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Efficacy data for 2L aRCC CABOMETYX® (cabozantinib) monotherapy

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The only single-agent TKI with superior OS, PFS and ORR in 2L aRCC1*

*After at least 1 prior anti-angiogenic therapy.1

    METEOR: STUDY DESIGN

    METEOR was a phase 3, randomized, open-label trial vs everolimus in aRCC (N=658).1,2

    1:1 randomization
    Patients had ≥1 prior anti-angiogenic therapy
    CABOMETYX 60-mg QD
    (n=330)    		 everolimus 10-mg QD
    (n=328)
    Treatment until disease progression or unacceptable toxicity†
    Primary endpoint
    PFS confirmed by blinded IRRC‡    		 Secondary endpoints
    OS
    ORR confirmed by blinded IRRC
    Safety
    The METEOR trial allowed for enrollment of patients who received prior IO therapy.
    †

    Tumor assessments were conducted every 8 weeks for the first 12 months, then every 12 weeks thereafter, per RECIST v1.1. Treatment was continued after disease progression at the discretion of the investigator.

    ‡

    The primary PFS analysis was conducted in the first 375 subjects randomized to treatment. The ITT population included all 658 patients.

    Inclusion criteria1,3,4:

    • Clear-cell component
    • Measurable disease, as defined by RECIST v1.1
    • Radiographic progression within 6 months of enrollment
    • Radiographic progression during treatment with a VEGFR-TKI or within 6 months of last dose
    • No limit to the number of prior therapies
    • Prior treatment with antibodies targeting PD-1/PD-L1/L2 allowed
    • Brain metastases allowed, if adequately treated and stable
    • Karnofsky performance status ≥70%

    Prespecified stratification1,4:

    • MSKCC risk groups: favorable, intermediate, poor
    • Number of prior VEGFR-TKIs: 1, ≥2

    Baseline Characteristics

    METEOR evaluated a broad range of patients who had received prior therapy, including prior immunotherapy.

    Baseline Patient Characteristics

      No. (%)
      CABOMETYX
    (n=330)    		 everolimus
    (n=328)
    Age (years)    
    Median (IQR) 63 (56-68) 62 (55-68)
    Sex    
    Male 253 (77) 241 (73)
    Female 77 (23) 86 (26)
    Geographic region    
    Europe 167 (51) 153 (47)
    North america 118 (36) 122 (37)
    Asia-Pacific 39 (12) 47 (14)
    Latin America 6 (2) 6 (2)
    Race    
    White 269 (82) 263 (80)
    Asian 21 (6) 26 (8)
    Black 6 (2) 3 (<1)
    Other 19 (6) 13 (4)
    Not Reported 15 (5) 22 (7)
    ECOG PS    
    0 226 (68) 217 (66)
    1 104 (32) 111 (34)
    MSKCC prognostic risk category    
    Favorable 150 (45) 150 (46)
    Intermediate 139 (42) 135 (41)
    Poor 41 (12) 43 (13)
    Metastatic site per IRRC    
    Lung 204 (62) 212 (65)
    Liver 88 (27) 103 (31)
    Bone 77 (23) 65 (20)
    Lymph node 206 (62) 199 (61)
    Brain 2 (<1) 1 (<1)
    Other 23 (7) 21 (6)
    Previous VEGFR-TKIs    
    1 235 (71) 229 (70)
    ≥2 95 (29) 99 (30)
    Previous systemic therapy    
    Sunitib 210 (64) 205 (62)
    Pazapanib 144 (44) 136 (41)
    Axitinib 52 (16) 55 (17)
    Sorafonib 21 (6) 31 (9)
    Bevacizumab 5 (2) 11 (3)
    Interleukin 2 20 (6) 29 (9)
    Interferon a 19 (6) 24 (7)
    Nivolumab§ 17 (5) 14 (4)
    Radiotherapy 110 (33) 108 (33)
    Nephrectomy 283 (86) 279 (85)
    §

    One additional patient in the cabozantinib group received prior atezolizumab.

    Data are n (%) or median (IQR)

    METEOR Study Efficacy Data

    Secondary Endpoint in METEOR: Median OS1

    21.4
    months
    CABOMETYX
    (n=330)

    VS

    16.5
    months
    everolimus
    (n=328)

    HR=0.66 (95% CI: 0.53-0.83) P=0.0003

    Primary Endpoint in METEOR: Median PFS||¶

    7.4
    months
    CABOMETYX
    (n=187)

    VS

    3.8
    months
    everolimus
    (n=188)

    HR=0.58 (95% CI: 0.45-0.74); P<0.0001

    ||

    In the METEOR trial, the primary PFS analysis was conducted in the first 375 subjects randomized to treatment.

    PFS was confirmed by blinded IRRC.

    Secondary Endpoint in METEOR: ORR**

    17%
    CABOMETYX
    (n=330)
    (95% CI:13.0%-22.0%)

    VS

    3%
    everolimus
    (n=328)
    (95% CI: 2.0%-6.0%)

    (P<0.0001); partial responses only

    **ORR was assessed by blinded IRRC using RECIST v1.1.

     
    OTHER RECOMMENDED OPTION‡ IN 2L CLEAR-CELL RCC5

    Regardless of prior IO therapy status, cabozantinib is a recommended option.                                                

    ‡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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    2L=second-line; aRCC=advanced renal cell carcinoma; ECOG PS=Eastern Cooperative Oncology Group performance status; IO=immuno-oncology; IQR=interquartile range; IRRC=independent radiology review committee; ITT=intent to treat; MSKCC=Memorial Sloan Kettering Cancer Center; NCCN=National Comprehensive Cancer Network; ORR=objective response rate; OS=overall survival; PD-1=programmed cell death protein-1; PD-L1/L2=programmed death ligand-1/2; PFS=progression-free survival; QD=once daily; RECIST=Response Evaluation Criteria in Solid Tumors; TKI=tyrosine kinase inhibitor; VEGFR=vascular endothelial growth factor receptor.

    References:

    1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2022.
    2. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917-927. doi:10.1016/S1470-2045(16)30107-3.
    3. Heng DYC, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor–targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794-5799.
    4. Data on file. Exelixis, Inc.
    5. 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, 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 accompanying 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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