Combination therapies in clinical trials for renal cell carcinoma: how could they impact future treatments?

References

• Celo G, Larose TL. Epidemiology and risk factors for kidney cancer. J Clin Oncol. 2018;36(36).
   Web of Science ®Google Scholar
• Du Z, Chen W, Xia Q, et al. Trends and projections of kidney cancer incidence at the global and national levels, 1990–2030: a Bayesian age-period-cohort modeling study. Biomark Res. 2020;8(1). https://doi.org/10.1186/s40364-020-00195-3.
   Google Scholar
• Cairns P, Srivastava S, Grizzle WE. Renal cell carcinoma. Cancer Biomarkers. 2010;9(1–6):461–473.
   PubMed Web of Science ®Google Scholar
• Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer. 2015;15(1):55–64.
   PubMed Web of Science ®Google Scholar
• Gläsker S, Vergauwen E, Koch CA, et al. Von Hippel-Lindau disease: current challenges and future prospects. Onco Targets Ther. 2020;13:5669–5690.
   PubMed Web of Science ®Google Scholar
• Heidegger I, Pircher A, Pichler R. Targeting the tumor microenvironment in renal cell cancer biology and therapy. Front Oncol. 2019;9:490. Published 2019 June 14.
   PubMed Web of Science ®Google Scholar
• Maxwell PH, Wiesener MS, Chang GW, et al., The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 399(6733): 271–275. 1999.
   PubMed Web of Science ®Google Scholar
• Creighton C, Morgan M, Preethi H, et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499:43–49.
   PubMed Web of Science ®Google Scholar
• Fingar D, Blenis J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene. 2004;23(18):3151–3171.
   PubMed Web of Science ®Google Scholar
• Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell. 2010;40(2):310–322.
   PubMed Web of Science ®Google Scholar
• Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease [published correction appears in cell. Cell. 2017;168(6):960–976.
   PubMed Web of Science ®Google Scholar
• Santoni M, Conti A, Piva F, et al. Role of STAT3 pathway in genitourinary tumors. Future Sci OA. 2015 [Published 2015 Nov 1];1(3):FSO15.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol. 2000;163(2):408–417.
   PubMed Web of Science ®Google Scholar
• Lilleby W, Fosså SD. Chemotherapy in mccRCC. World J Urol. 2005;23(3):175–179.
   PubMed Web of Science ®Google Scholar
• Amin A, White RL. Interleukin-2 in renal cell carcinoma: a has-been or a still-viable option?J Kidney Cancer VHL. 2014 [2014 Nov 23];1(7):74–83.
   PubMedGoogle Scholar
• Wilhelm SM, Adnane L, Newell P, et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signalling. Mol Cancer Ther. 2008;7(10):3129–3140.
   PubMed Web of Science ®Google Scholar
• Escudier B, Eisen T, Stadler WM, et al., Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 356(2): 125. 2007.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–124.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722–731.
   PubMed Web of Science ®Google Scholar
• Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of Axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931–1939.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013;31(30):74–83.
   Web of Science ®Google Scholar
• Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN Trial. J Clin Oncol. 2017 Feb 20;35(6):591–597.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, Oudard S, et al. RECORD‐1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer.2010 Sep 15;116(18):4256–4265.
   PubMed Web of Science ®Google Scholar
• Bumpus HC. The apparent disappearance of pulmonary metastasis in a case of hypernephroma following nephrectomy. J Urol. 1928;20(2):185–192.
   Google Scholar
• Şenbabaoğlu Y, Gejman RS, Winer AG, et al. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures.Genome. Biol. 2016;17:231.
   Google Scholar
• Vuong L, Kotecha RR, Voss MH, et al. Tumor microenvironment dynamics in clear-cell renal cell carcinoma. Cancer Discov. 2019;9(10):1349–1357.
   PubMed Web of Science ®Google Scholar
• Maruhashi T, Sugiura D, Okazaki IM, et al. LAG-3: from molecular functions to clinical applications. J Immunother Cancer. 2020Sep;8(2):e001014. PMID: 32929051; PMCID: PMC7488795.
   PubMed Web of Science ®Google Scholar
• Morgan DA, Ruscetti FW, Gallo RC. Selective in vitro growth of T lymphocytes from normal human bone marrow. Science. 1976;193(4257):1007–1009.
   PubMed Web of Science ®Google Scholar
• Negrier S, Escudier B, Lasset C. Recombinant human interleukin-2, recombinant human interferon Alfa-2a, or both in metastatic renal-cell carcinoma. N Engl J Med. 1998;338(18):1272–1278.
   PubMed Web of Science ®Google Scholar
• Clark JI, Gaynor ER, Martone B, et al. Daily subcutaneous ultra-low-dose interleukin 2 with daily low-dose interferon-alpha in patients with advanced renal cell carcinoma. Clin Cancer Res. 1999 Sep;5(9):2374–2380.
   PubMed Web of Science ®Google Scholar
• Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007 Nov-Dec;30(8):825–830.
   PubMed Web of Science ®Google Scholar
• Topalian S, Hodi F, Brahmer J, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–2454.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, George S, et al. Nivolumab versus 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 Sep 15;126(18):4156–4167.
   PubMed Web of Science ®Google Scholar
• Amin A, Hammers H. The evolving landscape of immunotherapy-based combinations for frontline treatment of advanced renal cell carcinoma. Front Immunol. 2019;9:3120.
   PubMed Web of Science ®Google Scholar
• Ribatti D, Crivellato E. Immune cells and angiogenesis. J Cell Mol Med. 2009;13(9A):2822–2833.
   PubMed Web of Science ®Google Scholar
• Heng DYC, Xie W, Regan MM, et al., Prognostic factors for overall survival in patients with MccRCC treated with vascular endothelial growth factor–targeted agents: results from a large, multicenter study. J clin oncol. 27(34): 5794–5799. 2009.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17(8):2530–2540.
   PubMed Web of Science ®Google Scholar
• Hoefflin R, Harlander S, Schäfer S, et al. HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice. Nat Commun. 2020;11(1):4111.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC). J clin oncol. 2020;38(6_suppl):611.
   Google Scholar
• Voss MH, Gordon MS, Mita M, et al. Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer. Br J Cancer. 2020 Nov;123(11):1590–1598.
   PubMed Web of Science ®Google Scholar
• Nicholson HE, Tariq Z, Housden B, et al. HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species. Sci Signal. 2019;12(601). https://doi.org/10.1126/scisignal.aay0482.
   Google Scholar
• Holder SL, Warrick J, Zhu J, et al. A phase Ib study targeting PIM1 and CDK4/6 kinases in metastatic renal cell carcinoma (PICKRCC). J clin oncol. 2020;38(6_suppl):771.
   PubMed Web of Science ®Google Scholar
• Honma D, Kanno O, Watanabe J, et al. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 2017;108(10):2069–2078.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277–1290.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, McDermott DF. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891.
   PubMed Web of Science ®Google Scholar
• Hughes G, Carducci M, Tomczak P. Temsirolimus, interferon Alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271–2281. Motzer RJ
   PubMed Web of Science ®Google Scholar
• Amin A, Plimack ER, Ernstoff MS, et al. Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study. J Immunother Cancer. 2018 Oct 22;6(1):109.
   PubMed Web of Science ®Google Scholar
• Michaelson MD. Combination of targeted agents in metastatic renal cell carcinoma: a path forward or a dead-end street? Cancer. 2012;118(7):1744–1746.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, Everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473–1482.
   PubMed Web of Science ®Google Scholar
• Yamagishi M, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with mccRCC (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28(13):2144–2150. Cell Rep. 2019;29(8):2321-2337.e7 Escudier B, Bellmunt J, Négrier S et al
   PubMed Web of Science ®Google Scholar
• Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with mccRCC: CALGB 90206. J Clin Oncol. 2008 20; 26(33): 5422–5428.
   PubMed Web of Science ®Google Scholar
• Motzer R, Alekseev B, Rha S, et al. M.D., Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289–1300.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Powles T, Burotto M. Nivolumab + Cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: the CheckMate 9ER trial. Ann Oncol. 2020;31:S1159.
   Web of Science ®Google Scholar
• Rini BI, Powles T, Atkins MB, 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(10189):2404–2415.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Robbins PB, Powles T, et al. Avelumab plus Axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial. Nat Med. 2020;26(11):1733–1741.
   PubMed Web of Science ®Google Scholar
• Powles T, Plimack ER, Soulières D. 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. The New England Journal of Medicine. 2019Mar21;380(12):1116–1127.
   PubMedGoogle Scholar
• Choueiri TK, Bauer TM. McDermott D 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(suppl 6):abstr 272.
   Web of Science ®Google Scholar
• Braun DA, Bakouny Z, Hirsch L, et al. Beyond conventional immune-checkpoint inhibition — novel immunotherapies for renal cell carcinoma. Nat Rev Clin Oncol. 2021;18(4):199–214.
   PubMed Web of Science ®Google Scholar
• Meza LA, Dizman N. Paulo Gustavo Bergerot First results of a randomized phase IB study comparing Nivolumab/ipilimumab with or without CBM-588 in patients with metastatic renal cell carcinoma. J clin oncol. 2021;39(15_suppl):4513.
   Web of Science ®Google Scholar
• Lipson EJ, Tawbi HA-H, Schadendorf D, et al. Relatlimab (RELA) plus Nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). J clin oncol. 2021 May 20;39(15_suppl):9503.
   Google Scholar
• Diab A, Tannir NM. Bentebibel SE et al(NKTR-214) plus nivolumab in patients with advanced solid tumors: phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov. 2020 Aug;10(8):1158–1173. Epub 2020 May 21.
   PubMed Web of Science ®Google Scholar
• Schepisi G, Conteduca V, Casadei C, et al. Potential application of Chimeric Antigen Receptor (CAR)-T cell therapy in renal cell tumors. Front Oncol. 2020 Sep 23;10:565857.
   PubMed Web of Science ®Google Scholar
• Raimondi A, Sepe, P, Claps , M, et al. Do biomarkers play a predictive role for response to novel immunotherapeutic agents in metastatic renal cell carcinoma? Exp Op Biol Ther. 2019;19(11):1107–1110.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Banchereau R, Hamidi H, et al., Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade. Cancer Cell. 38(6): 803–817.e4. 2020.
   PubMed Web of Science ®Google Scholar
• Rühle A, Andratschke N, Siva S, et al. Is there a role for stereotactic radiotherapy in the treatment of renal cell carcinoma? Clin Transl Radiat Oncol. 2019;18:104–112.
   PubMed Web of Science ®Google Scholar
• Hammers HJ, Vonmerveldt D, Ahn C, et al. Combination of dual immune checkpoint inhibition (ICI) with stereotactic radiation (SBRT) in metastatic renal cell carcinoma (mRCC) (RADVAX RCC). J clin oncol. 2020;38(6_suppl):614.
   Web of Science ®Google Scholar
• Masini C, Iotti C, De Giorgi U, et al. Nivolumab in combination with stereotactic body radiotherapy in pretreated patients with metastatic renal cell carcinoma. Results of the Phase II NIVES study. Eur Urol. 2021 Sep 30;S0302-2838(21):2040–2046.
   Google Scholar
• Hoskin P, Sartor O, O’Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPA trial. Lancet Oncol. 2014 Nov;15(12):1397–1406. Epub 2014 October 17.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021 Aug 19;385(8):683–694.
   PubMed Web of Science ®Google Scholar
• Stewart GD, Welsh SJ, Ursprung S, et al. NAXIVA: a phase II neoadjuvant study of axitinib for reducing extent of venous tumor thrombus in clear cell renal cell cancer (RCC) with venous invasion. Journal of Clinical Oncology. 2021;39(6_suppl):275.
   Web of Science ®Google Scholar
• Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science. 2020;367(6477):eaax0182.
   PubMed Web of Science ®Google Scholar
• McDermott DF, Rini BI, Motzer RJ, et al. Treatment-free survival (TFS) after discontinuation of first-line nivolumab (NIVO) plus ipilimumab (IPI) or sunitinib (SUN) in intention-to-treat (ITT) and IMDC favorable-risk patients (pts) with advanced renal cell carcinoma (aRCC) from CheckMate 214. J clin oncol. 2019 March 01;37(7_suppl):564.
   Web of Science ®Google Scholar
• Regan M, Jegede OA. Mantia C et al Treatment-free survival, with and without toxicity, after immuno-oncology vs targeted therapy for advanced renal cell carcinoma; 42 month results of Checkmate 214. Annals of Oncology. 2020;31(suppl_4):S550.
   Google Scholar
• McDermott DF, Lee J-L, Bjarnason GA, et al. Open-Label, single-arm Phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced clear cell renal cell carcinoma. J clin oncol. 2021 March 20;39(9):1020–1028.
   PubMed Web of Science ®Google Scholar