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CABOMETYX® (cabozantinib) aRCC data in combination with OPDIVO® (nivolumab)

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1L aRCC Combination Treatment 

See the results from the CheckMate-9ER study—including efficacy, safety, and patient-reported quality of life data.

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    CHECKMATE-9ER: STUDY DESIGN

    CheckMate-9ER: a phase 3, randomized, head-to-head trial.1,2

    An open-label trial vs sunitinib in patients with previously untreated aRCC.1,2

    1:1 randomization2
    (N=651)
    Patients had previously untreated aRCC with a clear-cell component2
    Enrollment of patients with favorable IMDC risk score limited to 25% of population2

    CABOMETYX 40 mg PO once daily
    + OPDIVO 240 mg IV every 2 weeks1
    (n=323)

    Sunitinib 50 mg PO once daily
    for 4 weeks, followed by 2 weeks off, per cycle1
    (n=328)

    Treatment until disease progression or unacceptable toxicity1*

    Primary endpoint1,3
    PFS†

    Secondary endpoints1,3
    OS
    ORR†
    Safety

    Exploratory endpoint2‡
    HRQoL

    • Excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression1
    • Median follow-up was 18.1 months (range: 10.6-30.6 months) with an extended follow-up analysis at 44 months (range: 36.5-56.5 months)2,4
      • 32.9-month median follow-up data (range: 25.4-45.4 months) was a pre-planned final OS analysis that occurred after observation of 271 events1,5,6
    *

    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. OPDIVO dosing was not to exceed a total of 2 years (from cycle 1).1

    †

    PFS and ORR were assessed by BICR.1

    ‡

    Other exploratory endpoints included biomarkers, pharmacokinetics, immunogenicity, and PFS-2.2

    The starting dose of CABOMETYX was 40 mg in CheckMate-9ER1

    Stratification factors2,7

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

    IMDC risk distribution in CheckMate-9ER was representative of aRCC population1,3,7-9

    Baseline Characteristics WERE Balanced Across Treatment Arms6

      No. (%)
      CABOMETYX + OPDIVO
    (n=323)     		sunitinib
    (n=328)
    Age (years)2
    <65 191 (59.1) 210 (64.0)
    ≥65 132 (40.9) 118 (36.0)
    Geographic region7
    US/Canada/W Europe/N Europe§ 158 (48.9) 161 (49.1)
    Rest of world 165 (51.1) 167 (50.9)
    Karnofsky performance status7
    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 score2
    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 randomization7
    <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 nephrectomy7
    Yes 222 (68.7) 233 (71.0)
    No 101 (31.3) 95 (29.0)
    Prior radiotherapy7
    Yes 46 (14.2) 45 (13.7)
    No 277 (85.8) 283 (86.3)
    PD-L1+ status7
    ≥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 features7
    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 diagnosis7
    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)
    No. of metastatic sites2||
    1 63 (19.5) 69 (21.0)
    ≥2 259 (80.2) 256 (78.0)
    Most common sites of metastasis2
    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)
    §

    Western and Northern European countries included: Czechia, Germany, Greece, Italy, Poland, Romania, Russian Federation, Spain, and the United Kingdom of Great Britain and Northern Ireland.7

    ‖

    Data are for tumor sites defined at baseline by the investigators according to RECIST v1.1. The number of target or nontarget lesions at baseline was not reported for 1 patient in the CABOMETYX + OPDIVO group and for 3 patients in the sunitinib group.2

    See Safety Data

    Primary Analysis: Secondary Endpoint Overall Survival (OS)2

    OS outcomes show early and sustained separation of curves in the primary analysis

    Primary analysis results: OS2

    Median follow-up time of 18.1 months; range: 10.6-30.6 months

    Line graph shows secondary endpoint data for primary analysis of OS in CABOMETYX + OPDIVO vs sunitinib in CheckMate-9ER study
    • Pre-planned final analysis of OS (median follow-up: 32.9 months; range: 25.4-45.4 months): Median OS was 37.7 months for CABOMETYX + OPDIVO (95% Cl: 35.5-NR; n=323) compared with 34.3 months for sunitinib (95% Cl: 29.0-NR; n=328); HR=0.70 (95% Cl: 0.55-0.90)1,5,6

    44-month follow-up analysis: OS4,10

    Median follow up time of 44.0 months; range: 36.5-56.5 months4

    Line graph shows secondary endpoint data for extended followup of OS in CABOMETYX + OPDIVO vs sunitinib in CheckMate-9ER study

    Primary Analysis: Primary Endpoint Progression-Free Survival (PFS), Secondary Endpoint Objective Response Rate (ORR)3¶

    Median PFS and ORR doubled

    Primary analysis results in the ITT population: PFS1

    Median follow-up time of 18.1 months; range: 10.6-30.6 months2

    data chart compares primary analysis PFS data for CABOMETYX + OPDIVO vs sunitinib

    Primary analysis results in the ITT population: ORR1

    Median follow-up time of 18.1 months; range: 10.6-30.6 months2

    orr was doubled1

    data chart compares primary analysis ORR data for CABOMETYX + OPDIVO vs sunitinib
    At the time of primary analysis, only 5.6% of patients had progressive disease with CABOMETYX + OPDIVO vs 13.7% of patients with sunitinib2#

    PFS and ORR were assessed by BICR.1

    #

    Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance of 1 or more new lesions is also considered progression.)2

    44-month follow-up analysis results: PFS and ORR11

    Median follow-up time of 44.0 months; range: 36.5-56.5 months

     

    Median PFS11**

    data chart compares extended followup PFS data for CABOMETYX + OPDIVO vs sunitinib

    ORR11**

    data chart compares extended followup ORR data for CABOMETYX + OPDIVO vs sunitinib

    Longest available follow-up for CheckMate-9ER

    13.3% of patients achieved a CR with CABOMETYX + OPDIVO vs 4.9% with sunitinib11
    **

    PFS and ORR were assessed by BICR.1

    See Safety Data

    Cabozantinib (CABOMETYX) + nivolumab (OPDIVO) is the only TKI+IO regimen with an NCCN® recommendation in both clear cell and non-clear cell aRCC12

    Category 1, preferred option across all risk groups in 1L clear cell RCC12††
    Category 2A, other recommended option in non-clear cell RCC12‡‡

    Download Guidelines Flashcard
    ††

    NCCN Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

    ‡‡

    NCCN Category 2A: Based on lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

    NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 
    Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.4.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed January 18, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    The approval of CABOMETYX with OPDIVO in 1L aRCC was based on a randomized (1:1), open-label, Phase 3 trial vs sunitinib in patients with previously untreated aRCC with a clear-cell component.

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    1L=first-line; aRCC=advanced renal cell carcinoma; BICR=blinded independent central review; CI=confidence interval; CR=complete response; HR=hazard ratio; HRQoL=health-related quality of life; IMDC=International Metastatic RCC Database Consortium; IO=immunotherapy; ITT=intent to treat; IV=intravenous; NR=not reached; ORR=objective response rate; OS=overall survival; PD-L1=programmed cell death ligand 1; PFS=progression-free survival; PFS-2=progression-free survival after subsequent therapy; PO=by mouth; RECIST=Response Evaluation Criteria in Solid Tumors; TKI=tyrosine kinase inhibitor.

    References:

    1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2022.
    2. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841.
    3. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal cell carcinoma: outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. Poster presented at Genitourinary Cancers Symposium; February 11-13, 2021.
    4. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: 3-year follow-up from the phase 3 CheckMate 9ER trial. Presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium; February 16-18, 2023.
    5. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomized, phase 3 trial. Lancet Oncol. 2022;23(7):888-898.
    6. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with 2-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. Poster presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium; February 17-19, 2022.
    7. Data on file. Topline 9ER. Exelixis, Inc.
    8. Savard M-F, Wells JC, Graham J, et al. Real-world assessment of clinical outcomes among first-line sunitinib patients with clear cell metastatic renal cell carcinoma (mRCC) by the International mRCC Database Consortium risk group. Oncologist. 2020;25(5):422-430.
    9. 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.
    10. Data on file. Exelixis, Inc. 2022. 
    11. Data on file. Exelixis, Inc. 2023. 
    12. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.4.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed January 18, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    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, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. 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 37% (16% 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. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

    Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

    Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% 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. Withhold and resume at a reduced dose based on severity.

    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 and resume CABOMETYX at a reduced dose 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 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. 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, resume at a reduced dose.

    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. 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.

    Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

    Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

    Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

    In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

    Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

    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, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation.

    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.

    Indication

    CABOMETYX® (cabozantinib), in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

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

    CABOMETYX® (cabozantinib), in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

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

    OPDIVO® and the related logo are registered trademarks of Bristol-Myers Squibb Company.

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    © 2023 Exelixis, Inc.  04/23 CA-2808