Dean Bottino (1), Arijit Chakravarty (2), Eric Westin (3)
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceuticals Company Limited (1) Clinical Pharmacology, (2) Drug Metabolism & Pharmacokinetics, (3) Oncology Clinical Research
Objectives: To investigate and compare the operating characteristics of kinetic-based methods for quantifying antitumor effects of investigational anticancer agents, in particular the Change From Baseline (CFB) method and the Pre-treatment Tumor Kinetics (PTK) method which requires an additional pre-baseline tumor burden assessment [1-2].
Methods: Simulated data was generated from a (N=10^5) virtual patient population having log-normally distributed (exponential) tumor growth rates (TGRs), with median (mTGR) and %CV (cvTGR) of TGR tested over ranges encompassing clinically observed values [1,3,4]. Normalized kill rates K = (growth-kill)/growth were uniformly distributed from -1 to 1, resulting in simulated RECIST response frequencies similar to those observed in early phase oncology trials. Exponential tumor burden measurement error (8.5%) as fitted from a recent scan-to-scan variability study [5] was also simulated. For each virtual patient, the CFB estimate of K_CFB was calculated via log linear regression to assessments at -1 (baseline), 8 and 16 weeks after start of treatment. The PTK estimate K_PTK for each patient was calculated via piecewise log linear regression to assessments at -4 (pre-study), -1 (baseline), 8 and 16 weeks after start of treatment. Accuracy of each method for a given (mTGR, cvTGR) parameter set was defined as the fraction of K estimates falling within an arbitrary tolerance (+/- 0.1) of the true K values.
Results: While the PTK method was not universally more accurate than the CFB method over all (mTGR, cvTGR) parameter values tested, it was consistently more accurate than CFB over the clinically observed ranges. Specifically, PTK advantage over CFB was most pronounced in populations with fast growing tumors and highly heterogeneous TGRs, while CFB was actually more accurate than PTK in populations with very slow growing tumors and relatively homogenous TGRs. Increasing the time span between the pre-study assessment and the start of treatment from 4 weeks to 16 weeks further increased the advantage of PTK over CFB.
Conclusions: While the PTK method outperforms the CFB method in all clinically feasible scenarios tested thus far, the absolute accuracy advantage of PTK over CFB varies from negligible to significant with increasing mTGR, cvTGR, and time between pre-study baseline scans. This anticipated accuracy advantage should be weighed against the minimal additional cost of reading the pre-study scan required for the PTK method.
References:
[1] Charles Ferte et al, “Tumor Growth Rate Is an Early Indicator of Antitumor Drug Activity in Phase I Clinical Trials,” Clin Cancer Res January 1, 2014 20; 246.
[2] Sylvie Retout et al, “A model-based approach to optimize detection of treatment effects in early oncology trials,” J Clin Oncol 31, 2013 (suppl; abstr e13508).
[3] Louis Heuser et al, “Growth Rates of Primary Breast Cancers,” Cancer 43:1888- 1894, 1979.
[4] Katsuo Usuda et al, “Tumor Doubling Time and Prognostic Assessment of Patients with Primary Lung Cancer,” CANCER October 15,2994, Volume 74, No. 8.
[5] Geoffrey Oxnard et al, “Variability of Lung Tumor Measurements on Repeat Computed Tomography Scans Taken Within 15 Minutes,” J. Clinical Oncology, Volume 29, No. 23, August 10 2011. References:
Reference: PAGE 23 () Abstr 3204 [www.page-meeting.org/?abstract=3204]
Poster: Drug/Disease modeling - Oncology