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Efficacy data in 2L DTC CABOMETYX® (cabozantinib) monotherapy

In patients who are RAI-R or ineligible and progressed on a prior VEGFR-targeted therapy1

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Meaningful results led to early unblinding in the COSMIC-311 trial2

    COSMIC-311: STUDY DESIGN

    COSMIC-311 was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial.1,3

    2:1 randomization
    (N=187)
    RAI-R DTC progressed after prior VEGFR-targeting TKI

    Cabozantinib 60 mg QD + BSC*
    (n=125)

    Placebo + BSC*
    (n=62)

    Treatment until disease progression
    Eligible placebo patients were allowed to cross over to receive open-label cabozantinib after BIRC-confirmed PD per RECIST 1.1†

    UNBLINDED TRIAL‡

    Cabozantinib 60 mg

    Post-treatment follow-up§

    The multiple primary efficacy outcome measures assessed ORR in the first 100 patients (OITT) after 6 months of enrollment and PFS in all patients randomly assigned (ITT). The study was designed such that it would be considered positive if either of the primary endpoints were met. Median follow-up was 6.2 months (IQR: 3.4–9.2) for the ITT population and 8.9 months (IQR: 7.1–10.5) for the OITT population. Median duration of treatment exposure in the safety population was 4.4 months (IQR: 2.1-7.3) for the CABOMETYX patients and 2.3 months (IQR: 1.6-5.6) for the placebo group. An updated analysis, with median follow-up of 10.1 months, evaluated a total of 258 randomized patients.1,3,4​​​​​​​

    *

    BSC included dose modification and dose interruption. After unblinding, BSC included potentially receiving open-label cabozantinib.1,3

    †

    Tumor response and progression were assessed by MRI or CT. Tumor assessments were performed every 8 weeks after randomization for 12 months, then every 12 weeks thereafter.3

    ‡

    An IDMC for COSMIC-311 recommended ending enrollment and unblinding sites and patients based on cabozantinib reducing the risk of disease progression or death by 78% (HR=0.22; 95% CI: 0.14-0.35; P<0.0001).2

    Multiple primary efficacy outcome measures1

    • PFS

    • ORR
    Stratification factors1

    • Age ≤65 years

    • Prior lenvatinib

    Baseline characteristics in ITT population1,3

      Total Population
    Median age, years (range)

    ECOG 0

    ECOG 1    		 65 (31-85)

    46%

    54%
      CABOMETYX Placebo
    One previous VEGFR TKI

    Two previous VEGFR TKIs    		 73% (91/125)

    27% (34/125)    		 77% (48/62)

    23% (14/62)
    73% of patients received CABOMETYX after one previous systemic therapy3§
    §

    Updated analysis (N=258).1

    CABOMETYX delivered a significant benefit in the primary PFS analysis1

    Median PFS was not reached in the primary analysis (n=125, 95% CI: 5.7-NE) vs PFS of 1.9 months with placebo (n=62, 95% CI: 1.8-3.6); HR=0.22 (95% CI: 0.14-0.35); P<0.0001.
     

    Early and sustained separation demonstrated at updated analysis–with a median PFS of 11 months1

    Updated analysis

    Kaplan-Meier curve shows significant benefit in the primary PFS analysis from COSMIC-311

    No formal statistical testing was conducted at the time of the updated analysis.

    78% reduction in risk of progression or death in both primary and updated analyses

    Tumor response observed at the OITT analysis3

    In the COSMIC-311 trial, the ORR did not reach a prespecified endpoint for statistical significance (critical P value=0.01). Data below cover tumor response information collected, inclusive of ORR.1,3

     

    CABOMETYX

    Placebo

    ORR, % (95% CI)‖¶

    Stable disease, % (n/N)**

    Disease control rate, % (n/N)††

    15 (7-26)

    69 (46/67)

    84 (56/67)

    0 (0-11)

    42 (14/33)

    42 (14/33)

    ‖

    P=0.0281.1

    All responses confirmed were partial responses.3

    **

    Stable disease is defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for PD.5
    Stable disease may reflect the natural history of disease rather than any effect of the drug.

    ††

    Disease control rate was defined as the percentage of patients with a complete response, partial response, or stable disease, as measured by RECIST v1.1.3

    Descriptive analysis

    Reduction in target lesions from baseline3

    Of the 100 OITT patients, 89 were evaluable (n=58 in the CABOMETYX arm, n=31 in the placebo arm).

    76% of evaluable patients experienced tumor shrinkage with CABOMETYX vs 29% with placebo‡‡

    Bar graph shows 76% of patients experienced tumor shrinkage COSMIC-311 OITT analysis
    Bar graph shows 76% of patients experienced tumor shrinkage COSMIC-311 OITT analysis

    No formal statistical testing was conducted for the tumor assessment waterfall plots; interpret data with caution.

    Best reduction is maximum reduction in sum of diameters of target lesions. Patients with target lesion at baseline and at least 1 on-treatment tumor assessment are included. Some patients are not represented due to lack of evaluable postbaseline assessment, censoring before first evaluable postbaseline assessment, lack of target lesions, and/or incomplete or inevaluable target-lesion assessment. Data from time points after the first date of any of the censoring events defined for the primary PFS analysis were excluded.6

    ‡‡

    Each vertical line represents 1 patient.3

    §§

    Indicates confirmed partial responses per investigators.3

    National Comprehensive Cancer Network® (NCCN®)

    Cabozantinib (CABOMETYX) has a Category 1 recommendation for patients with RAI-R papillary thyroid cancerIIII that has progressed following VEGFR-targeted therapy¶¶

    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.
    NCCN Category 1: Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.

    ||||

    Locally recurrent, advanced, and/or metastatic.

    ¶¶

    If progression after lenvatinib and/or sorafenib.

    See Monotherapy Safety Data
    See BRAF V600E Data
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    2L=second-line; BIRC=blinded independent radiology committee; BSC=best supportive care; CI=confidence interval; CT=computed tomography; DTC=differentiated thyroid cancer; ECOG=Eastern Cooperative Oncology Group performance status; HR=hazard ratio; IDMC=independent data-monitoring committee; IQR=interquartile range; ITT=intent to treat; MRI=magnetic resonance imaging; NE=not estimable; OITT=ORR intent to treat; ORR=overall response rate; PD=progressive disease; PFS=progression-free survival; QD=every day; RAI-R=radioactive iodine-refractory; RECIST=Response Evaluation Criteria in Solid Tumors; SoD=sum of diameters; TKI=tyrosine kinase inhibitor; VEGFR=vascular endothelial growth factor receptor.

    References:

    1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
    2. Exelixis press release. December 21, 2020. https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-cabozantinib-significantly-improved
    3. Brose MS, Robinson B, Sherman SI, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8):1126-1138. doi:10.1016/S1470-2045(21)00332-6
    4. European Medicines Agency: Committee for Medicinal Products for Human Use (CHMP). Assessment report: CABOMETYX. September 2018. Accessed September 15, 2022.
    5. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
    6. Data on file. Exelixis, Inc.
    7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma V.1.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed March 27, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org.

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

    Pediatric Use: Physeal widening has been observed in children with open growth plates when treated with CABOMETYX. Physeal and longitudinal growth monitoring is recommended in children (12 years and older) with open growth plates. Consider interrupting or discontinuing CABOMETYX if abnormalities occur. The safety and effectiveness of CABOMETYX in pediatric patients less than 12 years of age have not been established.

    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.

    Indications

    CABOMETYX® (cabozantinib) is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET). 

    CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated extrapancreatic neuroendocrine tumors (epNET)​. 

    CABOMETYX, 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 is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 

    CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

    CABOMETYX® (cabozantinib) is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET). 

    CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated extrapancreatic neuroendocrine tumors (epNET)​. 

    CABOMETYX, 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 is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 

    CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

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