BERKELEY, CA (UroToday.com) - Angiogenesis is one of the hallmarks of renal cell carcinoma (RCC). It is well recognized that mutations or inactivation of the von Hippel-Lindau gene is a driver genetic event for RCC, leading to increased angiogenesis through VEGF overexpression. Exploration of VEGF as a target resulted in FDA approval of 5 agents for the treatment of metastatic RCC, including sunitinib and sorafenib. Nonetheless, development of resistance and tumor progression on these agents are inevitable. Results from axitinib after progression to a VEGF inhibitor on first line therapy suggested that RCC continues to be an angiogenesis-dependent tumor, even after failure to a prior antiangiogenic agent. In this context, the phase I trial by David Hong, et al., combining trebananib with sunitinib or sorafenib adds very important information to this field.
Trebananib prevents ligation of angiopoietin 1 and 2 to its receptor Tie2, blocking a different step of the angiogenesis pathway. The first important finding from this trial was the feasibility of the combination of two antiangiogenic drugs. This combination was quite well tolerated. The toxicity profile described with the combination is consistent with to the ones found with sorafenib and sunitib administered separately as monotherapies. One important caveat is that despite the low rate of grade 3 or more adverse events in the cohort using the highest dose of trebananib (10 mg/kg), the majority of the patients described some degree of toxicity, including events such as diarrhea and fatigue, which can be hard to tolerate in a chronic treatment as for metastatic RCC. In the future, it will be of extreme importance to establish the feasibility of the dose found in this study in a larger group of patients and for a longer period of time. Prior attempts to combine sunitinib with other anti-antiangiogenic agents (such as bevacizumab) and mTOR inhibitors (everolimus) led to development of limiting toxicities, preventing the clinical application of these combinations. Therefore, the feasibility of the trebananib with the other two VEGF tyrosine kinase inhibitors is already something to celebrate.
The second important point of this study is the antitumor activity observed with the combination. The pivotal trial for sunitinib monotherapy as first-line therapy for RCC demonstrated objective responses in about 30% of patients, while in studies with sorafenib, responses are closer to 25%. In this phase I trial, very few patients were treatment-naïve, and more than one third received at least two lines of prior therapy. Nonetheless, responses found in the trebananib/sorafenib and trebananib/sunitinib combinations (29% and 53%, respectively) are above the historical expectations for each drug as monotherapies. A phase II trial of sunitinib and trebananib also showed overall response rate above 50% range along with a reasonable tolerability. This finding suggests that horizontal blockage of the angiogenesis pathway (targeting simultaneously VEGF and angiopoietin) might result in enhanced antitumor activity and merits further investigation. Promising initial results with VEGF and MET blockage also strengthens the idea of horizontal blockage of angiogenesis in RCC. Unfortunately, enhanced antitumor activity may not be translated to more definitive endpoints. The results of a randomized trial with sorafenib and trebananib did not result in a prolonged PFS with the combination, despite higher responses rates.
This phase I trial in another piece in the puzzle of how to better target angiogenesis in RCC, adding a combination that, in fact, may be tolerable. Also, importantly, it was able to offer a potential benefit for some patients. Yet, a more fine selection of patients is needed in order to translate a promising antitumor activity in longer survival and better quality of life.
Denis L. Fontes Jardim and David S. Hong as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX USA