25.  Roche H  A Study of Atezolizumab in Combination With Cabozantinib Compared to Cabozantinib Alone in Participants With Advanced Renal Cell Carcinoma After Immune Checkpoint Inhibitor Treatment (CONTACT-03). [accessed 2020 Nov 17]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT04338269 ClinicalTrials.gov Identifier: NCT04338269.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Sharp M, Corp D.   A Study of Belzutifan (MK-6482) Versus Everolimus in Participants With Advanced Renal Cell Carcinoma (MK-6482-005). [accessed 2020 Nov 17]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT04195750 ClinicalTrials.gov Identifier: NCT04195750.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Exelixis  Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (COSMIC-313). [accessed 2020 Nov 17]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT03937219 ClinicalTrials.gov Identifier: ClinicalTrials.gov Identifier: NCT04195750.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  National Cancer Institute (NCI)  Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study. [accessed 2020 Nov 17]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT03793166 ClinicalTrials.gov Identifier: NCT03793166.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Squibb BM  A Study of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Participants With Advanced Kidney Cancer. [accessed 2020 Nov 17]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03873402 ClinicalTrials.gov Identifier: NCT03873402.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Tykodi SS, Donskov F, Lee JL, Szczylik C, Malik J, Alekseev BY, Larking J, Matveev VB, Gafanov R, Tomczak P, Geertsen P, Wiechno PJ, Shin SJ, Pouliot F, Alonso-Gordoa T, Silverman RK, Perini RF, Schloss C, McDermott DF, Atkins MB. First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): updated results for KEYNOTE-427 cohort A. J Clin Oncol. 2020;38:5069.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 5]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
31.  Chowdhury N, Drake CG. Kidney Cancer: An Overview of Current Therapeutic Approaches. Urol Clin North Am. 2020;47:419-431.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 53]  [Article Influence: 15.0]  [Reference Citation Analysis (0)]
32.  Motzer RJ, Lee CH, Emamekhoo H, Matrana M, Percent I, Hsieh JJ, Hussain A, Vaishampayan UN, Graham R, Liu S, McCune S, Shaheen M, Parmar H, Shen Y, Ehiting SH, Tannir NM. ENTRATA: Randomized, double-blind, phase II study of telaglenastat (tela; CB-839) + everolimus (E) vs placebo (pbo) + E in patients (pts) with advanced/metastatic renal cell carcinoma (mRCC). Ann Oncol. 2019;30:v889-v890.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 17]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
33.  Iacovelli R, Nolè F, Verri E, Renne G, Paglino C, Santoni M, Cossu Rocca M, Giglione P, Aurilio G, Cullurà D, Cascinu S, Porta C. Prognostic Role of PD-L1 Expression in Renal Cell Carcinoma. A Systematic Review and Meta-Analysis. Target Oncol. 2016;11:143-148.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 112]  [Cited by in F6Publishing: 109]  [Article Influence: 14.0]  [Reference Citation Analysis (0)]
34.  Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab vs sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019;393:2404-2415.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 541]  [Cited by in F6Publishing: 578]  [Article Influence: 135.3]  [Reference Citation Analysis (0)]
35.  Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499:43-49.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2246]  [Cited by in F6Publishing: 2378]  [Article Influence: 224.6]  [Reference Citation Analysis (0)]
36.  Roche HL  A Study of Atezolizumab (an Engineered Anti-Programmed Death-Ligand 1 [PD-L1] Antibody) as Monotherapy or in Combination With Bevacizumab (Avastin) Compared to Sunitinib (Sutent) in Participants With Untreated Advanced Renal Cell Carcinoma (IMmotion150). [accessed 2020 Nov 18]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT01375842 ClinicalTrials.gov Identifier: NCT01375842.  [PubMed]  [DOI]  [Cited in This Article: ]