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INDICATION

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

In the primary analysis, CABOMETYX + OPDIVO^® (nivolumab) demonstrated superior efficacy vs sunitinib in 1L aRCC across OS, PFS, and ORR¹

(Median follow-up time of 18.1 months; range: 10.6-30.6 months)²

Progression-free survival (PFS), primary endpoint, assessed by BICR

PFS doubled in the primary analysis in the ITT population¹

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Median PFS: 16.6 months for CABOMETYX + OPDIVO (95% CI: 12.5-24.9; n=323) vs 8.3 months for sunitinib (95% CI: 7.0-9.7; n=328); HR=0.51 (95% CI: 0.41-0.64); P<0.0001

Overall survival (OS), secondary endpoint

Superior OS outcomes in the primary analysis in the ITT population¹

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40% reduction in the risk of death, HR=0.60 (98.89% CI: 0.40-0.89; P=0.001); median OS was not reached in either treatment arm

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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)^1,3,4

Objective response rate (ORR), secondary endpoint, assessed by BICR

ORR doubled in the primary analysis in the ITT population¹

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55.7% with CABOMETYX + OPDIVO (95% CI: 50.1-61.2; n=323); CR: 8% (n=26/323); PR: 48% (n=154/323) vs 27.1% for sunitinib (95% CI: 22.4-32.3; n=328); CR: 4.6% (n=15/328); PR: 23% (n=74/328); P<0.0001

Study Design

CheckMate-9ER was a randomized (1:1), open-label, Phase 3 trial vs sunitinib in 651 patients with previously untreated aRCC with a clear-cell component. The trial evaluated CABOMETYX 40 mg (starting dose) PO once daily in combination with OPDIVO. The primary endpoint was PFS, and secondary endpoints included OS, ORR, and safety.^1,2,5

Select Important Safety Information

The full Prescribing Information for CABOMETYX includes Warnings and Precautions for: hemorrhage, perforations and fistulas, thrombotic events, hypertension and hypertensive crises, diarrhea, palmar-plantar erythrodysesthesia (PPE), hepatotoxicity, adrenal insufficiency, proteinuria, osteonecrosis of the jaw, impaired wound healing, reversible posterior leukoencephalopathy syndrome, thyroid dysfunction, hypocalcemia, and embryo-fetal toxicity.

See additional important safety information below.

SEE MORE DATA

Outcomes observed in CABOMETYX + OPDIVO patients with proactively managed Grade ≥3 TRAEs vs sunitinib patients^6,7

Data from a post hoc exploratory analysis support proactive AE management⁶

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Of all treated patients in CheckMate-9ER, 367/640 experienced Grade ≥3 TRAEs (199/320 in the CABOMETYX + OPDIVO arm vs 168/320 in the sunitinib arm)

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A post hoc analysis examined the impact of timely and proactively managed AEs on efficacy outcomes

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TRAEs were graded according to the NCI CTCAE v4.0 and classified according to the MedDRA v23.0

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Grade ≥3 TRAEs were reported between first dose and 30 days after last dose of study therapy

Exploratory analysis

PFS results in the ITT population and in patients with Grade ≥3 TRAEs⁶

Primary analysis in the ITT population¹

Exploratory post hoc analysis in patients with Grade ≥3 TRAEs^1,6

ORR results in the ITT population and in patients with Grade ≥3 TRAEs

Primary analysis in the ITT population¹

Exploratory post hoc analysis in patients with Grade ≥3 TRAEs⁶

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Consistent efficacy was observed regardless of whether CABOMETYX was interrupted and/or reduced to 20 mg daily or 20 mg every other day due to Grade ≥3 TRAEs

This post hoc exploratory analysis is descriptive in nature. No statistical procedure was employed. Results should be considered hypothesis generating.

Serious adverse reactions occurred in 48% of patients receiving CABOMETYX and nivolumab. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.¹

1L=first-line; aRCC=advanced renal cell carcinoma; AE=adverse event; BICR=blinded independent central review; CTCAE=Common Terminology Criteria for Adverse Events; CI=confidence interval; HR=hazard ratio; IO=immunotherapy; ITT=intent to treat; MedDRA=Medical Dictionary for Regulatory Activities; NCI=National Cancer Institute; NR=not reached; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; PO=by mouth; TKI=tyrosine kinase inhibitor; TRAE=treatment-related adverse event.

INDICATION

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

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: CABOMETYX can cause severe and fatal hemorrhages. The incidence of Grade 3-5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3-4 hemorrhage and before surgery. Do not administer to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, and gastrointestinal (GI) perforations, including fatal cases, each occurred in 1% of CABOMETYX patients. Monitor for signs and symptoms, and discontinue CABOMETYX in patients with Grade 4 fistulas or GI perforation.

Thrombotic Events: CABOMETYX can cause arterial or venous thromboembolic event. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events have occurred. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events.

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. In CABINET (n=195), hypertension occurred in 65% (26% Grade 3) 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; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with antihypertensive therapy or for hypertensive crisis.

Diarrhea: CABOMETYX can cause diarrhea and it occurred in 62% (10% Grade 3) of treated 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): CABOMETYX can cause PPE and it occurred in 45% of treated patients (13% Grade 3). Withhold CABOMETYX until PPE resolves or decreases to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab in RCC can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. Monitor liver enzymes before initiation of treatment and periodically. Consider more frequent monitoring as compared to when the drugs are administered as single agents. Consider withholding CABOMETYX and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life-threatening hepatotoxicity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. 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. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

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): CABOMETYX can cause ONJ and it occurred in <1% of treated patients. 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. Withhold CABOMETYX for development of ONJ until complete resolution; resume at a reduced dose.

Impaired Wound Healing: CABOMETYX can cause impaired wound healing. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer 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): CABOMETYX can cause RPLS. Perform evaluation for RPLS and diagnose by characteristic finding on MRI any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: CABOMETYX can cause thyroid dysfunction, primarily hypothyroidism, and it occurred in 19% of treated patients (0.4% Grade 3). Assess for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitor for signs and symptoms during treatment.

Hypocalcemia: CABOMETYX can cause hypocalcemia, with the highest incidence in DTC patients. Based on the safety population, hypocalcemia occurred in 13% of CABOMETYX patients (2% Grade 3 and 1% Grade 4).

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

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

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 or Moderate CYP3A4 Inducers: If coadministration with strong or moderate 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 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.

If you would like more information about CABOMETYX, please visit CABOMETYXhcp.com.

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References: 1. CABOMETYX^® (cabozantinib) Prescribing Information. Exelixis, Inc. 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, 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. 4. 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. 5. 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 followup of CheckMate 9ER. Poster presented at Genitourinary Cancers Symposium; February 11-13, 2021. 6. Kessler ER, Burotto M, Shah AY, et al. Outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma and treatment-related adverse event timing/management in CheckMate 9ER. Poster presented at the International Kidney Cancer Symposium; November 5-6, 2021. 7. Seery V, Andresen D, Martone B, et al. Management of adverse events associated with cabozantinib plus nivolumab in advanced renal cell carcinoma. Poster presented at the Oncology Nursing Society Congress; April 24–28, 2024.

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