FROM THE JOURNAL OF CLINICAL ONCOLOGY
Adding trebananib to sunitinib increased treatment toxicity but also appeared to enhance antitumor activity in an international phase II study involving 85 adults with metastatic renal-cell carcinoma, investigators reported online Aug. 24 in the Journal of Clinical Oncology.
Trebananib is an investigational recombinant protein that has a different pathway of anti–vascular endothelial growth factor (VEGF) activity than does sunitinib. Researchers hoped that combining the two agents would forestall the resistance to VEGF pathway blockade that typically develops within 8-12 months of beginning monotherapy. Most VEGF blockers, however, produce significant toxicity when combined. To examine the toxicity of the combination of trebananib and sunitinib, investigators conducted this open-label study at 18 sites in the United States, Europe, and Australia.
One cohort (43 patients) received 10 mg/kg intravenous trebananib once weekly plus oral sunitinib in a standard regimen; a second cohort (42 patients) received 15 mg/kg intravenous trebananib once weekly plus oral sunitinib. Treatment continued until disease progressed, unacceptable toxic effects developed, or participants withdrew consent, said Dr. Michael B. Atkins of Georgetown University Lombardi Comprehensive Cancer Center, Washington, D.C., and his associates.
The primary endpoint was treatment toxicity as measured by the incidence of adverse events, dose interruptions of sunitinib, or significant laboratory abnormalities. Grade 3 or higher treatment-related adverse events developed in 58% of the first cohort and 69% of the second cohort and included one case of fatal pulmonary edema considered possibly related to trebananib. Dose interruptions of sunitinib due to adverse events or laboratory abnormalities occurred in 70% of the first cohort and 86% of the second cohort. Other noteworthy adverse events included edema, which affected approximately 70% of both cohorts; pleural effusion; ascites; one GI perforation; one myocardial infarction; and two serious venous thromboembolisms, the investigators reported.
This represents a significant increase in toxicity for the combined therapy, compared with sunitinib monotherapy, Dr. Atkins and his associates said (J Clin Oncol. 2015 Aug 24. doi: 10.1200/JCO.2014.60.6012).
They noted, however, that 66% of the first cohort and 74% of the second cohort were able to continue full doses of the combined therapy despite frequent dose interruptions, and that 80% of the first cohort and 88% of the second cohort showed reductions in tumor burden. Median progression-free survival was 13.9 months and 16.3 months, respectively, which compares favorably to the median 8-11 month PFS reported in the literature for sunitinib monotherapy. Similarly, the overall response rate was 58% and 63%, respectively, which also bests the overall response rate reported in the literature.
Thus, the combination therapy may enhance antitumor activity and improve survival outcomes in larger phase III studies that focus on treatment efficacy rather than toxicity, Dr. Atkins and his associates said.
This study was supported by Amgen. Dr. Atkins reported serving as a consultant for Amgen, Merck, Genentech, Pfizer, Novartis, cCAM Biotherapeutics, X4 Pharmaceuticals, NeoStem, Eli Lilly, Alkermes, Infinity, and Bristol-Myers Squibb and receiving honoraria from Bristol-Myers Squibb. His associates reported ties to numerous industry sources.
