San Francisco, Calif.--(UroToday GUOncToday)--Sep. 7, 2018-- It was announced today that the National Comprehensive Cancer Network (NCCN) updated its Clinical Practice Guidelines to include new recommendations for CABOMETYX® (cabozantinib) tablets. With the updates, CABOMETYX is recommended by the NCCN for the treatment of advanced renal cell carcinoma (RCC) regardless of patient risk status (favorable-, intermediate-, and poor-risk).
Key CABOMETYX-related highlights from the updated NCCN Clinical Practice Guidelines for Kidney Cancer include:1
- CABOMETYX is the only preferred tyrosine kinase inhibitor (TKI) treatment option for first-line patients in the poor- and intermediate-risk groups (Category 2A)
- CABOMETYX is a recommended first-line treatment option for favorable-risk patients (Category 2B)
- CABOMETYX is the only preferred TKI treatment option for previously treated patients (Category 1)
The NCCN Clinical Practice Guidelines are the recognized standard for clinical policy in cancer care and are developed through review of evidence and recommendations from physicians and oncology researchers. The NCCN kidney cancer panel’s decision to include CABOMETYX as a Category 2A preferred option for the treatment of patients with previously untreated advanced RCC with poor- or intermediate-risk disease was based on the results of the phase 2 CABOSUN trial.
Additionally, in its recent update to the Clinical Practice Guidelines for Hepatobiliary Cancers, the NCCN added cabozantinib as a Category 1 option for the treatment of patients with hepatocellular carcinoma (HCC) (Child-Pugh Class A only) who have been previously treated with sorafenib.2 CABOMETYX is not FDA-approved for previously treated advanced HCC. On May 29, 2018, the U.S. FDA accepted the supplemental New Drug Application for CABOMETYX in previously treated advanced HCC and assigned it a Prescription Drug User Fee Act (PDUFA) action date of January 14, 2019.
About the CABOSUN Study
On May 23, 2016, Exelixis announced that the phase 2 CABOSUN study met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS compared with sunitinib in patients with advanced intermediate- or poor-risk RCC as determined by investigator assessment. The CABOSUN study was conducted by The Alliance for Clinical Trials in Oncology and was sponsored by the National Cancer Institute-Cancer Therapy Evaluation Program (NCI-CTEP) under the Cooperative Research and Development Agreement with Exelixis for the development of cabozantinib. These results were first presented by Dr. Toni Choueiri at the European Society for Medical Oncology (ESMO) 2016 Congress, and published in the Journal of Clinical Oncology (Choueiri, JCO, 2016).3 In June 2017, a blinded independent radiology review committee (IRC) confirmed that cabozantinib provided a clinically meaningful and statistically significant improvement in the primary efficacy endpoint of investigator-assessed PFS. Results from the IRC review were presented by Dr. Toni Choueiri at the ESMO 2017 Congress.
CABOSUN was a randomized, open-label, active-controlled phase 2 trial that enrolled 157 patients with advanced RCC determined to be intermediate- or poor-risk by the IMDC criteria. Patients were randomized 1:1 to receive cabozantinib (60 mg once daily) or sunitinib (50 mg once daily, 4 weeks on followed by 2 weeks off). The primary endpoint was PFS. Secondary endpoints included overall survival, objective response rate and safety. Eligible patients were required to have locally advanced or metastatic clear-cell RCC, ECOG performance status 0-2 and had to be intermediate- or poor-risk per the IMDC criteria (Heng, JCO, 2009).4 Prior systemic treatment for RCC was not permitted.
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2018 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.5 Clear cell RCC is the most common type of kidney cancer in adults.6 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.7 Approximately 30,000 patients in the U.S. and 68,000 globally require treatment, and an estimated 14,000 patients in the U.S. each year are in need of a first-line treatment for advanced kidney cancer.7
The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.8,9 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.10,11,12,13 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.9,10
About CABOMETYX® (cabozantinib)
CABOMETYX tablets are approved in the United States for the treatment of patients with advanced RCC. CABOMETYX tablets are also approved in the European Union, Norway, Iceland, Australia, Switzerland and South Korea for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy, and in the European Union for previously untreated intermediate- or poor-risk advanced RCC. In March 2017, the FDA granted orphan drug designation to cabozantinib for the treatment of advanced HCC. On March 28, 2018, Ipsen announced that the European Medicines Agency validated its application for a new indication for cabozantinib as a treatment for previously treated advanced HCC in the European Union. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan.
References:
1 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Kidney Cancer. Version 1.2019. Updated September 4, 2018.
2 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers. Version 3.2018. Updated August 29, 2018.
3 Choueiri, T.K., 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. Am J Clin Oncol. 2016; 35:591-597.
4 Heng D.Y., Xie W., Regan M.M., 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. Am J Clin Oncol. 2009; 27:5794-5799.
5 American Cancer Society: Cancer Facts and Figures 2018. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed September 2018.
6 Jonasch, E., Gao, J., Rathmell, W. Renal cell carcinoma. BMJ. 2014; 349:g4797.
7 Decision Resources Report: Renal Cell Carcinoma. October 2014 (internal data on file).
8 Harshman, L., and Choueiri, T. Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J. 2013; 19:316-323.
9 Rankin, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci USA. 2014; 111:13373-13378.
10 Zhou, L., Liu, X-D., Sun, M., et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016; 35:2687-2697.
11 Koochekpour, et al. The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999; 19:5902–5912.
12 Takahashi, A., Sasaki, H., Kim, S., et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994; 54:4233-4237.
13 Nakagawa, M., Emoto, A., Hanada, T., Nasu, N., Nomura, Y. Tubulogenesis by microvascular endothelial cells is mediated by vascular endothelial growth factor (VEGF) in renal cell carcinoma. Br J Urol. 1997; 79:681-687.
14 Cancer Incidence and Mortality Worldwide. Liver Cancer. International Agency for Research on Cancer, GLOBOCAN 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed September 2018.
15 Mittal S, El-Serag HB. Epidemiology of HCC: Consider the Population. Journal of Clinical Gastroenterology. 2013. 47:S2-S6.
16 Weledji E, Orock G, Ngowe M, NsaghaD. How grim is hepatocellular carcinoma? Annals of Medicine and Surgery. 2014. 3:71-76.