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Important Safety Information for CABOMETYX®

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.

 

Full Prescribing Information

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Clinical Overview | Dosing & Management Mechanism |  Exelixis Access Services® | Resources

aRCC First-Line Data  | aRCC Second-Line Data 

 

 First and only TKI with superior efficacy

to sunitinib in advanced RCC1*

 

First-Line aRCC

Trial Design | Baseline Characteristics | PFS | OS ORR | Safety Profile

 

CABOSUN: A US cooperative group head-to-head, randomized controlled trial1

A phase 2 trial vs sunitinib in first-line advanced RCC1,2

*PFS and ORR were assessed by a retrospective blinded IRRC.

Tumor assessments were conducted every 12 weeks from randomization until disease progression.

Inclusion Criteria1,3:

  • Clear-cell component
  • Measurable disease as defined by RECIST v1.1
  • IMDC intermediate or poor risk (patients must have 1 or more of the following):

-Time from diagnosis of RCC to systemic treatment < 1 year

-Hemoglobin < LLN

-Corrected calcium > ULN

-Karnofsky performance status <80%

-Neutrophil count > ULN

-Platelet count > ULN

  • No prior systemic treatment
  • ECOG PS 0-2
  • Adequate end-organ and marrow function with no uncontrolled significant illness
  • Brain metastases if adequately treated and stable for 3 months

Stratification factors2:

  • IMDC intermediate or poor
  • Bone metastases: presence or absence
ECOG=Eastern Cooperative Oncology Group; IRRC=independent radiology review committee; LLN=lower limit of normal; PS=performance status; RCC=renal cell carcinoma; RECIST=Response Evaluation Criteria in Solid Tumors; ULN=upper limit of normal.

 

CABOSUN evaluated a broad range of first-line patients with advanced RCC1

Primary Endpoint: PFS1

CABOMETYX demonstrated a statistically significant improvement in median PFS vs sunitinib2‡

  • Sustained separation of the PFS curve at 12 and 18 months (median follow-up of 25 months)1,2
  • PFS benefit was consistent across prespecified stratification factors1,2
 

First and only TKI to demonstrate superior efficacy vs sunitinib in first-line advanced RCC2

PFS was assessed by blinded IRRC.

Patients had ≥1 IMDC risk factors.

CI=confidence interval; HR=hazard ratio; PFS=progression-free survival.

  

 

Secondary Endpoint: OS2,3

 

  • The trial did not have a prespecified hypothesis for OS, and statistical testing of this endpoint was not performed1,2

OS=overall survival.

Secondary Endpoint: ORR1

CABOMETYX MORE THAN DOUBLED ORR VS SUNITINIB2

 

  • As assessed by a retrospective blinded IRRC, all responses were partial responses2
  • The trial did not have a prespecified hypothesis for ORR, and statistical testing of this endpoint was not performed1,2

 

ORR=objective response rate.

 

80% of patients experienced tumor shrinkage with CABOMETYX compared to 50% with sunitinib1,4§

REDUCTION IN TARGET LESION FROM BASELINE

 

  • Each vertical line corresponds to 1 patient. The plot represents the best percentage change in tumor size from baseline in the ITT population as determined by IRRC. Patients had at least 1 baseline and postbaseline assessment

 

§Data for the following subjects are not included in this figure: 14 subjects (cabozantinib 2, sunitinib 12) did not have postbaseline data. In addition, 3 subjects (cabozantinib 2, sunitinib 1) had only non-target lesions (response of non-CR/non-PD); 7 subjects (cabozantinib 3, sunitinib 4) were unevaluable due to NPACT; disease progression was assessed for 5 subjects (cabozantinib 2, sunitinib 3) on the basis of new lesions or progression in non-target lesions; target lesions did not contribute to the assessment. Additionally, 1 cabozantinib subject with an overall response of UE did not have any postbaseline target lesions measured.

CR=complete response; ITT=intent to treat; NPACT=non-protocol anticancer therapy; PD=progressive disease; UE=unevaluable. 

 

No new safety signals were observed with CABOMETYX in the CABOSUN trial2

  • The CABOSUN safety profile was generally consistent with that of the initial CABOMETYX product approval

Grade 3-4 ARs occurring in >1% patients who received CABOMETYX||

  • The following Grade 3-4 ARs were seen in 1% of patients receiving CABOMETYX: dyspnea (vs 6% with sunitinib), anemia (vs 3% with sunitinib), vomiting (vs 3% with sunitinib), angiopathy (vs 1% with sunitinib), confusional state (vs 1% with sunitinib), arthralgia (vs 0% with sunitinib), constipation (vs 0% with sunitinib), and dysphonia (vs 0% with sunitinib)

 AR=adverse reaction; PPE=palmar-plantar erythrodysesthesia.

||National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0).

Includes the following term: hypertension.

 

Laboratory-related Grade 3-4 ARs occurring in ≥1% patients who received CABOMETYX2#

  

 

   ALT=alanine aminotransferase; AST=aspartate aminotransferase.

   ARs were graded according to NCI–CTCAE v4.0.

#Laboratory abnormalities are reported as ARs and not based on shifts in laboratory values.

 

 
 
 
 
 

Second-Line Data

 

Trial Design | Baseline Characteristics | PFS | OS | ORR | Safety Profile

 

METEOR: A pivotal, phase 3, head-to-head, randomized controlled trial1,5,6

An open-label trial vs everolimus in advanced RCC after prior therapy**

 

  • Tumor assessment every 8 weeks for the first 12 months, then every 12 weeks thereafter2

** Anti-angiogenic.

††Dose reductions were allowed in both arms. 

‡‡The primary PFS analysis was conducted in the first 375 subjects randomized to treatment.

  The ITT population included all 658 patients.

§§Confirmed per IRRC.

 

Inclusion criteria2,5,7:

  • 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 stratification2,5:

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

MSKCC=Memorial Sloan Kettering Cancer Center; PD-1=programmed cell death protein-1; PD-L1/L2=programmed death ligand-1/2; RECIST=Response Evaluation Criteria In Solid Tumors; TKI=tyrosine kinase inhibitor; VEGFR=vascular endothelial growth factor receptor. 

METEOR evaluated a diverse set of patients who had received prior therapy2,5**

Nearly half of patients in the METEOR trial had favorable-risk disease

  Data are n (%) or median (IQR).
**Anti-angiogenic.
||One additional patient in the cabozantinib group received prior atezolizumab.5
  ECOG=Eastern Cooperative Oncology Group; IRRC=independent radiology review committee; PS=performance status.

First and only TKI to demonstrate significant improvement across 3 endpoints—OS, PFS, and ORR—in advanced RCC after prior therapy2**

Significant survival advantage2

SECONDARY ENDPOINT: OS

 

  • Nearly 5-month increase in median OS for patients taking CABOMETYX vs everolimus 
  • Sustained separation of the OS curve at 12 and 18 months (follow-up of at least 13 months)

 

 

Proven control of progression2,6

PRIMARY ENDPOINT: PFS¶¶ 

 

  • 42% reduction in risk of progression or death vs everolimus 

**Anti-angiogenic.
¶¶PFS was confirmed by IRRC.
  HR=hazard ratio; OS=overall survival; ORR=objective response rate; PFS=progression-free survival; RCC=renal cell carcinoma.

Significantly improved tumor control2

SECONDARY ENDPOINT: ORR##***

 ##ORR was assessed by blinded IRRC using RECIST v1.1.6

***Partial responses only.1

 

†††The proportion of patients achieving an overall response of confirmed CR or PR per RECIST v1.1.5
‡‡‡PR is defined by RECIST v1.1 as ≥30% decrease in tumor size following study treatment.7
§§§SD is defined by RECIST v1.1 as neither sufficient increase nor decrease in tumor size to qualify as PD or
   PR, respectively, following study treatment.7
|||PD is defined by RECIST v1.1 ≥20% relative increase and ≥5 mm absolute increase in tumor size
   following study treatment. The appearance of 1 or more new lesions is also considered progression.7 
¶¶¶No qualifying post baseline assessment for overall response.2

CABOMETYX safety in the METEOR study

ARs occurring in ≥10% of patients in the CABOMETYX arm2,4

 

Laboratory abnormalities occurring in ≥25% of patients in the CABOMETYX arm2

 

       ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase;
       GGT= gamma-glutamyltransferase.
### Percentages are treatment-emergent, all-causality events.
**** One subject randomized to everolimus received CABOMETYX

††††NCI–CTCAE

‡‡‡‡These ARs are grouped terms. For details, please see full Prescribing Information.

§§§§Based on laboratory abnormalities.

 

 

 

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References: 1. Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115-125. 2. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2019. 3. Heng DY, 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. Choueiri TK, Escudier B, Powles T, et al; METEOR investigators. 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. 6. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-1823. doi:10.1056/NEJMoa1510016. 7. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

 

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