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Journal of Clinical Oncology, Vol 25, No 17 (June 10), 2007: pp. 2340-2342 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.7318
Multitarget Tyrosine Kinase Inhibition: [And the Winner Is...]Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands 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,1 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 sorafenib2 and sunitinib3,4 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 al5 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,6 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. The study protocol seems to have used predefined dose levels, albeit this is described in a somewhat confusing manner. The authors on one hand indicate that the dose of 50, 100, and 175 mg was foreseen, and on the other hand indicate that dose escalations were based on discussions taking into account safety, PK, and so on. The use of predefined dose levels is something we see with increasing frequency, which presents a limitation that may be relevant. Most of the time, these predefined dose levels only present a mathematic multiplication and are not based on any practical or scientific ground. The availability of capsule or tablet strength can be an important consideration. Yet, availability of capsule or tablet strength was not completely guiding in this study, and it is not fully clear why the dose was increased from 100 to 175 mg daily instead of a dose doubling after the prior dose doubling, or a 50% increase: 175 mg clearly presented the dose-limiting toxicity and the subsequent dose reduction makes sense. However, a dose in between 125 and 175 mg was not assessed for unknown reasons, although it is likely that safety concerns were guiding the investigators. On the basis of the PK data, and the time of IC50 exposure, the investigators recommend the daily dose of 125 mg, whereas the dose of 100 mg also achieved an adequate exposure (if IC50 data were used as a guide) and with less toxicity. Conversely, given the large interpatient variation, the use of mean values on PK parameters, as the authors have done, can also be reason for concern. The coefficient of variation (CV%), for instance, in the trough levels that guided the decision on recommended dose, varies from 22% to 76% depending on the cohort assessed. Thus the CV% is large, and as a consequence, the mean value in itself is not particularly illustrative. In addition, in the area under the curve values, there is a large interindividual variation that is much larger than the variation in dose per cohort. On the one hand, although this would support a PK-guided individual dosing, which is extremely unpractical, on the other hand, it adds to the discussion on the recommended dose for additional studies. Just like the other member of the class of VEGFr2 inhibitors, AMG 706 induced hypertension. One of the problems in trying to compare results between agents is that the criteria used for treating the hypertension, and if necessary, for reducing the dose of the investigational agent, are largely different. In the article by Rosen et al,5 these criteria are not listed, which is also true for other encountered adverse effects. Although comparing data from different studies yields a major limitation, the lack of this information further limits our possibilities for comparison. It seems important to try to harmonize not only toxicity and response criteria, but also intervention and dose-reduction criteria. The profile of adverse effects of AMG 706 is quite similar to the profile reported for sunitinib, sorafenib, vatalanib, and pazopanib. However, with 52% of patients reporting grade 3 adverse events (AEs), the level of severe toxicity with AMG 706 may be high—at least it seems somewhat higher than that reported for related agents7-12; however, we need to realize that these are indirect comparisons. Moreover, a clear distinction between drug-related AEs and AEs due to the underlying disease was not made. As a consequence, it is difficult to assess the frequency and severity of drug-related adverse effects. Obviously, we will also have to take into account that this is only the first report on clinical safety on AMG 706, and it is still possible that this single study represents a chance observation on the incidence of adverse effects. To obtain a good pharmacologic profile the study allowed expansion of the MTD cohort to 50 patients. An expanded cohort at MTD occurs frequently in current phase I study protocols, but the numbers of patients vary largely among these studies. The aim of this expanded cohort, apart from adequate PK profiling, usually is to provide a better idea of the safety at MTD. However, there is no good guideline on the number of patients to be included. The number of six patients in phase I studies performed long ago may be too small a group on which to base important decisions, but a number of 50 patients is exceptionally high. In practice, the investigators entered 28 patients, six of whom could be considered as the screening cohort at the MTD of the continuous-dosing schedule. Interestingly, the CV% for the various PK parameters in this expanded cohort is much larger than at the limited initial cohort with the same dose administered intermittently. Thus, a better idea of the PK profile was obtained, but in view of the still large CV%, one wonders if a smaller group of patients would not have provided the same information. It might be effective to establish international guidelines for such expansions, especially given that they are sometimes wrongly used as surrogate phase II information. An expanded cohort in a phase I study can never replace a phase II study, which screens for activity of an agent in a certain disease. The activity of AMG 706 is certainly interesting. The high number of responses in thyroid cancer is remarkable, but may be understandable if RET expression is confirmed to be an important growth-related characteristic of thyroid cancers. Thyroid cancer is not commonly a disease that is abundantly represented in phase I studies, and the number of patients in this particular study likely reflects a purpose selection based on the target-specific profile of the drug. Sunitinib also inhibits RET, but a similar patient selection apparently was not pursued in the phase I studies of that agent. In their response assessment, the investigators indicate to have used [modified Response Evaluation Criteria in Solid Tumors (RECIST).] There is no formal modification of RECIST, and it is unfortunate that the investigators did not provide information on what their modification actually involved. This renders it difficult to compare activity of AMG 706 in this study with the activity of similar compounds in their respective phase I studies. As mentioned, the patient numbers described in the article related to response are somewhat confusing. In Results, there are 35 patients with stable disease, whereas in Discussion, there are 37 patients (the waterfall plot also suggests a different number); there seems to be a fair number of patients with absence of progression at first assessments. This is similar to the observations in the phase I studies of closely related agents that yielded no progression at first evaluation in 50% to 70% of patients entered.10-15 Stable disease may thus be important information and the first sign of clinical benefit. The best proof of this actually comes from the phase III study on sorafenib,2 in which a low objective regression percentage but a high stable disease percentage resulted in a significant increase in disease-free survival. To better assess stable disease in a noncontrolled study, it would be worthwhile to obtain prestudy information on the tumor growth rate in individual patients and to determine if the growth rate actually changes. It is crucial that information on the criteria used for assessment of tumor size be provided to enable readers to perform an appropriate evaluation. In conclusion, and despite the issues raised in this commentary, AMG 706 seems to be an interesting new MTKI. The different MTKIs yield different activities in different diseases, and as such it seems impossible to favor one over the other without taking disease details into account. It is important to try to harmonize trial design further for the novel targeted agents as best as we can, to enable early appropriate assessments of the data provided. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Jaap Verweij, Maja de Jonge Collection and assembly of data: Jaap Verweij, Maja de Jonge Manuscript writing: Jaap Verweij, Maja de Jonge Final approval of manuscript: Jaap Verweij, Maja de Jonge
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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