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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


January 14, 2019–cabozantinib (CABOMETYX, Exelixis, Inc.) for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.(with Pharmacist's Applications to Practice)

December 19, 2017–Cabozantinib (Cabometyx®, Exelixis, Inc.) granted regular approval for treatment of patients with advanced renal cell carcinoma (RCC). (with Pharmacist's Applications to Practice)

April 25, 2016–Cabozantinib (CABOMETYX®) approved for the treatment of advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy.


January 14, 2019, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208692s003lbl.pdf.

On January 14, 2019, the Food and Drug Administration approved cabozantinib (CABOMETYX, Exelixis, Inc.) for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Approval was based on CELESTIAL (NCT01908426), a randomized (2:1), double-blind, placebo-controlled, multicenter trial in patients with HCC who had previously received sorafenib and had Child Pugh Class A liver impairment. Patients were randomized to receive cabozantinib 60 mg orally once daily (n=470) or placebo (n=237) until disease progression or unacceptable toxicity.

The primary efficacy measure was overall survival (OS); additional outcome measures were progression-free survival (PFS) and overall response rate (ORR), as assessed by investigators per RECIST 1.1. Median OS was 10.2 months (95% CI: 9.1,12.0) for patients receiving cabozantinib and 8 months (95% CI: 6.8, 9.4) for those receiving placebo (HR 0.76; 95% CI: 0.63, 0.92; p=0.0049). Median PFS was 5.2 months (4.0, 5.5) and 1.9 months (1.9, 1.9), in the cabozantinib and placebo arms, respectively (HR 0.44; 95% CI: 0.36, 0.52; p<0.001). ORR was 4% (95% CI: 2.3, 6.0) in the cabozantinib arm and 0.4% (95% CI: 0.0, 2.3) in the placebo arm.

The most common adverse reactions in ≥ 25% of patients who received cabozantinib in clinical trials, in order of decreasing frequency, are diarrhea, fatigue, decreased appetite, palmar-plantar erythrodysesthesia, nausea, hypertension, and vomiting.

The recommended cabozantinib dose is 60 mg orally, once daily at least one hour before or 2 hours after eating.

View full prescribing information for CABOMETYX.

FDA granted this application orphan drug designation. Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.


Pharmacist’s Applications to Practice

Cabozantinib for the Treatment of Patients with Hepatocellular Carcinoma Who Have Been Previously Treated with Sorafenib

Author: Katie Murto, PharmD candidate
WVU School of Pharmacy
Morgantown, WV

What is the potential role for cabozantinib in the treatment of hepatocellular carcinoma?1-8

  • On January 14, 2019, the U.S. Food and Drug Administration (FDA) approved cabozantinib for patients with hepatocellular carcinoma (HCC) who had been previously treated with sorafenib.
  • Hepatocellular carcinoma is a relatively uncommon cancer with few systemic treatment options, so investigation of additional treatment options is warranted.
  • Sorafenib is the only National Comprehensive Cancer Network (NCCN) Category 1 recommendation for first-line systemic therapy for patients with Child-Pugh Class A liver function, although lenvatinib is also listed as a preferred option for Child-Pugh Class A only.
    • Although sorafenib is not a Category 1 recommendation, it is still the preferred first-line option for patients with Child Pugh Class B7.
    • Note: The Child-Pugh Score is a prognostic indicator in patients with liver disease that uses the following factors: encephalopathy, ascites, bilirubin, albumin, and prothrombin. The variables are scored on a scale of 1 to 3. The total is calculated to give a value of 5 to 15; Class A = 5–6, Class B = 7–9, Class C = 10–15.
      • Class A: Good operative risk
      • Class B: Moderate operative risk
      • Class C: Poor operative risk
  • The NCCN lists cabozantinib as a Category 1 recommendation for subsequent-line systemic therapy after disease progression on sorafenib in patients with Child-Pugh Class A liver function only.
    • Other NCCN Category 1 recommendations for treatment after disease progression on sorafenib include regorafenib and ramucirumab.
    • Although no head-to-head trials have compared subsequent-line therapies, overall response rates (ORRs) in this setting include these:
      • Regorafenib: mRECIST 10.6%; RECIST 1.1: 6.6%
      • Ramucirumab: 7.1%
  • Cabozantinib is a potent inhibitor of the tyrosine kinase receptors mesenchymal epithelial transition (MET); vascular endothelial growth factor (VEGF) 1, 2, and 3; and AXL. None is a target of sorafenib. It has been shown that a high expression of AXL and MET may correlate to poor prognosis for patients with hepatocellular carcinoma. MET expression is also elevated in patients who have been previously treated with sorafenib.
  • Cabozantinib was approved for HCC on the basis of data from the phase 3 CELESTIAL trial, which evaluated 707 patients randomly assigned to receive either cabozantinib or matched placebo. Patients must have received sorafenib previously and have demonstrated disease progression after systemic treatment with that agent. Additionally, patients were required to have Child-Pugh Class A liver function to be eligible for enrollment.
    • Patients were randomized 2:1 to receive either cabozantinib 60 mg daily or placebo until the disease progressed or an unacceptable level of toxicity was reached.
    • The primary endpoint, overall survival, was 10.2 months with cabozantinib, compared to 8 months with placebo (95% confidence interval [CI], 0.63–0.92; p = .005).
      • The stratified hazard ratio for death was 0.76 (95% CI, 0.63–0.92).
    • Secondary endpoints included progression-free survival and objective response rates according to RECIST, version 1.1.
      • Median progression-free survival: 5.2 months, compared with 1.9 months with placebo (95% CI, 0.36–0.52; p < .001)
      • Objective response rates: 4%, compared with <1% with placebo (p = .009).

What role can the pharmacist play in the management of patients on cabozantinib?2,6,8

  • Cabozantinib is also approved for advanced renal cell carcinoma at the same dosage—60 mg by mouth once daily.
  • Counsel patients on the importance of adherence and how to appropriately administer the drug.
    • Cabozantinib should be taken on an empty stomach, either 1 hour before or 2 hours after eating.
    • Cabozantinib tablets should be swallowed whole; tablets should not be crushed or chewed.
    • If a dose is missed, it should not be taken within 12 hours of the next dose.
    • For patients with moderate hepatic impairment, reduce the starting dose to 40 mg once daily.
    • Avoid cabozantinib in patients with severe hepatic impairment (Child-Pugh Class C liver function).
  • Monitor for drug-drug interactions and drug-food interactions.
    • Strong CYP3A4 inhibitors: reduce the dose by 20 mg, only resuming the dose that was used prior to initiating the strong CYP3A4 inhibitor 2–3 days after discontinuation of the strong inhibitor.
      • Patients should avoid grapefruit juice because it is a strong CYP3A4 inhibitor.
    • Strong CYP3A4 inducers: increase the daily dose by 20 mg as tolerated, not exceeding a daily dose of 80 mg.
  • Monitor and counsel patients regarding signs and symptoms of the following adverse reactions:
    • Common adverse events are diarrhea (54%), decreased appetite (46–48%), palmar-plantar erythrodysesthesia (44%), fatigue (41–56%), hypertension (36%), nausea (31–50%), and vomiting (24–32%).
    • Grade 3 or 4 adverse events are increased aspartate aminotransferase (24%), palmar-plantar erythrodysesthesia (17%), increased alanine aminotransferase (12%), diarrhea (10%), decreased platelets (10%), and neutropenia (7%).
    • Withhold doses for intolerable Grade 2 adverse reactions, Grade 3 or 4 adverse reactions, and osteonecrosis of the jaw. Dose-reduction algorithms for use following resolution of adverse reactions are outlined in the package insert.
    • Permanently discontinue medication for severe hemorrhage, gastrointestinal perforation or unmanageable fistula, serious thromboembolic event, hypertensive crisis or severe hypertension despite optimal medical management, nephrotic syndrome, or reversible posterior leukoencephalopathy syndrome.
    • Cabozantinib can cause reversible posterior leukoencephalopathy. Monitor patients for seizures, headache, visual disturbances, confusion, or altered mental status, and discontinue cabozantinib in patients who develop this syndrome.
  • Use of cabozantinib during pregnancy can cause fetal harm. A pregnancy test should be performed prior to the initiation of therapy.
  • Exelixis Access Services (EASE) Co-Pay Program: Patients who are commercially insured may be eligible for this program and pay $0 per month for Cabometyx. The program covers the remaining out-of-pocket drug costs, with a yearly limit of $25,000. Patients who have government insurance are excluded.8

Clinical Pearls2,6,7,9-11

  • Do not substitute Cabometyx (cabozantinib tablets) for Cometriq (cabozantinib capsules).
    • Cabometyx is approved for patients with advanced renal cell carcinoma and HCC in patients previously treated with sorafenib at a dose of 60 mg once daily.
    • Cometriq is approved for progressive, metastatic medullary thyroid carcinoma at a dose of 140 mg once daily.
  • When selecting a subsequent-line therapy, treatment choice may be dependent on liver function, institution-specific preferences, patient preference for intravenous (IV) versus oral (PO) therapy, and alpha fetoprotein (AFP) level.
    • Cabozantinib is a Category 1 recommendation only for patients with Child-Pugh Class A liver function; other subsequent-line therapies (nivolumab, sorafenib) may be used for patients with Class B7 liver function.
    • Cabozantinib and regorafenib are oral therapies, whereas ramucirumab is IV administered IV every 2 weeks and nivolumab is administered IV every 2 or 4 weeks depending on the dosage of the treatment.
    • Ramucirumab may be preferred for patients with elevated AFP (≥ 400 ng/mL).
  • Cabozantinib has a low emetic risk; therefore, medication is recommended only as needed. If a patient experiences nausea or vomiting, initiate one of the following prior to oral administration and continue daily throughout treatment (breakthrough treatment for chemotherapy-induced nausea and vomiting is outlined in the NCCN guidelines):
    • Metoclopramide 10–20 mg PO and then every 6 hours as needed
    • Prochlorperazine 10 mg PO and then every 6 hours as needed (maximum dose of 40 mg/d)
    • 5-HT3 RA (choose one):
      • Dolasetron 100 mg PO daily as needed
      • Granisetron 1–2 mg (total dose) PO daily as needed
      • Ondansetron 8–16 mg (total dose) PO daily as needed
  • Cabozantinib can cause hemorrhage and impaired wound healing.
  • Stop treatment with cabozantinib at least 28 days prior to a scheduled surgery, including dental surgery.
    • Cabozantinib can be resumed after surgery when adequate wound healing has occurred.
  • Palmar-plantar erythrodysesthesia is one of the more common adverse reaction patients may experience while taking cabozantinib. Counsel patients on the many prophylactic measures that can help prevent this adverse event.
    • Use moisturizing creams containing keratolytics, such as ammonium lactate 12%, urea 10%–50%, or a salicylic acid cream 3%–6% twice daily.
    • Use thick cotton gloves and socks or slippers.
    • Avoid the following:
      • the use of hot water in the shower or when washing dishes
      • trauma and friction during the first 2–4 weeks
      • vigorous exercise, particularly within the first month of treatment
      • tight-fitting shoes
      • excessive pressure when applying creams.
  • If the patient develops palmar-plantar erythrodysesthesia, management is based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events grading of hand-foot skin reaction:
    • Grade 0: use prophylactic measures.
    • Grade 1: use urea 20% cream twice daily and clobetasol 0.05% cream once daily. If after 2 weeks the reaction worsens or fails to improve, continue anticancer therapy and follow grade 2 recommendations.
    • Grade 2: use urea 20% cream twice daily and clobetasol 0.05% cream once daily. Initiate either a nonsteroidal anti-inflammatory drug (NSAID), a gamma-aminobutyric acid (GABA) agonist, or a narcotic medication for pain control. If after 2 weeks the reaction worsens or fails to improve, continue anticancer therapy and follow grade 3 recommendations.
    • Grade 3: Withhold treatment until severity decreases to grade 0 or 1. Continue the treatment of the skin reaction with clobetasol 0.05% cream twice daily and pain control with either NSAIDs, GABA agonists, or narcotics. If after 2 weeks the reaction worsens or fails to improve, follow package-insert recommendations for dose interruption or discontinuation.

References

  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers. Version 2.2019 (March 6, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed May 13, 2019.
  2. Cabometyx (cabozantinib) [package insert]. Alameda, CA: Exelixis Pharmaceuticals, Inc.; 2019.
  3. Durand F, Valla D. Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD. J Hepatol. 2005;42:S100-S107.
  4. Bruix J, Qin S, Merle P, Granito A, Huang YH, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66.
  5. Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;(7):859-870.
  6. Cabozantinib. In DRUGDEX System [Internet database]. Greenwood Village, CO: Thomson Micromedex. Accessed May 13, 2019.
  7. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63.
  8. EASE Exelixis Access Services for Cabometyx. Available at https://cabometyx.com/financial-support
  9. Nivolumab. In DRUGDEX System [Internet database]. Greenwood Village, CO: Thomson Micromedex. Accessed June 3, 2019.
  10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version 1.2019 (February 28, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed May 22, 2019.
  11. Belum VR, Serna-Tamayo C, Wu S, Lacouture ME. Incidence and risk of hand-foot skin reaction with cabozantinib, a novel multikinase inhibitor: a meta-analysis. Clin Exp Dermatol. 2016; 41(1):8-15.

December 19, 2017 with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208692s002lbl.pdf

On December 19, 2017, the Food and Drug Administration granted regular approval to cabozantinib (Cabometyx®, Exelixis, Inc.) for treatment of patients with advanced renal cell carcinoma (RCC).

The FDA previously approved Cabometyx in 2016 for treatment of patients with advanced RCC who have received prior anti-angiogenic therapy. Today’s approval provides for treatment in the first-line setting.

This approval was based on data from CABOSUN (NCT01835158), a randomized, open-label phase 2 multicenter study in 157 patients with intermediate and poor-risk previously untreated RCC. Patients received Cabometyx (n=79) 60 mg orally daily or sunitinib (N=78) 50 mg orally daily (4 weeks on treatment followed by 2 weeks off) until disease progression or unacceptable toxicity. Estimated median progression-free survival (as assessed by blinded independent radiology review committee) for patients taking Cabometyx was 8.6 months (95% CI: 6.8, 14.0) compared with 5.3 months (95% CI: 3.0, 8.2) for patients taking sunitinib (Hazard ratio 0.48; 95% CI: 0.31, 0.74; p=0.0008).

The most commonly reported (≥25%) adverse reactions in the Cabometyx clinical program are diarrhea, fatigue, nausea, decreased appetite, hypertension, palmar-plantar erythrodysesthesia, weight decreased, vomiting, dysgeusia, and stomatitis.

The most frequent grade 3-4 adverse reactions (≥5%) in patients treated with Cabometyx on CABOSUN were hypertension, diarrhea, hyponatremia, hypophosphatemia, PPE, fatigue, ALT increased, decreased appetite, stomatitis, pain, hypotension, and syncope.

The recommended dose of Cabometyx is 60 mg orally, once daily.

Cabozantinib is also approved for the treatment of medullary thyroid cancer and is marketed under the trade name Cometriq. Cometriq and Cabometyx have different formulations and are not interchangeable.

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208692s002lbl.pdf

FDA granted priority review to Cabometyx for this application. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist's Applications to Practice

Cabozantinib for Advanced Renal Cell Carcinoma

Author: Danielle Dunn, PharmD
PGY-2 Oncology Resident
Texas Tech University Health Science Center
Lubbock, TX

What is the potential role for cabozantinib in the treatment of advanced renal cell carcinoma (RCC)?

  • Cabozantinib (Cabometyx) was first approved for advanced RCC as a second-line option. Cabozantinib obtained additional approval for first-line therapy in December 2017 on the basis of the CABOSUN trial that compared cabozantinib to first-line sunitinib.1
    • Median progression-free survival (PFS) was 8.2 months for cabozantinib versus 5.6 months with sunitinib (p = .012). This correlated to a reduction in disease progression or death by 34% with cabozantinib.1
    • The median overall survival was 30.3 months with cabozantinib versus 21.8 months with sunitinib.1
  • Patients were eligible if they were classified as either intermediate risk (81%) or poor risk (19%) according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). When stratified by risk, the statistical significance was driven by the intermediate-risk population. The hazard ratio for poor risk was 0.75 and did not meet statistical significance. Likewise, only patients with bone metastases had a more favorable PFS rate with cabozantinib than those without.1 The current National Comprehensive Cancer Network (NCCN) guidelines for advanced RCC with clear-cell histology list cabozantinib as a first-line therapy of choice for intermediate-risk or poor-risk patients as defined by the IMDC.1,2
  • Additional first-line anti-angiogenic agents in this setting include pazopanib, sunitinib, and axitinib monotherapy.2
    • Pazopanib and sunitinib were compared head-to-head in a noninferiority trial (COMPARZ). The primary end point of PFS met noninferiority parameters. Although these agents exhibit comparable efficacy, a quality-of-life assessment performed as part of the trial favored pazopanib. The COMPARZ trial included all risk stratifications, classified by the Memorial Sloan Kettering Cancer Center criteria. However, most patients fell into the favorable-risk or intermediate-risk group. Poor risk was not an exclusion criterion; however, these patients were not included in the analysis because of the small sample size.3
  • Like sunitinib and pazopanib, cabozantinib is also a vascular endothelial growth factor (VEGF) inhibitor. However, cabozantinib has additional inhibitory effects on MET and AXL, which have been implicated with promoting tumorigenesis when activated. This unique mechanism could explain the advantage that cabozantinib appears to hold over sunitinib on the basis of the results of the CABOSUN trial.4

What role can the pharmacist play in the management of patients on cabozantinib?

  • Patients who are commercially insured can apply for financial assistance through the Exelixis Access Service (EASE) Co-Pay Program. If a patient is uninsured or is insured but still unable to afford cabozantinib, healthcare professionals can apply for the EASE Patient Assistance Program on behalf of the patient. This enrollment form also includes a Quick Start Program that will allow eligible patients to receive a free quantity of medication if delays in approval occur.5
  • Cabozantinib dosing for advanced RCC (60 mg by mouth daily)6 is lower than the dosing for metastatic thyroid cancer (140 mg by mouth daily). It is important to note that Cabometyx tablets for RCC are not interchangeable with Cometriq capsules for thyroid cancer.
    • Cabometyx is supplied as 20-mg, 40-mg, and 60-mg tablets.
    • No dose-adjustment recommendations exist for patients with an estimated glomerular filtration rate (eGFR) of more than 30 ml/min/1.73m2; however, eGFR less than 30 ml/min/1.73m2 has not been studied.6
    • It is recommended that the dose be reduced to 40 mg by mouth daily for hepatic impairment for Child-Pugh classes A and B. Use with Child-Pugh class C is not recommended because it has not been studied.6
  • Cabozantinib should be taken on an empty stomach 1 hour before or 2 hours after a meal.6
  • While on cabozantinib therapy, patients should, if possible, avoid concurrent treatment with strong cytochrome P450 3A4 (CYP 3A4) inhibitors and inducers. The cabozantinib dose should be reduced by 20 mg if strong inhibitors are necessary or increased by 20 mg for concomitant strong inducers.6
  • Patients should avoid grapefruit and grapefruit juice while they are taking cabozantinib.6
  • In the CABOSUN trial, common side effects reported with cabozantinib at any grade included fatigue (85%), hypertension (80%), diarrhea (71%), and palmar-plantar erythrodysesthesia (42%).1 Medication should be withheld for patients experiencing intolerable grade 2 or grade 3 and 4 toxicities for the aforementioned adverse events. Cabozantinib can be resumed at a lower dose if the symptoms resolve.6
    • The most common grade 3-4 toxicities include hypertension (28.2%), diarrhea (10.3%), palmar-plantar erythrodysesthesia syndrome (7.7%), and fatigue (6.4%).1 
  • Because of the risk of fetal harm, females of reproductive age should use effective contraception during therapy and continue it for 4 months after the final dose of cabozantinib.6
  • It is recommended that therapy with cabozantinib be withheld for at least 28 days prior to scheduled procedures.6 Cabozantinib can be resumed postprocedure if a clinical judgment is made that proper wound healing has occurred.7

Clinical Pearls

  • Cabozantinib should be considered first-line treatment in patients who are judged to be at intermediate risk according to the IMDC.1
  • Cabozantinib has not been studied in favorable-risk patients in the first-line setting.
  • Poor-risk patients did not preferentially favor cabozantinib when compared to sunitinib.1 However, cabozantinib is still a viable option for poor-risk patients per NCCN guidelines.2
  • To determine a patient’s risk status, the IMDC uses prognostic factors that each account for one point. The risk factors include reduced performance status; duration between diagnosis and initiation of systemic therapy less than 1 year; low hemoglobin; and elevated serum calcium, neutrophils, and platelet count. One to 2 prognostic factors place patients in the intermediate-risk group, and 3 or more qualify patients as poor risk.2
  • Cabozantinib has the potential to cause high rates of palmar-plantar erythrodysesthesia.
    • Patients should be counseled on preventive measures to minimize palmar-plantar erythrodysesthesia, including avoidance of hot water, direct sun exposure, and activities where the hands and feet are subjected to pressure, friction, or rubbing. Sunscreen with at least SPF 30 should be worn while the patient is on cabozantinib.8
    • Counseling should also include the removal of calloused areas before initiation of treatment. Topical creams containing urea can also be used throughout therapy to prevent new hyperkeratotic areas on the hands and feet.8

References

  1. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN Trial. J Clin Oncol. 2017;35(6):591-597.
  2. National Comprehensive Cancer Network. Kidney Cancer. Version 3.2018. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed March 20, 2018.
  3. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722-731.
  4. Tannir NM, Schwab G, Grunwald V. Cabozantinib: an active novel multikinase inhibitor in renal cell carcinoma. Curr Oncol Rep. 2017;19(2):14.
  5. Exelixis, Inc 2018. Financial assistance for Cabometyx®. https://www.cabometyx.com/support/. Accessed February 7, 2018.
  6. Cabometyx [package insert]: South San Francisco, CA: Exelixis, Inc. December 2017.
  7. Cabometyx [Annex I Summary of Product Characteristics]: Ipsen Pharma. Boulogne-Billancourt, France. Accessed February 7, 2018.
  8. Gerendash BS, Creel PA. Practical management of adverse events associated with cabozantinib treatment in patients with renal-cell carcinoma. Onco Targets Ther. 2017;10:5053-5064.

April 25, 2016

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208692s000lbl.pdf

On April 25, 2016, the U. S. Food and Drug Administration approved cabozantinib (CABOMETYX®, Exelixis, Inc.) for the treatment of advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy.  

The approval was based on a randomized study in which patients with advanced renal cell carcinoma who had received prior anti-angiogenic therapy received either cabozantinib 60 mg orally once daily (N=330) or everolimus 10 mg orally once daily (N=328).

The primary endpoint was progression-free survival among the first 375 randomized subjects. Median progression-free survival in this group was 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [HR 0.58 (95% CI: 0.45, 0.74); p<0.0001]. Median overall survival in the intent-to-treat population was 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively [HR 0.66 (95% CI: 0.53, 0.83); p=0.0003]. Confirmed response rate was 17% (95% CI: 13, 22) in the cabozantinib arm and 3% (95% CI: 2, 6) in the everolimus arm.

Safety was evaluated in 331 patients treated with cabozantinib. The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, hypertension, vomiting, weight decreased, and constipation. Sixty percent of patients treated with cabozantinib had at least one dose reduction while on study. Serious adverse events were reported in 40% of patients. The most common serious adverse events (greater than or equal to 2%) were abdominal pain, pleural effusion, diarrhea, and nausea.

The recommended dose and schedule for cabozantinib is 60 mg orally daily.

This application was granted Breakthrough Therapy Designation, Fast Track, and Priority Review. It was approved prior to the Priority Review deadline of June 22, 2016. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Full prescribing information is available at:   http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208692s000lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


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