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, including co-pay and 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 or 4 All Grades††† Grade 3 or 4
GI disorders        
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 disorders and administration site conditions        
Fatigue 56 9 47 7
Mucosal inflammation 19 <1 23 3
Asthenia 19 4 16 2
Metabolism and nutrition disorders        
Decreased appetite 46 3 34 <1
Skin and subcutaneous tissue disorders        
PPE 42 8 6 <1
Rash‡‡‡ 23 <1 43 <1
Dry skin 11 0 10 0
Vascular disorders        
Hypertension‡‡‡ 39 16 8 3
Investigations        
Weight decreased 31 2 12 0
Nervous system disorders        
Dysgeusia 24 0 9 0
Headache 11 <1 12 <1
Dizziness 11 0 7 0
Endocrine disorders        
Hypothyroidism 21 0 <1 <1
Respiratory, thoracic, and mediastinal disorders        
Dysphonia 20 <1 4 0
Dyspnea 19 3 29 4
Cough 18 <1 33 <1
Blood and lymphatic disorders        
Anemia 17 5 38 16
Musculoskeletal and connective tissue disorders        
Pain in extremity 14 1 8 <1
Muscle spasms 13 0 5 0
Arthralgia 11 <1 14 1
Renal and urinary disorders        
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 or 4 All Grades††† Grade 3 or 4
Chemistry        
AST increased 74 3 40 <1
ALT increased 68 3 32 <1
Creatinine increased 58 <1 71 0
Triglycerides increased 53 4 73 13
Hypophosphatemia 48 8 36 5
Hyperglycemia 37 2 59 8
Hypoalbuminemia 36 2 28 <1
ALP increased 35 2 29 1
Hypomagnesemia 31 7 4 <1
Hyponatremia 30 8 26 6
GGT increased 27 5 43 9
Hematology        
White blood cells decreased 35 <1 31 <1
Absolute neutrophil count decreased 31 2 17 <1
Hemoglobin decreased 31 4 71 17
Lymphocytes decreased 25 7 39 12
Platelets decreased 25 <1 27 <1

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.

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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. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2017. 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.