Avelumab and axitinib in the treatment of renal cell carcinoma: safety and efficacy

References

• Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
   PubMed Web of Science ®Google Scholar
• Kidney cancer incidence statistics | Cancer Research UK.
   Google Scholar
• Wilson KM, Cho E. Obesity and kidney cancer. Recent Results Cancer Res. 2016;208:81–93. Springer New York LLC.
   PubMedGoogle Scholar
• Hsieh JJ, Purdue MP, Signoretti S, et al. Renal cell carcinoma. Nat Rev Dis Prim. 2017;3:17009.
   PubMed Web of Science ®Google Scholar
• Heng DYC, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27:5794–5799.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019. DOI:10.1016/S1470-2045(19)30413-9.
   Google Scholar
• Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the Phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27:3312–3318.
   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;356:115–124.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116:4256–4265.
   PubMed Web of Science ®Google Scholar
• Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009;27:4462–4468.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–1813.
   PubMed Web of Science ®Google Scholar
• Escudier B, Porta C, Schmidinger M, et al. ESMO clinical practice guidelines for diagnostics, treatment and follow up. Ann Oncol. 2016;27(Suppl 5):v58–v68.
   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;369:722–731.
   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;31:3791–3799.
   PubMed Web of Science ®Google Scholar
• Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28:2144–2150.
   PubMed Web of Science ®Google Scholar
• Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. J Urol. 2008;179:497–498.
   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;16:1473–1482.
   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;378:1931–1939.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17:917–927.
   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;378:1277–1290.
   PubMed Web of Science ®Google Scholar
• Heng DYC, Choueiri TK, Rini BI, et al. Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials. Ann Oncol. 2014;25:149–154.
   PubMed Web of Science ®Google Scholar
• Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116–1127.
   PubMed Web of Science ®Google Scholar
• Highlights of Prescribing Information. Available from: www.fda.gov/medwatch
   Google Scholar
• NIH U.S. National Library of Medicine. No Title. Available from: https://chem.nlm.nih.gov/chemidplus/rn/1537032-82-8
   Google Scholar
• Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent cellular cytotoxicity activity of a novel Anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res. 2015;3:1148–1157.
   PubMed Web of Science ®Google Scholar
• Fujii R, Friedman ER, Richards J, et al. Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab. Available from: www.impactjournals.com/oncotarget
   Google Scholar
• Juliá EP, Amante A, Pampena MB, et al. Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against triple negative breast cancer cells. Front Immunol. 2018;9:1–12.
   PubMed Web of Science ®Google Scholar
• Giles AJ, Hao S, Padget M, et al. Efficient ADCC killing of meningioma by avelumab and a high-affinity natural killer cell line, haNK. JCI Insight. 2019;4. DOI:10.1172/jci.insight.130688
   Web of Science ®Google Scholar
• Heery CR, O’Sullivan-Coyne G, Madan RA, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18:587–598.
   PubMed Web of Science ®Google Scholar
• Vinay DS, Ryan EP, Pawelec G, et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;S185–S198. Academic Press. DOI:10.1016/j.semcancer.2015.03.004
   PubMed Web of Science ®Google Scholar
• Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;252–264. DOI:10.1038/nrc3239.
   PubMed Web of Science ®Google Scholar
• Khair DO, Bax HJ, Mele S, et al. Combining immune checkpoint inhibitors: established and emerging targets and strategies to improve outcomes in melanoma. Front Immunol. 2019. Frontiers Media S.A. DOI:10.3389/fimmu.2019.00453
   PubMed Web of Science ®Google Scholar
• Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017. Frontiers Media S.A. DOI:10.3389/fphar.2017.00561
   PubMed Web of Science ®Google Scholar
• Tatsugami K, Itsumi M. Immunotherapy for renal cell carcinoma. Clin Dev Immunol. 2010;2010:284581.
   PubMedGoogle Scholar
• Atkins MB, Sparano J, Fisher RI, et al. Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma. J Clin Oncol. 1993;11:661–670.
   PubMed Web of Science ®Google Scholar
• Atkins MB, Lotze MT, Dutcher JP, et al. High-Dose Recombinant Interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105.
   PubMed Web of Science ®Google Scholar
• Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688–696.
   PubMed Web of Science ®Google Scholar
• Gore ME, De Mulder P. Establishing the role of cytokine therapy in advanced renal cell carcinoma. BJU Int. 2008;101:1063–1070.
   PubMed Web of Science ®Google Scholar
• Wierecky J, Müller MR, Wirths S, et al. Immunologic and clinical responses after vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients. Cancer Res. 2006;66:5910–5918.
   PubMed Web of Science ®Google Scholar
• Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114: 1537–1544.
   PubMed Web of Science ®Google Scholar
• Wang Z, Peng S, Xie H, et al. Prognostic and clinicopathological significance of PD-L1 in patients with renal cell carcinoma: a meta-analysis based on 1863 individuals. Clin Exp Med. 2018;18:165–175.
   PubMed Web of Science ®Google Scholar
• Joseph RW, Millis SZ, Carballido EM, et al. PD-1 and PD-L1 expression in renal cell carcinoma with sarcomatoid differentiation. Cancer Immunol Res. 2015;3:1303–1307.
   PubMed Web of Science ®Google Scholar
• Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–268.
   PubMed Web of Science ®Google Scholar
• Novakovic AM, Wilkins JJ, Dai H, et al. Changing body weight–based dosing to a flat dose for avelumab in metastatic merkel cell and advanced urothelial carcinoma. Clin Pharmacol Ther. 2019;107:588-596.
   Web of Science ®Google Scholar
• Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008;14:7272–7283.
   PubMed Web of Science ®Google Scholar
• Goldstein R, Pickering L, Larkin J. Does axitinib (AG-01376) have a future role in metastatic renal cell carcinoma and other malignancies? Expert Rev Anticancer Ther. 2010;10:1545–1557.
   PubMed Web of Science ®Google Scholar
• INLYTA ® (axitinib) Product Monograph.
   Google Scholar
• Lee SH, Jeong D, Han YS, et al. Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis. Ann Surg Treat Res. 2015;1–8. Korean Surgical Society. DOI:10.4174/astr.2015.89.1.1
   PubMed Web of Science ®Google Scholar
• Ju L, Zhou Z, Jiang B, et al. Autocrine VEGF and IL-8 promote migration via Src/Vav2/Rac1/PAK1 signaling in human umbilical vein endothelial cells. Cell Physiol Biochem. 2017;41:1346–1359.
   PubMedGoogle Scholar
• Rini BI. Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions. Clin Cancer Res. 2007;1098–1106. DOI:10.1158/1078-0432.CCR-06-1989
   PubMed Web of Science ®Google Scholar
• Baldewijns MM, Van Vlodrop IJH, Vermeulen PB, et al. VHL and HIF signalling in renal cell carcinogenesis. J Pathol. 2010;125–138. DOI:10.1002/path.2689
   PubMedGoogle Scholar
• Heng D, Bukowski R. Anti-angiogenic targets in the treatment of advanced renal cell carcinoma. Curr Cancer Drug Targets. 2008;676–682. DOI:10.2174/156800908786733450
   PubMed Web of Science ®Google Scholar
• Mollica V, Di Nunno V, Gatto L, et al. Resistance to systemic agents in renal cell carcinoma predict and overcome genomic strategies adopted by tumor. Cancers (Basel). 2019. MDPI AG. DOI:10.3390/cancers11060830
   Web of Science ®Google Scholar
• Yasuda S, Sho M, Yamato I, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol. 2013;172:500–506.
   PubMed Web of Science ®Google Scholar
• Lapeyre-Prost A, Terme M, Pernot S, et al. Immunomodulatory activity of VEGF in cancer. Int Rev Cell Mol Biol. 2017;330:295–342. Elsevier Inc.
   PubMed Web of Science ®Google Scholar
• Yuan H, Cai P, Li Q, et al. Axitinib augments antitumor activity in renal cell carcinoma via STAT3-dependent reversal of myeloid-derived suppressor cell accumulation. Biomed Pharmacother. 2014;68:751–756.
   PubMed Web of Science ®Google Scholar
• Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: A randomised open-label phase 3 trial. Lancet Oncol. 2013;14:1287–1294.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103–1115.
   PubMed Web of Science ®Google Scholar
• Amin A, Plimack ER, Ernstoff MS, et al. Safety and efficacy of nivolumab I combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study. J Immunther Cancer. 2018;6(1):109.
   PubMed Web of Science ®Google Scholar
• Rini BI, Melichar B, Ueda T, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: A randomised double-blind phase 2 trial. Lancet Oncol. 2013;14:1233–1242.
   PubMed Web of Science ®Google Scholar
• Rini BI, Schiller JH, Fruehauf JP, et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res. 2011;17:3841–3849.
   PubMed Web of Science ®Google Scholar
• Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol. 2007;8:975–984.
   PubMed Web of Science ®Google Scholar
• Vaishampayan U, Schöffski P, Ravaud A, et al. Avelumab monotherapy as first-line or second-line treatment in patients with metastatic renal cell carcinoma: phase Ib results from the JAVELIN Solid Tumor trial. J Immunother Cancer. 2019;7. DOI:10.1186/s40425-019-0746-2
   Web of Science ®Google Scholar
• Choueiri TK, Larkin J, Oya M, et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol. 2018;19:451–460.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Motzer RJ, Campbell MT, et al. Subgroup analysis from JAVELIN Renal 101: outcomes for avelumab plus axitinib (A + Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). J Clin Oncol. 2019;37:544.
   Google Scholar
• Long GV, Tykodie SS, Schneider JG, et al. Assessment of nivolumab exposure and clinical safety of 480mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol. 2018 Nov;29(11):2208–2213.
   PubMed Web of Science ®Google Scholar
• Escudier B. Combination therapy as first-line treatment in metastatic renal-cell carcinoma. N Engl J Med. 2019 Mar;380:1176–1178.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Huang B. Immune checkpoint blockade plus axitinib for renal-cell carcinoma. N Engl J Med NLM (Medline). 2019;380(26):2581–2582.
   Google Scholar
• onclive peer exchange. No Title. Nov. Comb. mRCC Axi/Pembro vs Axi/Avelumab. p. Available from: https://www.onclive.com/peer-exchange/rcc-practica
   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;393:2404–2415.
   PubMed Web of Science ®Google Scholar
• Cheville J, Lohse C, Zincke H, et al. Sarcomatoid renal cell carcinoma. Saudi J Kidney Dis Transpl. 2011;22:120–122.
   PubMedGoogle Scholar
• Golshayan AR, George S, Heng DY, et al. Metastatic sarcomatoid renal cell carcinoma treated with vascular endothelial growth factor–targeted therapy. J Clin Oncol. 2009;27:235–241.
   PubMed Web of Science ®Google Scholar
• McDermott DF, Choueiri TK, Motzer RJ, et al. CheckMate 214 post-hoc analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features. J Clin Oncol. 2019;37:4513.
   Web of Science ®Google Scholar
• Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC): outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study. J Clin Oncol. 2019;37:4500.
   Web of Science ®Google Scholar
• Choueiri TK, Boston M. ESMO 2019: efficacy and biomarker analysis of patients with advanced renal cell carcinoma with sarcomatoid histology: subgroup analysis from the phase III JAVELIN renal 101 trial. 2019.
   Google Scholar
• Vera-Badillo FE, Templeton AJ, Duran I, et al. Systemic therapy for non-clear cell renal cell carcinomas: A systematic review and meta-analysis. Eur Urol. 2015;740–749. Elsevier B.V. DOI:10.1016/j.eururo.2014.05.010
   PubMed Web of Science ®Google Scholar
• Koshkin VS, Barata PC, Zhang T, et al. Clinical activity of nivolumab in patients with non-clear cell renal cell carcinoma. J Immunother Cancer. 2018;6:9.
   PubMed Web of Science ®Google Scholar
• Chahoud J, Msaouel P, Campbell MT, et al. Nivolumab for the treatment of patients with metastatic non‐clear cell renal cell carcinoma (nccRCC): a single‐institutional experience and literature meta‐analysis. The Oncologist. 2019;25(3):252–258.
   Web of Science ®Google Scholar
• Vogelzang NJ, McFarlane JJ, Kochenderfer MD, et al. Efficacy and safety of nivolumab in patients with non-clear cell renal cell carcinoma (RCC): results from the phase IIIb/IV CheckMate 374 study. J Clin Oncol. 2019;37:562.
   Google Scholar
• ASCO GU 2019: Results from KEYNOTE-427 Cohort Bb - First-line Pembrolizumab Monotherapy for Advanced Non-Clear Cell RCC.
   Google Scholar
• Daugherty M, Daugherty E, Jacob J, et al. Renal cell carcinoma and brain metastasis: questioning the dogma of role for cytoreductive nephrectomy. Urol Oncol Semin Orig Investig. 2019;37:182.e9-182.e15.
   PubMed Web of Science ®Google Scholar
• Flippot R, Dalban C, Laguerre B, et al. Safety and efficacy of nivolumab in brain metastases from renal cell carcinoma: results of the GETUG-AFU 26 NIVOREN multicenter phase II study. J Clin Oncol. 2019;2008–2016. American Society of Clinical Oncology. DOI:10.1200/JCO.18.02218
   PubMedGoogle Scholar
• Meeting Library | Safety and efficacy of nivolumab plus ipilimumab (NIVO+IPI) in patients with advanced renal cell carcinoma (aRCC) with brain metastases: Interim analysis of CheckMate 920.
   Google Scholar
• Rao A, Patel MR. A review of avelumab in locally advanced and metastatic bladder cancer. Ther Adv Urol. 2019;11:175628721882348.
   Web of Science ®Google Scholar
• CHMP. Bavencio; INN-avelumab. Available from: www.ema.europa.eu/contact
   Google Scholar
• Bex A, Van Thienen JV, Schrier M, et al. A phase 2, single-arm trial of neoadjuvant axitinb plus avelumab in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). J Clin Oncol. 2018;36. DOI:10.1200/JCO.2018.36.15_suppl.TPS4604
   Web of Science ®Google Scholar
• Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379:417–427.
   PubMed Web of Science ®Google Scholar
• Turajlic S, Xu H, Litchfield K, et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx Renal. Cell. 2018;173:581–594.
   PubMed Web of Science ®Google Scholar
• McDermott DF, Huseni MA, Atkins MB, 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.
   PubMed Web of Science ®Google Scholar