Background: Early tumor shrinkage (ETS, ≥20% decrease from baseline) is associated with improved progression-free survival (PFS) and overall survival (OS) in mCRC pts treated with epidermal growth factor receptor inhibitors. We compared the relative merits of ETS and early objective tumor response (EOTR; CR/PR by RECIST) vs. standard Best Overall Response (BOR) and Confirmed Response (ConfR) in mCRC pts treated with 1^st-line anti-ANG/CT. Methods: Data were available from 4,776 pts enrolled on 8 randomized trials of bevacizumab (N=6), cediranib (N=1), or both (N=1). ETS, EOTR, BOR and ConfR were assessed at 6, 8/9 and 12 weeks (wks). Associations were assessed by stratified Cox models with a landmark approach. The relative prediction accuracy of distinguishing pts at high vs. low risk of progression/death was compared by C-index (c, higher values indicate better accuracy). Results: All response endpoints were significantly associated with PFS and OS (P≤0.001 for all hazard ratios [HRs]) (see Table). Adjusting for age, performance status, # of metastases and prior therapy, significance remained. ETS showed larger effect size than EOTR. For PFS, the prediction accuracy was similar across time points or endpoints. For OS, compared with earlier time points, ETS and EOTR at 12 wks produced larger risk reduction, with similar prediction accuracy as BOR. Conclusions: Early response-based endpoints are significantly associated with improved PFS and OS in mCRC pts treated with anti-ANG/CT. The prediction performance of early response based on tumor measurement is as good as for standard RECIST response. Assessment of these endpoints as surrogates for PFS/OS at the trial level is ongoing.

Abbreviations: CI, confidence interval.