Dalantercept Plus Axitinib

“Another mechanism of targeting angiogenesis unrelated to VEGF is targeting the endoglin/activin receptor-like kinase 1 (ALK1) pathway,” Dr Choueiri told Cancer Therapy Advisor.

Dalantercept, an ALK1 receptor fusion protein that inhibits the maturation of vascular cells and impairs basic fibroblast growth factor (bEGF) and VEGF-A stimulated angiogenesis, is being assessed in combination with axitinib.4

Part 1 of the phase 2 DART study enrolled 29 patients with advanced RCC who had received 1 prior VEGFR kinase inhibitor and 3 or fewer lines of prior therapy. Participants received varying doses of dalantercept given subcutaneously every 3 weeks plus axitinib 5 mg orally twice daily for each 21-day cycle.4

Results showed that median progression-free survival was 8.3 months with the combination and the 12-month progression-free survival rate was 39%. Furthermore, dalantercept plus axitinib achieved a 12-month overall survival rate of 75%. Both endpoints compare favorably to historical data with axitinib in kinase inhibitor-pretreated patients.4

Part 2 of the study will enroll approximately 130 patients with advanced clear cell RCC who progressed following 1 VEGF pathway inhibitor, who will be randomly assigned to receive dalantercept 0.9 mg/kg or placebo once every 3 weeks and axitinib at a starting dose of 5 mg orally twice daily. Patients who have also had 1 mammalian target of rapamycin (mTOR) inhibitor, such as temsirolimus or everolimus, and/or any prior approved or investigational immunotherapies are eligible for the study. Final data collection for the primary endpoint of progression-free survival is estimated to be completed in December 2017.4


Tivozanib is a potent, selective inhibitor of VEGFR1, VEGFR2, and VEGFR3, being developed by AVEO Oncology. In 2013, the FDA rejected AVEO’s New Drug Application for tivozanib as first-line therapy for advanced RCC, after failing to demonstrate a favorable risk-benefit ratio compared with sorafenib.5

Now, tivozanib is being evaluated as second- and third-line therapy for RCC after sorafenib treatment failure. A presentation at the 2015 ASCO Annual Meeting in Chicago, IL, showed that median progression-free survival was 11 months and median overall survival was 21.6 months from the start of second-line tivozanib.5

“I have used tivozanib in trials and it is well tolerated,” Dr Choueiri said. “It is very interesting that it is making a resurgence.”

The most frequently reported tivozanib-related adverse events were hypertension, diarrhea, fatigue, and palmar-plantar erythryodysesthesia syndrome.6

This study was an extension of the phase 3 TIVO-1 study, which enrolled 517 patients with mRCC who had undergone a prior nephrectomy, received no more than 1 prior systemic treatment for mRCC, and had no prior VEGF-targeted or mTOR therapy. In the extension portion, patients who failed on sorafenib were allowed to cross over to the tivozanib treatment. Of the 257 who initially received sorafenib, 163 went on to receive second-line tivozanib.6

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AVEO Oncology also plans to initiate a multicenter, open-label, phase 3 study, in which approximately 314 patients will be enrolled and randomly assigned 1:1 to third-line tivozanib or sorafenib. Participants may include those who have received prior immunotherapy, such as nivolumab.5