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Lenvatinib in the Treatment of Differentiated Thyroid Cancer and Advanced Renal Cell Carcinoma

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Lenvatinib in the Treatment of Differentiated Thyroid Cancer and Advanced Renal Cell Carcinoma PRESCRIBER'S CORNER Section Editors: Christopher J. Campen and Beth Eaby-Sandy Lenvatinib in the Treatment of Differentiated Thyroid Cancer and Advanced Renal Cell Carcinoma URVI J. PATEL, PharmD, MPH, and MEGAN MAY, PharmD, BCOP From Emory University Hospital, Atlanta, ifferentiated thyroidmainly due to the unresectable na- Georgia, and Baptist Health Lexington Lexington, Kentucky cancer (DTC) is a ma- ture of the disease, which leads to Authors’ disclosures of potential conflicts of lignancy that is oc- disease progression. interest are found at the end of this article. curring with greater Until 2013, the only US Food Correspondence to: Urvi J. Patel, PharmD, MPH, Dfrequency. Between the years 2006 and Drug Administration (FDA)- Emory University Hospital, 1364 Clifton Road NE, and 2010, the incidence increased at approved treatment option for B712, Atlanta, GA 30322. E-mail: [email protected] an annual rate of 5.4% in men and these patients was doxorubicin, but https://doi.org/10.6004/jadpro.2017.8.7.9 6.5% in women (Siegel, Ma, Zou, & the treatment landscape is chang- Jemal, 2014). Although the progno- ing with the development of tar- © 2017 Harborside™ sis of this cancer is favorable, op- geted therapies. The first targeted timal outcomes are only achieved agent to be approved for the treat- through a multidimensional ap- ment of RAI-refractory DTC was proach, which includes initial sur- sorafenib (Nexavar; Shah, Clayman, gery to remove the thyroid and sur- & Wirth, 2015). rounding lymph nodes, followed by Renal cell carcinoma (RCC) ac- adjuvant therapy with radioactive counts for nearly 2.6% of all cancers iodine (RAI). in men and women (Jemal et al., Radioactive iodine is generally 2005). Primary treatment for local- considered in patients with a high ized RCC includes radical nephrec- risk of locoregional recurrence or tomy, involving the surgical removal metastatic disease (which represents of the kidney, the ipsilateral adrenal less than 10% of patients with clini- gland, and lymph nodes. Adjuvant cal disease). This has been the main- therapy would be preferred in pa- stay of treatment for extrathyroidal tients who are at high risk for locally disease, but it has been determined advanced disease, but chemotherapy that two-thirds of these patients do and immunomodulatory agents do not respond to RAI (RAI-refractory not provide effective responses, re- DTC; Durante et al., 2006; Trun- sulting in poor prognosis. (Chemo- nell & Brayer, 1953). Patients who therapy alone produces a 4%–6% develop RAI-refractory DTC have a rate of response in patients with ad- J Adv Pract Oncol 2017;8:757–764 10-year overall survival rate of 19%, vanced RCC [Cohen & McGovern, AdvancedPractitioner.com 757 Vol 8 . No 7 . Nov/Dec 2017 PRESCRIBER'S CORNER PATEL and MAY 2005].) Given the limited response rate of tradi- CLINICAL TRIALS tional therapies, an aggressive search for new Differentiated Thyroid Cancer therapies to abate the condition has ensued. The The SELECT trial was a multicenter, 2:1 random- findings of this search have led to targeted thera- ized, double-blind, placebo-controlled phase III pies (Cohen & McGovern, 2005). study that evaluated lenvatinib for the treatment Novel targeted therapies allow for an oppor- of recurrent, progressive and/or refractory DTC. tunity to significantly improve the treatment op- In this study, 392 patients with locally recurrent tions of difficult-to-treat cancers such as DTC and or metastatic RAI-refractory DTC who presented RCC. Lenvatinib (Lenvima) is an oral multiple re- with radiographic evidence of disease progression ceptor tyrosine kinase inhibitor initially approved within the 12 months prior to the initiation of the in February 2015 for the treatment of DTC that is trial were randomized in a 2:1 ratio to treatment recurrent, progressive, or refractory to RAI (FDA, and placebo groups. The treatment group received 2015). As of May 2016, the agent has also been ap- 24 mg of lenvatinib once daily (Schlumberger et proved, in combination with everolimus (Afini- al., 2015). tor), for the treatment of patients with advanced The major efficacy outcome measured was RCC who were previously treated with antiangio- progression-free survival (PFS) using the Re- genic therapy (FDA, 2016). sponse Evaluation Criteria in Solid Tumors (RE- CIST). Secondary endpoints included objective PHARMACOLOGY/MECHANISM response rate (ORR) and overall survival (OS). OF ACTION The study revealed the lenvatinib arm provided a Lenvatinib is a multitargeted tyrosine kinase inhib- statistically significant improvement in PFS (18.3 itor of vascular endothelial growth factor (VEGF) months, hazard ratio [HR], 0.21; 95% confidence receptors VEGFR1 (FLT1), VEGFR2 (KDR), and interval [CI] = 0.16–0.28; p < .001) in comparison VEGFR3 (FLT4); fibroblast growth factor recep- to the placebo arm (3.6 months). The lenvatinib tors FGFR 1, 2, 3, and 4; as well as platelet-derived arm also produced a statistically significant ORR growth factor receptor alpha, KIT, and RET. Each (65%, p < .001) in comparison to the placebo arm of these receptor tyrosine kinases plays a key role (2%). Median OS had not been achieved in either in angiogenesis, which is one of the main processes treatment arm at the time of data collection (Sch- that allows tumor growth and progress. Inhibition lumberger et al., 2015). of these receptors allows for the minimization of When the investigators focused on the sub- an essential factor that the tumor needs to grow, group of patients who had previously been treated allowing for a decrease in the tumor size and slow- with VEGF inhibitors (25% of the patients enrolled ing of the progression of the cancer (Lexicomp in the study), lenvatinib yielded significantly im- Online, 2017a). proved PFS (median, 15.1 months vs. 3.6 months When lenvatinib is used in combination in the placebo arm; HR, 0.22; 95% CI = 0.12–0.41; with everolimus, which is a mechanistic target Schlumberger et al., 2015). These results show that of rapamycin (mTOR) inhibitor, the antiangio- lenvatinib has efficacy in the first-line and second- genic and antitumor activity of the drug is en- line settings for metastatic RAI-refractory DTC hanced. This further minimizes the endothelial (Schlumberger et al., 2015). cell proliferation, tubule formation, and VEGF signaling that is an essential inhibitory mecha- Renal Cell Carcinoma nism necessary to combat RCC (Lexicomp On- Lenvatinib, in combination with everolimus, was line, 2017a). approved by the FDA for the treatment of ad- Lenvatinib is primarily metabolized by the vanced RCC following one prior antiangiogenic hepatic enzyme CYP3A4 and aldehyde oxidase. therapy after the completion of a phase II study. Its half-life nears 28 hours, and it is mostly ex- The combination therapy was granted Break- creted through feces. The drug’s peak effect ini- through Therapy designation, as preliminary evi- tiates 1 to 4 hours after consumption (Lexicomp dence suggested substantial improvements over Online, 2017a). existing therapies in at least one endpoint as well J Adv Pract Oncol 758 AdvancedPractitioner.com LENVATINIB FOR DTC AND RCC PRESCRIBER'S CORNER as the combination’s intent to treat a serious or but only a numerically improved ORR in compari- life-threatening disease (FDA, 2016). son to the lenvatinib-alone group (27%; p = .10; The lenvatinib and everolimus combination is Motzer et al., 2015). being studied in an ongoing 1:1:1 randomized, phase An independent radiologic review was con- II multicenter, open-label study (ClinicalTrials.gov, ducted to determine whether the efficacy results 2017) across five countries. This study aims to de- from the initial investigator assessment were re- termine the PFS among the three arms of the study: ported accurately. This independent review sup- lenvatinib alone (24 mg once daily), lenvatinib plus ported the PFS benefits of lenvatinib plus everoli- everolimus (18 mg once daily and 5 mg once daily, mus in comparison to everolimus alone for patients respectively), and everolimus alone (10 mg once dai- with metastatic RCC whose disease progressed ly). Each treatment was administered continuously after one previous VEGF-targeted treatment in 28-day cycles until disease progression or unac- (Motzer, Hutson, Ren, Dutcus, & Larkin, 2016). ceptable toxicity developed (Motzer et al., 2015). Although the data indicate both the single- Publication of the initial findings from March agent lenvatinib and combination lenvatinib ther- 2012 to June 2013 indicated that 153 patients were apies provide an adequate response, the length of randomized into the lenvatinib (n = 52), lenva- the ORR suggests the combination may prove to tinib plus everolimus (n = 51), and everolimus be more efficacious (Motzer et al., 2015). (n = 50) groups. The study found that lenvatinib plus everolimus significantly improved PFS (14.6 ADVERSE EFFECTS months) when compared against everolimus The primary adverse effects of any grade that oc- alone (5.5 months, p = .0005) but not against len- curred in more than 40% of patients in the phase III vatinib alone (7.4 months, p = .12). The study also SELECT trial in the lenvatinib group were hyper- found that single-agent lenvatinib significantly tension (67.8%), diarrhea (59.4%), fatigue or asthe- prolonged PFS in comparison to everolimus alone nia (59.0%), decreased appetite (50.2%), decreased (HR, 0.61; 95% CI = 0.38–0.98; p = .048). The len- weight (46.4%), and nausea (41.0%; see Table 1 vatinib plus everolimus arm also produced a sta- for additional
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