COMETRIQ was approved based on the phase 3, international, multicenter, randomized, double-blind EXAM study1,2

Metastatic MTC with documented mRECIST progression
2:1 Randomization
COMETRIQ 140 mg
Placebo

Patients were to continue treatment until disease progression or unacceptable toxicity occurred.

Primary endpoint: PFS

Secondary endpoints included: ORR and OS1

Randomization was stratified by age (≤65 years vs >65 years) and prior TKI exposure (yes/no). No crossover was allowed at the time of progression.


A first-line systemic therapy option for patients with progressive, metastatic MTC1

  • 61% of patients in the pivotal EXAM study had not received prior systemic therapy2
  • 78% of patients had not received prior TKI treatments2*
  • 25% of patients had received 2 or more prior systemic therapies1

*21% of patients in the EXAM study had been previously treated with a TKI; the TKI status of 1.5% of the patients was unknown.1,2


Please click here to see Important Safety Information for COMETRIQ and click here to see the full Prescribing Information.


Evaluated in a clinically relevant patient population1,2

The EXAM study included patients for whom systemic therapy was appropriate.

  • Inclusion criteria required radiographic evidence of actively progressive disease within 14 months prior to study entry1
  • Patients were eligible regardless of the number of therapies received prior to enrollment2

Patient characteristics (baseline)2,3
COMETRIQ
(n=219)		 Placebo
(n=111)
Gender
Male 68.9% 63.1%
Age
≤65 years 78.5% 77.5%
ECOG performance status
0 56.2% 50.5%
1-2 43.4% 49.5%
RET mutation status
Positive 46.1% 52.3%
Negative 14.2% 9.0%
Unknown 39.7% 38.7%
Measurable disease
Yes 95.0% 93.7%
Metastatic disease
Yes 100% 99.1%
Metastatic disease, by site
Lymph nodes 79.9% 77.5%
Liver 69.4% 60.4%
Lung 53.0% 57.7%
Bone 51.1% 50.5%
Prior thyroidectomy
Yes 91.8% 93.7%
Prior TKI use
Yes 20.1% 21.6%
Prior vandetanib therapy
Yes 11.4% 8.1%
Prior treatment
No systemic therapy 63.0% 57.7%
≥2 systemic therapies 23.7% 27.9%
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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas, including fatal cases, were reported in 3% and 1% of COMETRIQ-treated patients (N=214), respectively. Non-GI fistulas, including tracheal/esophageal fistulas, including fatal cases, were reported in 4% of COMETRIQ-treated patients. Monitor patients for symptoms of perforations and fistulas, including abscess and sepsis. Discontinue COMETRIQ in patients who experience a Grade 4 fistula or a GI perforation.

Hemorrhage: Severe and fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs 1%). Discontinue COMETRIQ for Grade 3 or 4 hemorrhage. Do not administer COMETRIQ to patients with a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Thrombotic Events: COMETRIQ treatment resulted in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or arterial or venous thromboembolic events that require medical intervention.

Impaired Wound Healing: Wound complications have been reported with COMETRIQ. Withhold COMETRIQ for at least 3 weeks prior to elective surgery. Do not administer COMETRIQ for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of COMETRIQ after resolution of wound healing complications has not been established.

Hypertension and Hypertensive Crisis: COMETRIQ treatment resulted in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Do not initiate COMETRIQ in patients with uncontrolled hypertension. Monitor blood pressure regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy and for hypertensive crisis.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, or persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ treatment. Advise patients regarding good oral hygiene practices. Withhold COMETRIQ treatment for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold COMETRIQ for development of ONJ until complete resolution.

Diarrhea: Diarrhea occurred in 63% of patients treated with COMETRIQ. Grade 3 to 4 diarrhea occurred in 16% of patients treated with COMETRIQ. Withhold COMETRIQ until improvement to Grade 1 and resume COMETRIQ at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 50% of patients treated with COMETRIQ and was severe (Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume COMETRIQ at a reduced dose.

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ, including 1 patient with nephrotic syndrome, vs 0% in placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in 1 (<1%) patient. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS.

Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during COMETRIQ treatment and for 4 months after the last dose.

Hypocalcemia: COMETRIQ can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 52% of patients treated with COMETRIQ, including Grade 3 or 4 in 12% of patients. Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at a reduced dose upon recovery or discontinue COMETRIQ depending on severity.

ADVERSE REACTIONS

The most commonly reported adverse drug reactions (≥25% and ≥5% difference vs placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPE (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%).

The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%), increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), hypoalbuminemia (43% vs 16%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).

Increased levels of thyroid-stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).

In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was 1 in patients receiving COMETRIQ compared to 0 in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: Reduce the dosage of COMETRIQ if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: Increase the dosage of COMETRIQ if concomitant use with strong CYP3A4 inducers cannot be avoided. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise lactating women not to breastfeed during treatment with COMETRIQ and for 4 months after the final dose.

Reproductive Potential: Verify the pregnancy status of females of reproductive potential before starting treatment with COMETRIQ. COMETRIQ may impair fertility in females and males of reproductive potential.

Hepatic Impairment: Reduce the COMETRIQ dosage in patients with mild to moderate hepatic impairment. COMETRIQ is not recommended for use in patients with severe hepatic impairment.

INDICATION

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

Please see full Prescribing Information.


You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

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ECOG=Eastern Cooperative Oncology Group; MTC=medullary thyroid cancer; mRECIST=modified Response Evaluation Criteria in Solid Tumors; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RET=rearranged during transfection; TKI=tyrosine kinase inhibitor.

References: 1. COMETRIQ® (cabozantinib) Prescribing Information. Exelixis, Inc,. 2. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639-3646. 3. Data on file. Exelixis, Inc.