L. Claret (1), M. Gupta (2), A. Joshi (2), N. Sarapa (3), J. He (4), B. Powell (4), R. Bruno (1)
(1) Pharsight Consulting Services, Pharsight, a CertaraTM Company, Marseille, France (2) Genentech Research and Early Development (gRED), Roche, South San Francisco, CA, (3) Pharmaceutical Research and Early Development (pRED), Roche, Nutley, NJ and (4) Beijing, China
Objectives: Change in tumor size from baseline at the end-of-cycle 2 has been proposed as a predictor of overall survival (OS) in metastatic colorectal cancer (CRC) (1, 2) and other tumor types (1, 3, 4). The goal of this project was to assess new metrics of tumor size response to predict clinical endpoints, i.e. OS and progression free survival (PFS), and to test for any ethnic differences in the link between tumor size response and clinical endpoints in CRC.
Methods: Various metrics of tumor size response were estimated using longitudinal tumor size models developed from two Phase III studies comparing bevacizumab plus chemotherapy vs. chemotherapy in Western (923 patients) (5) and Chinese patients (203) (6) as first-line therapy in patients with CRC. Effect of baseline prognostic factors and estimates of tumor size metrics were assessed in multivariate models to predict OS and PFS. Predictive performance of the models were assessed by simulating OS, PFS and hazard ratios (HR) of bevacizumab vs. chemotherapy in multiple replicates (n=1000) of the two Phase III studies.
Results: Time to tumor growth (TTG) was the best metric to predict OS and PFS in 991 evaluable patients. In the OS model, TTG fully captured bevacizumab effect, ECOG performance status (PS) and the number of metastatic sites were significant baseline prognostic factors. In the PFS model, TTG did not fully capture bevacizumab treatment effect and ECOG PS was a significant baseline prognostic factor. In both models, when other covariates like ECOG PS and TTG were accounted for, there was no impact of Chinese ethnicity on any of the endpoints, or on the TTG-OS or PFS relationships (no interactions). The models correctly predicted OS and PFS distributions in each study arm and each patient population as well as bevacizumab HRs (e.g. model prediction [95% prediction interval]: 0.78 [0.52 – 1.13] vs. 0.63 observed for OS in Chinese patients and 0.56 [0.39 – 0.76] vs. 0.43 observed for PFS in Chinese patients).
Conclusions: TTG is a better tumor size metric to capture drug effect and predict OS and PFS in first-line CRC patients than previously proposed ones. There is no impact of Chinese ethnicity on TTG survival or PFS relationships. Longitudinal tumor size data coupled with model-based approaches may offer a powerful alternative in the design and analysis of early clinical studies in both Western and Chinese patients (7).
References:
[1] Claret L, Girard P, O’Shaughnessy J et al. Model-based predictions of expected anti-tumor response and survival in Phase III studies based on phase II data of an investigational agent. J. Clin. Oncol. 24, 307s (suppl, abstract 2530), 2006.
[2] Claret L, Girard P, Hoff PM et al. Model-based prediction of Phase III overall survival in colorectal cancer based on Phase II tumor dynamics. J. Clin. Oncol. 27, 4103-4108, 2009.
[3] Wang Y, Sung YC, Dartois C et al. Tumor size-survival relationship in non-small cell lung cancer patients to aid early clinical development decision making. Clin. Pharmacol. Ther. 86, 167-174, 2009.
[4] Bruno R, Jonsson F, Zaki M et al. Simulation of clinical outcome for pomalidomide plus low-dose dexamethasone in patients with refractory multiple myeloma based on week 8 M-protein response. Blood, 118, 1881 (abstract), 2011.
[5] Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335-2342, 2004.
[6] Guan ZZ, Xu JM, Luo RC et al. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: A randomized ARTIST phase III trial. Chinese J. Cancer 30, 682-689, 2011.
[7] Bruno R., Claret L. On the use of change in tumor size to predict survival in clinical oncology studies: Toward a new paradigm to design and evaluate Phase II studies. Clin. Pharmacol. Ther. 86, 136-138, 2009.
Reference: PAGE 21 (2012) Abstr 2328 [www.page-meeting.org/?abstract=2328]
Poster: Oncology