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

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 thereafter1

*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 criteria1,2,5:

  • 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 stratification1,2:

  • 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 therapy1,2*

  No. (%)
  CABOMETYX
(n=330)		 everolimus
(n=328)
Median age (range) 63 (56-68) 62 (55-68)
Sex    
Male 253 (77) 241 (73)
Female 77 (23) 86 (26)
Geographic region    
Europe 167 (51) 153 (47)
North America 118 (36) 122 (37)
Asia-Pacific 39 (12) 47 (14)
Latin America 6 (2) 6 (2)
Ethnic origin    
White 269 (82) 263 (80)
Asian 21 (6) 26 (8)
Black 6 (2) 3 (<1)
Other 19 (6) 13 (4)
Not reported 15 (5) 22 (7)
ECOG PS    
0 226 (68) 217 (66)
1 104 (32) 111 (34)
MSKCC prognostic risk category    
Favorable 150 (45) 150 (46)
Intermediate 139 (42) 135 (41)
Poor 41 (12) 43 (13)
Metastatic site per IRRC    
Lung 204 (62) 212 (65)
Liver 88 (27) 103 (31)
Bone 77 (23) 65 (20)
Lymph node 206 (62) 199 (61)
Brain 2 (<1) 1 (<1)
Other 23 (7) 21 (6)
Previous VEGFR-TKIs    
1 235 (71) 229 (70)
≥2 95 (29) 99 (30)
Previous systemic therapy    
Sunitinib 210 (64) 205 (62)
Pazopanib 144 (44) 136 (41)
Axitinib 52 (16) 55 (17)
Sorafenib 21 (6) 31 (9)
Bevacizumab 5 (2) 11 (3)
Interleukin 2 20 (6) 29 (9)
Interferon α 19 (6) 24 (7)
Nivolumab|| 17 (5) 14 (4)
Radiotherapy 110 (33) 108 (33)
Nephrectomy 283 (86) 279 (85)

 

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

 

Data are n (%) or median (IQR).
*Anti-angiogenic.
IIOne additional patient in the cabozantinib group received prior atezolizumab.2

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 therapy1*

Significant survival advantage1

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)
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Exelixis Access Services® (EASE) enrollment form, including the 15-Day Free Trial Program, EASE Quick Start Program, EASE Co-Pay Program, and the EASE Patient Assistance Program (PAP)

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Results from the METEOR, second-line clinical trial

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Proven control of progression1,3

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 control1

SECONDARY ENDPOINT: ORR#**

 

#ORR was assessed by blinded IRRC using RECIST v1.1.3
**Partial responses only.1

Improved tumor control1,2

TUMOR RESPONSE AS ASSESSED BY IRRC

  CABOMETYX
(n=330)		 everolimus
(n=328)
ORR
(95% CI)††		 17% (13%-22%) 3% (2%-6%) Secondary endpoint2
P<0.0001
Best overall response, n (%)
Confirmed complete response (CR) 0 0
Confirmed partial response (PR)‡‡ 57 (17%) 11 (3%)
Stable disease (SD)§§ 216 (65%) 203 (62%)
Progressive disease (PD)|||| 41 (12%) 88 (27%)
Not evaluable or missing¶¶ 16 (5%) 26 (8%)

 

††The proportion of patients achieving an overall response of confirmed CR or PR per RECIST v1.1.2
‡‡PR is defined by RECIST v1.1 as ≥30% decrease in tumor size following study treatment.5
§§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.5
||||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.5
¶¶No qualifying postbaseline assessment for overall response.2

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CABOMETYX safety in the METEOR study

ARs occurring in ≥10% of patients in the CABOMETYX arm1,4

    Percentage (%) of Patients
ARs## CABOMETYX (n=331)*** everolimus (n=322)
All Grades††† Grade 3-4 All Grades††† Grade 3-4
Gastrointestinal        
Diarrhea 74 11 28 2
Nausea 50 4 28 <1
Vomiting 32 2 14 <1
Stomatitis 22 2 24 2
Constipation 25 <1 19 <1
Abdominal pain‡‡‡ 23 4 13 2
Dyspepsia 12 <1 5 0
General        
Fatigue 56 9 47 7
Mucosal inflammation 19 <1 23 3
Asthenia 19 4 16 2
Metabolism and nutrition        
Decreased appetite 46 3 34 <1
Skin and subcutaneous tissue        
Palmar-plantar erythrodysesthesia 42 8 6 <1
Rash‡‡‡ 23 <1 43 <1
Dry skin 11 0 10 0
Vascular        
Hypertension‡‡‡ 39 16 8 3
Investigations        
Weight decreased 31 2 12 0
Nervous system        
Dysgeusia 24 0 9 0
Headache 11 <1 12 <1
Dizziness 11 0 7 0
Endocrine        
Hypothyroidism 21 0 <1 <1
Respiratory, thoracic, and mediastinal        
Dysphonia 20 <1 4 0
Dyspnea 19 3 29 4
Cough 18 <1 33 <1
Blood and lymphatic        
Anemia 17 5 38 16
Musculoskeletal and connective tissue        
Pain in extremity 14 1 8 <1
Muscle spasms 13 0 5 0
Arthralgia 11 <1 14 1
Renal and urinary        
Proteinuria 12 2 9 <1
 

Laboratory abnormalities occurring in ≥25% of patients in the CABOMETYX arm1

    Percentage (%) of Patients
Test††† CABOMETYX (n=331)*** everolimus (n=322)
All Grades††† Grade 3-4 All Grades††† Grade 3-4
Chemistry        
Increased AST 74 3 40 <1
Increased ALT 68 3 32 <1
Increased creatinine 58 <1 71 0
Increased triglycerides 53 4 73 13
Hypophosphatemia 48 8 36 5
Hyperglycemia 37 2 59 8
Hypoalbuminemia 36 2 28 <1
Increased ALP 35 2 29 1
Hypomagnesemia 31 7 4 <1
Hyponatremia 30 8 26 6
Increased GGT 27 5 43 9
Hematology        
Leukopenia 35 <1 31 <1
Neutropenia 31 2 17 <1
Anemia§§§ 31 4 71 17
Lymphopenia 25 7 39 12
Thrombocytopenia 25 <1 27 <1

##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
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; GGT=gamma-glutamyltransferase.

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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. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2019. 2. 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. 3. 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. 4. Data on file. Exelixis, Inc. 5. 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.