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Monotherapy

CELESTIAL: largest phase 3 trial of previously treated patients with HCC1,2

The CELESTIAL trial was a randomized (2:1), double-blind, phase 3 trial of more than 707 patients with HCC.1,2 It is the only phase 3 trial of a TKI in HCC that enrolled patients previously treated with VEGF- (707/707) and immune checkpoint-inhibitor (17/707) therapies.

 

CELESTIAL Study Design1,2

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 criteria1:

  • 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 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


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 month median OS in the second line2,3

Subgroup Analysis: OS (Second-line)4

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 line2,3

SUBGROUP ANALYSIS: PFS (SECOND-LINE)4†

PFS Results

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


ORR results

With CABOMETYX, nearly 2-in-3 patients achieved disease control3

Disease control rate was defined as the percentage of patients with a complete response (0%), partial response (4%), or stable disease (60%), as measured by RECIST v1.1.1-3

Secondary Endpoint: ORR (ITT)1-3

Secondary endpoint: ORR chart

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

  • 21% experienced progressive disease with CABOMETYX (98/470) vs 55% with placebo (131/237)3
  • 15% were not evaluable or missing with CABOMETYX (72/470) vs 11% with placebo (27/237)3
     

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; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease.

References:

  1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2021.
  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.

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 and HCC studies. 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: 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 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 was observed 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 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.

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 is observed. 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.

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 (≥20%) adverse reactions are: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

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.

INDICATIONS

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

INDICATIONS

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