Early tumor shrinkage and long-term outcome in metastatic colorectal cancer (mCRC): Assessment of predictive utility across treatment arms in the CRYSTAL and OPUS studies.

Abstract

3572 Background: The relationship between tumor radiological (RX) response and long-term outcome is unclear for current drugs. Early response is a proposed efficacy endpoint for drug screening and on-treatment evaluation and warrants investigation as a predictor of long-term outcomes. We previously showed early tumor shrinkage (ETS) in combination chemotherapy (CT) + cetuximab (cet) regimens identified KRAS wild-type (wt) mCRC patients (pts) with improved outcome. We used the CRYSTAL and OPUS studies to quantify the predictive power of tumor size changes at week (wk) 8 for long-term outcome investigating heterogeneity across treatment arms (CT or CT + cet). Methods: Tumor KRAS status and RX data at wk 8 were available for 820 pts from the CRYSTAL study and 297 from the OPUS study. Using investigators’ assessments, a relative change in the sum of the longest diameters of target lesions compared to baseline was calculated. Time-Dependent Receiver-Operating-Characteristics (TDROC) were used to obtain Cτ indices. Cox regression models and Subpopulation Treatment Effect Pattern Plots (STEPP) identified interaction between ETS and treatment arm. Outcome measures were progression-free survival (PFS) and overall survival (OS). Results: In both studies TDROC indicated a strong relationship between change in tumor size at wk 8 and PFS in KRAS wt mCRC pts receiving CT + cet. This was weaker in the CT arm. Data were similar for OS with lower Cτ indices. Treatment interaction was confirmed by significant interaction terms for PFS in the Cox regression models and for both PFS and OS with STEPP methodology. Conclusions: These findings demonstrate a strong relationship between ETS and long-term outcome in KRAS wt mCRC pts receiving CT + cet compared with CT alone. This suggests a possible use for ETS as a predictor of outcome in this setting. Further studies are needed to see how this may impact on clinical decision making. CRYSTAL OPUS Cτ Cox (p value) STEPP (p value) Cτ Cox (p value) STEPP (p value) PFS KRAS wt/CT 0.604 0.020 0.048 0.547 0.004 0.053 KRAS wt/CT + cet 0.688 0.703 OS KRAS wt/CT 0.553 0.100 0.001 0.566 0.114 0.036 KRAS wt/CT + cet 0.606 0.655