Reply to M. Buyse et al

Abstract

We appreciate the thoughtful correspondence by Buyse et al with respect to this important developing area of clinical trials that use a molecular profiling approach. We have considered their remarks regarding the use of a progression-free survival (PFS) ratio in this setting. We do not consider the comments of Buyse et al to counter our conclusion, given thatwewerenotseekingtoshowthatmolecularprofilingyieldedahigher averagetimetotumorprogression.Theideawastoshowthat itworkedin some patients, more often than would have been expected, and to examine successes to help determine in which patients it was working and why. This is why we felt that it was appropriate to use the PFS ratio in this pilot trial, rather than to undertake formal comparisons of overall average treatment effect. However, to our knowledge, this is the first time that the PFS ratio end point has been used in a molecular profiling study, so discussion on this point is certainly warranted. Thedesignofourpilottrialwaschallengingbecauseourpatientshad progressed while receiving multiple other therapies and because of the nature of trying to treat individual patients with different histologic types of cancer (with potentially different natural histories of disease). To additionally address the comments by Buyse et al, in addition to PFS, other parameters such as tumor size were observed. We were encouraged that, in addition to the primary end point of the PFS ratio of 1.3, there was also shrinkage of some patients’ tumors (Fig 4, waterfall plot from the original article). Obviously, designing clinical trials to test molecular profiling is an evolving challenge. It is notable that other groups are exploring different end points for these studies; for instance, the BiomarkerIntegrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial is investigating the disease control rate at 8 weeks for patients with non–small-cell lung cancer, and in the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-Spy 2), the end point is pathologic complete response. There is no doubt that molecular profiling of patients’ tumor tissue using a variety of techniques will be important from now on, given the recently reported successes of molecular targeted agents. Designs for clinical trials to evaluate the utility of increasingly sophisticated methods of molecular characterization of patients’ tumors (and the microenvironments of their tumors) is obviously an important and evolving area for clinical research and clinical trial design. The continued work of Buyse et al with respect to those clinical trial designs is much appreciated.