Public Release: 

Results from Alliance CABOSUN trial lead to US FDA approval of extended indication

Alliance for Clinical Trials in Oncology

The Alliance for Clinical Trials in Oncology (the Alliance), in conjunction with industry partner Exelixis, today announced that the U.S. Food and Drug Administration (FDA) approved CABOMETYX® (cabozantinib) tablets for the expanded indication of patients with advanced renal cell carcinoma (RCC). RCC is the most common form of kidney cancer in adults. The FDA's priority review and approval of cabozantinib was based on results from the Alliance randomized phase II CABOSUN trial in patients with previously untreated RCC, which demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus sunitinib, a current standard of care. Today's label expansion follows the initial FDA approval of cabozantinib in April 2016 for the treatment of patients with advanced RCC who have previously received anti-angiogenic therapy.

"The CABOSUN trial enrolled treatment-naïve patients with advanced kidney cancer, including those who are known to fare poorly, such as patients with intermediate- or poor-prognostic factors and those with bone metastases or multiple sites of metastatic disease," said Toni Choueiri, MD, Director, Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and chair of the CABOSUN study. "Physicians are already experienced in using cabozantinib in the second-line advanced RCC setting, and it is a much-needed advance to also now have cabozantinib as an option for their patients with previously untreated advanced RCC."

The expanded approval of cabozantinib is based on results of the phase II CABOSUN trial, which met its primary endpoint of improving PFS. According to the independent radiology review committee analysis of the data, cabozantinib demonstrated a clinically meaningful and statistically significant 52 percent reduction in the rate of disease progression or death (HR 0.48, 95% CI 0.31-0.74, two-sided P=0.0008). Median PFS for cabozantinib was 8.6 months versus 5.3 months for sunitinib, corresponding to a 3.3-month (62 percent) improvement.

All causality Grade 3 or 4 adverse reactions occurred in 68 percent of patients receiving cabozantinib and 65 percent of patients receiving sunitinib. The most frequent all causality Grade 3-4 adverse reactions (less than or equal to 5 percent) in patients treated with cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia (PPE), fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. Twenty-one percent of patients in the cabozantinib arm compared to 22 percent of patients receiving sunitinib discontinued treatment due to adverse events.

"We at the Alliance are very gratified that the CABOSUN study supported the approval of cabozantinib for the potential first-line treatment of all patients with advanced renal cell carcinoma. This trial exemplifies how NCI-sponsored studies can be efficient, accrue rapidly, and yield results highly relevant to the field," said Michael J. Morris, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, and Chair of the Alliance Genitourinary (GU) Committee.

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The CABOSUN study (Alliance A031203 | NCT01835158) was conducted by the Alliance and 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.

About CABOSUN Study

CABOSUN was a randomized, open-label, active-controlled phase II trial that enrolled 157 patients with advanced RCC determined to be intermediate- or poor-risk. 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).2 Prior systemic treatment for RCC was not permitted.

About Advanced Renal Cell Carcinoma

The American Cancer Society's 2017 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.[1] Clear cell RCC is the most common type of kidney cancer in adults.[2] 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.[1] 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.[3]

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.[4,5] These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.[6-9] MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.[5,6]

About the Alliance

The Alliance for Clinical Trials in Oncology develops and conducts clinical trials with promising new cancer therapies, and utilizes the best science to develop optimal treatment and prevention strategies for cancer, as well as researches methods to alleviate side effects of cancer and cancer treatments. The Alliance has been awarded a grant by the National Cancer Institute (NCI) as a member of the NCI National Clinical Trials Network (NCTN) in addition to a grant to serve as a research base for the NCI Community Research Oncology Program (NCORP). Collectively, the Alliance comprises nearly 10,000 cancer specialists at hospitals, medical centers, and community clinics across the United States and Canada. To learn more about the Alliance, visit http://www.AllianceforClinicalTrialsinOncology.org.

Sources

1. American Cancer Society. Cancer Facts & Figures 2017. Atlanta: American Cancer Society; 2017.
2. Jonasch, E., Gao, J., Rathmell, W. Renal cell carcinoma. BMJ. 2014; 349:g4797.
3. Decision Resources Report: Renal Cell Carcinoma. October 2014 (internal data on file).
4. Harshman, L., and Choueiri, T. Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J. 2013; 19:316-323.
5. Rankin, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A. 2014; 111:13373-13378.
6. 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.
7. 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.
8. 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.
9. 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.

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