# 666 Trial-level association between response-based endpoints and progression-free/overall survival in 1st-line therapy for metastatic colorectal cancer in the ARCAD database Elisabeth Coart1, Everardo D. Saad1,2, Qian Shi3, Dirkje W. Sommeijer4,5, John R. Zalcberg6, Tim Maughan7, Richard M. Goldberg8, Hans-Joachim Schmoll9, Cornelis J. A. Punt5, Eric Van Cutsem10, Jean-Yves Douillard11, Paulo M. Hoff12, Niall C. Tebbutt13, Charles S. Fuchs14, Alfredo Falcone15, Christophe Tournigand16, Aimery De Gramont17, Daniel J. Sargent3, Tomasz Burzykowski1, Marc Buyse1, for the ARCAD Group 1International Drug Development Institute, Louvain-la-Neuve, Belgium; 2Dendrix Research, São Paulo, Brazil; 3Mayo Clinic, Rochester, MN; 4NHMRC Clinical Trials Centre, Sydney; 5 Academic Medical Centre, Amsterdam, The Netherlands; 6School of Public Health, Monash University, Melbourne, Australia; 7CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom; 8Ohio State University Medical Center, Columbus, OH; 9University Clinic Halle (Saale), Department of Internal Medicine IV, Halle, Germany; 10Leuven Cancer Institute (LKI), Leuven, Belgium; 11Centre René Gauducheau, Nantes, France; 12Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil; 13Austin Health, Melbourne, Australia; 14Dana-Farber Cancer Institute, Boston, MA; 15Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy; 16Hôpital Henri Mondor, UPEC, Creteil, France; 17Hôpital Saint Antoine, Paris, France. METHODS ABSTRACT RESULTS Early tumor shrinkage (≥20% decrease from baseline) and early objective tumor response (CR/PR by RECIST) are associated with improved progressionfree (PFS)/overall survival (OS) to a similar extent than best overall response, confirmed response and early non-progression rate (CR/PR/SD by RECIST) at the individual level in 1st-line metastatic colorectal cancer (mCRC). We now assess these response-based endpoints (RBEs) at the trial level. Methods Data were available on 12,167 pts enrolled in a total of 17 randomized trials of chemotherapy alone or with targeted agents. ETS, EOTR and eNPR were assessed at 6/8/9 and 12 weeks (wks), whereas BOR and ConfR were ascertained within 26 wks from randomization. Correlations between treatment effects on RBEs and on PFS/OS were assessed by coefficients of determination (R2, adjusted for estimation errors) using a copula model. Results None of the RBEs had consistently strong correlations with PFS or OS (Table 2). The number of trials was insufficient to obtain reliable estimates for antiangiogenics and anti-EGFR agents separately. Trial and Patient Features (Table 1) • 12,167 patients from 17 trials were included, with median follow-up of 15.7 months. Definitions of response based endpoints: Table 2 Long-term Outcomes • Overall survival (OS): time from randomization to death from any cause • Progression-free survival (PFS): time from randomization to 1st progressive disease (PD) or death from any cause Statistical Methods • The relationship between RBE and PFS or OS was evaluated by a meta-analytic approach using R2 statistics from weighted least squares regression of trial-specific estimates of odds ratios and hazard ratios using Cox, logistic and Copula models. When possible, reported R2 values are adjusted for estimation errors.3,4 • The meta-analytic unit for surrogacy was the comparison between two arms (experimental vs control), nested within trials. Pts of control groups were randomly divided for trials with more than one comparison. • R2, the coefficient of determination, ranges from 0 to 1, with higher values indicating stronger correlation. Study N pts (N comparisons) CT only Anti-ANG Anti-EGFR GERCOR (C97-3) 177 (1) CAIRO1 BICC-C 03-TTD-01 GONO N9741 FOCUS1 FOCUS2 HORIZON II NO16966 MAX HORIZON III PRIME (C203) 534 (1) 176 (2) 242 (1) 83 (1) 890 (4) 854 (2) 261 (2) 1009 (2) 897 (2) 52 (1) All PFS OBJECTIVES To assess, at the trial level, the correlation between early response-based endpoints (RBEs) and longterm outcomes in patients with metastatic colorectal cancer (mCRC) treated in the 1st line This analysis is the second and final step in the surrogacy evaluation of early RBEs in this setting (in the first step, strong associations were shown at the individual-patient level1,2) Early objective tumor response 939 (3) 423 (2) 1474 (2) CRYSTAL COIN PACCE (C249) 965 (2) 935 (2) 748 (4) CAIRO2 2888 (8) 393 (2) 4156 (11) Abbreviation Definition EOTR CR or PR by RECIST at 6/8/9, and 12 weeks from randomization ≥20% decrease from baseline in sum of longest diameters at 6/8/9, and 12 weeks from randomization Early tumor shrinkage ETS Early non-progression rate eNPR Best objective response BOR Confirmed response ConfR eNPR at 12 wks BOR ConfR 0.16 0.06 (0.00-0.57) (0.00-0.34) 0.25 0.07 0.92 0.23 0.54 0.25 0.26 0.32 (0.00-0.95) (0.00-0.49) (0.00-1.00) (0.00-0.80) (0.00-1.00) (0.00-0.57)* (0.00-0.97) (0.00-1.00) PFS 0.42 0.17 0.56 0.05 (0.00-1.00) (0.00-0.74) (0.10-1.00)* (0.00-0.44) OS 0.20 0.08 0.59 0.18 0.26 0.65 0.07 0.05 (0.00-0.97) (0.00-0.58) (0.16-1.00)* (0.00-0.88) (0.00-0.78)* (0.32-0.97)* (0.00-0.56) (0.00-0.54) CR, PR, or SD by RECIST at 6/8/9, and 12 weeks from randomization CR or PR by RECIST within initial 26 weeks of treatment CR or PR by RECIST, confirmed at least 4 weeks later, during initial 26 weeks of treatment 0.34 0.03 (0.00-1.00) (0.00-0.36) Chemotherapy + targeted agents PFS 0.13 0.08 0.13 0.01 (0.00-0.67) (0.00-0.72) (0.00-0.71) (0.00-0.13)* OS 0.19 0.24 0.00 0.00 0.17 0.73 0.26 0.18 (0.00-1.00) (0.00-1.00) (0.00-0.06)* (0.00-0.02)* (0.00-1.00) (0.00-1.00) (0.00-0.66)* (0.00-0.60)* Table 2. Definition of RBEs Endpoint EOTR at EOTR at eNPR at Overall Survival 6/8/9 wks 12 wks 6/8/9 wks 0.25 0.01 0.31 0.01 (0.00-0.72) (0.00-0.16) (0.00-0.93) (0.00-0.14) *Unadjusted R2 Despite their individual-level associations with PFS and OS, RBEs do not appear to be surrogate endpoints in 1st-line mCRC, given their poor predictive ability. • 6/8/9 wks ETS at 12 wks Chemotherapy alone 1115 (1) Totals 5123 (18) Treatment ETS at OS Conclusions • Table 3. Adjusted R2 (95% CI) Table 1. Trials Included Background MAIN FINDINGS Figure 1. Trial-specific correlations between odds ratios for ETS and hazard ratios for PFS/OS 0.13 0.17 (0.00-0.66) (0.00-0.74) • None of the RBEs had consistently strong correlations with PFS or OS (Table 3 and Figure 1). This was observed in the overall analyses and in the chemotherapy alone and chemotherapy + targeted agents treatment classes. • The RBEs present different levels of association with PFS/OS, ranging from 0.01 to 0.92. The observed width of the CIs for the R2 estimates either indicate a high level of uncertainty in the data or are informative and point to a rather weak association. • The number of treatment comparisons was insufficient to obtain reliable separate estimates for antiangiogenics (N=8) and anti-EGFR (N=11). DISCUSSION • Despite their individual-level associations with PFS and OS, RBEs do not appear to be surrogate endpoints in 1st-line mCRC, given their poor predictive ability. • This holds true for both the early RBEs (ETS, EOTR and eNPR at 6/8/9 and 12 weeks) and the conventional response endpoints BOR and ConfR. • Work is ongoing to assess the role of depth of response and other continuous endpoints as potential surrogates for PFS and OS in 1st-line mCRC. REFERENCES 1. Sommeijer DW, Shi Q, Saad ED, et al. Early predictors of prolonged overall survival (OS) in patients (pts) on first-line chemotherapy (CT) for metastatic colorectal cancer (mCRC): An ARCAD study with individual patient data (IPD) on 10,962 pts. J Clin Oncol 32:5s, 2014 (suppl; abstr 3538). 2. Saad ED, Coart E, Sommeijer DW, et al. Early predictors of improved long-term outcomes in first-line antiangiogenics plus chemotherapy (anti-ANG/CT) in metastatic colorectal cancer (mCRC): Analysis of individual patient (pt) data from the ARCAD database. J Clin Oncol 32:5s, 2014 (suppl; abstr 3578). 3. Burzykowski T. An ordinal surrogate for a survival true endpoint. In: Burzykowski T, Molenberghs G, Buyse M, eds: Evaluation of Surrogate Endpoints.New York: Springer, 2005. 4. Burzykowski T, Molenberghs G, Buyse M, et al. The validation of surrogate endpoints using data from randomized clinical trials: a case study in advanced colorectal cancer. Journal of the Royal Statistical Society, Series A 167,103 -124, 2004.
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