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Current evidence for second-line treatment in metastatic renal cell carcinoma after progression to immune-based combinations

  • Author Footnotes
    1 These authors contributed equally to the work.
    Roberto Iacovelli
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Medical Oncology Unit, Fondazione Policlinico A. Gemelli IRCCS. Largo Agostino Gemelli 8, 00168 Rome, Italy
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  • Author Footnotes
    1 These authors contributed equally to the work.
    Chiara Ciccarese
    Correspondence
    Corresponding author at: Oncologia Medica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, 00158 Rome, Italy.
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Medical Oncology Unit, Fondazione Policlinico A. Gemelli IRCCS. Largo Agostino Gemelli 8, 00168 Rome, Italy
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  • Giuseppe Procopio
    Affiliations
    Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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  • Serena Astore
    Affiliations
    Medical Oncology Unit, Fondazione Policlinico A. Gemelli IRCCS. Largo Agostino Gemelli 8, 00168 Rome, Italy
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  • Maria Antonella Cannella
    Affiliations
    Medical Oncology Unit, Fondazione Policlinico A. Gemelli IRCCS. Largo Agostino Gemelli 8, 00168 Rome, Italy
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  • Maria Grazia Maratta
    Affiliations
    Medical Oncology Unit, Fondazione Policlinico A. Gemelli IRCCS. Largo Agostino Gemelli 8, 00168 Rome, Italy
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  • Mimma Rizzo
    Affiliations
    Division of Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
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  • Elena Verzoni
    Affiliations
    Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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  • Author Footnotes
    2 These authors shared the last co-authorship.
    Camillo Porta
    Footnotes
    2 These authors shared the last co-authorship.
    Affiliations
    Division of Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy

    Department of Biomedical Sciences and Human Oncology, University of Bari 'A. Moro', Italy
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  • Author Footnotes
    2 These authors shared the last co-authorship.
    Giampaolo Tortora
    Footnotes
    2 These authors shared the last co-authorship.
    Affiliations
    Medical Oncology Unit, Fondazione Policlinico A. Gemelli IRCCS. Largo Agostino Gemelli 8, 00168 Rome, Italy

    Medical Oncology Unit, Università Cattolica del Sacro Cuore, Rome, Italy
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  • Author Footnotes
    1 These authors contributed equally to the work.
    2 These authors shared the last co-authorship.
Published:March 12, 2022DOI:https://doi.org/10.1016/j.ctrv.2022.102379

      Highlights

      • The change of first-line therapy has inevitably led to the modification of the second-line.
      • The first-line regimen, and the type and duration of response, are crucial factors to evaluate when choosing the second-line.
      • The efficacy of second-line VEGFR-TKIs seems to be greater after failure of a dual ICIs combination.
      • Data of ICIs re-challenge are scarce and suggested limited activity.
      • Novel molecules and different ICI-based combinations are under evaluation.

      Abstract

      The recent approval of immune checkpoint inhibitor (ICI)-based combinations has redefined the first-line standard of care of metastatic renal cell carcinoma (mRCC) patients. Although the undisputed advantage of these combinations, most patients progressed, requiring subsequent therapies. The change of first-line therapy inevitably led to modification of the all mRCC treatment algorithm; to date, the most appropriate second-line options remain still unclear. The aim of our review was to provide a useful summary of the available evidence in order to overcome the doubts about treatment sequences.
      Retrospectively, the efficacy of second-line VEGFR-TKIs seems to be greater after failure of a dual ICIs combination rather than after ICIs plus VEGFR-TKIs, nevertheless prospective data of second-line TKIs are limited. Moreover, ICI re-challenge could be an option but, again, most data derived from retrospective series emphasizing the identification of predictive factors of response to select mRCC patients that could benefit from this strategy. Novel molecules and different ICI-based combinations are under evaluation with the aim of implementing the second-line setting. In particular, belzutifan, ciforadenant (CPI-444), and talazoparib achieved encouraging objective response rates (ORR) in phase I/II trials. Phase III trials comparing these new molecules with the standard of care are currently ongoing.
      The first-line regimen, and the type and duration of response emerged as crucial factors that could influence the efficacy of second-line therapy. Prognostic models that integrate clinical features and molecular biomarkers with a predictive value are warranted to guide clinicians in the decision-making process with the ultimate goal of offering to the patients the most effective therapy in a personalized, precision medicine-based, therapeutic strategy.

      Keywords

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      References

        • Navani V.
        • Heng D.Y.C.
        Treatment selection in first-line metastatic renal cell carcinoma - The contemporary treatment paradigm in the age of combination therapy. A review.
        JAMA Oncol. 2022; 8: 292https://doi.org/10.1001/jamaoncol.2021.4337
        • Hahn A.W.
        • Klaassen Z.
        • Agarwal N.
        • et al.
        First-line treatment of metastatic renal cell carcinoma: A systematic review and network meta-analysis.
        Eur Urol Oncol. 2019; 2: 708-715
        • Iacovelli R.
        • Ciccarese C.
        • Schutz F.A.
        • Tortora G.
        • de Velasco G.
        Complete response to immune checkpoint inhibitors-based therapy in advanced renal cell carcinoma patients. A meta-analysis of randomized clinical trials.
        Urol Oncol. 2020; 38: 798.e17-798.e24https://doi.org/10.1016/j.urolonc.2020.06.021
        • Albiges L.
        • Tannir N.M.
        • Burotto M.
        • McDermott D.
        • Plimack E.R.
        • Barthélémy P.
        • et al.
        Nivolumab plus ipilimumab versus 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: e001079https://doi.org/10.1136/esmoopen-2020-001079
        • Powles T.
        • Plimack E.R.
        • Soulières D.
        • Waddell T.
        • Stus V.
        • Gafanov R.
        • et al.
        Pembrolizumab plus axitinib versus 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
        • Rini B.I.
        • Plimack E.R.
        • Stus V.
        • Waddell T.
        • Gafanov R.
        • Pouliot F.
        • et al.
        Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426.
        J Clin Oncol. 2021; 39 (4500–4500)https://doi.org/10.1200/JCO.2021.39.15_suppl.4500
        • Choueiri T.K.
        • Motzer R.J.
        • Rini B.I.
        • Haanen J.
        • Campbell M.T.
        • Venugopal B.
        • et al.
        Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma.
        Ann Oncol. 2020; 31: 1030-1039
        • Albiges L.
        • Voss M.H.
        • Rini B.I.
        • et al.
        “Outcomes of patients who progressed while receiving avelumab + axitinib (A + Ax) and received subsequent treatment (Tx) in JAVELIN Renal 101.
        J Clin Oncol. 2021; 3915_suppl (4514–4514)
        • Choueiri T.K.
        • Hessel C.
        • Halabi S.
        • et al.
        Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.
        N Engl J Med. 2021; 384: 829-841https://doi.org/10.1056/NEJMOA2026982
        • Motzer R.
        • Alekseev B.
        • Rha S.-Y.
        • Porta C.
        • Eto M.
        • Powles T.
        • et al.
        Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
        N Engl J Med. 2021; 384: 1289-1300https://doi.org/10.1056/NEJMoa2035716
        • Rini B.I.
        • Powles T.
        • Atkins M.B.
        • Escudier B.
        • McDermott D.F.
        • Suarez C.
        • et al.
        Atezolizumab plus bevacizumab versus 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
        • Choueiri T.K.
        • Hessel C.
        • Halabi S.
        • Sanford B.
        • Michaelson M.D.
        • Hahn O.
        • et al.
        Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update.
        Eur J Cancer. 2018; 94: 115-125
        • Porta C.
        • Schmidinger M.
        Renal cell carcinoma treatment after first-line combinations.
        Lancet Oncol. 2019; 20: 1332-1334
        • Albiges L.
        • Fay A.P.
        • Xie W.
        • Krajewski K.
        • McDermott D.F.
        • Heng D.Y.C.
        • et al.
        Efficacy of targeted therapies after PD-1/PD-L1 blockade in metastatic renal cell carcinoma.
        Eur J Cancer. 2015; 51: 2580-2586
        • Nadal R.
        • Amin A.
        • Geynisman D.M.
        • Voss M.H.
        • Weinstock M.
        • Doyle J.
        • et al.
        Safety and clinical activity of vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors after programmed cell death 1 inhibitor treatment in patients with metastatic clear cell renal cell carcinoma.
        Ann Oncol. 2016; 27: 1304-1311
        • Shah A.Y.
        • Kotecha R.R.
        • Lemke E.A.
        • Chandramohan A.
        • Chaim J.L.
        • Msaouel P.
        • et al.
        Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors.
        Eur J Cancer. 2019; 114: 67-75
        • Graham J.
        • Shah A.Y.
        • Wells J.C.
        • McKay R.R.
        • Vaishampayan U.
        • Hansen A.
        • et al.
        Outcomes of Patients with Metastatic Renal Cell Carcinoma Treated with Targeted Therapy After Immuno-oncology Checkpoint Inhibitors”.
        Eur Urol Oncol. 2021; 4: 102-111
        • Ged Y.
        • Gupta R.
        • Duzgol C.
        • Knezevic A.
        • Shapnik N.
        • Kotecha R.
        • et al.
        Systemic therapy for advanced clear cell renal cell carcinoma after discontinuation of immune-oncology and VEGF targeted therapy combinations.
        BMC Urol. 2020; 20https://doi.org/10.1186/s12894-020-00647-w
        • Wells J.C.
        • Dudani S.
        • Gan C.L.
        • et al.
        Clinical Effectiveness of Second-line Sunitinib Following Immuno-oncology Therapy in Patients with Metastatic Renal Cell Carcinoma: A Real-world Study.
        Clin Genitourin Cancer. 2021; 000: 1-8https://doi.org/10.1016/J.CLGC.2021.03.006
        • McGregor B.A.
        • Lalani A.-K.
        • Xie W.
        • Steinharter J.A.
        • E. Bakouny Z.
        • Martini D.J.
        • et al.
        Activity of cabozantinib after immune checkpoint blockade in metastatic clear-cell renal cell carcinoma.
        Eur J Cancer. 2020; 135: 203-210
        • Stukalin I.
        • Dudani S.
        • Wells C.
        • Gan C.L.
        • Pal S.K.
        • Dizman N.
        • et al.
        Second-line VEGF TKI after IO combination therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
        J Clin Oncol. 2020; 38 (684–684)https://doi.org/10.1200/JCO.2020.38.6_suppl.684
        • Dudani S.
        • Graham J.
        • Wells J.C.
        • Bakouny Z.
        • Pal S.K.
        • Dizman N.
        • et al.
        First-line Immuno-Oncology Combination Therapies in Metastatic Renal-cell Carcinoma: Results from the International Metastatic Renal-cell Carcinoma Database Consortium.
        Eur Urol. 2019; 76: 861-867
        • Auvray M.
        • Auclin E.
        • Barthelemy P.
        • Bono P.
        • Kellokumpu-Lehtinen P.
        • Gross-Goupil M.
        • et al.
        Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma.
        Eur J Cancer. 2019; 108: 33-40
        • Marteau F.
        • Harrow B.
        • McCarthy C.
        • Wallace J.
        • Monnette A.
        • Wang Y.
        • et al.
        Cabozantinib versus other TKIs after CPI treatment in the real-world management of patients with metastatic renal cell carcinoma (mRCC).
        J Cli Oncol. 2021; 39 (293–293)https://doi.org/10.1200/JCO.2021.39.6_suppl.293
      1. Derosa BEL, Rouche JA, Colomba E, et al. Efficacy of cabozantinib (C) after PD-1/PD-L1 checkpoint inhibitors in metastatic Renal Cell Carcinoma (mRCC): the Gustave Roussy experience. ESMO 2017; Abstr. 876P. Ann. Oncol. 28 v295-v329. 10.1093/annonc/mdx371, 2017.

        • Barata P.C.
        • De Liano A.G.
        • Mendiratta P.
        • Crolley V.
        • Szabados B.
        • Morrison L.
        • et al.
        The efficacy of VEGFR TKI therapy after progression on immune combination therapy in metastatic renal cell carcinoma.
        Br J Cancer. 2018; 119: 160-163
        • Powles T.
        • Motzer R.J.
        • Escudier B.
        • Pal S.
        • Kollmannsberger C.
        • Pikiel J.
        • et al.
        Outcomes based on prior therapy in the phase 3 METEOR trial of cabozantinib versus everolimus in advanced renal cell carcinoma.
        Br J Cancer. 2018; 119: 663-669
        • Iacovelli R.
        • Ciccarese C.
        • Facchini G.
        • et al.
        Cabozantinib after a previous immune checkpoint inhibitor in metastatic renal cell carcinoma: a restrospective multi-institutional analysis.
        Target Oncol. 2020; 15: 495-501
      2. Wiele AJ, Bathala T, Hahn AW, et al. Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies. Oncologist 2021; 26(6): 476–482.

        • Gul A.
        • Stewart T.F.
        • Mantia C.M.
        • Shah N.J.
        • Gatof E.S.
        • Long Y.
        • et al.
        Salvage ipilimumab and nivolumab in patients with metastatic renal cell carcinoma after prior immune checkpoint inhibitors.
        J Clin Oncol. 2020; 38: 3088-3094
        • Ravi P.
        • Mantia C.
        • Su C.
        • Sorenson K.
        • Elhag D.
        • Rathi N.
        • et al.
        Evaluation of the Safety and Efficacy of Immunotherapy Rechallenge in Patients with Renal Cell Carcinoma.
        JAMA Oncol. 2020; 6: 1606https://doi.org/10.1001/jamaoncol.2020.2169
        • Laccetti A.L.
        • Garmezy B.
        • Xiao L.
        • Economides M.
        • Venkatesan A.
        • Gao J.
        • et al.
        Combination antiangiogenic tyrosine kinase inhibition and anti-PD1 immunotherapy in metastatic renal cell carcinoma: A retrospective analysis of safety, tolerance, and clinical outcomes.
        Cancer Med. 2021; 10: 2341-2349
        • Anagnostou V.
        • Smith K.N.
        • Forde P.M.
        • Niknafs N.
        • Bhattacharya R.
        • White J.
        • et al.
        Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer.
        Cancer Discov. 2017; 7: 264-276
        • Pitt J.
        • Vétizou M.
        • Daillère R.
        • Roberti M.
        • Yamazaki T.
        • Routy B.
        • et al.
        Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors.
        Immunity. 2016; 44: 1255-1269
        • Hirsch L.
        • Flippot R.
        • Escudier B.
        • Albiges L.
        Immunomodulatory roles of VEGF pathway inhibitors in renal cell carcinoma.
        Drugs. 2020; 80: 1169-1181
      3. Procopio G, Melanie Claps M, Pircher C et al. A phase 2 single-arm study of cabozantinib in patients with advanced or unresectable renal cell carcinoma pretreated with one immune checkpoint inhibitor: the BREAKPOINT trial (MeetUro trial 03). J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4569-4569. DOI:10.1200/JCO.2021.39.15_suppl.4569.

        • Tannir N.M.
        • Agarwal N.
        • Porta C.
        • Lawrence N.J.
        • Motzer R.J.
        • Lee R.J.
        • et al.
        CANTATA: Primary analysis of a global, randomized, placebo (Pbo)-controlled, double-blind trial of telaglenastat (CB-839) + cabozantinib versus Pbo + cabozantinib in advanced/metastatic renal cell carcinoma (mRCC) patients (pts) who progressed on immune checkpoint inhibitor (ICI) or anti-angiogenic therapies..
        JCO. 2021; 39 (4501–4501)
        • Ornstein M.C.
        • Pal S.K.
        • Wood L.S.
        • Tomer J.M.
        • Hobbs B.P.
        • Jia X.S.
        • et al.
        Individualised axitinib regimen for patients with metastatic renal cell carcinoma after treatment with checkpoint inhibitors: a multicentre, single-arm, phase 2 study.
        Lancet Oncol. 2019; 20: 1386-1394https://doi.org/10.1016/S1470-2045(19)30513-3
      4. Grande E, Gordoa TA, Torras OR, et al. INMUNOSUN-SOGUG trial: a prospectve phase II study to assess the efficacy and safety of sunitinib as second-line (2L) treatment in patients (pts) with metastatic renal cell cancer (RCC) who received immunotherapy-based combination upfront. J Clin Oncol 38, no. 15_suppl (May 20, 2020) 5060-5060. DOI: 10.1200/JCO.2020.38.15_suppl.5060.

        • Rini B.I.
        • Pal S.K.
        • Escudier B.J.
        • Atkins M.B.
        • Hutson T.E.
        • Porta C.
        • et al.
        Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study.
        Lancet Oncol. 2020; 21: 95-104
        • McKay R.R.
        • McGregor B.A.
        • Xie W.
        • Braun D.A.
        • Wei X.
        • Kyriakopoulos C.E.
        • et al.
        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
        • Atkins M.B.
        • Jegede O.
        • Haas N.B.
        • et al.
        Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260).
        J Clin Oncol. 2020; 38 (5006–5006)https://doi.org/10.1200/JCO.2020.38.15_suppl.500
        • Grimm M.-O.
        • Esteban E.
        • Barthélémy P.
        • Schmidinger M.
        • Busch J.
        • Valderrama B.P.
        • et al.
        Efficacy of nivolumab/ipilimumab in patients with initial or late progression with nivolumab: Updated analysis of a tailored approach in advanced renal cell carcinoma (TITAN-RCC)..
        J Clin Oncol. 2021; 39 (4576–4576)
        • Choueiri T.K.
        • Kluger H.M.
        • George S.
        • Tykodi S.S.
        • Kuzel T.M.
        • Perets R.
        • et al.
        FRACTION-RCC: Innovative, high-throughput assessment of nivolumab + ipilimumab for treatment-refractory advanced renal cell carcinoma (aRCC)..
        J Clin Oncol. 2020; 38 (5007–5007)
        • Lee C.-H.
        • Shah A.Y.
        • Rasco D.
        • Rao A.
        • Taylor M.H.
        • Di Simone C.
        • et al.
        Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study.
        Lancet Oncol. 2021; 22: 946-958
        • Vauchier C.
        • Auclin E.
        • Barthelemy P.
        • Carril L.
        • Ryckewaert T.
        • Borchiellini D.
        • et al.
        Rechallenge of nivolumab in metastatic renal cell carcinoma, an ambispective multicenter study (RENIVO).
        J Clin Oncol. 2021; 39 (330–330)
        • Carril-Ajuria L.
        • Lora D.
        • Carretero-González A.
        • Martín-Soberón M.
        • Rioja-Viera P.
        • Castellano D.
        • et al.
        Systemic Analysis and Review of Nivolumab-ipilimumab Combination as a Rescue Strategy for Renal Cell Carcinoma After Treatment With Anti-PD-1/PD-L1 Therapy.
        Clin Genitourin Cancer. 2021; 19: 95-102
        • Massari F.
        • Santoni M.
        • Ciccarese C.
        • Santini D.
        • Alfieri S.
        • Martignoni G.
        • et al.
        PD-1 blockade therapy in renal cell carcinoma: current studies and future promises.
        Cancer Treat Rev. 2015; 41: 114-121
      5. Motzer RJ, Lee C, Emamekhoo H, et al. ENTRATA: Randomized, double-blind, phase 2 study of telaglenastat (tela; CB-839) + everolimus (E) vs. placebo (pbo) + E in patients (pts) with advanced/metastatic renal cell carcinoma (mRCC). Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394.

        • Jonasch E.
        • Donskov F.
        • Iliopoulos O.
        • Rathmell W.K.
        • Narayan V.K.
        • Maughan B.
        • et al.
        Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.
        N Engl J Med. 2021; 385: 2036-2046
        • Bauer T.M.
        • Choueiri T.K.
        • Papadopoulos K.P.
        • Plimack E.R.
        • Merchan J.R.
        • McDermott D.F.
        • et al.
        The oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC): Updated follow-up of a phase I/II study.
        J Clin Oncol. 2021; 39 (273–273)
        • Choueiri T.K.
        • Bauer T.M.
        • McDermott D.F.
        • Arrowsmith E.
        • Roy A.
        • Perini R.F.
        • et al.
        Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC).
        J Clin Oncol. 2021; 39 (272–272)
        • Young A.
        • Ngiow S.F.
        • Gao Y.
        • Patch A.-M.
        • Barkauskas D.S.
        • Messaoudene M.
        • et al.
        A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment.
        Cancer Res. 2018; 78: 1003-1016
        • Lokshin A.
        • Raskovalova T.
        • Huang X.
        • Zacharia L.C.
        • Jackson E.K.
        • Gorelik E.
        Adenosine-mediated inhibition of the cytotoxic activity and cytokine production by activated natural killer cells.
        Cancer Res. 2006; 66: 7758-7765
        • Fong L.
        • Hotson A.
        • Powderly J.D.
        • et al.
        Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer.
        Cancer Discov. 2020; 10: 40-53https://doi.org/10.1158/2159-8290.CD-19-0980
        • Heng D.YC.
        • Xie W.
        • Regan M.M.
        • Harshman L.C.
        • Bjarnason G.A.
        • Vaishampayan U.N.
        • et al.
        External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: A population-based study.
        Lancet Oncol. 2013; 14: 141-148https://doi.org/10.1016/S1470-2045(12)70559-4
      6. Dudani S, Gan CL, Wells C, et al. Application of IMDC criteria across first-line (1L) and second-line (2L) therapies in metastatic renal-cell carcinoma (mRCC): New and updated benchmarks of clinical outcomes. J Clin Oncol 2020; 38(15_suppl): 5063–63.

        • Lopez-Beltran A.
        • Henriques V.
        • Cimadamore A.
        • et al.
        The identification of immunological biomarkers in kidney cancers.
        Front Oncol. 2018; 8: 456https://doi.org/10.3389/FONC.2018.00456/BIBTEX
        • Iacovelli R.
        • Nolè F.
        • Verri E.
        • et al.
        Prognostic role of PD-L1 expression in renal cell carcinoma: a systemcatic reviwe and meta-analysis.
        Target Oncol. 2016; 11: 143-148
        • McDermott D.F.
        • Huseni M.A.
        • Atkins M.B.
        • Motzer R.J.
        • Rini B.I.
        • Escudier B.
        • et al.
        Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.
        Nat Med. 2018; 24: 749-757
        • Motzer R.J.
        • Robbins P.B.
        • Powles T.
        • et al.
        Avelumab plus axitinib verusu sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trail.
        Nat Med. 2020; 26: 1733-1741
        • Choueiri T.K.
        • Albiges L.
        • Haanen J.B.A.G.
        • Larkin J.M.G.
        • Uemura M.
        • Pal S.K.
        • et al.
        Biomarker analyses from JAVELIN Renal 101: Avelumab + axitinib (A+Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).
        J Clin Oncol. 2019; 37 (101–101)
        • Meylan M.
        • Beuselinck B.
        • Dalban C.
        • Vano Y.
        • Rioux Leclercq N.
        • Sautès-Fridman C.
        • et al.
        700O Kidney ccRCC immune classification (KIC) enhances the predictive value of T effector (Teff) and angiogenesis (Angio) signatures in response to nivolumab (N).
        Ann Oncol. 2020; 31: S553https://doi.org/10.1016/j.annonc.2020.08.772
        • Braun D.A.
        • Hou Y.
        • Bakouny Z.
        • et al.
        Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal carcinoma.
        Nat Med. 2020; 26: 909-918
        • Motzer R.J.
        • Banchereau R.
        • Hamidi H.
        • Powles T.
        • McDermott D.
        • Atkins M.B.
        • et al.
        Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade.
        Cancer Cell. 2020; 38: 803-817.e4
        • Au L.
        • Hatipoglu E.
        • Robert de Massy M.
        • et al.
        Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.
        Cancer Cell. 2021; 39: 1497-1518.e11
        • Tran H.T.
        • Liu Y.
        • Zurita A.J.
        • Lin Y.
        • Baker-Neblett K.L.
        • Martin A.-M.
        • et al.
        Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: A retrospective analysis of phase 2 and phase 3 trials.
        Lancet Oncol. 2012; 13: 827-837
        • Zurita A.J.
        • Gagnon R.C.
        • Liu Y.
        • Tran H.T.
        • Figlin R.A.
        • Hutson T.E.
        • et al.
        Integrating cytokines and angiogenic factors and tumour bulk with selected clinical criteria improves determination of prognosis in advanced renal cell carcinoma.
        Br J Cancer. 2017; 117: 478-484
        • Zizzari I.G.
        • Napoletano C.
        • Di Filippo A.
        • Botticelli A.
        • Gelibter A.
        • Calabrò F.
        • et al.
        Exploratory Pilot Study of Circulating Biomarkers in Metastatic Renal Cell Carcinoma.
        Cancers (Basel). 2020; 12: 2620https://doi.org/10.3390/cancers12092620
        • Chehrazi-Raffle A.
        • Meza L.
        • Alcantara M.
        • Dizman N.
        • Bergerot P.
        • Salgia N.
        • et al.
        Circulating cytokines associated with clinical response to systemic therapy in metastatic renal cell carcinoma.
        J Immunother Cancer. 2021; 9: e002009https://doi.org/10.1136/jitc-2020-002009
        • Choueiri T.K.
        • Fishman M.N.
        • Escudier B.
        • McDermott D.F.
        • Drake C.G.
        • Kluger H.
        • et al.
        Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma.
        Clin Cancer Res. 2016; 22: 5461-5471
        • Wang R.
        • Zheng J.
        • Shao X.
        • Ishii Y.
        • Roy A.
        • Bello A.
        • et al.
        Development of a prognostic composite cytokine signature based on the correlation with nivolumab clearance: Translational PK/PD analysis in patients with renal cell carcinoma.
        J Immunother Cancer. 2019; 7https://doi.org/10.1186/s40425-019-0819-2
        • Salgia N.J.
        • Bergerot P.G.
        • Maia M.C.
        • Dizman N.
        • Hsu JoAnn
        • Gillece J.D.
        • et al.
        Stool Microbiome Profiling of Patients with Metastatic Renal Cell Carcinoma Receiving Anti–PD-1 Immune Checkpoint Inhibitors.
        Eur Urol. 2020; 78: 498-502
        • Derosa L.
        • Routy B.
        • Fidelle M.
        • Iebba V.
        • Alla L.
        • Pasolli E.
        • et al.
        Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients.
        Eur Urol. 2020; 78: 195-206
      7. Dizman N, Meza L, Bergerot P, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med 2022 Feb 28. DOI: 10.1038/s41591-022-01694-6.

        • Powles T.
        • Albiges L.
        • Bex A.
        • et al.
        ESMO clinical practice guidelines update on the use of immunotherapy in early stage and advanced renal cell carcinoma.
        Ann of Oncol. 2021; 32: 1511-1519