u.s. food and drug administration approval:...

CCR Drug Updates

U.S. Food and Drug Administration Approval:Cabozantinib for the Treatment of AdvancedRenal Cell CarcinomaHarpreet Singh, Michael Brave, Julia A. Beaver, JoyceCheng, Shenghui Tang, Eias Zahalka,Todd R. Palmby, Rajesh Venugopal, Pengfei Song, Qi Liu, Chao Liu, Jingyu Yu, Xiao HongChen, XingWang,YaningWang, Paul G. Kluetz, SelenaR.Daniels, Elektra J. Papadopoulos,Rajeshwari Sridhara, Amy E. McKee, Amna Ibrahim, Geoffrey Kim, and Richard Pazdur

Abstract

On April 25, 2016, the FDA approved cabozantinib(Cabometyx; Exelixis, Inc.) for the treatment of advanced renalcell carcinoma (RCC) in patients who have received priorantiangiogenic therapy. The approval was based on data fromone randomized, open-label, multicenter study in whichpatients with RCC who had received prior antiangiogenictherapy were treated with either cabozantinib 60 mg orallyonce daily (n¼ 330) or everolimus 10mg orally once daily (n¼328). The major efficacy outcome measure was progression-freesurvival (PFS) as assessed by a blinded independent radiologyreview committee in the first 375 randomized patients. Astatistically significant improvement in PFS was seen, with a

median PFS of 7.4 and 3.8 months in the cabozantinib andeverolimus arms, respectively [hazard ratio (HR), 0.58; 95%confidence interval (CI), 0.45–0.74; P < 0.0001]. At a secondinterim analysis, a statistically significant improvement inoverall survival (OS) in the intent-to-treat population was alsodemonstrated, with a median OS of 21.4 and 16.5 months inthe cabozantinib and everolimus arms, respectively (HR, 0.66;95% CI, 0.53–0.83; P ¼ 0.0003). The most common (greaterthan or equal to 25%) adverse reactions included diarrhea,fatigue, nausea, decreased appetite, palmar–plantar erythrody-sesthesia syndrome, hypertension, vomiting, weight loss, andconstipation. Clin Cancer Res; 23(2); 330–5. �2016 AACR.

IntroductionIn 2015, it is estimated that there will be 61,560 new cases and

14,080 deaths from renal cell carcinoma (RCC) in the UnitedStates (1). Advanced RCC is most commonly treated with anti-angiogenic therapy in the first-line setting, and, after initialprogression, the median progression-free survival (PFS) andoverall survival (OS) can be as little as 5 and 20 months, respec-tively. Although there is an unmet medical need to improveclinical outcomes in advanced RCC, new treatment paradigmsare emerging. There are currently four approved therapies foradvanced RCC in the second-line setting: everolimus, axitinib,nivolumab, and lenvatinib in combination with everolimus.

Everolimus is an mTOR inhibitor that demonstrated a medianPFS improvement over placebo of 4.9 versus 1.9 months (2).Axitinib, a tyrosine kinase inhibitor (TKI), demonstrated a medi-an PFS improvement over sorafenib of 6.7 versus 4.7 months (3).Nivolumab, an immunotherapy, was approved in 2015 with amedianOS benefit over everolimus of 25 versus 19.6months (4).

Lenvatinib, a multiple TKI, was approved in combination witheverolimus in May 2016 based on an improved PFS of 14.6months compared with 5.5 months with everolimus alone (5).

Cabozantinib was previously approved in 2012 with a capsuleformulation (Cometriq; Exelixis, Inc.) for the treatment of met-astatic medullary thyroid cancer (MTC). During the developmentof cabozantinib for RCC, the application was granted Break-through Therapy designation, Fast Track, and Priority Review(6). The FDA approval summary of the marketing applicationfor cabozantinib tablets is provided below.

ChemistryThe(S)-malate salt of cabozantinib is described chemically

as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluoro-phenyl) cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutane-dioate. The commercial cabozantinib drug product tabletformulation (Cabometyx; Exelixis, Inc.) is marketed in threestrengths (20, 40, and 60 mg).

Nonclinical Pharmacology and ToxicologyCabozantinib is an inhibitor of receptor tyrosine kinases,

including MET; VEGFR-1, -2, and -3; AXL; RET; ROS1; TYRO3;MER; KIT; TRKB; FLT-3; and TIE-2. These receptor tyrosine kinasesare involved in both normal cellular function and pathologicprocesses, such as oncogenesis, metastasis, tumor angiogenesis,drug resistance, and maintenance of the tumor microenviron-ment (7). There is a rationale in targeting bothAXL andMETwhenconsidering acquired resistance to VEGR inhibitors in RCC. In

U.S. Food and Drug Administration, White Oak, Maryland.

Note: This is a U.S. Government work. There are no restrictions on its use.

Corresponding Author: Harpreet Singh, U.S. Food and Drug Administration,Center for Drug Evaluation and Research (CDER), 10903 New HampshireAvenue, WO 22 Room 2137, Silver Spring, MD 20993. Phone: 240-402-3561;Fax: 301-796-9845; E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-16-1073

�2016 American Association for Cancer Research.

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preclinical studies, the inhibition of AXL and MET suggested thattreatment with cabozantinib may overcome resistance to pro-longed VEGF therapy (8).

Supporting nonclinical pharmacology and toxicology datasubmitted for this New Drug Application (NDA) were previouslyreviewed during the metastatic MTC cabozantinib review, andupdated carcinogenicity data were submitted in fulfilment of apostmarketing requirement (PMR) under the MTC application(9). Cabozantinib was not carcinogenic in a 26-week carcinoge-nicity study in rasH2 transgenic mice.

Clinical PharmacologyFollowing oral administration of cabozantinib tablet formu-

lation, median time to peak cabozantinib plasma concentration(Tmax) ranged from2 to3hours after dosing. A19% increase in theCmax of the tablet formation compared with the capsule formu-lation was observed following a single 140 mg dose. A lessthan 10% difference in the AUC was observed between cabozan-tinib tablet and capsule formulations. The food effect on thepharmacokinetics of cabozantinib with the tablet formulationis unknown. Cabozantinib, therefore, is recommended to beadministered on an empty stomach to minimize the risk of anyclinically meaningful effect of food intake on plasma exposure.The oral volume of distribution (Vz/F) of cabozantinib is approx-imately 319 L. Cabozantinib is highly protein bound in humanplasma (�99.7%). The predicted terminal half-life is approxi-mately 99 hours, and the clearance (CL/F) at a steady state isestimated to be 2.2 L/hour. Increased exposure to cabozantinibhas been observed in patients with mild-to-moderate hepaticimpairment; thus, the dose of cabozantinib should be reducedin these patients. Although dosage adjustment is not required inpatients with mild or moderate renal impairment, there is noexperience with cabozantinib in patients with severe renalimpairment.

Cross-study pharmacokinetics analysis indicated similarsteady-state exposures (Ctrough,ss) at different doses across patientpopulations with MTC (140 mg capsule), RCC (60 mg tablet),and castration-resistant prostate cancer (60 mg tablet). In addi-tion, the apparent oral clearance estimated by population phar-macokinetics model was 4.4 L/hour in MTC and 2.2 L/hour inRCC. This result was unexpected, as Cmax and AUC of the tabletformulation (Cabometyx) and the capsule formulation (Come-triq) were similar following a single 140-mg dose. Therefore, apostmarketing commitment was requested to evaluate the poten-tial impact of patient population, formulations, and doses on thepharmacokinetics of cabozantinib in an integrated populationpharmacokinetics model with the pooled pharmacokinetics datafrom different patient populations and healthy patients.

Clinical TrialsThe approval of cabozantinib was based on a randomized,

open-label, multicenter trial (trial XL184-30/METEOR) compar-ing cabozantinib with everolimus in 658 patients with advancedRCC who had received at least one prior antiangiogenic therapy(10, 11). Patients were randomized to receive cabozantinib orallyat 60mg daily or everolimus orally at 10mg daily. Treatment wascontinued until disease progression or unacceptable toxicity.Patients in either arm who experienced disease progression wereable to continue treatment at the discretion of the investigator.The primary efficacy outcome measure was PFS as assessed by an

independent radiology review committee (IRC) according toRECIST v1.1 among the first 375 patients randomized [primaryendpoint intent-to-treat population (PITT)]. At the clinical trialdesign stage, it was determined that a sample size of 375 patientswith 259 PFS events observed would have 90% power to detect ahazard ratio (HR) of 0.667 at a two-sided 5% significance levelusing a stratified log-rank test. PFS was defined as the time fromrandomization to the earlier of the following events: documentedprogressive disease (PD) per RECIST v1.1 or death due to anycause. Other efficacy endpoints included OS defined as the timefrom randomization until death due to any cause and objectiveresponse rate (ORR) per RECIST v1.1 as assessed by the IRC. Itwas determined that a sample size of 650 patients with 408deaths observed would have 80% power to detect an HR of0.75 at a two-sided 4% level of significance using a stratifiedlog-rank test. Interim analyses were planned to be conducted atthe time of PFS analysis and when 135 events were observed. Asthe number of events necessary to evaluate the PFS endpointcould have occurred before the study was fully accrued and inorder not to bias the results toward subjects whose diseaseprogressed early, the PFS analysis was determined from only thefirst 375 patients randomized. The primary endpoint PFS andsecondary endpoint OS analyses by the applicant were stratifiedby the number of prior VEGFR-targeting TKI therapies (1 vs. 2 ormore) and Memorial Sloan Kettering Cancer Center (MSKCC,New York, NY) prognostic criteria for previously treated patientswith RCC (0 vs. 1 vs. 2 or 3) as collected on the electronic casereport forms. To follow the ITT principle, the review team con-ducted additional analyses based on interactive voice response(IVRS).

Patient-reported outcomes (PRO) were collected for explor-atory purposes every 4 weeks through W25D1, followed by every8 weeks until the date of the last tumor imaging assessment, andwere analyzed in the ITT population using two-sided statisticaltests without adjustment for multiplicity. The PRO instrumentsused included the 19-item Functional Assessment of CancerTherapy-Kidney Cancer Symptom Index (FKSI-19) and theEuroQol five-dimensions questionnaire (EQ-5D-5L).

Demographics, Disease Characteristics,and Prior Treatment

All patients had advanced RCC with a clear cell component byhistology or cytology. The majority of the patients were male(75%), with a median age of 62 years. Sixty-nine percent receivedonly one prior antiangiogenic therapy. Patient allocation byMSKCC risk groups included 46% of patients in the favorablegroup (no risk factors), 42% in the intermediate group (one riskfactor), and 13% in the poor group (two or three risk factors).Fifty-four percent of patients had three or more organs withmetastatic disease, including lung (63%), lymph nodes (62%),liver (29%), and bone (22%). Approximately 5% of patients hadprior treatment with PD-L1– or PD-1–blocking antibodies. Ingeneral, the treatment arms were balanced with respect to age,gender, race, ethnicity, enrollment region, number of prior ther-apies, MSKCC risk factors, and prior cancer therapies.

Efficacy ResultsPFS results at the time of the data cutoff are shown in Table 1

and Fig. 1. For the PITT population, the minimum timeof follow-up was 10.7 months. A statistically significant

FDA Approval Summary for Cabozantinib for RCC

www.aacrjournals.org Clin Cancer Res; 23(2) January 15, 2017 331




improvement in PFS was observed in patients receiving cabo-zantinib compared with everolimus, with a 3.6-month differ-ence in median PFS (7.4 months vs. 3.8 months, respectively).ORR showed a statistically significant improvement in thecabozantinib arm compared with the everolimus arm, with a17% ORR [95% confidence interval (CI), 13–22] and 3% ORR(95% CI, 2–6), respectively.

At the time of the primary PFS analysis, the OS data were notmature, and no statistically significant improvement was seen atan interim analysis. However, a second interim analysis wasconducted in the ITT population with at least 12 months offollow-up, and a statistically significant difference in OS wasobserved, with results shown in Table 2 and Fig. 2.

Safety ResultsSafety was evaluated in 331 patients treated with cabozanti-

nib. The most common (greater than or equal to 25%) adversereactions included diarrhea, fatigue, nausea, vomiting, consti-pation, decreased appetite, hypertension, palmar–plantar ery-throdysesthesia syndrome, and weight loss. Serious adverseevents (AE) were reported in 40% of patients receiving cabo-

zantinib and 43% of patients receiving everolimus. The mostcommon serious AEs in the cabozantinib-treated group (great-er than or equal to 2%) were abdominal pain, pleural effusion,diarrhea, nausea, and anemia. Fifteen deaths were reportedwithin 30 days of the last cabozantinib dose. Eight of thedeaths were attributed to PD, five deaths were due to generalphysical health deterioration, pneumonia, postproceduralhemorrhage, cardiac failure, and urosepsis, and two deathswere due to unexplained reasons. Sixty percent of patientstreated with cabozantinib had at least one dose reduction whileon study. Ten percent of patients in the cabozantinib grouprequired treatment discontinuation, and 70% required dosemodification, including dose interruption or dose reduction.The most frequent AEs leading to dose reduction of cabozanti-nib were diarrhea (16%), palmar–plantar erythrodysesthesiasyndrome (11%), fatigue (10%), and hypertension (7.6%).

The safety profile of cabozantinib in RCC appeared similar tothe previously characterized profile of the capsule formulation ofcabozantinib in the MTC population. Patients treated with the60-mg tablet formulation used in the RCC study experiencedfewer events, such as gastrointestinal perforations and fistulas,compared with those treated with the 140-mg capsule formula-tion in the MTC trial. However, the rates of other AEs, such asdiarrhea, hypertension, and palmar–plantar erythrodysesthesiasyndrome, were similar across tumor types.

Given the frequency of dose reductions, further simulationsand modeling were undertaken. In an FDA exposure–PFS rela-tionship analysis, the relationshipwas explored byCox regressionmodel, where the drug exposure effect on hazard was an Emax

function of the pharmacokinetic model–predicted cabozantinibexposure. The model indicated that exposure under lower doselevels (e.g., 40 or 20 mg) may result in an inferior PFS compared

Table 1. PFS (first 375 randomized)

Endpoint Cabozantinib Everolimus

n ¼ 187 n ¼ 188Number of events (%) 121 (65%) 126 (67%)Median PFS (95% CI), months 7.4 (5.6–9.1) 3.8 (3.7–5.4)HR (95% CI), Pa 0.58 (0.45–0.74), P < 0.0001aStratified log-rank test with prior VEGFR-targeting TKI therapy (1 vs. 2 or more)andMSKCCprognostic criteria for previously treatedpatientswithRCC (0vs. 1 vs.2 or 3) as stratification factors (per IVRS data).

© 2016 American Association for Cancer Research

Progression-free survival (months)Number at risk

Cabozantinib

Everolimus

CabozantinibEverolimus

187

188

152

99

92

46

68

29

20

10

6 2

2

Prob

abili

ty o

f pro

gres

sion

-fre

e su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18

Figure 1.

PFS per IRC (PITT population).

Singh et al.

Clin Cancer Res; 23(2) January 15, 2017 Clinical Cancer Research332




with 60 mg daily. Taking the cabozantinib concentration of1,125 ng/mL (median concentration at 60 mg every-day dose)as the reference, theHRwould be 1.1 and 1.39 if the exposure wasreduced to 67% and 33% of the reference concentration, respec-tively. Modeling and simulations showed a predicted medianpercentage change of tumor size from baseline of�4.5%,�9.1%,and�11.9% with 20-, 40-, and 60-mg starting dose, respectively.These reductions in tumor size correspond to a predicted ORR(based on target lesion) of 8.7%, 15.6%, and 19.1% with the 20-,40-, and 60-mg dose, respectively.

PRO ResultsExploratory PRO results were limited by the open-label clinical

trial design and moderate levels of missing data. A repeated-measures analysis of the change from baseline showed no clear,clinically meaningful differences for the EQ-5D and FKSI-totalscore and three of the four subscales. The treatment side effectssubscale of the FKSI-19 was numerically worse for patients on thecabozantinib arm, with the largest effect seen with numericallyworse diarrhea.

DiscussionThe landscape of metastatic RCC is evolving with newer ther-

apies, and it is unclear howclinical practicewill be impacted.Untilrecently, most of the available therapies for patients withadvanced RCC in the second-line setting were approved on thebasis of improvements in PFS. However, with the approvals ofnivolumab, lenvatinib in combination with everolimus, andcabozantinib, the landscape for FDA-approved available thera-pies in the second-line setting has shifted to include agents withOS benefit and varying toxicity profiles (Table 3). Clinical practicewill dictate which second-line regimen for patients with meta-static RCC is preferred. For the purposes of the cabozantinibapproval, despite other available therapies in this setting, ever-olimus, as an approveddrug for advancedRCC,was considered anappropriate active comparator.

A review issue revolved around appropriateness of doseselection given the high percentage of dose reductions.Although there was a high percentage of dose reductions inthe cabozantinib arm, there was a lower percentage of dosediscontinuation compared with everolimus, suggesting thatmost adverse reactions were successfully managed with doseinterruptions and supportive measures. A comprehensive anal-ysis of the adverse reactions causing dose reduction did notidentify a serious risk, a signal of a serious risk, or an unex-pected serious risk related to the use of the drug, and, therefore,criteria for a safety PMR were not met (12). In addition,exposure–response and pharmacometric modeling indicatedthat lower starting doses could possibly compromise activityof the drug with decreased response rates. Therefore, the reviewteam concluded that the dose selection of 60 mg daily wasadequate based on exposure–response analyses and a safetyprofile that is acceptable for the patient population. In addi-tion, the cabozantinib label specifies dose-reduction instruc-tions for the RCC population and describes the frequency of

© 2016 American Association for Cancer Research

OS (months)

Prob

abili

ty o

f OS

CabozantinibEverolimus

Number at risk

Cabozantinib

Everolimus

330

328

318

307

296

262

264

229

239

202

178 105 41 6 3

141 82 32 8 1

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24 27 30

Figure 2.

OS (second interim analysis; ITTpopulation).

Table 2. OS and ORR (ITT)

Endpoint Cabozantinib Everolimus

n ¼ 330 n ¼ 328Number of events (%) 140 (42%) 180 (55%)Median OS (95% CI), months 21.4 (18.7–NE) 16.5 (14.7–18.8)HR (95% CI), Pa 0.66 (0.53–0.83), P ¼ 0.0003Confirmed ORR (partialresponses only; 95% CI)

17% (13%–22%) 3% (2%–6%)

Pb P < 0.0001aStratified log-rank test with prior VEGFR-targeting TKI therapy (1 vs. 2 ormore)and MSKCC prognostic criteria for previously treated patients with RCC (0 vs. 1vs. 2 or 3) as stratification factors (per IVRS data).bc2 test.






dose reductions seen in the clinical trial to better informpractitioners.

Exploratory PRO data demonstrated a numerically worseFKSI-19 treatment side effect (TSE) subscale score in thecabozantinib arm. The TSE finding is challenging to interpretgiven that the TSE consists of only three questions (diarrhea,nausea, and side-effect bother), and important symptomatic AEsof both cabozantinib and everolimus are not incorporated intothe TSE score. The largest effect seen in the PRO results wasincreased diarrhea in the cabozantinib arm, consistent with thesubmitted safety data. In summary, cabozantinib demonstratedefficacy superior to everolimus, with a statistically significantimprovement in PFS, OS, and ORR. The improvements in esti-mated median PFS and OS are considered clinically meaningful.The safety profile of cabozantinib at 60 mg daily appears accept-able. Therefore, based on a favorable benefit–risk profile andsubstantial evidence of safety and efficacy, cabozantinib wasgranted regular approval for the treatment of adult patients withadvanced RCC who have received prior antiangiogenic therapy.

Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

DisclaimerTheDeputy Editor handling the peer review and decision-making process for

this article has no relevant employment associations to disclose.

Authors' ContributionsConception and design: H. Singh, M. Brave, J.A. Beaver, C. Liu, G. Kim,R. PazdurDevelopment of methodology: H. Singh, M. Brave, J.A. Beaver, Y. Wang,R. Sridhara, R. PazdurAcquisition of data (provided animals, acquired and managed patients,provided facilities, etc.): R. PazdurAnalysis and interpretation of data (e.g., statistical analysis, biostatistics,computational analysis): M. Brave, J.A. Beaver, J. Cheng, S. Tang, E. Zahalka,P. Song, Q. Liu, J. Yu, Y. Wang, P.G. Kluetz, S.R. Daniels, R. Sridhara, A. Ibrahim,G. Kim, R. PazdurWriting, review, and/or revision of the manuscript: H. Singh, M. Brave,J.A. Beaver, S. Tang, E. Zahalka, T.R. Palmby, P. Song, Q. Liu, C. Liu, J. Yu,X.H. Chen, X. Wang, Y. Wang, P.G. Kluetz, S.R. Daniels, E.J. Papadopoulos,R. Sridhara, A.E. McKee, A. Ibrahim, G. Kim, R. PazdurAdministrative, technical, or material support (i.e., reporting or organizingdata, constructing databases): M. Brave, J.A. Beaver, R. Venugopal, G. KimStudy supervision: M. Brave, R. Pazdur

Received July 12, 2016; revised August 29, 2016; accepted August 31, 2016;published OnlineFirst October 28, 2016.

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Table 3. FDA-approved therapies indicated for second-line treatment of patients with advanced RCC

FDA-approved drugApprovalyear Trial design/population Endpoint(s) Clinical benefit/effect

Afinitor (everolimus; Novartis) 2009 Multicenter, randomized,double blinded, two arm

PFS (by centralreview)

Everolimus vs. placebo

Prior sorafenib or sunitinib PFS: HR, 0.33 (95% CI, 0.25–0.43); median 4.9 vs. 1.9 m

Inlyta (axitinib; Pfizer) 2012 Multicenter, randomized,open label, two arm

PFS (by centralreview)

Axitinib vs. sorafenib

Prior antiangiogenic orcytokine therapy

PFS: HR, 0.67 (95% CI, 0.54–0.81); median 6.7 vs. 4.7 m

Opdivo (nivolumab;Bristol-Myers Squibb)

2015 Prior antiangiogenic therapy OS Nivolumab vs. everolimusOS: HR, 0.73 (95% CI, 0.60–0.89); median 25.0 vs. 19.6 mPFS: HR, 0.88 (95% CI, 0.75–1.03); median 4.6 vs. 4.4 m

Cabometyx (cabozantinib;Exelixis, Inc.)

2016 Prior antiangiogenic therapy PFS Cabozantinib vs. everolimusPFS: HR, 0.58 (95% CI, 0.45–0.74); median 7.4 vs. 3.8 mOS: HR, 0.66 (95% CI, 0.53–0.83); median 21.4 vs. 16.5 m

Lenvima (lenvatinib; Eisai)in combination witheverolimus

2016 Prior antiangiogenic therapy PFS Lenvatinib plus everolimus vs. lenvatinib vs. everolimusPFS: HR, 0.37 (95% CI, 0.22–0.62); median 14.6 vs. 5.5 m(lenvatinib plus everolimus vs. everolimus)

NOTE: Source: Affinitor USPI; Inlyta USPI; Opdivo USPI; Lenvima USPI.Abbreviation: m, months.

Singh et al.

Clin Cancer Res; 23(2) January 15, 2017 Clinical Cancer Research334




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2017;23:330-335. Published OnlineFirst October 28, 2016.Clin Cancer Res Harpreet Singh, Michael Brave, Julia A. Beaver, et al. Treatment of Advanced Renal Cell CarcinomaU.S. Food and Drug Administration Approval: Cabozantinib for the

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