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CABOMETYX aRCC Data in Combination with OPDIVO®

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A new approach in 1L aRCC treatment

See the data for the first and only 1L aRCC combination treatment to double PFS and ORR while delivering superior OS.1

CheckMate-9ER Study Design

CheckMate-9ER was a phase 3, randomized, open-label trial vs sunitinib in previously untreated aRCC (N=651).1,2

1:1 randomization
Patients had previously untreated aRCC with a clear cell component
CABOMETYX 40 mg PO QD
+ OPDIVO 240 mg flat dose IV Q2W (n=323)		 Sunitinib 50 mg PO QD
(4 weeks on/2 weeks off) 
(n=328)
Treatment until disease progression or unacceptable toxicity*
Primary endpoint
PFS confirmed by BICR†		 Secondary endpoints
OS
ORR confirmed by BICR†
Safety
The starting dose of CABOMETYX was 40 mg in CheckMate-9ER1
*

Tumor assessments were performed at baseline, after randomization at Week 12, then every 6 weeks until Week 60, and then every 12 weeks thereafter. Treatment beyond RECIST v1.1-defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator.

†

PFS and ORR were assessed by BICR.1

  • Median follow-up was approximately 18.1 months2

Stratification factors1

  • IMDC risk group (favorable vs intermediate vs poor)
  • PD-L1 tumor expression (≥1% vs <1% or indeterminate)
  • Geographic region (US, Canada, Western and Northern Europe vs rest of world)
See Safety Data

IMDC risk distribution in CheckMate-9ER representative of aRCC population2,3

Baseline Characteristics Balanced Across Treatment Arms2

  No. (%)
  CABOMETYX + OPDIVO
(n=323) 		sunitinib
(n=328)
Age (years)
<65 191 (59.1) 210 (64.0)
≥65 132 (40.9) 118 (36.0)
Geographic region
US/Canada/W Europe/N Europe 158 (48.9) 161 (49.1)
Rest of world 165 (51.1) 167 (50.9)
Karnofsky performance status
70 14 (4.3) 18 (5.5)
80 52 (16.1) 67 (20.4)
90 110 (34.1) 112 (34.1)
100 147 (45.5) 129 (39.3)
Not reported 0 2 (0.6)
Baseline IMDC prognostic score
Favorable 74 (22.9) 72 (22.0)
Intermediate 188 (58.2) 188 (57.3)
Poor 61 (18.9) 68 (20.7)
Time from diagnosis to randomization
<1 year 210 (65.0) 214 (65.2)
≥1 year 112 (34.7) 111 (33.8)
Not reported 1 (0.3) 3 (0.9)
Prior nephrectomy
Yes 222 (68.7) 233 (71.0)
No 101 (31.3) 95 (29.0)
Prior radiotherapy
Yes 46 (14.2) 45 (13.7)
No 277 (85.8) 283 (86.3)
PD-L1+ status
≥1% 81 (25.1) 81 (24.7)
<1% or indeterminate 232 (71.8) 240 (73.2)
Not reported 10 (3.1) 7 (2.1)
Sarcomatoid features
Yes 34 (10.5) 41 (12.5)
No 279 (86.4) 278 (84.8)
Not reported 10 (3.1) 9 (2.7)
Stage at initial diagnosis
Stage IV 167 (51.7) 173 (52.7)
Non-stage IV 150 (46.4) 148 (45.1)
Not reported 6 (1.9) 7 (2.1)
Most common sites of metastasis
Lung 238 (73.7) 249 (75.9)
Lymph node 130 (40.2) 131 (39.9)
Liver 73 (22.6) 53 (16.2)
Bone 78 (24.1) 72 (22.0)
Adrenal gland 36 (11.1) 36 (11.0)

CheckMate-9ER Clinical Efficacy Data

 

Primary Endpoint: PFS1‡

More than 16 months median PFS1‡

‡

PFS and ORR were assessed by BICR1

  • PFS benefits observed regardless of IMDC risk group1

Secondary Endpoints: ORR & OS1

More than double ORR1§

Superior OS Outcomes chart
§

PFS and ORR were assessed by BICR1

  • 5.6% of patients had progressive disease with CABOMETYX + OPDIVO vs 13.7% of patients with sunitinib2

Superior OS Outcomes1

Superior OS Outcomes chart
  • Median OS not reached in either treatment arm1
See Safety Data

aRCC=advanced renal cell carcinoma; BICR=blinded independent central review; CI=confidence interval; CR=complete response; HR=hazard ratio; IMDC=International Metastatic RCC Database Consortium; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; PR=partial response.

References:

  1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2021
  2. Data on file. Exelixis, Inc
  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.

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.

OPDIVO® and the related logo is a registered trademark of Bristol-Myers Squibb Company.

© 2021 Exelixis, Inc.  05/21 CA-1941