Phase III Study of Trifluridine/Tipiracil With and Without Bevacizumab in Refractory Metastatic Colorectal Cancer Patients

Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method.

Time frame: From date of randomization to the death due to any cause or cut-off date, whichever comes first (maximum duration: up to 20 months)

Population: Analysis was performed on FAS population.

Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method. In this outcome measure, data of survival probability at 12 months was reported.

Time frame: From date of randomization until 12 months post treatment

Population: Analysis was performed on FAS population.

Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method. In this outcome measure, data of survival probability at 18 months was reported.

Time frame: From date of randomization until 18 months post treatment

Population: Analysis was performed on FAS population.

Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method. In this outcome measure, data of survival probability at 6 months was reported.

Time frame: From date of randomization until 6 months post treatment

Population: Analysis was performed on FAS population.

The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist in 2 sections a descriptive system comprising 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and Visual Analog Scale (VAS). Each dimension has a 5-level response: no problems, slight problems, moderate problems, severe problems, and extreme problems. Response options are measured with a 5-point Likert scale. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state and lower score indicate worse health state.

Time frame: Baseline, Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13 and Cycle 14

Population: Analysis was performed on FAS population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist of 2 sections; descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and a VAS. The VAS records the respondent's self-rated health on a 20 centimeter (cm) vertical VAS; the scale went from 0 (worst imaginable health state) to 100 (best imaginable health state). This information can be used as a quantitative measure of health as judged by the individual respondents.

Time frame: Baseline, Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13 and Cycle 14

Population: Analysis was performed on FAS population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

EORTC QLQ-C30: 30 item questionnaires with 5 multi-item functional subscales (physical, role, cognitive, emotional, social functioning), 3 multi-item symptom scales (fatigue, nausea/vomiting, and pain), global health/quality of life (QOL) subscale and 6 single items assessing other cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation and financial impact of cancer). It employed twenty-eight 4-point Likert scales with responses from not at all to very much and GHS/QoL, scored on scale of 1 (very poor) to 7 (excellent). All scales are transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional & GHS/QoL = higher level of functioning, & higher score for symptoms scales = higher symptom burden. Time to definitive \>=10 points deterioration: time from date of randomization to first deterioration in QoL score \>=10 points compared to baseline with no later improvement or death due to any cause. Kaplan-Meier method was used.

Time frame: Date of randomization to first deterioration in QoL score >=10 points or death due to any cause, which ever occurred first (i.e., up to 20 months)

Population: Analysis was performed on FAS population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

EORTC QLQ-C30: 30 item questionnaires composed of 5 multi-item functional subscales (physical, role, cognitive, emotional, social functioning), 3 multi-item symptom scales (fatigue, nausea/vomiting, and pain), global health/QOL subscale and 6 single items assessing other cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation and financial impact of cancer). It employed twenty-eight 4-point Likert scales with responses from not at all to very much and GHS/QoL, scored on scale of 1 (very poor) to 7 (excellent). All scales are transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional & GHS/QoL = higher level of functioning, & higher score for symptoms scales = higher symptom burden. Time to definitive \>=10 points deterioration: time from date of randomization to the first deterioration in QoL score \>=10 points compared to baseline with no later improvement or death due to any cause. Kaplan-Meier method was used.

Time frame: Date of randomization to first deterioration in QoL score >=10 points or death due to any cause, which ever occurred first (i.e., up to 20 months)

Population: Analysis was performed on FAS population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Serious adverse events (SAEs) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (time from the first dose of study treatment up to 30 days after the last dose of study treatment). TEAEs included both SAEs and non-SAEs.

Time frame: From baseline (Cycle 1 Day 1) up to 30 days after the last dose of study drug (i.e., up to 30.7 months)

Population: Analysis was performed on safety set which included all participants who had taken at least one dose of investigational medicinal products and were analyzed according to the treatment they actually received.

Objective response was defined as percentage of participants who achieved complete response (CR) or partial response (PR) according to the RECIST version 1.1 and using investigator's tumour assessment. As per RECIST 1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.

Time frame: From the date of randomization to the date of documentation of progression or death due to any cause or data cut-off, whichever occurred first (i.e., up to 20 months)

Population: Analysis was performed on FAS population.

Disease control is defined as percentage of participants who achieved CR or PR, or stable disease (SD) as per RECIST 1.1 and using investigator's tumour assessment from the date of randomization to until disease progression or death due to any cause. As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions.

Time frame: From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (i.e., up to 20 months)

Population: Analysis was performed on FAS population.

PFS was defined as the time elapsed between the date of randomisation and the date of radiological tumour progression as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by investigator, or death (from any cause), whichever comes first. Progressive Disease (PD) as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method. In this outcome measure, data of PFS at 3 months was reported.

Time frame: From randomization until 3, 6, 9, and 12 months post treatment

Population: Analysis was performed on FAS population.

PFS was defined as the time elapsed between the date of randomisation and the date of radiological tumour progression as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by investigator, or death (from any cause), whichever comes first. Progressive Disease (PD) as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method.

Time frame: From randomization to the date of radiological tumour progression or death due to any cause or data cut-off date whichever comes first (i.e., up to 20 months)

Population: Analysis was performed on FAS population.