Background: The C-cubed (C3) study demonstrated a sequential approach start from fluoropyrimidines (FP) plus bevacizumab (Bmab) followed by oxaliplatin (OX) adding significantly improved a median Treatment failure of strategy (TFS) for a combination approach start from FP+OX+Bmab [15.2 months vs. 7.6 months, HR, 0.475; 95% CI, 0.362 to 0.623; p < 0.0001] in first-line metastatic colorectal cancer (mCRC). In this congress, we focus on the quality of life (QOL) assessments as a pre-planned analysis. (Study information: UMIN000015405). Methods: The C3 study was a randomized phase III study which evaluated the time to discontinuation of OX-containing therapy (sequential approach [Capecitabine/5-FU (FP)+Bmab followed by OX-FP+Bmab] vs. combination approach [OX-FP+Bmab]. The primary endpoint was TFS and secondary endpoints were ORR, OS, PFS, Safety and QoL. QOL assessments included European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) (EORTC QLQ C-30), EuroQol 5D 5L (EQ5D) and the Patient Neurotoxicity Questionnaire (PNQ) in both arm as a pre-planned analysis. Each questionnaire was collected at the time of enrolment, 6, 12, 18 months and end of treatment. QOL scores were compared using a mixed-effects models for repeated measures (MMRM). Results: A total 292 patients participated in QoL part (arm A: n =148; arm B: n =144). The returned questionnaire sheets were 292 (reply rate: 97%), 206 (68%), 199 (65%), 61 (20%) at baseline, 6, 12, 18 months, respectively. Sequential approach was statistically improved than combination approach as follows: Physical functioning (p<0.001), Cognitive functioning (p=0.012), Social functioning (p=0.0004), and Fatigue (p=0.013) in EORTC QLQ C-30. In addition, at 6 months (after which attrition in the combination arm was more than 50%) after randomization, the mean change rate from baseline of EQ5D score in the sequential approach versus combination approach were: –1.91 (SD 27.57) versus –9.62 (29.60). In contract, PNQ sensory score showed that sequential approach was not statistically improved for combination approach (0.22 [SD: 0.89] vs. 0.61 [SD: 0.95], p=0.115). Conclusions: The further clarification of patients’ characteristics are needed, but this sequential approach can be advocated as a valuable treatment option in first-line mCRC for current guideline based on these QoLs and main efficacy data.