Early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial. DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR image) were analyzed. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex. In 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%; = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; < 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in / wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS: < 0.001; OS: = 0.012) and molecular subgroup (PFS: < 0.001; OS: < 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS: < 0.001, HR 0.532; OS: < 0.001, HR 0.574 vs. PFS: = 0.107; OS: = 0.965). Initial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.