CELESTIAL: A randomized, double-blind, phase 3 trial of 2L+ patients with HCC1,2

The pivotal trial of >700 patients was initiated in 2013 to address the unmet needs in HCC2,3*

 

*At the start of the CELESTIAL trial (2013), there was no standard-of-care treatment post sorafenib.4
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
  • ECOG PS of 0 or 1

Prespecified stratification2

  • 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 had a broad population and did not exclude patients based on5:

  • Bile duct invasion
  • Main portal vein invasion
  • >50% liver involvement
  • Prior immunotherapy
  • Intolerance to prior systemic therapy
  • AFP level
  • Viral load

AFP=alpha-fetoprotein tumor marker; ECOG=Eastern Cooperative Oncology Group; HBV=hepatitis B virus; HCC=hepatocellular carcinoma; HCV=hepatitis C virus; PS=performance status.

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Results from the CELESTIAL clinical trial in a broad, 2L+ population

Read the NEJM article

CELESTIAL included a broad range of HCC patients2,5

BASELINE PATIENT CHARACTERISTICS

No. (%)
  CABOMETYX
(n=470)
placebo
(n=237)
Median age, years (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)
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 performance status    
0/1/2 245 (52) / 224 (48) / 1 (<1) 131 (55) / 106 (45) / 0
BCLC Stage    
B (intermediate) / C (advanced) 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

 

BCLC=Barcelona Clinic Liver Cancer.

Among patients who received CABOMETYX, 71% were 2L5

First and only TKI with proven, significant OS and PFS in a broad, 2L+ HCC population1

CABOMETYX Celestial ITT efficacy

 

CI=confidence interval; HR=hazard ratio; ITT=intent to treat; TKI=tyrosine kinase inhibitor.

image

Clinical guidelines recommend CABOMETYX as a "preferred" regimen

Find out more

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

CABOMETYX exceeded 11 months median OS and 5 months median PFS in the second line2,5

 

CABOMETYX Celestial subgroup efficacy

No statistical procedure was employed for controlling type I error. Results should be considered hypothesis generating.2

CABOMETYX improved tumor control for patients with HCC6

With CABOMETYX, 47% of patients experienced tumor shrinkage in the ITT analysis§

REDUCTION IN TARGET LESION FROM BASELINE

CABOMETYX CELESTIAL tumor control

  • Each vertical line corresponds to 1 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 out of 388 patients on the CABOMETYX arm and 27 out of 205 patients on the placebo arm had a decrease from baseline

§Stars denote confirmed partial responses.
Subjects 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.3

With CABOMETYX, 64% of patients achieved disease control2

SECONDARY ENDPOINT: ORR (ITT)1,5

No. (%)
Best overall response 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 v1.11
  • Disease control rate was defined as the percentage of patients with a complete response, partial response, or stable disease, as measured by RECIST v1.11,2

ORR=objective response rate; RECIST=Response Evaluation Criteria In Solid Tumors.

No new safety signals were observed with CABOMETYX in the CELESTIAL trial1

  • The safety profiles across 3 pivotal trials in aRCC and HCC have been generally consistent with that of the initial CABOMETYX product approval

ARs occurring at a higher incidence in patients treated with CABOMETYX (Between-arm difference of ≥5% [All Grades] or ≥2% [Grade 3-4])1

Percentage (%) of Patients
  CABOMETYX
(n=467)
placebo
(n=237)
All Grades Grade 3-4 All Grades Grade 3-4
Gastrointestinal        
Diarrhea 54 10 19 2
Nausea 31 2 18 2
Vomiting 26 <1 12 3
Stomatitis 13 2 2 0
Dyspepsia 10 0 3 0
General        
Fatigue 45 10 30 4
Asthenia 22 7 8 2
Mucosal inflammation 14 2 2 <1
Metabolism and Nutrition        
Decreased appetite 48 6 18 <1
Skin and Subcutaneous Tissue        
PPE 46 17 5 0
Rash# 21 2 9 <1
Vascular        
Hypertension** 30 16 6 2
Investigations        
Weight decreased 17 1 6 0
Nervous System        
Dysgeusia 12 0 2 0
Endocrine        
Hypothyroidism 8 <1 <1 0
Respiratory, Thoracic, and Mediastinal        
Dysphonia 19 1 2 0
Dyspnea 12 3 10 <1
Musculoskeletal and Connective Tissue        
Pain in extremity 9 <1 4 1
Muscle spasms 8 <1 2 0

 

National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
#Includes the following terms: rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, rash vesicular, dermatitis, dermatitis acneiform, dermatitis contact, dermatitis diaper, dermatitis exfoliative, dermatitis infected.
**Includes the following terms: hypertension, blood pressure diastolic increased, blood pressure increased.

 

Laboratory abnormalities occurring at a higher incidence in patients treated with CABOMETYX (Between-arm difference of ≥5% [All Grades] or ≥2% [Grade 3-4])1

 

Percentage (%) of Patients
  CABOMETYX
(n=467)
placebo
(n=237)
All Grades Grade 3-4 All Grades Grade 3-4
Chemistry        
Increased LDH 84 9 29 2
Increased ALT 73 12 37 6
Increased AST 73 24 46 19
Hypoalbuminemia 51 1 32 1
Increased ALP 43 8 38 6
Hypophosphatemia 25 9 8 4
Hypokalemia 23 6 6 1
Hypomagnesemia 22 3 3 0
Increased amylase 16 2 9 2
Hypocalcemia 8 2 0 0
Hematology        
Decreased platelets 54 10 16 1
Neutropenia 43 7 8 0
Increased hemoglobin 8 0 1 0

 

ALP=alkaline phosphatase; ALT=alanine aminotransferase; AR=adverse reaction; aRCC=advanced renal cell carcinoma; AST=aspartate aminotransferase; LDH=blood lactate dehydrogenase; PPE=palmar-plantar erythrodysesthesia.

icon data

Helpful tips for management with CABOMETYX

Read the Treatment Management Guide

National Comprehensive Cancer Network® (NCCN®)

NCCN Category 1Cabozantinib (CABOMETYX) is RECOMMENDED AS A CATEGORY 1, SUBSEQUENT-LINE TREATMENT OPTION FOR HCC, following disease progression (Child-Pugh A)7ll

Category 1: Based upon high-level evidence, there is uniform consensus that the intervention is appropriate.

llData reflect use after sorafenib.
The National Comprehensive Cancer Network 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.

 

INDICATIONS

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

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

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. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: GastrointestinaI (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed 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 event requiring medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred in 36% (17% 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. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume 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 44% 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 occurred in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. 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 28 days prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution.

Wound Complications: Wound complications were reported with CABOMETYX. Stop CABOMETYX at least 28 days prior to scheduled surgery. Resume CABOMETYX after surgery based on clinical judgment of adequate wound healing. Withhold CABOMETYX in patients with dehiscence or wound healing complications requiring medical intervention.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding 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.

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 commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, and vomiting.

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. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information.

References: 1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2019. 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. doi:10.1056/NEJMoa1717002. 3. Data on file. Exelixis, Inc. 4. Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin Cancer Res. 2014;20(8):2072-2079. doi:10.1158/1078-0432.ccr-13-0547. 5. 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. doi:10.1056/NEJMoa1717002 [supplementary appendix]. 6. Merle P, Rimassa L, Ryoo BY, 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 the ESMO 20th World Congress on Gastrointestinal Cancer; June 20-23, 2018; Barcelona, Spain. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancers V.1.2019. ©National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed February 28, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org.

CABOMETYX now #1 TKI in new prescriptions for aRCC
CABOMETYX now approved in treatment of HCC