Kidney Cancer Journal – 2019 – Number 1

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Kidney Cancer Journal – 2019 – Number 1

EDITOR’S MEMO

Remembering Professor Martin Gore, 1951–2019

Tributes pour in, honoring him as ‘force of nature,’ brilliant clinician

lthough most of the 4500 or so attendees at this year’s GU ASCO meeting may not have been aware, the death of Professor Martin Gore cast a long shadow over the proceedings for those of us who knew this brilliant clinician and outstanding human being. Dr Gore, 67, one of the UK’s leading oncologists, died in January after experiencing total organ failure following a yellow fever vaccination, an extremely rare complication.
A report in the Journal of Travel Medicine found that between 2007 and 2013, there were just under four cases of serious adverse effects from the vaccine per 100,000 doses. This increased to 6.5 per 100,000 for those aged between 60 and 69, and 10.3 per 100,000 for those aged 70 and above. The vaccination is recommended for anyone visiting Sub-Saharan Africa, South and Central America, and the Caribbean.
Dr Gore, who inspired generations of physicians, was a professor at the Institute of Cancer Research and former Medical Director of the Royal Marsden Hospital, London. Prof Mel Greaves, from The Institute of Cancer Research, said: “Martin was something of a force of nature, very energetic, clear thinking and compassionate.” In the following recollection, Professor Tim Eisen highlights his memories of Dr Gore.
Robert A. Figlin, MD
Editor-in-Chief

A Tribute From Prof Tim Eisen: Remembering His ‘Extraordinary Array of Talents’

Professor Tim Eisen

I first met Martin when I was being interviewed for a junior doctor’s job at the Royal Marsden Hospital in London. Martin’s sense of humor and infectious enthusiasm were immediately obvious. It took me a little longer to recognize his extraordinary array of talents: Martin combined great self-confidence with a real sensitivity for how others felt, clear and decisive thinking and a penetrating intelligence.
One of Martin’s most endearing traits was his ability to laugh at himself. After any ludicrous or embarrassing event, there would always be a theatrical and exaggerated rendition which entertained and instructed. Nobody should have been fooled by the stream of wit and humor. Martin could be as direct and firm as the situation demanded. Martin made an international impact in ovarian cancer, melanoma and renal cancer. He was a long-serving and extremely successful Medical Director of the Royal Marsden Hospital and in recent years, he took leading roles advising the UK government on tricky subjects such as gene therapy, biological security and enquiries into healthcare failings in the NHS.
Martin was fabulously loyal to the Marsden. Two things rang particularly true about the press coverage of Martin’s death; the first was a description of him as the beating heart of the Marsden and the second was that, when the terrible news spread, many of the cleaning staff were in tears. Martin appreciated everybody who was part of the Marsden; his authenticity as a leader was palpable and people loved him for it.
What do I miss most about Martin? I miss the friendship of this funny, brilliant, kind and unforgettable man.
Tim Eisen
Professor of Medical Oncology
University of Cambridge and Vice President Oncology Early Clinical Projects
AstraZeneca

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CABOMETYX® (cabozantinib) TABLETSBRIEF SUMMARY OF PRESCRIBING INFORMATION. PLEASE SEE THE CABOMETYX PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. INITIAL U.S. APPROVAL: 20121 INDICATIONS AND USAGE1.1 Renal Cell CarcinomaCABOMETYX is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).1.2 Hepatocellular CarcinomaCABOMETYX is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 HemorrhageSevere and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX-treated patients.Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena. 5.2 Perforations and FistulasFistulas, including fatal cases, occurred in 1% of CABOMETYX-treated patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX-treated patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula which cannot be appropriately managed or a GI perforation.5.3 Thrombotic EventsCABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism occurred in 2% of CABOMETYX-treated patients. Fatal thrombotic events occurred in CABOMETYX-treated patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention. 5.4 Hypertension and Hypertensive CrisisCABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX-treated patients.Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.5.5 Diarrhea Diarrhea occurred in 63% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 11% of patients treated with CABOMETYX. Withhold CABOMETYX until improvement to Grade 1 and resume CABOMETYX at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea. 5.6 Palmar-Plantar ErythrodysesthesiaPalmar-plantar erythrodysesthesia (PPE) occurred in 44% of patients treated with CABOMETYX. Grade 3 PPE occurred in 13% of patients treated with CABOMETYX. Withhold CABOMETYX until improvement to Grade 1 and resume CABOMETYX at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE. 5.7 ProteinuriaProteinuria was observed in 7% of patients receiving CABOMETYX. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.5.8 Osteonecrosis of the JawOsteonecrosis of the jaw (ONJ) occurred in <1% of patients treated with CABOMETYX. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of CABOMETYX and periodically during CABOMETYX. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 28 days prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.5.9 Wound Complications Wound complications have been reported with CABOMETYX. Stop CABOMETYX at least 28 days prior to scheduled surgery. Resume CABOMETYX after surgery based on clinical judgment of adequate wound healing. Withhold CABOMETYX in patients with dehiscence or wound healing complications requiring medical intervention.5.10 Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with CABOMETYX. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.5.11 Embryo-Fetal ToxicityBased on data from animal studies and its mechanism of action, CABOMETYX can cause fetal harm when administered to a pregnant woman. Cabozantinib administration to pregnant animals during organogenesis resulted in embryolethality at exposures below those occurring clinically at the recommended dose, and in increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.6 ADVERSE REACTIONSThe following clinically significant adverse reactions are discussed above and in the Warnings and Precautions section of the prescribing information: Hemorrhage, Perforations and Fistulas, Thrombotic Events, Hypertension and Hypertensive Crisis, Diarrhea, Palmar-plantar Erythrodysesthesia, Proteinuria, Osteonecrosis of the Jaw, Wound Complications, Reversible Posterior Leukoencephalopathy Syndrome6.1 Clinical Trial ExperienceThe data described in the WARNINGS AND PRECAUTIONS section below reflect exposure to CABOMETYX as a single agent in 409 patients with RCC enrolled in randomized, active-controlled trials (CABOSUN, METEOR) and 467 patients with HCC enrolled in a randomized, placebo-controlled trial (CELESTIAL).

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Renal Cell CarcinomaMETEORThe safety of CABOMETYX was evaluated in METEOR, a randomized, open-label trial in which 331 patients with advanced renal cell carcinoma received CABOMETYX 60 mg once daily and 322 patients received everolimus 10 mg once daily until disease progression or unacceptable toxicity. Patients on both arms who had disease progression could continue treatment at the discretion of the investigator. The median duration of treatment was 7.6 months (range 0.3 – 20.5) for patients receiving CABOMETYX and 4.4 months (range 0.21 – 18.9) for patients receiving everolimus. Adverse reactions which occurred in ≥ 25% of CABOMETYX-treated patients, in order of decreasing frequency, were: diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia (PPE), hypertension, vomiting, weight decreased, and constipation. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of patients were hypertension, diarrhea, fatigue, PPE, hyponatremia, hypophosphatemia, hypomagnesemia, lymphopenia, anemia, hypokalemia, and increased GGT.The dose was reduced in 60% of patients receiving CABOMETYX and in 24% of patients receiving everolimus. Twenty percent (20%) of patients received CABOMETYX 20 mg once daily as their lowest dose. The most frequent adverse reactions leading to dose reduction in patients treated with CABOMETYX were: diarrhea, PPE, fatigue, and hypertension. Adverse reactions leading to dose interruption occurred in 70% patients receiving CABOMETYX and in 59% patients receiving everolimus. Adverse reactions led to study treatment discontinuation in 10% of patients receiving CABOMETYX and in 10% of patients receiving everolimus. The most frequent adverse reactions leading to permanent discontinuation in patients treated with CABOMETYX were decreased appetite (2%) and fatigue (1%).

Table 1. Adverse Reactions Occurring in ≥ 10% Patients Who Received CABOMETYX in METEOR

 

 

Adverse Reaction

CABOMETYX (n=331) 1 Everolimus (n=322)
All Grades2 Grade 3-4 All Grades2 Grade 3-4
Percentage (%) of Patients
Gastrointestinal
Diarrhea 74 11 28 2
Nausea 50 4 28 <1
Vomiting 32 2 14 <1
Stomatitis 22 2 24 2
Constipation 25 <1 19 <1
Abdominal pain 3 23 4 13 2
Dyspepsia 12 <1 5 0
General
Fatigue 56 9 47 7
Mucosal inflammation 19 <1 23 3
Asthenia 19 4 16 2
Metabolism and Nutrition
Decreased appetite 46 3 34 <1
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia 42 8 6 <1
Rash 4 23 <1 43 <1
Dry skin 11 0 10 0
Vascular
Hypertension 5 39 16 8 3
Investigations
Weight decreased 31 2 12 0
Nervous System
Dysgeusia 24 0 9 0
Headache 11 <1 12 <1
Dizziness 11 0 7 0
Endocrine
Hypothyroidism 21 0 <1 <1
Respiratory, Thoracic, and Mediastinal
Dysphonia 20 <1 4 0
Dyspnea 19 3 29 4
Cough 18 <1 33 <1
Blood and Lymphatic
Anemia 17 5 38 16
Musculoskeletal and Connective Tissue
Pain in extremity 14 1 8 <1
Muscle spasms 13 0 5 0
Arthralgia 11 <1 14 1
Renal and Urinary
Proteinuria 12 2 9 <1
1   One subject randomized to everolimus received cabozantinib.

2 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0

3 Includes the following terms: abdominal pain, abdominal pain upper, and abdominal pain lower

4 Includes the following terms: rash, rash erythematous, rash follicular, rash macular, rash papular, rash pustular, rash vesicular, genital rash, intermittent leg rash, rash on scrotum and penis, rash maculo-papular, rash pruritic, contact dermatitis, dermatitis acneiform

5 Includes the following terms hypertension, blood pressure increased, hypertensive crisis, blood pressure fluctuation

 

Other clinically important adverse reactions (all grades) that were reported in <10% of patients treated with CABOMETYX included: wound complications (2%), convulsion (<1%), pancreatitis (<1%), osteonecrosis of the jaw (<1%), and hepatitis cholestatic (<1%).

Table 2. Laboratory Abnormalities Occurring in ≥ 25% Patients Who Received CABOMETYX in METEOR

 

 

Laboratory  Abnormality

CABOMETYX (n=331) Everolimus (n=322)
All Grades Grade 3-4 All Grades Grade 3-4
Percentage (%) of Patients
Chemistry
Increased AST 74 3 40 <1
Increased ALT 68 3 32 <1
Increased creatinine 58 <1 71 0
Increased triglycerides 53 4 73 13
Hypophosphatemia 48 8 36 5
Hyperglycemia 37 2 59 8
Hypoalbuminemia 36 2 28 <1
Increased ALP 35 2 29 1
Hypomagnesemia 31 7 4 <1
Hyponatremia 30 8 26 6
Increased GGT 27 5 43 9
Hematology
Leukopenia 35 <1 31 <1
Neutropenia 31 2 17 <1
Anemia1 31 4 71 17
Lymphopenia 25 7 39 12
Thrombocytopenia 25 <1 27 <1
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase.

NCI CTCAE, Version 4.0

1 Based on laboratory abnormalities

 

CABOSUN The safety of CABOMETYX was evaluated in CABOSUN, a randomized, open-label trial in patients with advanced renal cell carcinoma, in which 78 patients received CABOMETYX 60 mg once daily and 72 patients received sunitinib 50 mg once daily (4 weeks on treatment followed by 2 weeks off), until disease progression or unacceptable toxicity. The median duration of treatment was 6.5 months (range 0.2 – 28.7) for patients receiving CABOMETYX and 3.1 months (range 0.2 – 25.5) for patients receiving sunitinib. Within 30 days of treatment, there were 4 deaths in patients treated with CABOMETYX and 6 deaths in patients treated with sunitinib. Of the 4 patients treated with CABOMETYX, 2 patients died due to gastrointestinal perforation, 1 patient had acute renal failure, and 1 patient died due to clinical deterioration. All Grade 3-4 adverse reactions were collected in the entire safety population. The most frequent Grade 3-4 adverse reactions (≥5%) in patients treated with CABOMETYX were hypertension, diarrhea, hyponatremia, hypophosphatemia, PPE, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. The median average daily dose was 50.3 mg for CABOMETYX and 44.7 mg for sunitinib (excluding scheduled sunitinib non-dosing days). The dose was reduced in 46% of patients receiving CABOMETYX and in 35% of patients receiving sunitinib. The dose was held in 73% of patients receiving CABOMETYX and in 71% of patients receiving sunitinib. Based on patient disposition, 21% of patients receiving CABOMETYX and 22% of patients receiving sunitinib discontinued due to an adverse reaction.

Table 3. Grade 3-4 Adverse Reactions Occurring in ≥ 1% Patients Who Received CABOMETYX in CABOSUN

 

 

Adverse Reaction

CABOMETYX (n = 78) Sunitinib (n = 72)
Grade 3-41 Grade 3-41
Percentage (%) of Patients
Patients with any Grade 3-4 Adverse Reaction 68 65
Gastrointestinal
Diarrhea 10 11
Stomatitis 5 6
Nausea 3 4
Vomiting 1 3
Constipation 1 0
General
Fatigue 6 17
Pain 5 0
Metabolism and Nutrition
Hyponatremia2 9 8
Hypophosphatemia2 9 7
Decreased appetite 5 1
Dehydration 4 1
Hypocalcemia2 3 0
Hypomagnesemia2 3 0
Hyperkalemia2 1 3
Skin and Subcutaneous Tissue
Palmar-plantar   erythrodysesthesia 8 4
Skin ulcer 3 0
Vascular
Hypertension3 28 21
Hypotension 5 1
Angiopathy 1 1
Investigations
Increased ALT2 5 0
Weight decreased 4 0
Increased AST 2 3 3
Increased blood creatinine 2 3 3
Lymphopenia 2 1 6
Thrombocytopenia 2 1 11
Nervous System
Syncope 5 0
Respiratory, Thoracic, and Mediastinal
Dyspnea 1 6
 

 

Adverse Reaction

CABOMETYX (n = 78) Sunitinib (n = 72)
Grade 3-41 Grade 3-41
Percentage (%) of Patients
Dysphonia 1 0
Blood and Lymphatic
Anemia 1 3
Psychiatric
Depression 4 0
Confusional state 1 1
Infections
Lung infection 4 0
Musculoskeletal and Connective Tissue
Back pain 4 0
Bone pain 3 1
Pain in extremity 3 0
Arthralgia 1 0
Renal and Urinary
Renal failure acute 4 1
Proteinuria 3 1
ALT, alanine aminotransferase; AST, aspartate aminotransferase

1    NCI CTCAE Version 4.0

2   Laboratory abnormalities are reported as adverse reactions and not based on shifts in laboratory values

3   Includes the following term: hypertension

 

Hepatocellular CarcinomaThe safety of CABOMETYX was evaluated in CELESTIAL, a randomized, double-blind, placebo-controlled trial in which 704 patients with advanced hepatocellular carcinoma were randomized to receive CABOMETYX 60 mg orally once daily (n=467) or placebo (n=237) until disease progression or unacceptable toxicity. The median duration of treatment was 3.8 months (range 0.1 – 37.3) for patients receiving CABOMETYX and 2.0 months (range 0.0 – 27.2) for patients receiving placebo. The population exposed to CABOMETYX was 81% male, 56% White, and had a median age of 64 years. Adverse reactions occurring in ≥ 25% of CABOMETYX-treated patients, in order of decreasing frequency were: diarrhea, decreased appetite, PPE, fatigue, nausea, hypertension, and vomiting. Grade 3-4 adverse reactions which occurred in ≥ 5% of patients were PPE, hypertension, fatigue, diarrhea, asthenia, and decreased appetite. There were 6 adverse reactions leading to death in patients receiving CABOMETYX (hepatic failure, hepatorenal syndrome, esophagobronchial fistula, portal vein thrombosis, pulmonary embolism, upper gastrointestinal hemorrhage). The median average daily dose was 35.8 mg for CABOMETYX. The dose was reduced in 62% of patients receiving CABOMETYX; 33% of patients required a reduction to 20 mg daily. The most frequent adverse reactions or laboratory abnormalities leading to dose reduction of CABOMETYX were: PPE, diarrhea, fatigue, hypertension, and increased AST. Adverse reactions leading to dose interruption occurred in 84% patients receiving CABOMETYX. Adverse reactions leading to permanent discontinuation of CABOMETYX occurred in 16% of patients. The most frequent adverse reactions leading to permanent discontinuation of CABOMETYX were PPE (2%), fatigue (2%), decreased appetite (1%), diarrhea (1%), and nausea (1%).

Table 4. Adverse Reactions Occurring in ≥ 5% of CABOMETYX-Treated Patients in CELESTIAL1

 

 

 

Adverse Reaction

CABOMETYX (n = 467) Placebo (n = 237)
All Grades2 Grade 3-4 All Grades2 Grade 3-4
Percentage (%) of Patients
Gastrointestinal
Diarrhea 54 10 19 2
Nausea 31 2 18 2
Vomiting 26 <1 12 3
Stomatitis 13 2 2 0
Dyspepsia 10 0 3 0
General
Fatigue 45 10 30 4
Asthenia 22 7 8 2
Mucosal inflammation 14 2 2 <1
Metabolism and Nutrition
Decreased appetite 48 6 18 <1
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia 46 17 5 0
Rash3 21 2 9 <1
Vascular
Hypertension4 30 16 6 2
Investigations
Weight decreased 17 1 6 0
Nervous System
Dysgeusia 12 0 2 0
Endocrine
Hypothyroidism 8 <1 <1 0
Respiratory, Thoracic, and Mediastinal
Dysphonia 19 1 2 0
Dyspnea 12 3 10 <1
Musculoskeletal and Connective Tissue
Pain in extremity 9 <1 4 1
Muscle spasms 8 <1 2 0
1  Includes terms with a between-arm difference of ≥ 5% (all grades) or

≥ 2% (Grade 3-4)

2    NCI CTCAE Version 4.0

3 Includes the following terms: rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, dermatitis, dermatitis acneiform, dermatitis contact, dermatitis diaper, dermatitis exfoliative, dermatitis infected

4 Includes the following terms: hypertension, blood pressure diastolic increased, blood pressure increased

 

Table 5. Laboratory Abnormalities Occurring in ≥ 5% of CABOMETYX-Treated Patients in CELESTIAL1

 

 

 

 

Laboratory  Abnormality

CABOMETYX N=467 Placebo N=237
All Grades Grade 3-4 All Grades Grade 3-4
Percentage of Patients
Chemistry
Increased LDH 84 9 29 2
Increased ALT 73 12 37 6
Increased AST 73 24 46 19
Hypoalbuminemia 51 1 32 1
Increased ALP 43 8 38 6
Hypophosphatemia 25 9 8 4
Hypokalemia 23 6 6 1
Hypomagnesemia 22 3 3 0
Increased amylase 16 2 9 2
Hypocalcemia 8 2 0 0
Hematology
Decreased platelets 54 10 16 1
Neutropenia 43 7 8 1
Increased hemoglobin 8 0 1 0
1    Includes laboratory abnormalities with a between-arm difference of ≥ 5% (all grades) or ≥ 2% (Grade 3 4)

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, blood lactate dehydrogenase

 

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on CABOMETYXStrong CYP3A4 InhibitorsCoadministration of a cabozantinib capsule formulation with a strong CYP3A4 inhibitor increased the exposure of cabozantinib, which may increase the risk of exposure-related adverse reactions. Avoid coadministration of CABOMETYX with strong CYP3A4 inhibitors. Reduce the dosage of CABOMETYX if coadministration with strong CYP3A4 inhibitors cannot be avoided. Avoid grapefruit or grapefruit juice which may also increase exposure of cabozantinib.Strong CYP3A InducersCoadministration of a cabozantinib capsule formulation with a strong CYP3A4 inducer decreased the exposure of cabozantinib, which may reduce efficacy. Avoid coadministration of CABOMETYX with strong CYP3A4 inducers. Increase the dosage of CABOMETYX if coadministration with strong CYP3A4 inducers cannot be avoided. Avoid St. John’s wort which may also decrease exposure of cabozantinib.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyRisk SummaryBased on findings from animal studies and its mechanism of action, CABOMETYX can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies administration of cabozantinib to pregnant rats and rabbits during organogenesis resulted in embryofetal lethality and structural anomalies at exposures that were below those occurring clinically at the recommended dose (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataIn an embryo-fetal development study in pregnant rats, daily oral administration of cabozantinib throughout organogenesis caused increased embryo-fetal lethality compared to controls at a dose of 0.03 mg/kg (approximately 0.12-fold of human area under the curve [AUC] at the recommended dose). Findings included delayed ossification and skeletal variations at a dose of 0.01 mg/kg/day (approximately 0.04-fold of human AUC at the recommended dose).In pregnant rabbits, daily oral administration of cabozantinib throughout organogenesis resulted in findings of visceral malformations and variations including reduced spleen size and missing lung lobe at 3 mg/kg (approximately 1.1-fold of the human AUC at the recommended dose). In a pre- and postnatal study in rats, cabozantinib was administered orally from gestation day 10 through postnatal day 20. Cabozantinib did not produce adverse maternal toxicity or affect pregnancy, parturition or lactation of female rats, and did not affect the survival, growth or postnatal development of the offspring at doses up to 0.3 mg/kg/day (0.05-fold of the maximum recommended clinical dose).8.2 LactationRisk SummaryThere is no information regarding the presence of cabozantinib or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX.ContraceptionCABOMETYX can cause fetal harm when administered to a pregnant woman.FemalesAdvise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose.InfertilityFemales and MalesBased on findings in animals, CABOMETYX may impair fertility in females and males of reproductive potential.8.4 Pediatric UseThe safety and effectiveness of CABOMETYX in pediatric patients have not been established.Juvenile Animal Toxicity DataJuvenile rats were administered cabozantinib at doses of 1 or 2 mg/kg/day from Postnatal Day 12 (comparable to less than 2 years in humans) through Postnatal Day 35 or 70. Mortalities occurred at doses ≥1 mg/kg/day (approximately 0.16 times the clinical dose of 60 mg/day based on body surface area). Hypoactivity was observed at both doses tested on Postnatal Day 22. Targets were generally similar to those seen in adult animals, occurred at both doses, and included the kidney (nephropathy, glomerulonephritis), reproductive organs, gastrointestinal tract (cystic dilatation and hyperplasia in Brunner’s gland and inflammation of duodenum; and epithelial hyperplasia of colon and cecum), bone marrow (hypocellularity and lymphoid depletion), and liver. Tooth abnormalities and whitening as well as effects on bones including reduced bone mineral content and density, physeal hypertrophy, and decreased cortical bone also occurred at all dose levels. Recovery was not assessed at a dose of 2 mg/kg (approximately 0.32 times the clinical dose of 60 mg based on body surface area) due to high levels of mortality. At the low dose level, effects on bone parameters were partially resolved but effects on the kidney and epididymis/testis persisted after treatment ceased.8.5 Geriatric UseIn CABOSUN and METEOR, 41% of 409 patients treated with CABOMETYX were age 65 years and older, and 8% were 75 years and older. In CELESTIAL, 49% of 467 patients treated with CABOMETYX were age 65 years and older, and 15% were 75 years and older.No overall differences in safety or effectiveness were observed between these patients and younger patients.8.6 Hepatic ImpairmentIncreased exposure to cabozantinib has been observed in patients with moderate (Child-Pugh B) hepatic impairment. Reduce the CABOMETYX dose in patients with moderate hepatic impairment. Avoid CABOMETYX in patients with severe hepatic impairment (Child-Pugh C), since it has not been studied in this population.8.7 Renal ImpairmentNo dosage adjustment is recommended in patients with mild or moderate renal impairment. There is no experience with CABOMETYX in patients with severe renal impairment.10 OVERDOSAGEOne case of overdosage was reported following administration of another formulation of cabozantinib; a patient inadvertently took twice the intended dose for 9 days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.17 PATIENT COUNSELING INFORMATIONAdvise the patient to read the FDA-approved patient labeling (Patient Information).Hemorrhage: Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage. Perforations and fistulas: Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during CABOMETYX treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking CABOMETYX.Thrombotic events: Venous and arterial thrombotic events have been reported. Advise patients to report signs or symptoms of an arterial thrombosis. Venous thromboembolic events including pulmonary embolus have been reported. Advise patients to contact their health care provider if new onset of dyspnea, chest pain, or localized limb edema occurs.Hypertension: Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension.Diarrhea: Advise patients to notify their healthcare provider at the first signs of poorly formed or loose stool or an increased frequency of bowel movements.Palmar-plantar erythrodysesthesia: Advise patients to contact their healthcare provider for progressive or intolerable rash.Wound healing: Advise patients to contact their healthcare provider before any planned surgeries, including dental surgery.Reversible posterior leukoencephalopathy syndrome: Advise patients to immediately contact their health care provider for new onset or worsening neurological function. Drug interactions: Advise patients to inform their healthcare provider of all prescription or nonprescription medications, vitamins or herbal products. Inform patients to avoid grapefruit, grapefruit juice, and St. John’s wort.Embryo-fetal toxicity: Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with CABOMETYX.Females of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose of CABOMETYX.Lactation: Advise women not to breastfeed during treatment with CABOMETYX and for 4 months following the last dose.Important administration information• Instruct patients not to take CABOMETYX at least 1 hour before or at least 2 hours after eating.

This brief summary is based on the CABOMETYX Prescribing Information Revision 01/2019
Distributed by Exelixis, Inc. Alameda, CA 94502

CABOMETYX is a registered trademark of Exelixis, Inc.
© 2019 Exelixis, Inc.
Printed in USA 01/19 CA-1121

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