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Efficacy data in HCC CABOMETYX® (cabozantinib) monotherapy

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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 (Child-Pugh A).1,2 

    CELESTIAL: STUDY DESIGN

    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

    Inclusion criteria2:

    • Pathologic diagnosis of HCC not amenable to curative treatment
    • Child-Pugh 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)


    Child-Pugh scores were assessed by the investigator at the time of each radiographic disease assessment every 8 weeks.3

    In CELESTIAL, 71% of CABOMETYX patients were second-line5

    CELESTIAL did not exclude patients who had4,5:

    CELESTIAL included a range of patients4

    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

    Patients who progressed from Child-Pugh A to Child-Pugh B within the first 8 weeks of treatment remained in the trial until disease progression or unacceptable toxicity (73/707)3

    OS results

    Superior OS in the treatment of 2L HCC1

     
    Primary endpoint: OS (ITT population who received at least one prior therapy, including sorafenib; median)
    10.2 MONTHS
    CABOMETYX (n=470)    		 VS 8.0 MONTHS
    Placebo (n=237)    		 (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 (second-line)2

    Subgroup analysis: OS5†

    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: PFS (ITT population who received at least one prior therapy, including sorafenib; median)

    5.2

    MONTHS 
    CABOMETYX (n=470)

    VS

    1.9

    MONTHS 
    Placebo (n=237)

    (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 (second-line)2

    Subgroup analysis: PFS5‡

    PFS Results

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

    CABOMETYX improved tumor control for patients with HCC1,4-7
    With CABOMETYX, 47% of patients experienced tumor shrinkage in the ITT analysis6§

     
    Reduction in target lesion from baseline

    Inclusion criteria6

    • Each vertical line corresponds to one patient. The plot represents the best percentage change in tumor size from baseline in the evaluable patient population, as determined by the investigators, per RECIST v1.1

    • Among patients with baseline and postbaseline target-lesion assessment, 222 of 388 patients in the CABOMETYX arm and 27 of 205 patients in the placebo arm had a decrease from baseline

    Some patients are not represented due to lack of evaluable postbaseline assessment, censoring (per PFS rules) before first evaluable postbaseline assessment, lack of target lesions, and/or incomplete or inevaluable target-lesion assessment. Data from time points after the first date of any of the censoring events defined for the primary PFS analysis were excluded.5
    §Confirmed partial responses.5

    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 v1.1.1,7

    Secondary Endpoint: ORR (ITT)1,2,4

     

    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 v1.1.4

    • 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. Stable disease may reflect the natural history of disease rather than any effect of the drug
    With CABOMETYX, 64% disease control rate was observed4

    National Comprehensive Cancer Network® (NCCN®)

    Cabozantinib (CABOMETYX) is recommended as a Category 1 subsequent-line treatment option for HCC

    NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
    NCCN Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

    For certain patients with Child-Pugh Class A liver function only, following disease progression on first-line systemic treatment. Data reflect use after sorafenib.

    See Monotherapy Safety Data
    See Child-Pugh B Data
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    2L=second-line; BCLC=Barcelona Clinic Liver Cancer; CI=confidence interval; ECOG PS=Eastern Cooperative Oncology Group performance status; 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.

    References:

    1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
    2. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63.
    3. El-Khoueiry AB, Meyer T, Cheng AL, et al. Safety and efficacy of cabozantinib for patients with advanced hepatocellular carcinoma who advanced to Child–Pugh B liver function at study week 8: a retrospective analysis of the CELESTIAL randomized controlled trial. BMC Cancer. 2022;22(1):377.
    4. 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.
    5. Data on file. Exelixis, Inc.
    6. Merle P, Rimassa L, Ryoo B-Y, et al. Assessment of tumor response, AFP response, and time to progression in the phase 3 CELESTIAL trial of cabozantinib versus placebo in advanced hepatocellular carcinoma. Poster presented at: ESMO 20th World Congress on Gastrointestinal Cancer; June 20-23, 2018; Barcelona, Spain. 
    7. 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(2):228-247.
    8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancers V.1.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed April 4, 2022. 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 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.

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