Lenvatinib in the management of metastatic renal cell carcinoma: a promising combination therapy?

References

• Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–E386.
   PubMed Web of Science ®Google Scholar
• Athar U, Gentile TC. Treatment options for metastatic renal cell carcinoma: a review. Can J Urol. 2008;15:3954–3956.
   PubMed Web of Science ®Google Scholar
• Baldewijns MM, van Vlodrop IJ, Vermeulen PB, et al. VHL and HIF signalling in renal cell carcinogenesis. J Pathol. 2010;221:125–138.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol. 2017;35:3916–3923.
   PubMed Web of Science ®Google Scholar
• Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375:2246–2254.
   PubMed Web of Science ®Google Scholar
• Koneru R, Hotte SJ. Role of cytokine therapy for renal cell carcinoma in the era of targeted agents. Curr Oncol. 2009;16:S40–S44.
   PubMed Web of Science ®Google Scholar
• Harshman LC, Drake CG, Choueiri TK. PD-1 blockade in renal cell carcinoma: to equilibrium and beyond. Cancer Immunol Res. 2014;2:1132–1141.
   PubMed Web of Science ®Google Scholar
• Farolfi A, Schepisi G, Conteduca V, et al. Pharmacokinetics, pharmacodynamics and clinical efficacy of nivolumab in the treatment of metastatic renal cell carcinoma. Expert Opin Drug Metab Toxicol. 2016;12:1089–1096.
   PubMed Web of Science ®Google Scholar
• Bukowski RM, Kabbinavar FF, Figlin RA, et al. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007;25:4536–4541.
   PubMed Web of Science ®Google Scholar
• Feldman DR, Baum MS, Ginsberg MS, et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1432–1439.
   PubMed Web of Science ®Google Scholar
• Ravaud A, Barrios CH, Alekseev B, et al. RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon alpha-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma. Ann Oncol. 2015;26:1378–1384.
   PubMed Web of Science ®Google Scholar
• Powles T, Foreshew SJ, Shamash J, et al. A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer. Eur J Cancer. 2014;50:2057–2064.
   PubMed Web of Science ®Google Scholar
• Hainsworth JD, Waterhouse DM, Penley WC, et al. Sorafenib and everolimus in advanced clear cell renal carcinoma: a phase I/II trial of the SCRI Oncology Research Consortium. Cancer Invest. 2013;31:323–329.
   PubMed Web of Science ®Google Scholar
• Kanesvaran R, Watt K, Turnbull JD, et al. A single-arm phase 1b study of everolimus and sunitinib in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. 2015;13:319–327.
   PubMed Web of Science ®Google Scholar
• Dorff TB, Pal SK, Quinn DI. Novel tyrosine kinase inhibitors for renal cell carcinoma. Expert Rev Clin Pharmacol. 2014;7:67–73.
   PubMed Web of Science ®Google Scholar
• Graves A, Hessamodini H, Wong G, et al. Metastatic renal cell carcinoma: update on epidemiology, genetics, and therapeutic modalities. Immunotargets Ther. 2013;2:73–90.
   PubMedGoogle Scholar
• Escudier B, Tannir N, McDermott D, et al. LBA5–CheckMate 214: efficacy and safety of nivolumab + ipilimumab vs sunitinib for treatment-naive advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Ann Oncol. 2017;28(Suppl 5):v605–v649.
   Google Scholar
• Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592–603.
   PubMed Web of Science ®Google Scholar
• Ravaud A, Gross-Goupil M. Overcoming resistance to tyrosine kinase inhibitors in renal cell carcinoma. Cancer Treat Rev. 2012;38:996–1003.
   PubMed Web of Science ®Google Scholar
• Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10:992–1000.
   PubMed Web of Science ®Google Scholar
• Négrier S, Gravis G, Pérol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12:673–680.
   PubMed Web of Science ®Google Scholar
• Rini BI, Bellmunt J, Clancy J, et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014;32:752–759.
   PubMed Web of Science ®Google Scholar
• Buti S, Leonetti A, Dallatomasina A, et al. Everolimus in the management of metastatic renal cell carcinoma: an evidence-based review of its place in therapy. Core Evid. 2016;11:23–36.
   PubMed Web of Science ®Google Scholar
• Welti JC, Gourlaouen M, Powles T, et al. Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib. Oncogene. 2011;30:1183–1193.
   PubMed Web of Science ®Google Scholar
• Yusuke A, Masahiro M, Atsumi Y, et al. Lenvatinib in combination with everolimus demonstrated enhanced antiangiogenesis and antitumor activity in human RCC xenograft models. Cancer Res. 2016;76:3264.
   Web of Science ®Google Scholar
• Tsimafeyeu I, Demidov L, Stepanova E, et al. Overexpression of fibroblast growth factor receptors FGFR1 and FGFR2 in renal cell carcinoma. Scand J Urol Nephrol. 2011;45:190–195.
   PubMed Web of Science ®Google Scholar
• Matsuki M, Adachi Y, Ozawa Y, et al. Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus. Cancer Sci. 2017;108:763–771.
   PubMed Web of Science ®Google Scholar
• Kaoru M, Takayuki K, Taisuke H, et al. Effects of lenvatinib mesilate in combination with everolimus on VEGF and FGF-driven angiogenesis and tumor growth. Cancer Res. 2015;15:3264.
   Google Scholar
• Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061–1068.
   PubMed Web of Science ®Google Scholar
• Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103–2111.
   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
• Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO clinical practice guidelines. Ann Oncol. 2016;27(Suppl 5):58–68.
   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
• Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–2281.
   PubMed Web of Science ®Google Scholar
• Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016;17:378–388.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1814–1823.
   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;373:1803–1813.
   PubMed 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;35:591–597.
   PubMed Web of Science ®Google Scholar
• Escudier B, Michaelson MD, Motzer RJ, et al. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014;110:2821–2828.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–456.
   PubMed Web of Science ®Google Scholar
• Yamamoto Y, Matsui J, Matsushima T, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 2014;6:18-824X-6-18.eCollection 2014.
   PubMedGoogle Scholar
• Matsui J, Funahashi Y, Uenaka T, et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008;14:5459–5465.
   PubMed Web of Science ®Google Scholar
• Tohyama O, Matsui J, Kodama K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014;2014:638747.
   PubMedGoogle Scholar
• Okamoto K, Ikemori-Kawada M, Jestel A, et al. Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett. 2014;6:89–94.
   PubMed Web of Science ®Google Scholar
• Okamoto K, Kodama K, Takase K, et al. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett. 2013;340:97–103.
   PubMed Web of Science ®Google Scholar
• Bruheim S, Kristian A, Uenaka T, et al. Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts. Int J Cancer. 2011;129:742–750.
   PubMed Web of Science ®Google Scholar
• Boss DS, Glen H, Beijnen JH, et al. A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer. 2012;106:1598–1604.
   PubMed Web of Science ®Google Scholar
• Ikeda M, Okusaka T, Mitsunaga S, et al. Safety and pharmacokinetics of lenvatinib in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2016;22:1385–1394.
   PubMed Web of Science ®Google Scholar
• Lenvatinib Summary of Product Characteristics. 2017. [Cited 2017 Sep 23]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003727/WC500188674.pdf
   Google Scholar
• Shumaker R, Aluri J, Fan J, et al. Influence of hepatic impairment on lenvatinib pharmacokinetics following single-dose oral administration. J Clin Pharmacol. 2015;55:317–327.
   PubMed Web of Science ®Google Scholar
• Molina AM, Hutson TE, Larkin J, et al. A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer Chemother Pharmacol. 2014;73:181–189.
   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;16:1473–1482.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Ren M, et al. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016;17:e4–e5.
   PubMed Web of Science ®Google Scholar
• Shumaker RC, Zhou M, Ren M, et al. Effect of lenvatinib (E7080) on the QTc interval: results from a thorough QT study in healthy volunteers. Cancer Chemother Pharmacol. 2014;73:1109–1117.
   PubMed Web of Science ®Google Scholar
• Yamada K, Yamamoto N, Yamada Y, et al. Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res. 2011;17:2528–2537.
   PubMed Web of Science ®Google Scholar
• Glen H, Hsieh J, Michaelson MD, et al. Correlative analyses of serum biomarkers and clinical outcomes in the phase 2 study of lenvatinib, everolimus, and the combination, in patients with metastatic renal cell carcinoma following 1 VEGF-targeted therapy. Eur J Cancer. 2015;51(Suppl 3):S89.
   Google Scholar
• Atkins MB, Gravis G, Drosik K, et al. Trebananib (AMG 386) in combination with sunitinib in patients with metastatic renal cell cancer: an open-label, multicenter, phase II study. J Clin Oncol. 2015;33:3431–3438.
   PubMed Web of Science ®Google Scholar
• Kato Y, Tabata K, Hori Y, et al. Effects of lenvatinib on tumor-associated macrophages enhance antitumor activity of PD-1 signal inhibitors. Mol Cancer Ther. 2015;14(12 Suppl 2):A92.
   Google Scholar