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.

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

BASELINE PATIENT CHARACTERISTICS

  No. (%)
  CABOMETYX
(n=79)
sunitinib
(n=78)
Age, years    
Median (range) 63 (56-69) 64 (57-71)
Sex    
Male
Female
66 (84)
13 (16)
57 (73)
21 (27)
Ethnic origin    
White
Black or African American
Other
70 (89)
3 (4)
7 (9)
75 (96)
2 (3)
1 (1)
ECOG PS    
0
1
2
36 (46)
33 (42)
10 (13)
36 (46)
32 (41)
10 (13)
IMDC risk group    
Intermediate
Poor
64 (81)
15 (19)
63 (81)
15 (19)
Bone metastases    
Yes
No
29 (37)
50 (63)
28 (36)
50 (64)
Prior nephrectomy    
Yes
No
57 (72)
22 (28)
60 (77)
18 (23)
Sum of diameters of lesions per RECIST per investigator (cm)    
Median (range) 7.2 (4.3-11.7) 8.1 (4.7-13.4)
Number of metastatic sites per investigator    
1
2
≥3
17 (22)
37 (47)
25 (32)
26 (33)
20 (26)
32 (41)
Metastatic sites per investigator    
Nodal
Lung
Liver
Bone
CNS/brain
45 (57)
55 (70)
15 (19)
31 (39)
3 (4)
42 (54)
54 (69)
20 (26)
30 (38)
2 (3)

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Primary Endpoint: PFS1‡

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.

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Clinical guidelines recommend CABOMETYX as a "preferred" regimen

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

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Secondary Endpoint: OS2,3

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

OS=overall survival.

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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.

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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
  • The most commonly reported (≥25%) adverse reactions for CABOMETYX were: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, and vomiting

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    
Diarrhea 8 (10) 8 (11)
Stomatitis 4 (5) 4 (6)
Nausea 2 (3) 3 (4)
General    
Fatigue 5 (6) 12 (17)
Pain 4 (5) 0
Metabolism and Nutrition    
Decreased appetite 4 (5) 1 (1)
Dehydration 3 (4) 1 (1)
Skin and Subcutaneous Tissue    
PPE 6 (8) 3 (4)
Skin ulcer 2 (3) 0
Vascular    
Hypertension# 22 (28) 15 (21)
Hypotension 4 (5) 1 (1)
Investigations    
Weight decreased 3 (4) 0
Nervous System    
Syncope 4 (5) 0
Psychiatric    
Depression 3 (4) 0
Infections    
Lung infection 3 (4) 0
Musculoskeletal and Connective Tissue    
Back pain 3 (4) 0
Bone pain 2 (3) 1 (1)
Pain in extremity 2 (3) 0
Renal and Urinary    
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)

National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0).
#Includes the following term: hypertension.

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

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

  No. (%)
  CABOMETYX (n=78) sunitinib (n=72)
Metabolism and Nutrition    
Hyponatremia 7 (9) 6 (8)
Hypophosphatemia 7 (9) 5 (7)
Hypocalcemia 2 (3) 0
Hypomagnesemia 2 (3) 0
Hyperkalemia 1 (1) 2 (3)
Investigations    
Increased ALT 4 (5) 0
Increased AST 2 (3) 2 (3)
Increased blood creatinine 2 (3) 2 (3)
Lymphopenia 1 (1) 4 (6)
Thrombocytopenia 1 (1) 8 (11)
Renal and Urinary    
Proteinuria 2 (3) 1 (1)

ARs were graded according to NCI–CTCAE v4.0.
**Laboratory abnormalities are reported as ARs and not based on shifts in laboratory values.

ALT=alanine aminotransferase; AST=aspartate aminotransferase.

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Helpful tips for management with CABOMETYX

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Additional details around dosing and administration

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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. 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.