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• W2129673587 abstract "In this issue of Journal of Clinical Oncology, Hainsworth et al report the first phase II combination of everolimus and bevacizumab in renal cell carcinoma (RCC), which was considered very promising when presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO), May 30 to June 3, 2008, Chicago, IL. Based on these promising preliminary data, two large studies were designed to test this regimen, one a first-line, large, randomized phase II study comparing this everolimus and bevacizumab regimen to the combination of bevacizumab and interferon (RECORD [Renal Cell Cancer Treatment With Oral RAD 001 Given Daily] 2 study), and one second-line phase III postsunitinib study, comparing the same regimen to everolimus plus placebo (proposed by the Cancer and Leukemia GroupB). When reading the Hainsworth et al article, several issues should be raised. The first one is linked to the difference between the preliminary data reported at ASCO and the current article. The progressionfree survival (PFS) reported at ASCO was, respectively, 12 and 11 months in the previously untreated and the tyrosine kinase inhibitor (TKI) –pretreated groups. These numbers will probably remain in the mind of many investigators and are used as the rationale for the two protocols described above. However, the final PFS reported herein are, respectively, 9.1 and 7.1 months in the untreated and TKI-pretreated groups, which are 3 and 4 months fewer than in the preliminary report. Knowing these final PFS data, the rationale for the two large, ongoing or planned studies described above is becoming much weaker, and the necessity to embark on these large studies becomes questionable. It should be emphasized, for example, that the control arm in the RECORD 2 study (bevacizumab plus interferon) results in PFS of 8.5 to 10.2 months, which is very likely to be similar to the everolimus plus bevacizumab arm. In addition, the chance that this combined regimen will be superior to the 11-month PFS obtained with other current standards of care, such as sunitinib or pazopanib, appears rather low. A second issue raised by this study concerns the usefulness of small phase II studies to build a rationale for large randomized studies. Interestingly, the Hainsworth et al study really reports two small phase II trials, a 50-patient study in untreated patients and a 30-patient study in TKI-pretreated patients. Mixing these two populations in the same study can obviously be justified by avoiding the administrative burden required by two separate studies, but does not help to interpret the data. It could be argued that, in terms of safety, these two phase II trials allow better estimate of the tolerability of the combined regimen. However, the conclusion that the regimen is well tolerated should be weighed by the median duration of treatment of only 6 months, much less than the median PFS, suggesting that such therapy has to be stopped without progressive disease in a large number of patients. In the group of 30 patients previously treated with TKIs (sunitinib and/or sorafenib), the promise of a 7.1-month PFS, compared with a 5.1month PFS with everolimus alone in a large phase III, is now less obvious, and a randomized phase II would have provided much better estimate of the efficacy of the combination before starting the Cancer and Leukemia Group B phase III described above. Finally, the Hainsworth et al study raises the issue of how to interpret small phase II trials, especially when conducted by an academic group, without external review of the primary end point, when this end point is PFS or response rate. The RCC literature is rich with promising phase II trials, never confirmed by further studies. As examples, thalidomide was initially reported as very active, although a large number of phase II trials never confirmed this promise. Similarly, the combination of bevacizumab and erlotinib was initially reported as very active in a small phase II study, but efficacy was not confirmed by a randomized phase II trial. Recently, based on the high response rate of a combination of temsirolimus and bevacizumab in just 12 patients, a large phase III trial of 822 patients was launched to compare this regimen to bevacizumab plus interferon. However, based on previous experience, starting with a small randomized phase II trial might have provided a better estimate of the likelihood that such a phase III study will be positive. In conclusion, readers should be advised, first, that data presented in a meeting should always be confirmed in the final report of the study; and second, that small phase II studies have many potential biases and that randomized phase II trials may provide much more reliable rationale to design large phase III studies. This should avoid embarking on phase III studies with a large number of patients; such studies are likely to be negative, especially when so many important questions need to be addressed by well-designed studies." @default.
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• W2129673587 date "2010-05-01" @default.
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• W2129673587 title "How to Interpret Phase II Data for Everolimus Plus Bevacizumab in Renal Cell Carcinoma" @default.
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