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Efficacy data for 1L aRCC CABOMETYX® (cabozantinib) monotherapy

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CABOMETYX is the only single-agent TKI to deliver superior PFS vs sunitinib in 1L aRCC1,3*

CABOSUN was a phase 2, randomized, open-label, multicenter trial of CABOMETYX vs sunitinib in first-line patients with aRCC who had ≥1 IMDC risk factors (N=157).

*

Patients were intermediate or poor risk and had ≥1 IMDC risk factors.

    CABOSUN: STUDY DESIGN

    1:1 randomization
    Patients had ≥1 IMDC risk factors: IMDC intermediate- or poor-risk disease, clear-cell component, measurable disease, and ECOG PS 0-2

    CABOMETYX 60 mg QD 
    (n=79)
    (6-week cycle)

    Sunitinib 50 mg QD
    (n=78)
    (4 weeks on/2 weeks off)

    Treatment continued until disease progression or unacceptable toxicity

    Primary endpoint
    PFS assessed by a retrospective blinded IRRC

    Secondary endpoints
    OS
    ORR assessed by a retrospective blinded IRRC
    Safety

    • Tumor assessments were conducted every 12 weeks from randomization until disease progression

    Inclusion criteria2-5:

    • Clear-cell component
    • Measurable disease, as defined by RECIST v1.1
    • IMDC intermediate or poor risk (patients must have 1 or more of the following):

    2 CLINICAL RISK FACTORS

    Time from diagnosis to treatment < 1 year
    Karnofsky performance status < 80%

    4 LABORATORY RISK FACTORS (routine tests)

    Hemoglobin < lower limit of normal
    Absolute neutrophil count > upper limit of normal
    Platelet count > upper limit of normal
    Corrected calcium > upper limit of normal
    • No prior systemic treatment
    • ECOG PS of 0-2
    • Adequate end-organ and marrow function with no uncontrolled significant illness
    • Brain metastases if adequately treated and stable for 3 months


    Stratification factors2:

    • IMDC intermediate or poor
    • Bone metastases: presence or absence

    CABOSUN study efficacy data

    Primary endpoint: Median PFS1,2†

    8.6
    months
    CABOMETYX
    (n=79)

    VS

    5.3
    months
    sunitinib
    (n=78)

    HR=0.48 (95% CI: 0.31-0.74) P=0.0008

    †

    Assessed by a retrospective blinded IRRC.

    Secondary endpoints: OS and ORR1,2

    OS

    20% 

    reduction in
    risk of death

    HR=0.80 (95% CI: 0.53-1.21)

    ORR

    20% 
    CABOMETYX 
    (n=79) 
    (95% CI: 12.0%-30.8%)

    VS

    9%
    sunitinib
    (n=78)
    (95% CI: 3.7%-17.6%)

    • ORR was assessed by a retrospective blinded IRRC and all responses were partial responses.1
    • The trial did not have a prespecified hypothesis for OS and ORR, and statistical testing of these endpoints was not performed.2
     
    PREFERRED OPTION‡ IN 1L CLEAR-CELL RCC6

    Cabozantinib is the only single-agent TKI with an NCCN-preferred recommendation in 1L intermediate-/poor-risk clear-cell RCC.

     

    ‡NCCN Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

    See Monotherapy Safety Data
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    1L=first-line; aRCC=advanced renal cell carcinoma;  CI=confidence interval; ECOG PS=Eastern Cooperative Oncology Group performance status; HR=hazard ratio; IMDC=International Metastatic Renal Cell Carcinoma Database Consortium; IRRC=independent radiology review committee; NCCN=National Comprehensive Cancer Network; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; QD=once daily; RECIST=Response Evaluation Criteria in Solid Tumors; TKI=tyrosine kinase inhibitor.

    References:

    1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
    2. Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115-125.
    3. Data on file. Exelixis, Inc.
    4. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35(6):591-597. doi:10.1200/JCO.2016.70.7398.
    5. Heng DYC, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141-148. doi:10.1016/S1470-2045(12)70559-4.
    6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.4.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed January 18, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    IMPORTANT SAFETY INFORMATION

    WARNINGS AND PRECAUTIONS

    Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

    Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

    Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

    Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX 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 at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

    Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

    Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

    Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

    Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. 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 CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose. 

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

    Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

    Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

    Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

    Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

    In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

    Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

    Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

    ADVERSE REACTIONS

    The most common (≥20%) adverse reactions are:

    CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation. 

    DRUG INTERACTIONS

    Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

    Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

    USE IN SPECIFIC POPULATIONS

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

    Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

    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.

    Indication

    CABOMETYX is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

    CABOMETYX is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

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