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

A phase 2 trial vs sunitinib in first-line advanced RCC1-3

*PFS and ORR were assessed by a retrospective blinded IRRC.
Tumor assessments were conducted every 12 weeks from randomization until disease progression.

Inclusion criteria1,3,4:

  • 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.

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CABOSUN evaluated a broad range of first-line patients with advanced RCC1,3

BASELINE PATIENT CHARACTERISTICS

  No. (%)
  CABOMETYX
(n=79)
sunitinib
(n=78)
Age, years    
Median (range) 63.0 (40.0-82.0) 64.0 (31.0-87.0)
Sex    
Male 66 (83.5) 57 (73.1)
Female 13 (16.5) 21 (26.9)
Ethnic origin    
White 70 (88.6) 75 (96.2)
Non-white 6 (7.6) 2 (2.6)
Not reported/unknown (patient unsure) 3 (3.8) 1 (1.3)
ECOG PS    
0 36 (45.6) 36 (46.2)
1 33 (41.8) 32 (41.0)
2 10 (12.7) 10 (12.8)
IMDC risk group    
Intermediate 64 (81.0) 63 (80.8)
Poor 15 (19.0) 15 (19.2)
Bone metastases    
Yes 29 (36.7) 28 (35.9)
No 50 (63.3) 50 (64.1)
Prior nephrectomy    
Yes 57 (72.2) 60 (76.9)
No 22 (27.8) 18 (23.1)
Number of metastatic sites per investigator, %    
1 22 33
2 47 26
≥3 32 41
Metastatic sites per investigator, %    
Nodal 57 54
Lung 70 69
Bone 39 38
Liver 19 26
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Primary Endpoint: PFS2‡

CABOMETYX demonstrated a statistically significant improvement in median PFS vs sunitinib


  • 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 RCC

PFS was assessed by a retrospective blinded IRRC.
§Patients had ≥1 IMDC risk factors.
CI=confidence interval; HR=hazard ratio; PFS=progression-free survival.

Dosing

Results from the CABOSUN, first-line vs TKI, clinical trial

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Dosing

Additional details around dosing and administration

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Secondary Endpoint: OS2,3

image

  • The trial did not have a prespecified hypothesis for OS, and statistical testing of this endpoint was not performed1-3

OS=overall survival.

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Secondary Endpoint: ORR3

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 sunitinib||

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.

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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

  No. (%)
  CABOMETYX (n=78) sunitinib (n=72)
PATIENTS WITH ANY GRADE 3-4 AR 53 (68) 47 (65)
Gastrointestinal Disorders    
Diarrhea 8 (10) 8 (11)
Stomatitis 4 (5) 4 (6)
Nausea 2 (3) 3 (4)
General Disorders and Adminsitration Site Conditions    
Fatigue 5 (6) 12 (17)
Pain 4 (5) 0
Metabolism and Nutrition Disorders    
Decreased appetite 4 (5) 1 (1)
Dehydration 3 (4) 1 (1)
Skin and Subcutaneous Skin Disorders    
PPE 6 (8) 3 (4)
Skin Ulcer 2 (3) 0
Vascular Disorders    
Hypertension# 22 (28) 15 (21)
Hypotension 4 (5) 1 (1)
Investigations    
Weight decreased 3 (4) 0
Nervous System Disorders    
Syncope 4 (5) 0
Psychiatric Disorders    
Depression 3 (4) 0
Infections and Infestations    
Lung infection 3 (4) 0
Musculoskeletal and Connective Tissue Disorders    
Back pain 3 (4) 0
Bone pain 2 (3) 1 (1)
Pain in extremity 2 (3) 0
Renal and Urinary Disorders    
Renal failure acute 3 (4) 1 (1)
  • 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 preferred term “hypertension.”

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

  No. (%)
  CABOMETYX (n=78) sunitinib (n=72)
Metabolism and Nutrition Disorders    
Hyponatremia 7 (9) 6 (8)
Hypophosphatemia 7 (9) 5 (7)
Hypocalcemia 2 (3) 0
Hypomagnesemia 2 (3) 0
Hyperkalemia 1 (1) 2 (3)
Investigations    
ALT increased 4 (5) 0
AST increased 2 (3) 2 (3)
Blood creatinine increased 2 (3) 2 (3)
Lymphocyte count decreased 1 (1) 4 (6)
Platelet count decreased 1 (1) 8 (11)
Renal and Urinary Disorders    
Proteinuria 2 (3) 1 (1)

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.

Dosing

Helpful tips for management with CABOMETYX

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Dosing

Additional details around dosing and administration

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INDICATION

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

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In RCC trials, the incidence of Grade ≥3 hemorrhagic events was 3% in CABOMETYX patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

Gastrointestinal (GI) Perforations and Fistulas: In RCC trials, GI perforations were reported in 1% of CABOMETYX patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, fistulas were reported in 1% of CABOMETYX patients. Monitor patients for symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a GI perforation or a fistula that cannot be appropriately managed.

Thrombotic Events: Thrombotic events increased with CABOMETYX. In RCC trials, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.

Hypertension and Hypertensive Crisis: Treatment-emergent hypertension, including hypertensive crisis, increased with CABOMETYX. In RCC trials, hypertension was reported in 44% (18% Grade ≥3) of CABOMETYX patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX if there is evidence of hypertensive crisis or for severe hypertension that cannot be controlled with antihypertensive therapy or medical management.

Diarrhea: In RCC trials, diarrhea occurred in 74% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): In RCC trials, PPE occurred in 42% of CABOMETYX patients. Grade 3 PPE occurred in 8% of CABOMETYX patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. 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 of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most commonly reported (≥25%) adverse reactions were: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.

Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose.

Hepatic Impairment: In patients with mild to 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. Data on file. Exelixis, Inc. 2. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2017. 3. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35(6):591-597. 4. 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.