A Study of Efficacy and Safety of Fruquintinib (HMPL-013)... | NCT04322539

Label	Type	Description	Intervention Names
Fruquintinib Plus Best Supportive Care (BSC) Group	Experimental	Participants will be orally administered Fruquintinib 5 mg in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break (with each cycle length of 28 days).	Drug: Fruquintinib
Placebo Plus BSC Group	Placebo Comparator	Participants will be orally administered Placebo 5 mg in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break (with each cycle length of 28 days).	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Fruquintinib	Drug	Oral VEGFR inhibitor	Fruquintinib Plus Best Supportive Care (BSC) Group

Measure	Description	Time Frame
Overall Survival (OS)	OS was defined as the time (months) from date of randomization to death from any cause. OS was calculated as (date of death or last known alive - date of randomization + 1)/30.4375. Participants without report of death at the time of analysis will be censored at the date last known alive.	From date of randomization to death from any cause (up to 22 months)

Measure	Description	Time Frame
Progression Free Survival (PFS), as Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1	PFS was defined as the time (months) from randomization until the first radiographic documentation of objective progression as assessed by investigator using RECIST v1.1, or death from any cause, whichever comes first. More specifically, PFS was determined using all data until the last evaluable visit prior to or on the date of: (i) radiographic disease progression (PD) per RECIST v1.1; (ii) withdrawal of consent to obtain additional scans on study; or (iii) initiation of subsequent anticancer therapy other than the study drugs, whichever was earlier. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Provide written informed consent;
Age ≥18 years;
Histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS, BRAF, and microsatellite instability microsatellite instability (MSI)/mismatch repair (MMR) status for each patient must be documented, according to country level guidelines;
Participants must have progressed on or been intolerant to treatment with either trifluridine/tipiracil (TAS-102) or regorafenib. Participants are considered intolerant to TAS-102 or regorafenib if they have received at least 1 dose of either agents and were discontinued from therapy for reasons other than disease progression. Participants who have been treated with both TAS-102 and regorafenib are permitted. Participants must also have been previously treated with standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFR therapy;
Participants with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors must have been treated with immune checkpoint inhibitors if approved and available in the participant's country unless the patient is ineligible for treatment with a checkpoint inhibitor;
Participants who received oxaliplatin in the adjuvant setting and developed metastatic disease during or within 6 months of completing adjuvant therapy are considered eligible without receiving oxaliplatin in the metastatic setting. Participants who developed metastatic disease more than 6 months after completion of oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based therapy in the metastatic setting to be eligible;
Body weight ≥40kg;
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
Have measurable disease according to RECIST Version 1.1, assessed locally. Tumors that were treated with radiotherapy are not measurable per RECIST Version 1.1, unless there has been documented progression of those lesions;
Expected survival >12 weeks.
For female participants of childbearing potential and male participants with partners of childbearing potential, agreement to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include: oral hormonal contraception (combined estrogen/ progestogen, or progestogen-only) associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or true sexual abstinence in line with the preferred and usual lifestyle of the participant. Highly effective contraception should always be combined with an additional barrier method (eg, diaphragm, with spermicide). The same criteria are applicable to male participants involved in this clinical trial if they have a partner of childbirth potential, and male participants must always use a condom.
Participants with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available in the participant's home country unless the patient is ineligible for treatment with a BRAF inhibitor.

Exclusion Criteria:

Absolute neutrophil count (ANC) <1.5×109/L, platelet count <100×109/L, or hemoglobin <9.0 g/dL. Blood transfusion within 1 week prior to enrollment for the purpose of increasing the likelihood of eligibility is not allowed;
Serum total bilirubin >1.5 × the upper limit of normal (ULN). Participants with Gilbert syndrome, bilirubin <2 X ULN, and normal AST/ALT are eligible;
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN in participants without hepatic metastases; ALT or AST >5 × ULN in participants with hepatic metastases;
Serum creatinine >1.5 × ULN or creatinine clearance <60 mL/min. Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockroft-Gault equation.
Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Participants with greater than 2+ proteinuria by dipstick must undergo a 24-hour urine collection to assess urine protein level;
Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg despite optimal medical management. Participants were required to have blood pressure values below both limits. Repeated assessments were permitted;
International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the patient is currently receiving or intended to receive anticoagulants for prophylactic purposes;
History of, or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas; or any other condition that could, in the investigator's judgment, result in gastrointestinal hemorrhage or perforation; within the 6 months prior to screening;
History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening;
History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial embolism within 6 months prior to screening.
Stroke and/or transient ischemic attack within 12 months prior to screening;
Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction (LVEF) <50% by echocardiogram;
Mean corrected QT interval using the Fridericia method (QTcF) >480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in a first-degree relative.
Concomitant medications with a known risk of causing QT prolongation and/or Torsades de Pointes.
Systemic anti-neoplastic therapies (except for those described in Exclusion 18) or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy;
Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;
Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug;
Brachytherapy (i.e., implantation of radioactive seeds) within 60 days prior to the first dose of study drug.
Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug;
Surgery or invasive procedure (i.e., a procedure that includes a biopsy; central venous catheter placement is allowed) within 60 days prior to the first dose of study drug or unhealed surgical incision;
Any unresolved toxicities from a previous antitumor treatment greater than CTCAE v5.0 Grade 1 (except for alopecia or neurotoxicity grade≤2);
Known human immunodeficiency virus (HIV) infection;
Known history of active viral hepatitis. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Participants with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
Clinically uncontrolled active infection requiring IV antibiotics;
Tumor invasion of a large vascular structure, eg, pulmonary artery, superior or inferior vena cava;
Women who are pregnant or lactating;
Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; participants requiring steroids within 4 weeks prior to start of study treatment are excluded;
Other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder ca (Tis and T1) that have been adequately treated during the 5 years prior to screening;
Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery (eg, gastric bypass) or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product;
Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition (e.g., current alcohol or drug abuse) that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the patient at undue risk of harm based on the investigator's assessment;
Known hypersensitivity to fruquintinib (or placebo) or any of its inactive ingredients including the azo dyes Tartrazine - FD&C Yellow 5 and Sunset yellow FCF - FD&C Yellow 6;
Participants who have received prior fruquintinib;
Live vaccine <28days before the first dose of study drug(s). Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.

Name	Affiliation	Role
William Schelman, MD, PhD	HUTCHMED International Corporation	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Mayo Clinic Arizona		Phoenix	Arizona	85054	United States
Arizona Oncology Associates, PC-HOPE

PubMed Identifier	Type	Citation	Retractions
40888992	Derived	Kotani D, Yoshino T, Masuishi T, Sunakawa Y, Takashima A, Yamazaki K, Kawakami H, Nishina T, Komatsu Y, Esaki T, Eng C, Ukrainskyj S, Pallai R, Nanda S, Yang Z, Schelman W, Kania M, Satoh T. Efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer: a FRESCO-2 subgroup analysis of patients enrolled in Japan. Int J Clin Oncol. 2025 Oct;30(10):2043-2052. doi: 10.1007/s10147-025-02852-9. Epub 2025 Sep 1.
40485075

ID	Title	Description
FG000	Fruquintinib + Best Supportive Care (BSC) Group	Participants received 5 milligrams (mg) of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
FG001	Placebo + BSC Group

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Jul 21, 2022

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Overall Survival (OS)

OS was defined as the time (months) from date of randomization to death from any cause. OS was calculated as (date of death or last known alive - date of randomization + 1)/30.4375. Participants without report of death at the time of analysis will be censored at the date last known alive.

ITT population included all randomized participants.

Posted

Median

95% Confidence Interval

months

From date of randomization to death from any cause (up to 22 months)

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
OG001	Placebo + BSC Group	Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Units	Counts
Participants	OG000461 OG001230

Title

Denominators

Categories

Title	Measurements
	OG0007.4(6.7 to 8.2) OG0014.8(4.0 to 5.8)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		stratified log-rank test		< .001	Raw unadjusted p-value was obtained by using a stratified log-rank test accounting for the randomization schedule stratification factors.	Stratified Hazard Ratio	0.662			2-Sided	95	0.549	0.800			The HR between 2 treatment groups (fruquintinib vs placebo), together with its 95 percent (%) confidence interval (CI), was calculated from a stratified Cox proportional hazards model accounting for the randomization schedule stratification factors.		Superiority

Secondary

Progression Free Survival (PFS), as Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1

PFS was defined as the time (months) from randomization until the first radiographic documentation of objective progression as assessed by investigator using RECIST v1.1, or death from any cause, whichever comes first. More specifically, PFS was determined using all data until the last evaluable visit prior to or on the date of: (i) radiographic disease progression (PD) per RECIST v1.1; (ii) withdrawal of consent to obtain additional scans on study; or (iii) initiation of subsequent anticancer therapy other than the study drugs, whichever was earlier. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

ITT population included all randomized participants.

Posted

Median

95% Confidence Interval

months

From randomization until the first documentation of objective progression or death, whichever comes first (up to 22 months)

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
OG001	Placebo + BSC Group

Secondary

Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

ORR was defined as the percentage of participants who achieved a best overall response of confirmed complete response (CR) or partial response (PR), per RECIST v1.1, as determined by the investigator. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 millimeters (mm).

ITT population included all randomized participants.

Posted

Number

95% Confidence Interval

percentage of participants

From randomization until the first documentation of best overall response (up to 22 months)

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
OG001	Placebo + BSC Group	Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Secondary

Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

DCR was defined as percentage of participants achieving a best overall response of confirmed CR, PR, or stable disease (SD) (for at least 7 weeks) per RECIST v1.1, as determined by the investigator. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum on study. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline.

ITT population included all randomized participants.

Posted

Number

95% Confidence Interval

percentage of participants

From randomization until the first documentation of best overall response (up to 22 months)

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
OG001	Placebo + BSC Group	Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Secondary

Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

DOR was defined as the time (in months) from the first occurrence of PR or CR by RECIST Version 1.1, until the first date that progressive disease is documented by RECIST Version 1.1, or death, whichever comes first. Only those participants with confirmed responses of CR or PR were included in this analysis. DOR was calculated as (date of death or PD or last assessment - date of first occurrence of confirmed CR or PR + 1)/30.4375.

Analysis was performed on subset of participants who had a response. Here, '0' in 'overall number of participants analyzed represents that DOR could only be analyzed in participants who achieved a response. As no participant in the Placebo Plus BSC Group cohort achieved any response, no DOR is available.

Posted

Median

95% Confidence Interval

months

From first occurrence of PR or CR until the first documentation progression or death, whichever comes first (up to 22 months

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
OG001	Placebo + BSC Group	Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Secondary

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE was considered a TEAE if the onset date was on or after the start of study treatment or if the onset date was missing, or if the AE had an onset date before the start of study treatment but worsened in severity after the study treatment until 30 days after the last dose of study treatment or a new treatment of anti-tumor therapy, whichever was earlier. After this period, treatment-related SAEs were also considered as TEAEs. AEs with an unknown/not reported onset date were also included.

SP included all randomized participants who received at least 1 dose of study drug.

Posted

Count of Participants

Participants

From start of study drug administration up to approximately 40 months

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
OG001	Placebo + BSC Group	Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Secondary

Observed Plasma Concentrations of Fruquintinib and Metabolite M11

Plasma samples were collected from the participants at the defined time points. Plasma concentrations were measured using a validated, specific, and sensitive liquid chromatography tandem mass spectrometry method. M11 is the active metabolite for the study drug.

PK population was used for tabulation of fruquintinib and M11 concentrations from PK plasma samples collected from the Fruquintinib + BSC Group. PK samples for the Placebo + BSC Group were not analyzed. Here, "Overall Number of Participants Analyzed" signifies those participants in the Fruquintinib + BSC Group who were evaluable for this outcome measure and "number analyzed" signifies those participants who were evaluable at the specified timepoints.

Posted

Mean

Standard Deviation

nanogram/milliliter (ng/mL)

Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 (Day 21): Predose and 2 hours, Cycle 3 (Day 1): Pre-dose, Cycle 3 (Day 21): Pre-dose and 2 hours, Cycle 5, 7, 9, 11, 13, 15 and 17 (Day 1): Pre-dose (Each cycle = 28 days)

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Units	Counts
Participants

Secondary

Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula

QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 milliseconds (msec). QTc: QT interval corrected based on the patient's heart rate. QTcF: An electrocardiographic finding in which the QT interval corrected for heart rate using Fridericia's formula. QTc = QT/∛(RR) RR = Respiration rate.

SP included all randomized participants who received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "number analyzed" signifies those participants who were evaluable at the specified time points.

Posted

Mean

Standard Deviation

millisecond (msec)

Baseline, Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 and 3 (Day 21): Pre-dose (Each cycle = 28 days)

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
OG001	Placebo + BSC Group	Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Secondary

Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula

QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 msec. QTc: QT interval corrected based on the patient's heart rate. QTcB: An electrocardiographic finding in which the QT interval corrected for heart rate using Bazzett's formula.

SP included all randomized participants who received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number analyzed" signifies those participants who were evaluable at the specified timepoints.

Posted

Mean

Standard Deviation

msec

Baseline, Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 and 3 (Day 21): Pre-dose (Each cycle = 28 days)

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
OG001	Placebo + BSC Group	Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Secondary

Correlation Between Fruquintinib Exposure (CminSS) and Efficacy Parameters (OS)

Model-predicted steady-state minimum plasma concentrations (CminSS) of fruquintinib based on the starting dose or adjusted for relative dose intensity [RDI] were used as the exposure measures in the efficacy exposure-response analyses. The correlation between OS and exposure was estimated using multivariable Cox proportional hazards modeling. OS was analyzed as time-to-event variable using a survival model. The efficacy exposure-response analyses included participants with mCRC and pooled the data from the fruquintinib group of current Study 2019-013-GLOB1 (N=328) and from Cohort B of Study 2015-013-00US1 (NCT03251378) (N=40) as per planned analysis. Here, the "unit of measure" i.e., '1/(nanogram per milliliter [ng/mL])', corresponds to the coefficient that describes the relationship between the probability of survival and CminSS value.

The efficacy exposure-response analyses included participants who were evaluable for the population PK analysis and therefore had PK parameter estimates to enable estimation of fruquintinib exposure and evaluated for the parameter/endpoint in question. Here, "overall number of participants analyzed" signified those participants who were evaluable for this outcome measure. The population for this measure included participants from both studies 2015-013-00US1 and the current study.

Posted

Number

1/(ng/mL)

Up to 22 months

ID	Title	Description
OG000	Fruquintinib: Pooled Studies for Exposure and Efficacy Analysis	Participants in the current 2019-013-GLOB1 (NCT04322539) study received 5 mg of fruquintinib oral capsules with BSC once daily for 3 weeks of continuous dosing, followed by a 1-week break during each 28-day treatment cycle. Participants in Cohort B of Study 2015-013-00US1 (NCT03251378) with metastatic colorectal carcinoma (mCRC) and treatment with chemotherapy and trifluridine, tipiracil, and/or regorafenib received fruquintinib 5 mg capsules, once daily, for 3 weeks on and 1 week off in each 28-day treatment cycle until disease progression, unacceptable toxicity, use of other antitumor treatment, withdrawal of consent, or discontinuation by the Investigator, whichever occurred first.

Secondary

Correlation Between Fruquintinib Exposure (CmaxSS) and Safety Parameters (Any Grade [Gr] and Grade 3+ (Gr3+): Dermatological Toxicity, Proteinuria and Gr Hemorrhage)

Model-predicted steady-state maximum plasma concentration (CmaxSS) of fruquintinib based on the assigned dose of fruquintinib were investigated as fruquintinib exposure measure for the safety exposure-response analyses. The correlation between exposure and the probability of experiencing these AEs was evaluated using logistic regression analysis, with the slope serving as the estimate. The safety exposure-response analysis included participants with cancer, and the data of this outcome measure were pooled with data from the following studies as per the planned analysis: 2019-013-GLOB1 (NCT04322539) (N=334), 2009-013-00CH1 (NCT01645215) (N=40), 2012-013-00CH3 (NCT01975077) (N=40), and 2015-013-00US1 (NCT03251378) (N=101). Here, the "unit of measure" i.e., '1/(ng/mL)', corresponds to the coefficient that describes the relationship between the probability of occurrence of the safety parameter and CmaxSS value.

Safety exposure-response analyses included participants who were evaluable for population PK analysis and therefore had PK parameter estimates to enable estimation of fruquintinib exposure and evaluated for parameter/endpoint in question. Here, "overall number of participants analyzed" signified those participants who were evaluable for this outcome measure. The population for this measure included participants from 2019-013-GLOB1, 2009-013-00CH1, 2012-013-00CH3, and 2015-013-00US1.

Posted

Number

1/(ng/mL)

Up to 22 months

ID	Title	Description
OG000	Fruquintinib: Pooled Studies for Exposure and Safety Analysis	Participants in the current 2019-013-GLOB1 (NCT04322539) study received 5 mg of fruquintinib oral capsules once daily for 3 weeks of continuous dosing, followed by a 1-week break during each 28-day treatment cycle. Participants in the 2009-013-00CH1 (NCT01645215) study received 1 mg to 6 mg of fruquintinib oral capsule once daily and 5 mg to 6 mg of fruquintinib oral capsule for 3 weeks on and 1 week off during each 28-day treatment cycle. Participants in the 2012-013-00CH3 (NCT01975077) study received 4 mg of fruquintinib capsule once daily in 28-day cycles. Participants in the Study 2015-013-00US1 (NCT03251378) with advanced solid tumors of any type or with mCRC received fruquintinib 3 mg or 5 mg once daily for 3 weeks on and 1 week off in each 28-day treatment cycle until disease progression, unacceptable toxicity, use of other antitumor treatment, withdrawal of consent, or discontinuation by the Investigator, whichever occurred first.

Secondary

Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life Scale Score

EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and global health status/QOL scale. EORTC QLQ-C30 contains 28 questions (4-point scale where 1=Not at all [best] to 4=Very Much [worst]) and 2 questions (7-point scale where 1=Very poor [worst] to 7= Excellent [best]). Raw scores are standardized and converted into scale scores ranging from 0 to 100. For global health status/QOL scale, higher scores represent better QOL. A negative change from baseline value indicates patient condition worsened. Change from baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life Scale scores was performed by visit (i.e., cycle), using a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach.

ITT population included all randomized participants. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number analyzed" signifies those participants who were evaluable at the specified timepoints.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Cycle 2, 3 and 4 (Each cycle=28 days)

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Secondary

Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scale (VAS) Score

The EQ-5D-5L is a self-reported health status questionnaire that consisted of six questions used to calculate a health utility score. There were two components to the EQ-5D-5L: a five-item health state profile that assessed mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score and a general VAS score for health status. EQ-5D VAS was used to record participant's rating for his/her current health-related quality of life state on a vertical VAS with scores ranging from 0 to 100, where 0 = worst imaginable health state and 100 = best imaginable health state. The higher the score the better the health status. A negative change from baseline value represents patient condition worsened. Change from baseline in the EQ-5D-5L VAS scores was performed by visit (i.e. cycle), using a REML-based MMRM approach.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Cycle 2, 3 and 4 (Each cycle=28 days)

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Secondary

Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Health Utility Index Scores

EQ-5D-5L consisted of 2 components: health state profile and optional VAS. EQ-5D health state profile had 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 levels: 1= no problem, 2= slight problem, 3= moderate problem, 4= severe problem, and 5= extreme problem. The response levels collected from the EQ-5D-5L five dimensions as a health profile are converted into an EQ-5D-5L index (utility) scores to represent participants' utility value. The range of health utility index score is from -0.285 to 1, where higher value indicates perfect health and a negative value represents a state worse than dead. Change from baseline in EQ-5D-5L health utility index scores was performed by visit (i.e., cycle), using a REML-based MMRM approach.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline, Cycle 2, 3 and 4 (Each cycle=28 days)

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
OG001	Placebo + BSC Group

Secondary

Health Care Resource Utilization: Duration of Hospital Visits by Participants

Duration of hospital visit was calculated as = stop date - start date + 1. Mean and standard deviation data for duration of hospital visits (in days) by participants was reported in this outcome measure.

ITT population included all randomized participants.

Posted

Mean

Standard Deviation

days per visit

From start of study drug administration up to 22 months

Number of visits

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
OG001	Placebo + BSC Group	Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Units	Counts
Participants

Secondary

Health Care Resource Utilization: Number of Participants With Any Concomitant Medications Prescribed

Number of participants with any concomitant medications prescribed were reported.

ITT population included all randomized participants.

Posted

Count of Participants

Participants

From start of study drug administration up to 22 months

ID	Title	Description
OG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
OG001	Placebo + BSC Group	Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal pain	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0007 affected456 at risk EG0012 affected230 at risk
Intestinal obstruction	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0007 affected456 at risk EG0016 affected230 at risk
Small intestinal obstruction	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0005 affected456 at risk EG0011 affected230 at risk
Rectal haemorrhage	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0004 affected456 at risk EG0010 affected230 at risk
Constipation	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0003 affected456 at risk EG0010 affected230 at risk
Ileus	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0015 affected230 at risk
Intestinal perforation	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0004 affected456 at risk EG0010 affected230 at risk
Vomiting	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0003 affected456 at risk EG0013 affected230 at risk
Colitis	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Small intestinal perforation	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Stomatitis	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0011 affected230 at risk
Subileus	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0012 affected230 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Colonic fistula	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Gastric haemorrhage	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Gastric perforation	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Gastrointestinal perforation	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Haematemesis	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Large intestine perforation	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Nausea	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Oesophageal obstruction	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Oesophagitis	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Pancreatitis	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Pancreatitis acute	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Rectal perforation	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0012 affected230 at risk
Ascites	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Enterovesical fistula	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Large intestinal obstruction	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Rectal stenosis	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0012 affected230 at risk
Disease progression	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG00027 affected456 at risk EG00128 affected230 at risk
General physical health deterioration	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG00010 affected456 at risk EG0015 affected230 at risk
Asthenia	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0005 affected456 at risk EG0010 affected230 at risk
Pyrexia	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0004 affected456 at risk EG0012 affected230 at risk
Condition aggravated	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0003 affected456 at risk EG0012 affected230 at risk
Non-cardiac chest pain	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Chest pain	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Chills	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Death	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0012 affected230 at risk
Discomfort	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Malaise	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Multiple organ dysfunction syndrome	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0011 affected230 at risk
Ulcer	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Generalised oedema	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Pain	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Sudden death	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Pneumonia	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0009 affected456 at risk EG0011 affected230 at risk
Sepsis	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0005 affected456 at risk EG0010 affected230 at risk
Urinary tract infection	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0003 affected456 at risk EG0013 affected230 at risk
Abscess limb	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Biliary tract infection	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Bronchitis	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Bronchopulmonary aspergillosis	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
COVID-19 pneumonia	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Cellulitis	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Clostridium difficile colitis	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Clostridium difficile infection	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Device related infection	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Empyema	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0011 affected230 at risk
Fournier's gangrene	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Infection	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Perirectal abscess	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Pyelonephritis	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Septic shock	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0011 affected230 at risk
COVID-19	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0013 affected230 at risk
Coronavirus infection	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Urosepsis	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0011 affected230 at risk
Wound infection bacterial	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Wound sepsis	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0006 affected456 at risk EG0012 affected230 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0005 affected456 at risk EG0010 affected230 at risk
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Bronchospasm	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Hydrothorax	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0012 affected230 at risk
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0011 affected230 at risk
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Atelectasis	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Bronchopleural fistula	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Interstitial lung disease	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Respiratory distress	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0005 affected456 at risk EG0011 affected230 at risk
Urinary tract obstruction	Renal and urinary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0003 affected456 at risk EG0010 affected230 at risk
Hydronephrosis	Renal and urinary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Ureteric obstruction	Renal and urinary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Haematuria	Renal and urinary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0011 affected230 at risk
Proteinuria	Renal and urinary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Renal impairment	Renal and urinary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0011 affected230 at risk
Vesicocutaneous fistula	Renal and urinary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Biliary obstruction	Hepatobiliary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0003 affected456 at risk EG0011 affected230 at risk
Cholangitis	Hepatobiliary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0003 affected456 at risk EG0011 affected230 at risk
Hepatic failure	Hepatobiliary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0003 affected456 at risk EG0012 affected230 at risk
Cholecystitis	Hepatobiliary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Bile duct stenosis	Hepatobiliary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Bile duct stone	Hepatobiliary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Hepatic function abnormal	Hepatobiliary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0012 affected230 at risk
Hypertransaminasaemia	Hepatobiliary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Jaundice	Hepatobiliary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0012 affected230 at risk
Hyperbilirubinaemia	Hepatobiliary disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Encephalopathy	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Spinal cord compression	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0011 affected230 at risk
Cerebral haemorrhage	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Cerebral infarction	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Depressed level of consciousness	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Epilepsy	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Headache	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0011 affected230 at risk
Hepatic encephalopathy	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Posterior reversible encephalopathy syndrome	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Transient ischaemic attack	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Ischaemic stroke	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA 26.0.	Non-systematic Assessment	EG0003 affected456 at risk EG0011 affected230 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Diabetes mellitus inadequate control	Metabolism and nutrition disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Hypernatraemia	Metabolism and nutrition disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Hypovolaemia	Metabolism and nutrition disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 26.0.	Non-systematic Assessment	EG0006 affected456 at risk EG0011 affected230 at risk
Fistula	Musculoskeletal and connective tissue disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Hypertension	Vascular disorders	MedDRA 26.0.	Non-systematic Assessment	EG0006 affected456 at risk EG0010 affected230 at risk
Hypertensive crisis	Vascular disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Deep vein thrombosis	Vascular disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Haemorrhage	Vascular disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Hypotension	Vascular disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA 26.0.	Non-systematic Assessment	EG0003 affected456 at risk EG0010 affected230 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Joint injury	Injury, poisoning and procedural complications	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Recall phenomenon	Injury, poisoning and procedural complications	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Sternal fracture	Injury, poisoning and procedural complications	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Lung cancer metastatic	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Metastases to central nervous system	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0012 affected230 at risk
Metastases to liver	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Metastases to meninges	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Metastasis	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Tumour invasion	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Malignant neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Tumour associated fever	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Blood bilirubin increased	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG0004 affected456 at risk EG0012 affected230 at risk
Blood creatinine increased	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Alanine aminotransferase increased	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Aspartate aminotransferase increased	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Liver function test abnormal	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
SARS-CoV-2 test positive	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0011 affected230 at risk
Atrial fibrillation	Cardiac disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Cardiac failure	Cardiac disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Tachycardia	Cardiac disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Cardiac arrest	Cardiac disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0011 affected230 at risk
Polycythaemia	Blood and lymphatic system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Leukocytosis	Blood and lymphatic system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0012 affected230 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0000 affected456 at risk EG0011 affected230 at risk
Confusional state	Psychiatric disorders	MedDRA 26.0.	Non-systematic Assessment	EG0002 affected456 at risk EG0010 affected230 at risk
Anxiety	Psychiatric disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Female genital tract fistula	Reproductive system and breast disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Intermenstrual bleeding	Reproductive system and breast disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Skin necrosis	Skin and subcutaneous tissue disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Hypothyroidism	Endocrine disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Hypersensitivity	Immune system disorders	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Device dislocation	Product Issues	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk
Osteomyelitis chronic	Infections and infestations	MedDRA 26.0.	Non-systematic Assessment	EG0001 affected456 at risk EG0010 affected230 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Asthenia	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG000153 affected456 at risk EG00152 affected230 at risk
Fatigue	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG00093 affected456 at risk EG00137 affected230 at risk
Mucosal inflammation	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG00062 affected456 at risk EG0016 affected230 at risk
Pyrexia	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG00043 affected456 at risk EG00122 affected230 at risk
Oedema peripheral	General disorders	MedDRA 26.0.	Non-systematic Assessment	EG00023 affected456 at risk EG00117 affected230 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG000113 affected456 at risk EG00124 affected230 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG00080 affected456 at risk EG00136 affected230 at risk
Nausea	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG00082 affected456 at risk EG00143 affected230 at risk
Constipation	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG00075 affected456 at risk EG00122 affected230 at risk
Stomatitis	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG00067 affected456 at risk EG0017 affected230 at risk
Vomiting	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG00067 affected456 at risk EG00125 affected230 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG00035 affected456 at risk EG0018 affected230 at risk
Hypertension	Vascular disorders	MedDRA 26.0.	Non-systematic Assessment	EG000165 affected456 at risk EG00121 affected230 at risk
Weight decreased	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG00058 affected456 at risk EG00121 affected230 at risk
Aspartate aminotransferase increased	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG00050 affected456 at risk EG00110 affected230 at risk
Alanine aminotransferase increased	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG00049 affected456 at risk EG0018 affected230 at risk
Blood bilirubin increased	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG00033 affected456 at risk EG00110 affected230 at risk
Blood thyroid stimulating hormone increased	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG00032 affected456 at risk EG0013 affected230 at risk
Platelet count decreased	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG00028 affected456 at risk EG0012 affected230 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA 26.0.	Non-systematic Assessment	EG00024 affected456 at risk EG00110 affected230 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA 26.0.	Non-systematic Assessment	EG000127 affected456 at risk EG00141 affected230 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 26.0.	Non-systematic Assessment	EG00029 affected456 at risk EG0014 affected230 at risk
Dysphonia	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG00075 affected456 at risk EG00112 affected230 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG00039 affected456 at risk EG00121 affected230 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 26.0.	Non-systematic Assessment	EG00039 affected456 at risk EG00122 affected230 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 26.0.	Non-systematic Assessment	EG00052 affected456 at risk EG00110 affected230 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 26.0.	Non-systematic Assessment	EG00048 affected456 at risk EG00117 affected230 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 26.0.	Non-systematic Assessment	EG00028 affected456 at risk EG0016 affected230 at risk
Hypothyroidism	Endocrine disorders	MedDRA 26.0.	Non-systematic Assessment	EG00094 affected456 at risk EG0011 affected230 at risk
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA 26.0.	Non-systematic Assessment	EG00089 affected456 at risk EG0016 affected230 at risk
Proteinuria	Renal and urinary disorders	MedDRA 26.0.	Non-systematic Assessment	EG00081 affected456 at risk EG00112 affected230 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA 26.0.	Non-systematic Assessment	EG00038 affected456 at risk EG00128 affected230 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 26.0.	Non-systematic Assessment	EG00030 affected456 at risk EG0013 affected230 at risk
Headache	Nervous system disorders	MedDRA 26.0.	Non-systematic Assessment	EG00040 affected456 at risk EG00110 affected230 at risk
Insomnia	Psychiatric disorders	MedDRA 26.0.	Non-systematic Assessment	EG00026 affected456 at risk EG00112 affected230 at risk

ID	Term
D015179	Colorectal Neoplasms
D003110	Colonic Neoplasms

ID	Term
D007414	Intestinal Neoplasms
D005770	Gastrointestinal Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D004066	Digestive System Diseases
D005767	Gastrointestinal Diseases
D003108	Colonic Diseases
D007410	Intestinal Diseases
D012002	Rectal Diseases

ID	Title	Description
BG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
BG001	Placebo + BSC Group	Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Fruquintinib + BSC Group	Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).	411	461	173	456	446	456
EG001	Placebo + BSC Group	Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).	203	230	88	230	205	230