Clinical Trials

Date: 2017-09-09

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2017 Congress

Company: Exelixis (USA - CA)

Product: Cabometyx™ (cabozantinib)

Action mechanism:

• tyrosine kinase inhibitor. Cabozantinib is a kinase inhibitor that blocks abnormal kinase proteins involved in the development and growth of medullary cancer cells. Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGFRs and AXL. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. In April 2015, cabozantinib received Fast Track designation by the FDA for the potential treatment of advanced renal cell carcinoma patients who have received one prior therapy.  Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib.
• On April 25, 2016 Cabometyx™ was approved by the FDA for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy.

Disease: previously untreated advanced renal cell carcinoma (RCC)

Therapeutic area: Cancer - Oncology

Country:

Trial details:

• CABOSUN is a randomized, open-label, active-controlled phase 2 trial that was designed to enroll 150 patients with advanced renal cell carcinoma determined to be intermediate- or poor-risk by the International Metastatic RCC Database Consortium (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 randomization was stratified by the IMDC risk strata (intermediate or poor risk) and presence of bone metastasis (yes, no). Enrollment was completed in March 2015. The primary endpoint was PFS, defined as time from randomization to disease progression or death, whichever occurs first. Positive PFS results have formed the basis for previous regulatory approvals of treatments in the first-line setting, including sunitinib. Secondary endpoints included overall survival and objective response rate. 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). Prior systemic treatment for RCC was not permitted. With 123 events (disease progression or death), the log-rank statistic has 85 percent power (with a one-sided type I error rate=0.12) to detect a hazard ratio of 0.67. Between July 9, 2013 and April 6, 2015, 157 patients were randomized: 79 patients on the cabozantinib arm and 78 patients on the sunitinib arm.
• CABOSUN was conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP).

Latest news:

• • On September 9, 2017, Exelixis and Ipsen  announced updated results from the CABOSUN randomized phase 2 trial of cabozantinib in patients with previously untreated advanced renal cell carcinoma with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). These data have been presented at the European Society for Medical Oncology (ESMO) 2017 Congress. The data included the analysis from a blinded independent radiology review committee (IRC), which confirmed the primary efficacy endpoint results of investigator-assessed progression-free survival (PFS), as well as an updated investigator-assessed analysis. Per the IRC analysis, 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). The median PFS for cabozantinib was 8.6 months versus 5.3 months for sunitinib, corresponding to a 3.3 month (62 percent) improvement favoring cabozantinib over sunitinib. “These updated analyses from CABOSUN consistently show that cabozantinib provided a statistically significant decrease in the rate of disease progression or death compared to sunitinib, a current standard of care – potentially offering a new treatment option for physicians to treat patients in the first-line advanced renal cell carcinoma setting,” said Toni K. Choueiri, M.D., Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. “The CABOSUN trial included patients with intermediate or poor prognostic factors per the IMDC criteria; in addition, patients had a notable number of other independent adverse prognostic risk factors. These included a high rate of bone metastases, two or more sites of metastatic disease, ECOG 2 performance status, and lack of prior nephrectomy. This patient population fares poorly and is in need of new therapies to better control their disease.”
• The following chart outlines data from the CABOSUN trial presented  at ESMO 2017, as compared to the data previously published in the Journal of Clinical Oncology (JCO) in October 2016:

  	JCO Investigator-assessed (April 11, 2016 Cut-off)								ESMO 2017  Investigator-assessed (Sept 15, 2016 Cut-off)								ESMO 2017 IRC Review (Sept 15, 2016 Cut-off)
  	Cabozantinib N = 79				Sunitinib N = 78				Cabozantinib N = 79				Sunitinib N = 78				Cabozantinib N = 79				Sunitinib N = 78
  Progression-free survival
  Median PFS, months	8.2				5.6				8.3				5.4				8.6				5.3
  Stratified HR  (95% CI)	0.66 (0.46-0.95)								0.56 (0.37-0.83)								0.48 (0.31-0.74)
  P value	0.012 (1-sided)								0.0042 (2-sided)								0.0008 (2-sided)
  Tumor Response
  Objective response rate (95% CI),a %	46 (34-57)				18 (10-28)				33 (23-44)				12 (5-21)				20 (12-31)				9 (4-18)
  Disease control rate,b %	78				54				76				49				75				47
  Progressive disease,c %	18				26				18				24				18				29
  Not evaluable or missing, %	4				21				6				27				8				23
  Any reduction in target lesions, %	87				44				85				38				80				50

  a One complete response was observed with cabozantinib for both investigator assessments, and one complete response was observed with sunitinib for the original investigator assessment, all other responses were partial responses;

  b Complete response + partial response + stable disease;

  c Progressive disease as best overall response.
  The updated 2017 data sets and methods differ from the initial investigator analyses presented in 2016. The comprehensive image collection for IRC review used a later cut-off point (5 months) than the initial investigator analysis and followed a rigorous IRC review process. The analysis of IRC data applied FDA guidance for PFS analyses in oncology studies, including recommended censoring rules (i.e., censoring at the last adequate tumor assessment prior to initiation of subsequent anti-cancer therapy, and censoring for events that occur after two or more missing adequate tumor assessments)
• The updated overall survival (OS) analysis had a data cut-off of July 1, 2017, and showed a favorable trend for patients randomized to cabozantinib compared to sunitinib that was not statistically significant. Median overall survival was 26.6 months for patients receiving cabozantinib versus 21.2 months for those receiving sunitinib (HR= 0.80, 95% CI 0.53-1.21, two-sided P=0.29).   The most common all-causality grade 3 or 4 adverse events in more than 5 percent of patients for cabozantinib (N=78) and sunitinib (N=72), respectively, were diarrhea (10 vs. 11 percent), hypertension (28 vs. 21 percent), fatigue (6 vs. 17 percent), increased alanine aminotransferase (ALT; 5 vs. 0 percent), decreased appetite (5 vs. 1 percent), palmar-plantar erythrodysesthesia syndrome (PPES; 8 vs. 4 percent), decreased platelet count (1 vs. 11 percent) and stomatitis (5 vs. 6 percent). Twenty-one percent of patients in the cabozantinib arm and 22 percent of patients in the sunitinib arm discontinued treatment due to adverse events.   • On June 19, 2017, Exelixis announced that the analysis of the review by a blinded independent radiology review committee (IRC) has confirmed the primary efficacy endpoint results of investigator-assessed progression-free survival (PFS) from the CABOSUN randomized phase 2 trial of cabozantinib as compared with sunitinib in patients with previously untreated advanced renal cell carcinoma (RCC) with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Per the IRC analysis, cabozantinib demonstrated a clinically meaningful and statistically significant reduction in the rate of disease progression or death as measured by PFS. Exelixis remains on target to complete a supplemental New Drug Application (sNDA) for cabozantinib as a treatment of first-line advanced renal cell carcinoma in the third quarter of 2017.
• • On October 10, 2016, Exelixis announced detailed results from the CABOSUN randomized phase 2 trial of cabozantinib in patients with previously untreated advanced renal cell carcinoma (RCC) with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Principal investigator Toni K. Choueiri, M.D. has presented detailed data from late-breaking CABOSUN abstract [#LBA30_PR] at the European Society for Medical Oncology (ESMO) 2016. In CABOSUN, with a median follow-up of 20.8 months, cabozantinib demonstrated a clinically meaningful and statistically significant 31 percent reduction in the rate of disease progression or death [HR 0.69, 95% CI (0.48-0.99), one-sided P=0.012]. The median progression-free survival (PFS) for cabozantinib was 8.2 months versus 5.6 months for sunitinib, corresponding to a 2.6 months (46 percent) improvement favoring cabozantinib over sunitinib. PFS benefits were independent of IMDC risk group (intermediate or poor risk) and presence or absence of bone metastases at baseline. The results for sunitinib were in line with a previously published retrospective analysis of 1,174 intermediate- and poor-risk RCC patients from the IMDC database, which documented a median PFS of 5.6 months with a first-line targeted therapy, mainly sunitinib, in this patient population.
• Objective response rate (ORR) was also significantly improved, at 46 percent (95% CI 34% – 57%) for cabozantinib versus 18 percent (95% CI 10% to 28%) for sunitinib. With a median follow up of 22.8 months, median overall survival was 30.3 months for cabozantinib versus 21.8 months for sunitinib [HR 0.80, 95% CI (0.50 - 1.26)].
• Based on these results, Exelixis plans to submit a Supplemental New Drug Application (sNDA) for cabozantinib as a treatment of first-line advanced renal cell carcinoma, and is working with the Alliance to transfer the complete CABOSUN clinical database to Exelixis.
• CABOSUN enrolled 157 patients with previously untreated advanced RCC: 80.9 percent of patients were intermediate risk per IMDC criteria and 19.1 percent were poor risk, 36.3 percent of patients had bone metastases, 46 percent of patients had ECOG Performance Status (PS) 0, 41 percent had ECOG PS 1, and 13 percent had ECOG PS 2. All patients were included in the efficacy analyses that followed the intent-to-treat principle. Tumor assessments were performed by the investigators following RECIST criteria. At the time of the analysis of the primary endpoint of PFS, the median duration of treatment in CABOSUN was 6.9 months with cabozantinib and 2.8 months with sunitinib; 13 patients continued on cabozantinib treatment versus 2 patients on sunitinib treatment. Dose reductions occurred for 58 percent and 49 percent of patients, respectively. Discontinuation rate due to an adverse event was 20 percent with cabozantinib and 21 percent with sunitinib.
• One hundred and fifty patients were evaluable for safety. Ninety-nine percent of patients on both arms experienced at least one adverse event. The most common all causality grade 3 or 4 adverse events observed in more than 5 percent of patients were hypertension (28 percent), diarrhea (10 percent), palmar-plantar erythrodysesthesia (8 percent), and fatigue (6 percent) in the cabozantinib arm, and hypertension (22 percent), fatigue (15 percent), diarrhea and thrombocytopenia (both 11 percent), and oral mucositis (6 percent) in the sunitinib arm. Treatment-related grade 5 events occurred in three patients in the cabozantinib arm (acute kidney injury, sepsis and jejunal perforation) and two patients in the sunitinib arm (sepsis and vascular disorder).
• • On May 23, 2016, Exelixis announced positive top-line results from the CABOSUN randomized phase 2 trial of cabozantinib in patients with previously untreated advanced renal cell carcinoma. The trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for cabozantinib compared with sunitinib in patients with advanced intermediate- or poor-risk renal cell carcinoma. The safety data in the cabozantinib-treated arm of the study were consistent with those observed in previous studies in patients with advanced renal cell carcinoma. CABOSUN is being conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP).

       

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