PRESCRIBER'S CORNER

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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,

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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

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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 adverse events). Discontinuation of tistically significant ORR (43%,p < .0001) in com- the study drug due to adverse effects occurred in parison to the single-agent everolimus arm (4%) 37 patients who received lenvatinib (14.2%) and 3

Table 1. Incidence of Adverse Effects in at Least 25% of Lenvatinib Patients in the SELECT Trial Lenvatinib (n = 261) Placebo (n = 131) Adverse effect Any grade (%) Grade ≥ 3 (%) Any grade (%) Grade ≥ 3 (%) Any adverse event during treatment 97.3 75.9 59.5 9.9 Hypertension 67.8 41.8 9.2 2.3 Diarrhea 59.4 8.0 8.4 0 Fatigue or asthenia 59.0 9.2 27.5 2.3 Decreased appetite 50.2 5.4 11.5 0 Decreased weight 46.4 9.6 9.2 0 Nausea 41.0 2.3 13.7 0.8 Stomatitis 35.6 4.2 3.8 0 Palmar-plantar erythrodysesthesia syndrome 31.8 3.4 0.8 0 Proteinuria 31.0 10.0 1.5 0 Vomiting 28.4 1.9 6.1 0 Headache 27.6 2.7 6.1 0 Note. Information from Lexicomp Online (2017a).

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patients who received placebo (2.3%). In the len- currently FDA approved for this indication can be vatinib group, 6 of 20 deaths that occurred during considered if no clinical trials are available (NCCN, the treatment period were considered to be drug- 2016). The monthly cost differential for the FDA- related (Schlumberger et al., 2015). indicated regimens can be seen in Table 2. The NCCN Guidelines for RCC state that the CURRENT PLACE IN THERAPY combination of lenvatinib plus everolimus is an The FDA approval of lenvatinib supports its use option for the second-line treatment of meta- as monotherapy in metastatic, progressive, or static RCC. This recommendation is based upon RAI-refractory DTC and combination therapy high-level evidence and a uniform consensus with everolimus in RCC that has been previously from the panelists who developed the guide- treated with an antiangiogenic agent. Progression- lines. Although this is a strong recommendation, free survival associated with these regimens has phase III studies (METEOR and CheckMate 025) proved to be significantly greater than that of its state that eligible patients should receive cabo- comparators (FDA, 2015, 2016). zantinib (Cabometyx) and nivolumab (Opdivo) Several VEGF inhibitors have been studied over everolimus. In these trials, cabozantinib and in the treatment of both DTC and RCC as first- nivolumab were only studied against everolim- and second-line therapies. The trials looking at us as monotherapy, so their preference over the these agents include efficacy, comparative, and combination of lenvatinib and everolimus cannot placebo-controlled studies. Each of these studies be accurately extrapolated (NCCN, 2017). The has demonstrated that targeted therapies provide monthly cost differential for these regimens can beneficial antitumor activity in both cancers, es- be seen in Table 2. pecially in the second-line setting, where effec- tive alternative systemic therapies have not been IMPLICATIONS FOR THE ADVANCED identified (Patel, Chaganti, & Motzer, 2006; Shah PRACTITIONER et al., 2015). Lenvatinib is a once-daily oral capsule used for The National Comprehensive Cancer Net- DTC that is progressive, metastatic, or refracto- work (NCCN) Guidelines for thyroid carcinoma ry to RAI and for RCC that has previously been support the use of lenvatinib in the treatment treated with an antiangiogenic agent. This is an of metastatic thyroid cancer that is structurally agent likely to be actively utilized by prescribers persistent, refractory to RAI, and/or recurrent. due to the lack of substantial treatment options The guidelines also state that other agents such for the previously mentioned indications as well as sorafenib can be used as alternative agents. Of as the development of resistance to alternative the two agents, lenvatinib is the preferred drug, treatments within the same class (Lexicomp On- but the agent ultimately used is dependent on pa- line, 2017a). tient-specific factors such as comorbidities. These The recommended dosing of lenvatinib is in- therapies are listed as an option, meaning they are dication-based: 24 mg (two 10-mg capsules and based upon a lower level of evidence, but there is one 4-mg capsule) for patients with DTC and 18 uniform consensus that the therapy is appropri- mg (one 10-mg capsule and two 4-mg capsules) ate among the panelists who developed the guide- for patients with RCC. Lenvatinib is dispensed in lines. Other small-molecule kinase inhibitors not 30-day therapy packs. The 24-mg therapy pack

Table 2. 30-Day Supply Cost Analysis of Agents for Differentiated Thyroid Cancer and Renal Cell Carcinoma Differentiated thyroid cancer Renal cell carcinoma Lenvatinib 24 mg daily $2,945.80 Lenvatinib 18 mg and everolimus 5 mg daily $3,512.93 ($2,945.80 + $567.13) Sorafenib 400 mg bid $19,775.32 Cabozantinib 60 mg daily $17,746.61 Nivolumab 240 mg daily $7,330.03 Note. bid = twice a day. Information from FDA (2016); Lexicomp Online (2017b, 2017c, 2017d).

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comes with 90 capsules: sixty 10-mg capsules and uation. The primary reactions that led to dose thirty 4-mg capsules. The 18-mg therapy pack also reduction included hypertension and protein- comes with 90 capsules: thirty 10-mg capsules and uria (Cohen & McGovern, 2005). Dose inter- sixty 4-mg capsules. ruptions and modifications are called for when Regardless of indication, the medication is to persistent or intolerable grade 2 or 3 toxicities be taken at the same time once a day without re- or grade 4 lab abnormalities are present. Dose gard to food. The capsules should be swallowed interruptions should occur until the patient has whole, but if the patient is unable to do so, the recovered from the toxicity or it is minimized capsules can be dissolved in a small amount of to a grade 1 or lower. The dose modifications liquid. A missed dose should not be taken within occur based on the frequency of the ADR. The 12 hours of the next dose, and the patient should dose will be limited to 20 mg daily for a first- never take two doses at one time. It is important to time ADR, 14 mg daily for the second time, and hydrate well throughout therapy (Lexicomp On- 10 mg daily for the third time. Table 4 provides line, 2017a). a breakdown of the dose adjustments discussed Dosing adjustments for lenvatinib are needed here (Lexicomp Online, 2017a). for preexisting renal and hepatic impairment. If In the RCC study, 49% of patients taking len- the patient presents with a creatinine clearance of vatinib and everolimus suffered ADRs that led less than 30 mL/min, the dose must be adjusted to to dose reduction, and 24% had ADRs that led 14 mg once daily for DTC and 10 mg once daily for to treatment discontinuation. The most com- RCC. If the patient suffers severe hepatic impair- mon grade 3 and 4 toxicities associated with the ment (presents with Child-Pugh class C disease), combination regimen included diarrhea and hy- the dose must be adjusted to 14 mg once daily for pertension (FDA, 2015). Dose interruptions and DTC and 10 mg once daily for RCC (Lexicomp On- modifications are called for when persistent or line, 2017a). intolerable grade 2 or 3 toxicities or grade 4 lab Major interactions associated with lenvatinib abnormalities are present. Dose interruptions include the worsening of QTc prolongation when should occur until the patient is recovered or administered with other moderate- or high-risk the toxicity is minimized to a grade 1 or lower. QTc-prolonging agents. The risk associated with The dose modifications should occur based on QTc-prolonging agents is stratified by the follow- the frequency of the ADR. The dose will be lim- ing categories: X (avoid combination), D (consider ited to 14 mg daily for a first-time ADR, 10 mg therapy modification), and C (monitor therapy). daily for the second time, and 8 mg daily for the If combinations of lenvatinib and these drugs are third time. Table 4 provides a breakdown of the used, electrocardiograms should be obtained to dose adjustments discussed here (Lexicomp monitor for the prolongation of QTc. A complete Online, 2017a). list of agents and their risk stratification is provid- For patients who have or develop hyperten- ed in Table 3 (Lexicomp Online, 2017a). sion, it is imperative to monitor blood pressure As lenvatinib is a UGT1A1 inhibitor, it can in- prior to and throughout the treatment course. crease serum concentrations of irinotecan prod- Antihypertensive medications should be adjusted ucts, which are active metabolites of UGT1A1. The and maximized to achieve blood pressure con- combination of lenvatinib and irinotecan products trol. If the patient’s hypertension is not controlled should be avoided. Although lenvatinib is primar- with a maximal antihypertensive regimen, lenva- ily metabolized through CYP3A4, it is a minor tinib therapy should be held until hypertension is substrate of the enzyme, so no dose adjustments ≤ grade 2. or drug interactions need to be monitored (Lexi- For patients who develop ≥ 2 g proteinuria comp Online, 2017a). in 24 hours, lenvatinib therapy should be held. In the DTC study, 68% of patients taking len- Proteinuria can be associated with an increase in vatinib suffered adverse drug reactions (ADRs) blood pressure and an early sign of kidney damage. that led to dose reduction (average 17.2 mg), and A dipstick test should be used to monitor these pa- 18% had ADRs that led to treatment discontin- tients before initiation and periodically through-

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Table 3. Risk Stratification for Use of Lenvatinib With QTc-Prolonging Agents Category X Category D Category C Ajmaline Azithromycin (systemic) Albuterol Loperamide Amiodarone Bedaquiline Alfuzosin Loperamide oxide Anagrelide Benperidol Amantadine Maprotiline Arsenic trioxide Ceritinib Amisulpride Mefloquine Artemether Chloroquine Amitriptyline Methotrimeprazine Asenapine Chlorpromazine Amoxapine Metoclopramide Astemizole Ciprofloxacin (systemic) Apomorphine Metronidazole (systemic) Bepridil Clarithromycin Arformoterol Mianserin Cisapride Clozapine Aripiprazole Mirabegron Citalopram Crizotinib Aripiprazole lauroxil Mirtazapine Deutetrabenazine Delamanid Atazanavir Moexipril Disopyramide Dolasetron Atomoxetine Nelfinavir Dofetilide Droperidol Bortezomib Nicardipine Domperidone Efavirenz Bosutinib Norfloxacin Dosulepin Erythromycin (systemic) Buserelin Nortriptyline Dronedarone Escitalopram Capecitabine Octreotide Eliglustat Flecainide Chloral hydrate Olanzapine Fluoxetine Gadobenate dimeglumine Clomipramine Olodaterol Flupentixol Gemifloxacin Dabrafenib Oteracil Halofantrine Goserelin Dasatinib Oxaliplatin Hydroxychloroquine Granisetron Degarelix Oxytocin Ibutilide Haloperidol Desflurane Paroxetine Iloperidone Inotuzumab ozogamicin Desipramine Pasireotide Irinotecan Leuprolide Diphenhydramine (systemic) Pentamidine (oral inhalation) (conventional) Levofloxacin (oral inhalation) Donepezil Periciazine Irinotecan (liposomal) Levofloxacin (systemic) Doxepin (systemic) Posaconazole Lopinavir Lofexidine Doxepin (topical) Promethazine Lumefantrine Mequitazine Ebastine Propofol Mifepristone Methadone Eperisone Protriptyline Nilotinib Midostaurin Eribulin Ranolazine Paliperidone Moxifloxacin (systemic) Ezogabine Rilpivirine Pimavanserin Ofloxacin (systemic) Famotidine Risperidone Pimozide Ondansetron Felbamate Ritonavir Pipamperone Osimertinib Fingolimod Romidepsin Probucol Panobinostat Fluconazole Salmeterol Procainamide Pazopanib Fluorouracil (systemic) Sertraline Promazine Pentamidine (systemic) Formoterol Sevoflurane Quetiapine Pilsicainide Foscarnet Solifenacin Quinidine Primaquine Fosphenytoin Sorafenib Quinine Propafenone Gadofosveset Sulfamethoxazole Radotinib Roxithromycin Galantamine Sunitinib Ribociclib Saquinavir Halothane Tacrolimus (systemic) Sotalol Sodium stibogluconate Histrelin Tamoxifen Sparfloxacin Telavancin Hydroxyzine Tegafur Sulpiride Telithromycin Ibandronate Terbutaline Terfenadine Terlipressin Imipramine Thiothixene Tetrabenazine Indacaterol Tizanidine Thioridazine Indapamide Tolterodine Toremifene Isoflurane Trazodone Vandetanib Isoproterenol Treprostinil Vemurafenib Isradipine Trimethoprim Vernakalant Itraconazole Trimipramine Vinflunine Ivabradine Triptorelin Ziprasidone Ketoconazole (systemic) Tropisetron Zuclopenthixol Lacidipine Vardenafil Lapatinib Venlafaxine Levalbuterol Vilanterol Levosimendan Voriconazole Levosulpiride Vorinostat Lithium Xipamide Lofepramine

Note. X = avoid combination; D = consider therapy modification; C = monitor therapy. Information from FDA (2016).

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Table 4. Lenvatinib Dose Reductions per Disease State Renal cell carcinoma Differentiated thyroid cancer First occurrence Reduce dose to 14 mg once daily Reduce dose to 20 mg once daily Second occurrence Reduce dose to 10 mg once daily Reduce dose to 14 mg once daily Third occurrence Reduce dose to 8 mg once daily Reduce dose to 10 mg once daily Note. Information from FDA (2016). out treatment. If the urine dipstick proteinuria is ≥ effects (hypertension and diarrhea) can be medi- 2+, then the patient needs a 24-hour urine protein cally managed prior to any dose reduction or dis- level. Once the condition has resolved to < 2 g pro- continuation of therapy. Proteinuria, on the other teinuria in 24 hours, lenvatinib can be resumed at hand, requires a hold in therapy followed by a a reduced dose. dose reduction upon continuation. These side ef- The suggested dose reductions are specific to fects are comparable, and in some cases minimal, the disease state being treated. For patients who to the other agents that would be used for DTC develop diarrhea, prompt medical management is and RCC. suggested prior to interrupting lenvatinib therapy. Another factor to consider is the cost. Table Once the diarrhea has resolved, lenvatinib may be 2 provides a breakdown of the average wholesale reinitiated at the current or reduced dose. If di- price associated with each lenvatinib regimen arrhea persists regardless of optimal medication based on specific disease states. This table also management, lenvatinib therapy should be dis- compares lenvatinib with the FDA-approved ther- continued and not resumed. Disease-specific dose apeutic alternatives for each indication. In both reductions can be found in Table 4 (Lexicomp On- DTC and RCC, the monthly cost of lenvatinib is line, 2017a). lower than that of the other alternative regimens. Targeted therapies such as VEGF inhibitors SUMMARY have the potential to serve as first- and second- As seen in the SELECT study, lenvatinib alone can line treatment options for difficult-to-treat -ma serve as primary and secondary options for the lignancies such as DTC and RCC. Their unique treatment of DTC refractory to RAI. The agent mechanism of action hinders a key process in provides a positive PFS and durable response rate tumor growth and survival, thus limiting disease to a disease state with a previously poor progno- progression and allowing for tumor shrinking. sis. The currently ongoing trial evaluating lenva- The response of these agents in patients whose tinib use in advanced RCC shows that lenvatinib, malignancies have poor prognoses has garnered alone or in combination with everolimus, provides much excitement. l greater PFS, but the length of the ORR indicates the combination regimen may be more beneficial. Disclosure In either case, this agent offers a safer and more The authors have no potential conflicts of interest efficacious treatment alternative to patients who to disclose. may not have had that opportunity previously. Clinical data discussed in this review have References proved lenvatinib serves as an effective medica- ClinicalTrials.gov. (2017). A study of E7080 alone, and in com- tion option in DTC and RCC, but there are other bination with everolimus in subjects with unresectable advanced or metastatic renal cell carcinoma following factors to consider prior to administering it. One one prior vascular endothelial growth factor (VEGF)- such factor is the adverse-effect profile of lenva- targeted treatment. Retrieved from https://clinicaltrials. tinib. The SELECT and RCC studies reported the gov/ct2/show/NCT01136733 three primary adverse effects of lenvatinib that Cohen, H. T., & McGovern, F. J. (2005). Renal cell carcino- ma. New England Journal of Medicine, 353(23), 2477– led to dose modifications were hypertension, 2490. https://doi.org/10.1056/NEJMra043172 proteinuria, and diarrhea. Two of these adverse Durante, C., Haddy, N., Baudin, E., Leboulleux, S., Hartl, D.,

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