`RESEARCH
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`APPLICATION NUMBER:
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`203756Orig1s000
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`OFFICE DIRECTOR MEMO
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`Office Director Decisional Memo
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`NDA 203756_Comelriq (cabozantinib)
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`Page 1 of 8
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`Summary Review for Regulatory Action
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`electronic stam .
`
`From
`Richard Pazdur, MD
`Sub'ect
`Office Director Decisional Memo
`NDA 203756
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`Date of Submission
`PDUFA Goal Date
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`Proprietary Name I
`Established USAN Name
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`Dosage Forms I Strength
`
`May 21, 2012 (receipt date May 29, 2012)
`November 29, 2012
`COMETRIQ
`cabozantinib
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`COMETRIQ 20-mg gelatin capsules; grey capsules with "XL184 20mg” printed in
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`black on the capsule
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`COMETRIQ 80—mg gelatin capsules: Swedish orange with "XL184 80mg” printed
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`in black on the capsule
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`Proposed lndication(s)
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`Recommended Action for NME:
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`COMETRIQ is indicated for the treatment of patients with progressive,
`unresectable locall advanced or metastatic medulla
`th oid cancer MTC
`A r I oval
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`
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`Material Reviewed/Consulted
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`OND Action Packae, includi :
`Division Director
`R- : ulato Pro'ect Manaoer Review
`Medical Officer Review
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`Statistical Review
`Phannaool - . Toxicol- - Review
`CMC Review
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`Microbiology Review
`Clinical Pharmacolo ~ Review
`OPDP
`OMPIDMPP Review
`DMHS Review
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`CDTL Review
`OSE/DMEPA
`OSEIDRISK
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`Names of disci u line reviewers
`Patricia K- - an
`Gina Davis
`Ruthann Giusti
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`Yuan-Li Shen
`Mar aret Brower
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`Minerva Huhes, William M. Adams, Li-Shan Hsieh
`Denise Miller
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`Jun Yan .
`Carole Broadnax & Karen Munoz-Nero
`Karen Dowd
`Jeanine Best
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`Ro Bla
`Suzanne Demko
`James Schlick
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`Joyce Weaver
`Sa {it Brar
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`QTIIRT Consult
`OND=0ffice of New Dmgs
`OMP=0ffice Medical Policy
`DMPP=Division of Medical Policy Program
`OPDP= Office of Prescription Drug Promotion
`PMHS= Pediatric and Maternal Health Staff
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`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medicafion Error Prevention and Analysis
`OSI=Office of Scientific Invesfigafions
`DRISK=DiVIIion of Risk Management
`CDTL=Cross—Discip|ine Team Leader
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`Reference ID: 3223482
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`Office Director Decisional Memo
`NDA 203756_Cometriq (cabozantinib)
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` Page 2 of 8
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`Introduction
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`1.
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`Cabozantinib is an inhibitor of multiple tyrosine kinases, including RET, MET, and VEGFR2. Cabozantinib in medullary
`thyroid cancer (MTC) is a targeted therapy, based on the known correlation between mutation in the RET gene and both the
`hereditary and sporadic forms of MTC. Cabozantinib has the same mechanism of action (inhibition of RET tyrosine kinase)
`as vandetanib, which was approved for the treatment of metastatic MTC in 2011, based on a similarly designed trial and
`endpoints (progression-free survival and durable objective response rate) as cabozantinib.
`
`This NDA is supported by a single, well-conducted, placebo-controlled, randomized (2:1), multi-national trial (Protocol
`XL184-301), which enrolled 330 patients with metastatic MTC. Assessment for RET mutation was not a requirement of the
`protocol but was assessed retrospectively in approximately 70% of patients with “research-use only” assays. Protocol
`XL184-301 demonstrated that treatment with cabozantinib results in a statistically significant and clinically important
`improvement in progression free survival [HR 0.28 (95% CI: 0.19, 0.40); p<0.0001], with an estimated median PFS of 11.2
`months for cabozantinib compared to 4 months for patients receiving no treatment (placebo arm). The favorable results from
`the cabozantinib arm were robust based on various sensitivity analyses and consistent within relevant patient subgroups,
`including subgroups retrospectively identified as RET mutation positive, RET mutation negative, and RET mutation status
`unknown. In addition, there was a significantly higher overall response rate (27%) for cabozantinib-treated patients as
`compared to no responses in the placebo arm.
`
`In a planned interim analysis (conducted after 44% of the total deaths for the final analysis of survival), and in an unplanned
`analysis (conducted at FDA’s request with 75% of the planned deaths for the final analysis), there was no evidence of
`significant improvement in overall survival (OS) for cabozantinib-treated patients. The estimated median survival times were
`26 months for cabozantinib-treated patients and 20.3 months for placebo-treated patients.
`
`The safety database of 289 patients included the results of the major efficacy trial and two additional, single-arm trials in
`patients with various cancers, treated with cabozantinib 140 mg daily. In the major efficacy trial, dose modifications occurred
`in the majority (86%) of patients; the most common adverse reactions resulting in dose modification were palmar-plantar
`erythrodysesthia syndrome, weight loss, decreased appetite, fatigue, diarrhea, stomatitis, asthenia and nausea.
`
`There was no difference in OS between the two treatment arms, although four deaths in the cabozantinib arm were
`considered probably related to treatment (1 death due to fatal hemorrhage, 2 deaths in patients with esophageal fistula
`formation, and 1 death due to respiratory failure in a patient with hemorrhage and possible fistula). The most common
`serious adverse reactions of cabozantinib are gastrointestinal (GI) perforations, GI and non-GI fistulas, thrombotic events,
`hemorrhage, wound complications, hypertension, osteonecrosis, and reversible posterior leukoencephalopathy syndrome.
`The most common (≥ 30%) adverse reactions of cabozantinib are diarrhea, stomatitis, palmar-plantar erythrodysesthesia
`syndrome, weight loss, decreased appetite, nausea, fatigue, oral pain, dysgeusia, oral pain, depigmentation of hair, and
`hypertension.
`
`
`The major issue considered during this review was the acceptability of the proposed dose in light of the adverse reaction
`profile and given the lack of a clear exposure-response relationship in exploratory analyses conducted by the Clinical
`Pharmacology reviewers. Based on this concern, a post-marketing trial will be required to explore the safety and activity of a
`lower dose of cabozantinib.
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`Reference ID: 3223482
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` Page 3 of 8
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`Office Director Decisional Memo
`NDA 203756_Cometriq (cabozantinib)
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`2.
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`Indicated population/available therapy
`Medullary thyroid cancer arises from the parafollicular cells of the thyroid and is reported to account for 3-5% of estimated
`56, 460 cases of cancers of the thyroid gland estimated to occur in 2012. 1,2 Approximately one-quarter of MTC are
`hereditary and mutations of the RET (REarranged during Transfection) gene occur in 95% of these hereditary MTC cases,
`while the proportion of sporadic MTC with RET mutations is reportedly lower (25%)3. Mutation of RET leads to activation of
`receptor tyrosine kinases, with downstream activation of pathways involved in cell proliferation. Cabozantinib is designed to
`target this pathway common to hereditary MTC and some cases of sporadic MTC.
`
`Background
`
`On April 6, 2011 Caprelsa (vandetanib), an inhibitor of the RET, VEGFR2, and other kinases, was approved for “the
`treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or
`metastatic disease. Use of vandetanib in patients with indolent, asymptomatic or slowly progressing disease should be
`carefully considered because of the treatment related risks of vandetanib.” Vandetanib was approved under a Risk
`Evaluation and Mitigation Strategy (REMS) with elements to assure safe use (ETASU) based on the risks of Torsades de
`pointes and sudden death due QT prolongation. In addition, vandetanib labeling contains Warnings and Precautions
`describing the following additional clinically important adverse reactions: skin reactions and Stevens-Johnson Syndrome,
`interstitial lung disease, ischemic cerebrovascular events, hemorrhage, heart failure, diarrhea, hypothyroidism, hypertension,
`Reversible Posterior Leukoencephalopathy Syndrome, drug interactions, renal impairment, hepatic impairment, and
`Pregnancy Category D.
`
`
`CMC
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`3.
`
`There are no outstanding CMC issues that preclude approval. Chemistry reviewers have provided an overall acceptability of
`the manufacturing of the drug product and drug substance. There were no microbiology deficiencies noted in the NDA
`submission. Manufacturing site inspections were acceptable. Stability testing supports an expiry of 24 months at ambient
`room temperature. All quality and compliance reviewers recommended approval.
`
`
`Nonclinical Pharmacology/Toxicology
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`4.
`
`There are no outstanding pharmacology/toxicology issues that preclude approval.
`
`This NDA contained nonclinical studies assessing the pharmacology, safety pharmacology, chronic toxicology, and
`reproductive toxicology of cabozantinib. The pharmacology of cabozantinib itself was similar to that in humans; however, the
`concentration of active metabolites of cabozantinib were substantially lower in animals than in humans requiring that a post-
`marketing study be required for to assess the potential genotoxicity of the M4 metabolite.
`
`Studies in rats and dogs suggest that fertility may be impaired in cabozantinib-treated males and females. In safety
`pharmacology trials, cabozantinib did not inhibit hERG channel activity at relevant concentrations and no effects on
`cardiovascular parameters were observed in dogs. In safety pharmacology studies conducted in rats, behavioral and
`physiological changes were not observed following single doses of up to 300 mg/kg cabozantinib and single doses of 900
`mg/kg cabozantinib had no effects on respiratory parameters.
`
`
`1 http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/HealthProfessional/page7
`2 Pitt SC, Moley JF: Medullary, Anaplastic, and Metastatic Cancers of the Thyroid. Semin Oncol 37 (6): 567-579, 2010.
`3 Liu Z, Falola J, Zhu X, et al: Antiproliferative effects of Src inhibition on medullary thyroid cancer. J Clin Endocrinol Metab 89:3503-
`3509, 2004.
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`Reference ID: 3223482
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` Page 4 of 8
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`Office Director Decisional Memo
`NDA 203756_Cometriq (cabozantinib)
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`Cabozantinib was not mutagenic or clastogenic. Genotoxic impurities were considered adequately characterized. The four
`major metabolites of cabozantinib were not mutagenic but have not been assessed for induction of chromosomal
`aberrations. However, based on the potential for long-term survival in some patients with medullary MTC (median survival
`from diagnosis is X), the nonclinical review team has identified the requirement for 2-year carcinogenicity studies in rats and
`mice.
`
`Embryofetal development studies were conducted in rats and rabbits. In both species, there was increased risk of post-
`implantation losses at cabozantinib exposures of < 1% (rats) and 9-11% (rabbits) of the human exposure at the
`recommended dose of 140 mg compared to controls. Additional findings includes cardiac anomalies, and dose-dependent
`increases in skeletal variations in rats and a dose-dependent decrease in fetal body weight, increases in the incidence of
`visceral variations and malformations including reduced spleen size and missing lung lobes in rabbits at exposures
`significantly lower than the human exposure at the recommended dose. Reproductive toxicity findings suggest that male and
`female fertility can be impaired by treatment with cabozantinib. Based on these findings, product labeling identifies this
`product as Pregnancy Category D. In addition, based on the potential for extended survival in some patients with medullary
`thyroid cancer, and the known pharmacologic effects of inhibition of MET and VEGF pathways which may result in altered
`bone development, a post-marketing requirement for a pre/post-natal developmental toxicity study has been identified.
`
`
`Clinical Pharmacology
`
`5.
`
`There are no outstanding clinical pharmacology issues that preclude approval.
`
`The pharmacokinetics of cabozantinib capsules and cabozantinib “powder in bottle” dosage forms were evaluated in healthy
`subjects and in patients with cancer. Results from a population PK analysis demonstrate that the half-life of cabozantinib at
`steady state was approximately 55 hours, the oral volume of distribution is approximately 349 L, and clearance (CL/F) was
`estimated to be 4.4 L/hr. The median Tmax was approximately 2-4 hours in cancer patients following a single oral dose.
`Mass balance studies in healthy subjects demonstrated that 54% of administered radioactivity was recovered in the feces
`and 27% was recovered in the urine. The dose proportionality of the cabozantinib capsules has not been evaluated, however
`dose-proportional AUC and Cmax were observed with the “powder in bottle” dosage form. Absolute oral bioavailability of
`cabozantinib capsule has not been determined. Significant increases in Cmax (41%) and AUC (57%) were observed when
`cabozantinib was administered with a high-fat, high calorie meal in healthy subjects, thus product labeling states that
`cabozantinib should be taken without food.
`
`The Clinical Pharmacology review team recommended that the dosing regimen in product labeling be based on PK
`modeling, with a proposed starting dose of 100 mg daily, to be increased to 140 mg or decreased to 60 mg based on
`observed toxicity. This recommendation was based on the observation that 86.4% of the patients in the major efficacy trial
`required dose modification (interruption, reduction, or termination), on exposure-response analyses suggesting that
`progression-free survival was similar across all quartiles for cabozantinib exposure, and a correlation observed between
`model-predicted steady state exposure (AUCSS PRED) and time to first dose medication (shorter time with higher exposure). It
`is noted that there was no correlation between exposure and the incidence of the most common adverse reactions resulting
`in dose modification (palmar-plantar erythrodysesthesia or diarrhea). Dr. Jun concluded that “These E-R relationships for
`efficacy and safety suggest that a lower dose might be effective with improved tolerability; therefore, label should include a
`starting dose of 100 mg with a provision to increase the dose to 140 mg or decreased to 60 mg as tolerated.”
`
`Given the exploratory nature of the exposure-response analysis performed using the results for sparse PK sampling
`techniques in 200 patients per Table 5 of Dr. Jun’s review, it is Dr. Keegan’s opinion that the data are inadequate to support
`a recommended dose that has not been studied. As an alternative, the clinical and clinical pharmacology review teams have
`agreed that a postmarketing trial is required to confirm that an alternative dosing regimen is safer and retains sufficient
`efficacy.
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`Reference ID: 3223482
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` Page 5 of 8
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`Office Director Decisional Memo
`NDA 203756_Cometriq (cabozantinib)
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`The results of the population PK analyses do not identify clinically relevant differences in exposures based on gender, age,
`or race (White versus non-White) and that the effect of mild and moderate renal impairment on clearance of cabozantinib is
`minimal. Since cabozantinib is cleared by the kidneys and metabolized, via CYP3A4, in the liver and formal studies of the
`PK of cabozantinib in patients with renal or hepatic organ impairment have not been conducted, PK studies in patients with
`severe renal impairment and hepatic impairment are required. Pending the completion of the hepatic impairment trial,
`product labeling contains a Warning that cabozantinib is not indicated for the treatment of patients with hepatic impairment.
`In addition, product labeling contains recommendations to avoid use of strong CYP3A4 inducers or inhibitors in patients
`receiving cabozantinib, and proposes specific recommendations for dose modification based on the dedicated drug
`interactions studies of cabozantinib in patients taking strong CYP3A4 inducers or inducers. Dedicated studies have shown
`that cabozantinib exposure is increased by 38% when administered to subjects taking a strong CYP3A4 inhibitor and that
`cabozantinib exposure is decreased by 77% in subjects taking a strong CYP3A4 inducer.
`
`Population PK studies were inconclusive regarding the effects of gastric pH modifying agents on cabozantinib PK. Since the
`solubility of cabozantinib is pH-dependent, the clinical pharmacology review team has stated that a post-marketing trial to
`conduct a dedicated study assessing the effects on pH modifying agents on cabozantinib pharmacokinetics also be required.
`
`The effects of cabozantinib on the QT interval were assessed in a dedicated substudy within the major efficacy trial. The
`IRQT consultant’s assessment of this substudy was that no large increases in mean QT interval (>20 ms) were detected at
`steady state (pre-dose on Cycle 2, Day 1) compared to baseline values in the 166 cabozantinib-treated patients assessed on
`C2D1. The mean change was 11.3 ms (90% CI: 8.7, 13.95). There were no new changes in cardiac wave form morphology
`or new rhythms in patients with increased QT interval and no cabozantinib -treated patient had a QTcF >500 ms. These
`results have been described in the Clinical Pharmacology section of product labeling, however based on these data, no
`Warnings or Precautions are required.
`
`Clinical Microbiology
`
`6.
`
`There are no outstanding sterility issues that preclude approval.
`
`
`Clinical/Statistical-Efficacy
`
`7.
`
`This NDA was primarily supported by a single international, multi-center, randomized (2:1), placebo-controlled trial enrolling
`330 patients with metastatic MTC. Patients were required to have progressive disease within 14 months prior to entry.
`Patients were randomized to receive cabozantinib 140 mg (n = 219) or placebo (n = 111) orally once daily. Randomization
`was stratified by age and prior tyrosine kinase inhibitor (TKI) use. Patients were treated until disease progression or
`intolerable toxicity. At the time of disease progression, cross-over to cabozantinib was not permitted in patients receiving
`placebo. An independent radiology review committee (IRC), using the modified RECIST criteria, determined radiographic
`progression and tumor response.
`
`Of 330 patients, 67% were male, the median age was 55 years, 23% were 65 years or older, 54% had a baseline ECOG
`performance status of 0, and 92% had undergone thyroidectomy. Twenty-five percent (25%) received two or more prior
`systemic therapies and 21% had been previously treated with a TKI.
`
` statistically significant PFS prolongation was demonstrated in the cabozantinib arm compared to the placebo arm [HR 0.28
`(95% CI: 0.19, 0.40); p <0.0001]. The estimated median PFS was 11.2 and 4.0 months for the cabozantinib and placebo
`arms, respectively.
`
`The ORR was significantly higher in the cabozantinib arm (27% versus 0%; p<0.0001) and all were partial responses. The
`median response duration was 14.7 months (95% CI: 11.1, 19.3). No statistically significant difference in overall survival
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`Reference ID: 3223482
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`Office Director Decisional Memo
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`NDA 203756_Cornelriq (cabozantinib)
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`Page 6 of 8
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`was observed between the treatment arms at the planned interim analysis and in an updated survival analysis requested by
`FDA.
`
`
`The efficacy results, as presented in the statistical review, are abstracted and presented below.
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`
`_—
`-_———
`_—‘___
`—=————
`
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`‘ confidence intervals-2 stratified log4ank test-3 not reached-4 All responses were partial responses5 not applicable6 stratified Cochran—Mantel—
`Haenszel test
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`Reference ID: 3223482
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` Page 7 of 8
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`Office Director Decisional Memo
`NDA 203756_Cometriq (cabozantinib)
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`The treatment effect on PFS was consistent across both demographic subgroups (age, gender) and prognostic subgroups
`(ECOG PS 0 vs. 1 vs. 2), prior lines of therapy (0 vs. 1 vs. ≥2), prior treatment with TKI (yes vs. no) and by RET mutation
`status. In patients retrospectively identified to have a RET mutation, the hazard ratio was 0.23 (95% CI 0.14, 0.38), while in
`those identified as RET mutation negative, the hazard ratio was 0.44 (95% CI 0.15, 1.30) and in those without assessment of
`RET mutation status, the hazard ratio was 0.30 (95% CI 0.16, 0.56). Due to the retrospective nature of the RET mutation
`testing, convenience sample (31% missing data), and lack of validation of the assay, these results should be viewed
`cautiously but do suggest that the presence of RET mutation may not be required to achieve a treatment effect. Treatment
`effects were observed both in patients with hereditary MTC [HR 0.09 (95% CI 0.01, 0.82)] and in those with sporadic MTC
`[HR 0.32 (95% CI 0.22, 0.46)].
`
`
`Safety
`
`8.
`
`The size of the safety database, which was primarily limited to the major efficacy trial and two additional trials that evaluated
`the safety of cabozantinib monotherapy in 295 cabozantinib-treated patients, is small but adequate to identify serious
`adverse reactions. Comparative safety data are available only from the major efficacy trial, with comparison of adverse
`events in 214 cabozantinib-treated patients with those observed in 109 placebo-treated patients.
`
`There was no difference in overall survival between the two treatment arms; the number of adverse reactions resulting in
`death during treatment or within 30 days of the last dose of study drug was comparable. Four deaths in the cabozantinib
`arm were considered probably related to treatment (1 death due to fatal hemorrhage, 2 deaths in patients with esophageal
`fistula formation, and 1 death due to respiratory failure in a patient with hemorrhage and possible fistula), while the rate of
`deaths due to sepsis or aspiration pneumonia were similar between the treatment arms.
`
`Selected adverse reactions observed in ≥ 25% of cabozantinib-treated patients and at a higher incidence than in patients
`receiving placebo (difference ≥ 5%), were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES),
`decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes (hypopigmentation/graying),
`dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) were
`increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia,
`thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions which occurred in ≥ 5% of
`cabozantinib-treated patients and at a higher incidence than in patients receiving placebo (difference ≥ 2%), were diarrhea,
`PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and
`decreased appetite. The following serious adverse reactions attributed to cabozantinib included osteonecrosis of the jaw
`(n=1), reversible posterior leukoencephalopathy syndrome (n=1), pancreatitis (n=3), nephrotic syndrome (n=1), fatal
`hemorrhage (n=2), and fatal perforation/fistula (n=2).
`
`
`Advisory Committee Meeting
`
`9.
`
`The NDA was not presented to the Oncologic Drugs Advisory Committee for all of the following reasons: the clinical study
`design was acceptable; the application did not raise significant safety or efficacy issues that were unexpected for a drug
`indicated for the treatment of metastatic MTC; and there were no controversial issues that would benefit from advisory
`committee discussion.
`
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`Pediatrics
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`10.
`
`Orphan drug designation, therefore, PREA is not applicable.
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`Reference ID: 3223482
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`Office Director Decisional Memo
`NDA 203756_Cometriq (cabozantinib)
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`11.
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`There are no other unresolved relevant regulatory issues.
`
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`Other Relevant Regulatory Issues
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` Page 8 of 8
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`12.
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`13.
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`Labeling
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` Proprietary name: Cometriq (cabozantinib) capsules is acceptable.
` Physician labeling: There are no unresolved issues. There will be a Boxed Warning for treatment-related adverse
`reactions of Hemorrhage and Perforation/Fistula Formation, which resulted in significant morbidity and treatment-
`related mortality.
` Carton and immediate container labels: All proposed revisions by ONDQA and DMEPA have been incorporated
`into carton & container labeling.
` Patient labeling: There are no unresolved issues.
`
`Decision/Action/Risk Benefit Assessment
`
` Regulatory Action: Approval.
`
` Risk Benefit Assessment
`Medullary thyroid cancer (MTC) is an indolent cancer, with approximately 3000 new cases expected in 2012. Prior
`to the approval of vandetanib in 2011, there were no FDA-approved agents for metastatic MTC and off-label use of
`antineoplastic agents yielded limited activity, thus there was a clear unmet need for new treatments.
`
`Results from the trial that primarily support this NDA show that cabozantinib demonstrated an improvement in
`median PFS of 7 months, and treatment results in durable tumor responses (27% ORR with median duration of
`response of 14.7 months). The magnitude of these effects is clinically important and statistically robust. The risks
`of cabozantinib are well-understood risks common to many antineoplastic agents and considered generally
`acceptable. The most common serious adverse reactions of cabozantinib are gastrointestinal (GI) perforations, GI
`and non-GI fistulas, thrombotic events, hemorrhage, wound complications, hypertension, osteonecrosis, and
`reversible posterior leukoencephalopathy syndrome. The most common (≥ 30%) adverse reactions of cabozantinib
`are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, weight loss, decreased appetite, nausea,
`fatigue, oral pain, dysguesia, oral pain, depigmentation of hair, and hypertension.
`
`The Risk benefit profile, which was also discussed by Dr. Keegan, Ms. Demko and Dr. Giusti is acceptable. In
`addition, the review team recommends approval of this NDA, and I concur.
`
` Recommendation for Postmarketing Risk Evaluation and Mitigation Strategies
`A REMS is not required to ensure safe use.
`
` Recommendation for other Postmarketing Requirements and Commitments
`See action letter.
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`Reference ID: 3223482
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`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TAMY E KIM
`11/29/2012
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`RICHARD PAZDUR
`11/29/2012
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`Reference ID: 3223482
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`(
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