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

被引：10

作者：

De Lisi, Delia ^{[1
]}

De Giorgi, Ugo ^{[2
]}

Lolli, Cristian ^{[2
]}

Schepisi, Giuseppe ^{[2
]}

Conteduca, Vincenza ^{[2
]}

Menna, Cecilia ^{[2
]}

Tonini, Giuseppe ^{[1
]}

Santini, Daniele ^{[1
]}

Farolfi, Alberto ^{[2
]}

机构：

[1] Campus Biomed Univ, Med Oncol Dept, Rome, Italy

[2] IRCCS IRST, Oncol Unit, Meldola, Italy

来源：

EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY | 2018年 / 14卷 / 04期

关键词：

Everolimus; lenvatinib; metastatic renal cell carcinoma; second line therapy; target therapy; TYROSINE KINASE INHIBITOR; PHASE-III TRIAL; INTERFERON-ALPHA; OPEN-LABEL; ANTITUMOR-ACTIVITY; TARGETED THERAPY; DOUBLE-BLIND; EVEROLIMUS; SUNITINIB; BEVACIZUMAB;

D O I：

10.1080/17425255.2018.1455826

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Introduction: To date, results of combination therapy studies have shown no meaningful clinical benefit over monotherapy and an unacceptably high degree of toxicity in the treatment of metastatic renal cell carcinoma (RCC), with the exception of a combination of immune-checkpoint inhibitors and the association of lenvatinib with everolimus. Lenvatinib is a potent multi-targeted tyrosine kinase inhibitor that targets VEGFR pathways. Everolimus inhibits primarily mTORC1 complex, a downstream effecter of the intracellular PI3K/AKT/mTOR pathway. The association of these two drugs was demonstrated to enhance the inhibitory activity against VEGF and FGF-induced angiogenesis by a vertical inhibition of angiogenic signaling pathways, suggesting a synergistic activity. Areas covered: In this review we summarize the lenvatinib pharmacokinetics, pharmacodynamics, characteristics and the main clinical trial that showed lenvatinib activity in advanced RCC. Expert opinion: Lenvatinib plus everolimus showed promising results in a phase II trial, leading to FDA approval of this combination. Their synergic action on inhibiting the VEGF/VEGFR, FGF (a compensatory mechanism to VEGFR inhibition) and mTOR pathway could be a potential mechanism to overcome treatment resistance. Given that the activity of lenvatinib as an immune-regulator in tumor microenvironment has been demonstrated in cell lines, novel combinations, in particular with immune-checkpoint inhibitors, are under development.

引用

页码：461 / 467

页数：7

共 58 条

[11] Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma [J].

Choueiri, T. K. ;

Escudier, B. ;

Powles, T. ;

Mainwaring, P. N. ;

Rini, B. I. ;

Donskov, F. ;

Hammers, H. ;

Hutson, T. E. ;

Lee, J-L ;

Peltola, K. ;

Roth, B. J. ;

Bjarnason, G. A. ;

Geczi, L. ;

Keam, B. ;

Maroto, P. ;

Heng, D. Y. C. ;

Schmidinger, M. ;

Kantoff, P. W. ;

Borgman-Hagey, A. ;

Hessel, C. ;

Scheffold, C. ;

Schwab, G. M. ;

Tannir, N. M. ;

Motzer, R. J. .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (19) :1814-1823

[12] 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].

Choueiri, Toni K. ;

Halabi, Susan ;

Sanford, Ben L. ;

Hahn, Olwen ;

Michaelson, M. Dror ;

Walsh, Meghara K. ;

Feldman, Darren R. ;

Olencki, Thomas ;

Picus, Joel ;

Small, Eric J. ;

Dakhil, Shaker ;

George, Daniel J. ;

Morris, Michael J. .

JOURNAL OF CLINICAL ONCOLOGY, 2017, 35 (06) :591-+

[13] Novel tyrosine kinase inhibitors for renal cell carcinoma [J].

Dorff, Tanya B. ;

Pal, Sumanta K. ;

Quinn, David I. .

EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2014, 7 (01) :67-73

[14]

Escudier B, 2017, ANN ONCOL, V28

[15] Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [J].

Escudier, B. ;

Porta, C. ;

Schmidinger, M. ;

Rioux-Leclercq, N. ;

Bex, A. ;

Khoo, V. ;

Gruenvald, V. ;

Horwich, A. .

ANNALS OF ONCOLOGY, 2016, 27 :v58-v68

[16] Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial [J].

Escudier, B. ;

Michaelson, M. D. ;

Motzer, R. J. ;

Hutson, T. E. ;

Clark, J. I. ;

Lim, H. Y. ;

Porfiri, E. ;

Zalewski, P. ;

Kannourakis, G. ;

Staehler, M. ;

Tarazi, J. ;

Rosbrook, B. ;

Cisar, L. ;

Hariharan, S. ;

Kim, S. ;

Rini, B. I. .

BRITISH JOURNAL OF CANCER, 2014, 110 (12) :2821-2828

[17] Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial [J].

Escudier, Bernard ;

Pluzanska, Anna ;

Koralewski, Piotr ;

Ravaud, Alain ;

Bracarda, Sergio ;

Szczylik, Cezary ;

Chevreau, Christine ;

Filipek, Marek ;

Melichar, Bohuslav ;

Bajetta, Emilio ;

Gorbunova, Vera ;

Bay, Jacques-Olivier ;

Bodrogi, Istvan ;

Jagiello-Gruszfeld, Agnieszka ;

Moore, Nicola .

LANCET, 2007, 370 (9605) :2103-2111

[18] Pharmacokinetics, pharmacodynamics and clinical efficacy of nivolumab in the treatment of metastatic renal cell carcinoma [J].

Farolfi, Alberto ;

Schepisi, Giuseppe ;

Conteduca, Vincenza ;

Burgio, Salvatore Luca ;

Lolli, Cristian ;

De Giorgi, Ugo .

EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2016, 12 (09) :1089-1096

[19] Phase I Trial of Bevacizumab Plus Escalated Doses of Sunitinib in Patients With Metastatic Renal Cell Carcinoma [J].

Feldman, Darren R. ;

Baum, Michael S. ;

Ginsberg, Michelle S. ;

Hassoun, Hani ;

Flombaum, Carlos D. ;

Velasco, Susanne ;

Fischer, Patricia ;

Ronnen, Ellen ;

Ishill, Nicole ;

Patil, Sujata ;

Motzer, Robert J. .

JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (09) :1432-1439

[20] Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 [J].

Ferlay, Jacques ;

Soerjomataram, Isabelle ;

Dikshit, Rajesh ;

Eser, Sultan ;

Mathers, Colin ;

Rebelo, Marise ;

Parkin, Donald Maxwell ;

Forman, David ;

Bray, Freddie .

INTERNATIONAL JOURNAL OF CANCER, 2015, 136 (05) :E359-E386

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