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          FDA D.I.S.C.O.: FDA approval of cabozantinib for hepatocellular carcinomaResources for Information | Approved Drugs FDA D.I.S.C.O.: FDA approval of cabozantinib for hepatocellular carcinoma
  
  	
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*FDA medical oncologists discuss the January 14, 2019, approval of cabozantinib for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.*

Dr. Sanjeeve Bala: Welcome back to the DISCO, the FDA’s Drug Information Soundcast in Clinical Oncology from the Oncology Center of Excellence. During our soundcasts, we discuss recent FDA approvals of cancer drugs and therapies. We hope this information will help you in better understanding these approvals and how new drugs and therapies are benefitting cancer patients. Today we’ll be discussing the recent approval of cabozantinib for the treatment of patients with hepatocellular carcinoma who progressed following systemic therapy. I’m Dr. Sanjeeve Bala, a medical oncologist and clinical team leader at the FDA, and I’m joined by my colleague Dr. Abhi Nair, also a medical oncologist at the Oncology Center of Excellence.

Dr. Abhi Nair: Hi everyone. Thanks for joining us. Patients with hepatocellular carcinoma that has progressed following initial systemic therapy have a median survival of less than one year, despite the availability of three drugs to use in this setting—namely, regorafenib, nivolumab, and pembrolizumab. Clearly, treatment of refractory hepatocellular carcinoma is an unmet medical need.

SB: Cabozantinib is an oral inhibitor of the cMET and VEGFR2 tyrosine kinases, as well as several others, and was initially approved for the treatment of patients with medullary thyroid cancer in 2012 and patients with advanced renal carcinoma in 2016. The current approval is for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib. The recommended dose is 60 mg orally, once daily. Of note, this approval is for the Cabometyx tablets, not the Cometriq capsules used to treat medullary thyroid cancer at a different dosage regimen.

AN: Cabozantinib received orphan drug designation from FDA during development and has now received regular approval for this indication. Sanjeeve, tell us about the trial and endpoints.

SB: Cabozantinib was evaluated in the CELESTIAL trial, a double-blind trial in 707 patients with hepatocellular carcinoma previously treated with sorafenib who were randomized 2:1 to cabozantinib, 60 mg orally once daily, or placebo.

AN: These patients also had Child-Pugh Class A liver impairment, right?

SB: That’s right, Abhi. And they were stratified on the study by disease etiology, that is, hepatitis B and/or hepatitis C, vs hepatitis C alone, vs other etiology. Additional stratification factors included geographic region, with categories Asia vs other regions, and presence of extrahepatic spread and/or microvascular invasion.

AN: And this trial used overall survival as the primary endpoint, which strengthens the interpretability of these results.

SB: Additional endpoints included progression-free survival and objective response rate, with investigator assessments every 8 weeks.

AN: Of the patients enrolled, the median age was 64 years; 82% were male, 56% were White and 34% were Asian. As far as the etiology of their HCC, 38% were attributed to hepatitis B virus infection, 21% were associated with hepatitis C infection, and 40% had other etiologies; 27% of patients also had two prior systemic therapies. OK, now let’s hear the trial results.

SB: Median overall survival for patients treated with cabozantinib was 10.2 months, while it was 8 months for those receiving placebo. Median progression-free survival was 5.2 months for patients on the treatment arm, and 1.9 months on the placebo arm. The overall response rate was 4% for the treatment arm, and 0.4% on the placebo arm.

AN: Sanjeeve, how about a run-down of the most important safety signals in the trial?

SB: Cabozantinib has been on the market since 2012. As compared with patients receiving placebo, patients with hepatocellular carcinoma receiving cabozantinib on the CELESTIAL trial had more hepatotoxicity. Elevated transaminases occurred more commonly in patients with hepatocellular carcinoma receiving cabozantinib as compared to the renal cell carcinoma and medullary thyroid cancer indications, which is not unexpected given the underlying disease. The observed hepatotoxicity was largely controlled via dose modifications. The most common adverse reactions were diarrhea, fatigue, decreased appetite, palmar-plantar erythrodysesthesia, nausea, hypertension, and vomiting. Practitioners will recognize these symptoms as common to many tyrosine kinase inhibitors. There are some additional rare, more serious toxicities, including osteonecrosis of the jaw, fistula, and reversible posterior leukoencephalopathy.

AN: What about dose reductions and discontinuations?

SB: Doses were reduced for 62% of patients, and 33% of patients required dose reduction to 20 mg daily from the starting dose of 60 mg daily. These were generally prompted by palmar-plantar-erythrodysesthesia, diarrhea, fatigue, and increased aspartate aminotransferase (AST). Detailed safety information is available in the product label.

AN: Why don’t you give us the three take-aways for this DISCO.

SB: 1) Cabozantinib was recently approved for the treatment of patients with advanced hepatocellular carcinoma following treatment with sorafenib; 2) the clinical trial that led to approval demonstrated an overall survival advantage; and 3) safety on this trial was generally similar to prior studies, with diarrhea, fatigue, and decreased appetite occurring most commonly.

You can find more detailed prescribing and safety information in the approved prescribing information, also available on the web at drugs@fda. For a transcript of this Soundcast, visit the FDA Oncology Center of Excellence D.I.S.C.O. website at www.fda.gov/DISCO. The FDA analysis and review were conducted by a multidisciplinary team of FDA experts. More information can be found on the FDA website.

AN: Thank you Sanjeeve. Are there other FDA oncology drug approvals that you would like to hear about? Leave us your questions and comments on Twitter @FDAOncology and as always, we welcome your feedback at our email address, FDAOncology@fda.hhs.gov. I’m Abhi Nair, thank you for tuning in to DISCO today.

SB: And until next time at the DISCO, I’m Sanjeeve Bala.

Acknowledgements

This Drug Information Soundcast in Clinical Oncology was developed by Sanjeeve Bala, Abhilasha Nair, Martha Donoghue, Kirsten B. Goldberg, and Richard Pazdur, of the Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the Division of Drug Information was the sound producer.

                                                                                  Content current as of:
      03/12/2019
              
              
Regulated Product(s)
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						  OncologyResources for Information | Approved Drugs

          
                        Oncology (Cancer) / Hematologic Malignancies Approval Notifications
          Ongoing | Cancer Accelerated Approvals
          Verified Clinical Benefit | Cancer Accelerated Approvals
          Withdrawn | Cancer Accelerated Approvals
          Other | Cancer Accelerated Approvals


                        Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description
 
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