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2L Monotherapy

The only single-agent TKI with superior OS, PFS and ORR in 2L aRCC1*

NCCN Preferred

The only TKI monotherapy with an NCCN® Category 1 Preferred recommendation in 2L clear cell aRCC2

METEOR Study Design

METEOR was a phase 3, randomized, open-label trial vs everolimus in 2L aRCC (N=658).1,3

1:1 randomization
Patients had ≥1 prior anti-angiogenic therapy
CABOMETYX 60 mg QD
(n=330)
everolimus 10 mg QD
(n=328)
Treatment until disease progression or unacceptable toxicity
Primary endpoint
PFS confirmed by blinded IRRC
Secondary endpoints
OS
ORR confirmed by blinded IRRC
Safety
The METEOR trial allowed for enrollment of patients who received prior IO therapy.

After at least 1 prior anti-angiogenic therapy.1

Tumor assessments were conducted every 8 weeks for the first 12 months, then every 12 weeks thereafter, per RECIST v1.1. Treatment was continued after disease progression at the discretion of the investigator.

The primary PFS analysis was conducted in the first 375 subjects randomized to treatment. The ITT population included all 658 patients.

Inclusion criteria1,4,5:

  • 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 stratification1,5:

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

Baseline Characteristics

METEOR evaluated a broad range of patients who had received prior therapy, including prior immunotherapy.

Baseline Patient Characteristics

  No. (%)
  CABOMETYX
(n=330)
everolimus
(n=328)
Age (years)    
Median (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)
Race    
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    
Sunitib 210 (64) 205 (62)
Pazapanib 144 (44) 136 (41)
Axitinib 52 (16) 55 (17)
Sorafonib 21 (6) 31 (9)
Bevacizumab 5 (2) 11 (3)
Interleukin 2 20 (6) 29 (9)
Interferon a 19 (6) 24 (7)
Nivolumab§ 17 (5) 14 (4)
Radiotherapy 110 (33) 108 (33)
Nephrectomy 283 (86) 279 (85)
§

One additional patient in the cabozantinib group received prior atezolizumab.

Data are n (%) or median (IQR)

2L=second-line; aRCC=advanced renal cell carcinoma; ECOG PS=Eastern Cooperative Oncology Group performance status; IO=immuno-oncology; IRRC=independent radiology review committee; ITT=intent to treat; MSKCC=Memorial Sloan Kettering Cancer Center; NCCN=National Comprehensive Cancer Network; ORR=objective response rate; OS=overall survival; PD-1=programmed cell death protein-1; PD-L1/L2=programmed death ligand-1/2; PFS=progression-free survival; QD=once daily; RECIST=Response Evaluation Criteria in Solid Tumors; TKI=tyrosine kinase inhibitor; VEGFR=vascular endothelial growth factor receptor.

References:

  1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2021.
  2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.1.2021. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed September 8, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org.
  3. Heng DYC, 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. 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.

The only single-agent TKI with superior OS, PFS and ORR in 2L aRCC*

 

METEOR Study Efficacy Data

CABOMETYX is the only TKI with superior OS in 2L aRCC1†

Secondary Endpoint in METEOR: OS

*

vs everolimus in patients who had received ≥1 prior anti-angiogenic therapy.

After ≥1 prior anti-angiogenic therapy.

Primary Endpoint in METEOR: Median PFS‡§

7.4
months
CABOMETYX
(n=187)

VS

3.8
months
everolimus
(n=188)

HR=0.58 (95% CI: 0.45-0.74); P<0.0001

In the METEOR trial, the primary PFS analysis was conducted in the first 375 subjects randomized to treatment.

§

PFS was confirmed by blinded IRRC.

Secondary Endpoint in METEOR: ORR||

17%
CABOMETYX
(n=330)
(95% CI:13.0%-22.0%)

VS

3%
everolimus
(n=328)
(95% CI: 2.0%-6.0%)

(P<0.0001); partial responses only

||

ORR was assessed by blinded IRRC using RECIST v1.1.


2L=second-line; aRCC=advanced renal cell carcinoma; CI=confidence interval; HR=hazard ratio; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumors; TKI=tyrosine kinase inhibitor.

References:

  1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2021.

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 in RCC and HCC studies. 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: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula 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 events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported 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.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed 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 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings 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 common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

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. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

INDICATIONS

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

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced RCC.

INDICATIONS

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

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced RCC.