Abstract CT113: The time to progression ratio: a new individualized volumetric parameter for early detection of clinical benefit of targeted therapies
Authors: Weeber Fleur , Cirkel Geert A. , Gadellaa - van Hooijdonk Christa G.M. , Bins Sander , Hoogstraat Marlous , van Werkhoven Erik , Willems Stefan M. , van Stralen Marijn , Veldhuis Wouter B. , Besselink Nicolle J.M. , Steeghs Neeltje , de Jonge Maja J. , Langenberg Marlies H.G. , Cuppen Edwin , Schellens Jan H. , Sleijfer Stefan , Lolkema Martijn P.J.K. , Voest Emile E. 
Published: July 2016

Abstract
Introduction: Early signs of clinical activity are an important factor in the decision to advance development of novel targeted drugs. Response Evaluation Criteria In Solid Tumors (RECIST) has limited value however, as many patients with relatively slowly growing tumors will end up in the Stable Disease (SD) group, obscuring the distinction between a slow natural course of disease or treatment effect. Furthermore, when determining therapeutic efficacy across tumor types using progression free survival, there is also no correction for the individual tumor's natural growth rate. To address this, we developed the Time To Progression (TTP) ratio, a novel clinical trial efficacy endpoint that is based on volumetrics and an intra-patient control.
Methods: A prospective multicenter biomarker discovery study (CPCT-03, NCT01566279) was designed. Unselected cancer patients, without regular treatment options, were included and received treatment with the mTOR inhibitor everolimus. Treatment response was determined using both RECIST and the volumetric TTP ratio. The TTP ratio was defined as TTP1/TTP2, i.e. the quotient of the time to a prospectively determined ?30% volumetric increase in target lesions or occurrence of new lesions before treatment (TTP1) and on-treatment (TTP2). Response was classified as a TTP ratio of &lt;0.7. Volumetric measurements were performed by two observers, independent from each other, using EncoreUnFoie v5.0. TTP ratio was correlated with Overall Survival (OS).
Results: Seventy-three patients were included, of whom 59 patients started treatment with everolimus. A TTP ratio could be determined in 43 of these patients (73%). According to RECIST, 35 patients (59%) had SD and one patient demonstrated a partial response (PR), while only 21 patients (36%) met the pre-specified criteria for treatment success according to our volumetric TTP ratio. Whereas RECIST (SD+PR) and TTP ratio were both correlated with OS (p&lt;0.001, log-
rank test), TTP ratio also differentiated which patients had a longer median OS within the SD RECIST group (n = 28). TTP ratio responders had a median OS of 11 months (95% CI 4.4-17.6), compared to 5 months (95%CI 3.2-6.8) for non-responders (p = 0.0496, log-rank test). The inter-observer agreement (Krippendorff's alpha) for volumetric measurements was 0.78 (95%CI 0.70-0.87) for a total of 199 evaluated scans.
Conclusion: These results suggest that volumetric TTP ratio is a reliable method to determine response, with a high inter-observer agreement. The TTP ratio correlates to OS and distinguishes which patients within the RECIST SD group had longer survival, which could be interpreted as a sign of clinical benefit. The TTP ratio may be an important tool to guide early clinical drug development and deserves further investigation.
Citation Format: Fleur Weeber, Geert A. Cirkel, Christa G.M. Gadellaa - van Hooijdonk, Sander Bins, Marlous Hoogstraat, Erik van Werkhoven, Stefan M. Willems, Marijn van Stralen, Wouter B. Veldhuis, Nicolle J.M. Besselink, Neeltje Steeghs, Maja J. de Jonge, Marlies H.G. Langenberg, Edwin Cuppen, Jan H. Schellens, Stefan Sleijfer, Martijn P.J.K. Lolkema, Emile E. Voest. The time to progression ratio: a new individualized volumetric parameter for early detection of clinical benefit of targeted therapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT113.