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Efficacy data in HCC CABOMETYX® (cabozantinib) monotherapy

CELESTIAL: largest phase 3 trial of HCC patients previously treated with sorafenib1,2

The CELESTIAL trial was a randomized (2:1), double-blind, phase 3 trial of 707 patients with HCC.1,2 

    2:1 Randomization (N=707)*
    Patients had progressed on ≥1 prior systemic therapy;
    all patients received prior sorafenib
    CABOMETYX
    60 mg QD
    (n=470)
    Placebo
    Once daily
    (n=237)
    Treatment until disease progression or unacceptable toxicity
    Primary endpoint
    OS
    Secondary endpoints
    PFS
    ORR
    *

    707 patients were randomized at the time of the second interim analysis for OS. In total, CELESTIAL enrolled 773 patients.2

    Tumor assessments were performed at baseline and every 8 weeks thereafter until radiographic progression per RECIST v1.1 or discontinuation, whichever occurred later. Patients were allowed to receive CABOMETYX beyond radiographic progression if the patient was considered to be deriving clinical benefit by the investigator.

    Inclusion criteria2:

    • Pathologic diagnosis of HCC not amenable to curative treatment
    • Child-Pugh class A
    • Received prior sorafenib
    • Prior treatment with 1-2 systemic therapies, with progression following at least 1 therapy
    • ECOG PS of 0 or 1


    Prespecified stratification1:

    • Disease etiology (HBV with or without HCV, HCV without HBV, other)
    • Region (Asia, other)
    • Presence of macrovascular invasion and/or extrahepatic spread of disease (yes, no)

    CELESTIAL did not exclude patients who had:3,4

    The only phase 3 trial of a TKI in HCC that enrolled patients previously treated with VEGF inhibitors (707/707) and immune checkpoint inhibitors (17/707)2,3

    In CELESTIAL, 71% of CABOMETYX patients were 2L2,3

    Baseline Patient Characteristics

      No. (%)
      CABOMETYX
    (n=470)
    placebo
    (n=237)
    Age (years)    
    Median (range) 64 (22-86) 64 (24-86)
    Sex    
    Male / Female 379 (81) / 91 (19) 202 (85) / 35 (15)
    Geographic region    
    Asia / Europe 116 (25) / 231 (49) 59 (25) / 108 (46)
    United States and Canada 108 (23) 59 (25)
    Australia and New Zealand 15 (3) 11 (5)
    Race    
    White / Asian 264 (56) / 159 (34) 130 (55) / 82 (35)
    Black or African American 8 (2) 11 (5)
    Other and Not Reported 39 (9) 14 (6)
    Number of prior systemic anticancer regimens for HCC    
    1 335 (71) 174 (73)
    2 130 (28) 62 (26)
    ≥3 2 (<1) 1 (<1)
    Prior systemic anticancer therapy    
    Sorafenib 470 (100) 237 (100)
    Anti-PD-1 or PD-L1 14 (3) 3 (1)
    Other 116 (25) 56 (24)
    Etiology of disease    
    HBV 178 (38) 89 (38)
    HCV 113 (24) 55 (23)
    Dual HBV / HCV infection 8 (2) 4 (2)
    Alcohol 112 (24) 39 (16)
    Nonalcoholic steatohepatitis 43 (9) 23 (10)
    Other and Unknown 99 (21) 63 (27)
    ECOG PS    
    0 / 1 / 2 245 (52) / 224 (48) / 1 (<1) 131 (55) / 106 (45) / 0
    BCLC Stage    
    B / C 42 (9) / 427 (91) 23 (10) / 214 (90)
    Alpha-fetoprotein    
    <400 ng/mL 278 (59) 136 (57)
    ≥400 ng/mL 192 (41) 101 (43)
    Extrahepatic spread of disease 369 (79) 182 (77)
    Macrovascular invasion 129 (27) 81 (34)
    Extrahepatic spread of disease and/or macrovascular invasion 398 (85) 200 (84)
    Local liver-directed non-radiation anticancer therapy 209 (44) 113 (48)
    Total duration of treatment of prior sorafenib    
    Median, months 5.3 4.8

    OS results

    Superior OS in the treatment of 2L HCC1

    • Primary endpoint: Median OS was 10.2 months with CABOMETYX (n=470) vs 8.0 months with placebo (n=237) in the ITT population of patients who received at least one prior therapy (HR=0.76; 95% CI: 0.63-0.92; P=0.0049)

     

    In a prespecified exploratory subgroup analysis of patients who received only 1 prior systemic therapy

    CABOMETYX exceeded 11 months median OS in the second line2

    Subgroup Analysis: OS4‡

    2L OS Chart

    No statistical procedure was employed for controlling type 1 error. Results should be considered hypothesis generating.

     

    PFS results

    Superior PFS in the treatment of 2L HCC1

    • Secondary endpoint: Median PFS was 5.2 months with CABOMETYX (n=470) vs 1.9 months with placebo (n=237) in the ITT population of patients who received at least one prior therapy (HR=0.44; 95% CI: 0.36-0.52; P<0.0001)

     

    In a prespecified exploratory subgroup analysis of patients who received only 1 prior systemic therapy

    CABOMETYX exceeded 5 months median PFS in the second line2

    SUBGROUP ANALYSIS: PFS

    PFS Results

    §No statistical procedure was employed for controlling type 1 error. Results should be consider hypothesis generating.

    ORR results

    Tumor response observed in the ITT population in the CELESTIAL trial1,5

    ORR was 4% among patients receiving CABOMETYX.|| ORR was defined as a ≥30% reduction in target tumor size from baseline, per RECIST v1.1.1,5

    Secondary Endpoint: ORR (ITT)1-3

      No. (%)
      CABOMETYX
    (n=470)
    placebo
    (n=237)
    Confirmed ORR|| [95% CI] 18 (4)
    [2.3-6.0]
    1 (0.4)
    [0.0-2.3]
    P=0.0086
    Stable disease 282 (60) 78 (33)
    Progressive disease 98 (21) 131 (55)
    Not evaluable or missing 72 (15) 27 (11)

    ||All responses were confirmed partial responses, as assessed by the investigators per RECIST v1.1.1

    • Disease control rate was defined as the percentage of patients with a complete response, partial response, or stable disease, as measured by RECIST v1.1
    With CABOMETYX, 64% disease control rate was observed3

    2L=second-line; BCLC=Barcelona Clinic Liver Cancer; CI=confidence interval; HBV=hepatitis B virus; HCC=hepatocellular carcinoma; HCV=hepatitis C virus; HR=hazard ratio; ITT=intent to treat; 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; VEGF=vascular endothelial growth factor.

    References:

    1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2022.
    2. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63.
    3. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma [supplementary appendix]. N Engl J Med. 2018;379(1):54-63.
    4. Data on file. Exelixis, Inc.
    5. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.

    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 DysfunctionThyroid 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 hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

    CABOMETYX is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.