Multitarget Tyrosine Kinase Inhibition: [And the Winner Is…]
Authors: Jaap Verweij, Maja de Jonge
Journal: Journal of Clinical Oncology (2007)

In the era of molecular targeting, the last development seems to be the shift away from selective targeting to multiple targeting. Given the multifaceted character of cancer, this shift makes sense. In addition, with the introduction of bevacizumab, there is evidence that inhibition of the process of tumor angiogenesis may add efficacy to cytotoxic treatment. Most of the recently developed tyrosine kinase inhibitors target multiple mechanisms (multitarget tyrosine kinase inhibitors [MTKIs]), sharing a focus on both the angiogenesis process and additional receptors located mostly on the surface of the cancer cell. Both of the already approved and registered MTKIs sorafenib and sunitinib are members of a similar family, with similarities and distinct differences. The MTKIs currently in the spotlight all inhibit KIT, platelet-derived growth factor, and vascular endothelial growth factor receptor 2 (VEGFr2). Most also inhibit VEGFr1, some inhibit VEGFr3, and in addition, they each inhibit one or more additional receptor tyrosine kinases, introducing a distinct subtle difference between the agents. This obviously leads to the question of whether any of those distinctions would lead to a favorite MTKI, or as one could ask: “Is there any winner?” In this issue of the Journal of Clinical Oncology, Rosen et al report on a phase I study of a new member of this family of MTKIs: AMG 706. This agent inhibits VEGFr1, VEGFr2, VEGFr3, KIT, platelet-derived growth factor receptor, and RET, and thus shares its major targets with sunitinib (Table 1). The article has a few interesting elements that we will try to put into perspective. First, the study seemed to have had multiple primary end points, including the establishment of the maximum-tolerated dose (MTD), characterization of dose-limiting toxicities, and assessment of pharmacokinetic (PK) profiles. Most commonly, a study only has a single primary end point and can have multiple secondary end points, where the primary end point guides the decision making in study performance. Having multiple primary end points could introduce confusion in this regard, and there are some data in the report that could indicate this. In addition, pharmacodynamic profiling is called both a secondary end point and an exploratory end point by the authors, which also could lead to some confusion. One of the concerns that could be raised in an era in which time pressure and demands are increasing in collaborations between investigators and the pharmaceutical industry is that decisions may be made in a rush, without appropriate information being available for appropriate scientific arguments. Whether this has also been the case in the current study is unknown to us, but there are a few topics that seem to be suggestive. There seems to be a discrepancy in numbers of patients in the current report of the study (they indicate in the paragraph on accrual to have entered 59 patients onto the study, but they discuss safety data for 71 patients). It is conceivable that this error is due to a drive for quick reporting. Likewise, dropping study aims without appropriate scientific arguments is a cause for concern. The investigators report they have dropped the bid dosing, and that it will be investigated in future studies. This seems somewhat in conflict with data they present on the obtained PK studies. They justify the dose selection for additional studies with the single dose by the fact that the achieved exposure would provide continuous coverage above the concentration that inhibits 50% (IC50) of proliferation in human umbilical vein endothelial cells in vitro. They also indicate that it is not inconceivable that an even better exposure can be achieved by bid dosing. This sounds like an argument to first fully explore this schedule before starting a phase II and III program, rather than starting that program with the possibility of a suboptimal single dose per day. The recent worrisome experience in the phase III program on the agent vatalanib in colorectal cancer possibly exemplifies this. Although time is important in drug development, we have to make sure that our decision-making process in general remains guided by scientific arguments and does not get overrun by other considerations. Table 1. A Selection of MTKIs and Selection of Their Respective Targets