A Study of Efficacy and Safety of Fruquintinib (HMPL-013) in Participants With Metastatic Colorectal Cancer (FRESCO-2)

• ClinicalTrials.gov Identifier: NCT04322539
• Recruitment Status: Active, not recruiting
• First Posted: March 26, 2020
• Results First Posted: September 14, 2023
• Last Update Posted: September 14, 2023
• Sponsor: Hutchison Medipharma Limited
• Information provided by (Responsible Party): Hutchmed ( Hutchison Medipharma Limited )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Metastatic Colorectal Cancer; Metastatic Colon Cancer
• Interventions: Drug: Fruquintinib; Drug: Placebo
• Enrollment: 691

Participant Flow

Recruitment Details	The study was conducted at 124 study sites in the United States, Europe region, Japan, and Australia.
Pre-assignment Details	A total of 691 participants were randomized in this study. Data were reported based on data cut-off analysis date (24 June 2022) and the study is still ongoing.

Arm/Group Title	Fruquintinib + Best Supportive Care (BSC) Group	Placebo + BSC Group
Arm/Group Description	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).	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).
Period Title: Overall Study
Started	461	230
Safety Population (SP) [1]	456	230
Pharmacokinetic (PK) Population [2]	329	2
Completed	0	0
Not Completed	461	230
Reason Not Completed
Withdrawal of consent	14	8
Death	317	173
Adverse Event	1	0
Lost to Follow-up	3	0
Other	2	3
Ongoing	124	46
[1] The Safety population (SP) included all randomized participants who received at least 1 dose of study drug.; [2] The Pharmacokinetic (PK) population included all participants who received at least 1 dose of study drug and had at least 1 post dose PK sample collected and analyzed.

Baseline Characteristics

Arm/Group Title		Fruquintinib + BSC Group	Placebo + BSC Group	Total
Arm/Group Description		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).	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).	Total of all reporting groups
Overall Number of Baseline Participants		461	230	691
Baseline Analysis Population Description		Intent-to-Treat (ITT) population included all randomized participants.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	461 participants	230 participants	691 participants
		62.2 (10.41)	62.4 (9.67)	62.2 (10.16)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	461 participants	230 participants	691 participants
	Female	216 46.9%	90 39.1%	306 44.3%
	Male	245 53.1%	140 60.9%	385 55.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	461 participants	230 participants	691 participants
	Hispanic or Latino	20 4.3%	14 6.1%	34 4.9%
	Not Hispanic or Latino	405 87.9%	202 87.8%	607 87.8%
	Unknown or Not Reported	36 7.8%	14 6.1%	50 7.2%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Race	Number Analyzed	461 participants	230 participants	691 participants
	American Indian or Alaska Native	0 0.0%	1 0.4%	1 0.1%
	Asian	43 9.3%	18 7.8%	61 8.8%
	Black or African American	13 2.8%	7 3.0%	20 2.9%
	Native Hawaiian or Other	3 0.7%	2 0.9%	5 0.7%
	White	367 79.6%	192 83.5%	559 80.9%
	Other	5 1.1%	2 0.9%	7 1.0%
	Multiple races	2 0.4%	0 0.0%	2 0.3%
	Not reported/unknown	28 6.1%	8 3.5%	36 5.2%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	From date of randomization to death from any cause (up to 22 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	461	230
Median (95% Confidence Interval); Unit of Measure: months
	7.4; (6.7 to 8.2)	4.8; (4.0 to 5.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fruquintinib + BSC Group, Placebo + BSC Group
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< .001
	Comments	Raw unadjusted p-value was obtained by using a stratified log-rank test accounting for the randomization schedule stratification factors.
	Method	stratified log-rank test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.662
	Confidence Interval	(2-Sided) 95%; 0.549 to 0.800
	Estimation Comments	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.

2. Secondary Outcome

Title	Progression Free Survival (PFS), as Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1
Description	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.
Time Frame	From randomization until the first documentation of objective progression or death, whichever comes first (up to 22 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	461	230
Median (95% Confidence Interval); Unit of Measure: months
	3.7; (3.5 to 3.8)	1.8; (1.8 to 1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fruquintinib + BSC Group, Placebo + BSC Group
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< .001
	Comments	Raw unadjusted p-value was obtained by using a stratified log-rank test accounting for the randomization schedule stratification factors.
	Method	stratified log-rank test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.321
	Confidence Interval	(2-Sided) 95%; 0.267 to 0.386
	Estimation Comments	The HR between the 2 treatment groups (fruquintinib vs placebo), together with its 95% CI, was calculated from a stratified Cox proportional hazards model accounting for the randomization schedule stratification factors.

3. Secondary Outcome

Title	Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Description	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).
Time Frame	From randomization until the first documentation of best overall response (up to 22 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	461	230
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	1.5; (0.6 to 3.1)	0; (0.0 to 1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fruquintinib + BSC Group, Placebo + BSC Group
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.059
	Comments	p-value was calculated from a stratified Cochran-Mantel Haenszel test accounting for the randomization schedule stratification factors.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Adjusted difference
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; 0.4 to 2.7
	Estimation Comments	The adjusted difference and its 95% CI were calculated using the Wald method from Cochran-Mantel Haenszel test to account for the randomization schedule stratification factors.

4. Secondary Outcome

Title	Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Description	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.
Time Frame	From randomization until the first documentation of best overall response (up to 22 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	461	230
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	55.5; (50.9 to 60.1)	16.1; (11.6 to 21.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fruquintinib + BSC Group, Placebo + BSC Group
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.001
	Comments	p-value was calculated from a stratified Cochran-Mantel Haenszel test accounting for the randomization schedule stratification factors.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Adjusted difference
	Estimated Value	39.4
	Confidence Interval	(2-Sided) 95%; 32.8 to 46.0
	Estimation Comments	The adjusted difference and its 95% CI were calculated using the Wald method from Cochran-Mantel Haenszel test to account for the randomization schedule stratification factors.

5. Secondary Outcome

Title	Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Description	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.
Time Frame	From first occurrence of PR or CR until the first documentation progression or death, whichever comes first (up to 22 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	7	0
Median (95% Confidence Interval); Unit of Measure: months
	10.7 [1]; (3.9 to NA)

[1]

Upper limit of 95% CI was not estimable due to limited number of participants with events.

6. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
Description	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 37 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.
Time Frame	From start of study drug administration up to 22 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	456	230
Measure Type: Count of Participants; Unit of Measure: Participants
Participants with TEAEs	451 98.9%	213 92.6%
Participants with Serious TEAEs	172 37.7%	88 38.3%

7. Secondary Outcome

Title	Observed Plasma Concentrations of Fruquintinib and Metabolite M11
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Fruquintinib + BSC Group
Arm/Group Description:		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).
Overall Number of Participants Analyzed		312
Mean (Standard Deviation); Unit of Measure: nanogram/milliliter (ng/mL)
Cycle 1 Day 1 - Pre-dose (Plasma Concentrations of Fruquintinib)	Number Analyzed	312 participants
		2.90 (19.9)
Cycle 1 Day 1 - Pre-dose (Plasma Concentrations of M11)	Number Analyzed	312 participants
		0.585 (6.61)
Cycle 1 Day 1 - 1 hour (Plasma Concentrations of Fruquintinib)	Number Analyzed	171 participants
		59.9 (51.0)
Cycle 1 Day 1 - 1 hour (Plasma Concentrations of M11)	Number Analyzed	171 participants
		1.06 (8.36)
Cycle 1 Day 1 - 2 hours (Plasma Concentrations of Fruquintinib)	Number Analyzed	304 participants
		91.5 (48.2)
Cycle 1 Day 1 - 2 hours (Plasma Concentrations of M11)	Number Analyzed	304 participants
		1.03 (6.81)
Cycle 1 Day 1 - 3 hours (Plasma Concentrations of Fruquintinib)	Number Analyzed	171 participants
		98.5 (47.1)
Cycle 1 Day 1 - 3 hours (Plasma Concentrations of M11)	Number Analyzed	171 participants
		1.96 (9.51)
Cycle 1 Day 1 - 4 hours (Plasma Concentrations of Fruquintinib)	Number Analyzed	171 participants
		99.7 (44.6)
Cycle 1 Day 1 - 4 hours (Plasma Concentrations of M11)	Number Analyzed	171 participants
		2.71 (10.7)
Cycle 1 Day 21 - Pre-dose (Plasma Concentrations of Fruquintinib)	Number Analyzed	227 participants
		219 (82.6)
Cycle 1 Day 21 - Pre-dose (Plasma Concentrations of M11)	Number Analyzed	227 participants
		94.5 (52.6)
Cycle 1 Day 21 - 1 hour (Plasma Concentrations of Fruquintinib)	Number Analyzed	112 participants
		255 (101)
Cycle 1 Day 21 - 1 hour (Plasma Concentrations of M11)	Number Analyzed	112 participants
		92.0 (54.3)
Cycle 1 Day 21 - 2 hours (Plasma Concentrations of Fruquintinib)	Number Analyzed	214 participants
		279 (91.6)
Cycle 1 Day 21 - 2 hours (Plasma Concentrations of M11)	Number Analyzed	214 participants
		89.9 (49.5)
Cycle 1 Day 21 -3 hours (Plasma Concentrations of Fruquintinib)	Number Analyzed	113 participants
		293 (95.2)
Cycle 1 Day 21 - 3 hours (Plasma Concentrations of M11)	Number Analyzed	113 participants
		88.0 (50.4)
Cycle 1 Day 21 - 4 hours (Plasma Concentrations of Fruquintinib)	Number Analyzed	114 participants
		294 (88.0)
Cycle 1 Day 21 - 4 hours (Plasma Concentrations of M11)	Number Analyzed	114 participants
		89.2 (49.0)
Cycle 2 Day 21 - Predose (Plasma Concentrations of Fruquintinib)	Number Analyzed	204 participants
		222 (82.0)
Cycle 2 Day 21 - Predose (Plasma Concentrations of M11)	Number Analyzed	204 participants
		97.6 (53.7)
Cycle 2 Day 21 - 2 hours (Plasma Concentrations of Fruquintinib)	Number Analyzed	193 participants
		284 (95.2)
Cycle 2 Day 21 - 2 hours (Plasma Concentrations of M11)	Number Analyzed	193 participants
		94.2 (52.8)
Cycle 3 Day 1 - Pre-dose (Plasma Concentrations of Fruquintinib)	Number Analyzed	177 participants
		16.7 (18.9)
Cycle 3 Day 1 - Pre-dose (Plasma Concentrations of M11)	Number Analyzed	177 participants
		22.6 (18.2)
Cycle 3 Day 21 - Pre-dose (Plasma Concentrations of Fruquintinib)	Number Analyzed	137 participants
		212 (74.6)
Cycle 3 Day 21 - Pre-dose (Plasma Concentrations of M11)	Number Analyzed	137 participants
		90.6 (54.1)
Cycle 3 Day 21 - 2 hours (Plasma Concentrations of Fruquintinib)	Number Analyzed	123 participants
		275 (78.6)
Cycle 3 Day 21 - 2 hours (Plasma Concentrations of M11)	Number Analyzed	123 participants
		92.8 (54.2)
Cycle 5 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	Number Analyzed	103 participants
		16.9 (20.5)
Cycle 5 Day 1 - Pre-Dose (Plasma Concentrations of M11)	Number Analyzed	103 participants
		23.2 (20.9)
Cycle 7 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib	Number Analyzed	46 participants
		18.2 (33.0)
Cycle 7 Day 1 - Pre-Dose (Plasma Concentrations of M11)	Number Analyzed	46 participants
		20.1 (12.1)
Cycle 9 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	Number Analyzed	13 participants
		12.2 (12.6)
Cycle 9 Day 1 - Pre-Dose (Plasma Concentrations of M11)	Number Analyzed	13 participants
		19.1 (17.1)
Cycle 11 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	Number Analyzed	6 participants
		13.4 (13.4)
Cycle 11 Day 1 - Pre-Dose (Plasma Concentrations of M11)	Number Analyzed	6 participants
		17.1 (15.3)
Cycle 13 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	Number Analyzed	1 participants
		15.4
Cycle 13 Day 1 - Pre-Dose (Plasma Concentrations of M11)	Number Analyzed	1 participants
		23.1
Cycle 15 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	Number Analyzed	1 participants
		10.8
Cycle 15 Day 1 - Pre-Dose (Plasma Concentrations of M11)	Number Analyzed	1 participants
		19.2
Cycle 17 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	Number Analyzed	1 participants
		10.6
Cycle 17 Day 1 - Pre-Dose (Plasma Concentrations of M11)	Number Analyzed	1 participants
		15.2

8. Secondary Outcome

Title	Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		272	131
Mean (Standard Deviation); Unit of Measure: millisecond (msec)
Cycle 1 Day 1 - Pre-dose	Number Analyzed	261 participants	126 participants
		1.9 (21.33)	0.1 (17.95)
Cycle 1 Day 1 - 1 hour	Number Analyzed	149 participants	71 participants
		-0.1 (19.60)	2.5 (19.70)
Cycle 1 Day 1 - 2 hours	Number Analyzed	272 participants	131 participants
		1.9 (22.58)	3.5 (20.13)
Cycle 1 Day 1 - 3 hours	Number Analyzed	143 participants	70 participants
		2.6 (19.77)	3.3 (18.03)
Cycle 1 Day 1 - 4 hours	Number Analyzed	136 participants	67 participants
		1.2 (20.48)	0.9 (17.66)
Cycle 1 Day 21 - Pre-dose	Number Analyzed	184 participants	95 participants
		3.2 (20.94)	-2.2 (20.31)
Cycle 1 Day 21 - 1 hour	Number Analyzed	109 participants	62 participants
		4.0 (19.56)	-0.2 (16.77)
Cycle 1 Day 21 - 2 hours	Number Analyzed	222 participants	121 participants
		5.0 (20.06)	2.8 (18.23)
Cycle 1 Day 21 - 3 hours	Number Analyzed	111 participants	61 participants
		5.9 (19.46)	0.2 (14.70)
Cycle 1 Day 21 - 4 hours	Number Analyzed	103 participants	58 participants
		3.9 (20.98)	-0.6 (18.13)
Cycle 2 Day 21 - 2 hours	Number Analyzed	229 participants	86 participants
		1.4 (22.41)	4.9 (24.28)
Cycle 3 Day 21 - 2 hours	Number Analyzed	141 participants	28 participants
		2.6 (31.61)	2.0 (20.08)

9. Secondary Outcome

Title	Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		258	122
Mean (Standard Deviation); Unit of Measure: msec
Cycle 1 Day 1 - Pre-dose	Number Analyzed	249 participants	118 participants
		2.9 (39.49)	0.3 (20.55)
Cycle 1 Day 1 - 1 hour	Number Analyzed	142 participants	69 participants
		-3.1 (23.95)	1.9 (20.11)
Cycle 1 Day 1 - 2 hours	Number Analyzed	258 participants	122 participants
		-2.0 (23.95)	1.9 (20.11)
Cycle 1 Day 1 - 3 hours	Number Analyzed	136 participants	68 participants
		-0.9 (24.47)	3.9 (19.75)
Cycle 1 Day 1 - 4 hours	Number Analyzed	130 participants	65 participants
		-1.9 (24.47)	2.4 (20.11)
Cycle 1 Day 21 - Pre-dose	Number Analyzed	177 participants	91 participants
		3.9 (49.99)	5.0 (50.43)
Cycle 1 Day 21 - 1 hour	Number Analyzed	177 participants	60 participants
		-1.3 (25.60)	0.9 (20.48)
Cycle 1 Day 21 - 2 hours	Number Analyzed	212 participants	117 participants
		1.6 (42.28)	4.3 (19.57)
Cycle 1 Day 21 - 3 hours	Number Analyzed	107 participants	59 participants
		1.2 (25.41)	2.9 (18.29)
Cycle 1 Day 21 - 4 hours	Number Analyzed	99 participants	56 participants
		0.2 (25.91)	2.8 (20.13)
Cycle 2 Day 21 - 2 hours	Number Analyzed	213 participants	83 participants
		1.7 (40.61)	5.9 (24.96)
Cycle 3 Day 21 - 2 hours	Number Analyzed	132 participants	28 participants
		4.2 (72.35)	1.6 (22.06)

10. Secondary Outcome

Title	Correlation Between Fruquintinib Exposure-response With Efficacy (OS) and Safety (AEs) Endpoints
Description	As pre-specified in Exposure-Response final analysis report, fruquintinib exposures response with efficacy and safety endpoints were performed along with data from other clinical studies and the integrated analyses were to be reported separately. Data is not reported for this outcome measure as its analysis is still ongoing and will be reported after study completion.
Time Frame	Up to 42 months

Outcome Measure Data Not Reported

11. Secondary Outcome

Title	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
Description	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 became worst. 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.
Time Frame	Baseline, Cycle 2, 3 and 4 (Each cycle=28 days)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		330	149
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
Cycle 2	Number Analyzed	330 participants	149 participants
		-2.1 (1.59)	-3.7 (1.95)
Cycle 3	Number Analyzed	229 participants	53 participants
		-4.5 (1.69)	-6.1 (2.54)
Cycle 4	Number Analyzed	182 participants	29 participants
		-4.2 (1.76)	-2.1 (3.03)

12. Secondary Outcome

Title	Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scale (VAS) Score
Description	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 became worse. Change from baseline in the EQ-5D-5L VAS scores was performed by visit (i.e. cycle), using a REML-based MMRM approach.
Time Frame	Baseline, Cycle 2, 3 and 4 (Each cycle=28 days)

Outcome Measure Data

Analysis Population Description

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 categories.

Arm/Group Title		Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		388	230
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
Cycle 2	Number Analyzed	337 participants	151 participants
		-0.3 (1.38)	-0.9 (1.69)
Cycle 3	Number Analyzed	232 participants	54 participants
		-1.1 (1.48)	-2.5 (2.22)
Cycle 4	Number Analyzed	185 participants	30 participants
		-4.0 (1.59)	-2.1 (2.79)

13. Secondary Outcome

Title	Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Health Utility Index Scores
Description	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.
Time Frame	Baseline, Cycle 2, 3 and 4 (Each cycle=28 days)

Outcome Measure Data

Analysis Population Description

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 categories.

Arm/Group Title		Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		337	151
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
Cycle 2	Number Analyzed	337 participants	151 participants
		0.0 (0.01)	0.0 (0.02)
Cycle 3	Number Analyzed	232 participants	54 participants
		0.0 (0.01)	0.0 (0.02)
Cycle 4	Number Analyzed	185 participants	30 participants
		-0.1 (0.02)	0.0 (0.03)

14. Secondary Outcome

Title	Health Care Resource Utilization: Duration of Hospital Visits by Participants
Description	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.
Time Frame	From start of study drug administration up to 22 months

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	461	230
Overall Number of Units Analyzed; Type of Units Analyzed: Number of visits	545	232
Mean (Standard Deviation); Unit of Measure: days per visit
	3.3 (6.81)	4.4 (7.53)

15. Secondary Outcome

Title	Health Care Resource Utilization: Number of Participants With Any Concomitant Medications Prescribed
Description	Number of participants with any concomitant medications prescribed were reported.
Time Frame	From start of study drug administration up to 22 months

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	461	230
Measure Type: Count of Participants; Unit of Measure: Participants
	116 25.2%	63 27.4%

Adverse Events

Time Frame	From start of study drug administration up to 22 months
Adverse Event Reporting Description	All-Cause Mortality data collected during the study was assessed for all randomized participants. Serious AEs and Non-Serious AEs data were collected based on safety population that included all randomized participants who received at least 1 dose of study drug.
Arm/Group Title	Fruquintinib + BSC Group	Placebo + BSC Group
Arm/Group Description	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).	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).
All-Cause Mortality
	Fruquintinib + BSC Group	Placebo + BSC Group
	Affected / at Risk (%)	Affected / at Risk (%)
Total	317/461 (68.76%)	173/230 (75.22%)
Serious Adverse Events
	Fruquintinib + BSC Group	Placebo + BSC Group
	Affected / at Risk (%)	Affected / at Risk (%)
Total	172/456 (37.72%)	88/230 (38.26%)
Blood and lymphatic system disorders
Anaemia * 1	2/456 (0.44%)	1/230 (0.43%)
Polycythaemia * 1	1/456 (0.22%)	0/230 (0.00%)
Leukocytosis * 1	0/456 (0.00%)	2/230 (0.87%)
Thrombocytopenia * 1	0/456 (0.00%)	1/230 (0.43%)
Cardiac disorders
Cardiac failure congestive * 1	2/456 (0.44%)	1/230 (0.43%)
Atrial fibrillation * 1	1/456 (0.22%)	0/230 (0.00%)
Cardiac failure * 1	1/456 (0.22%)	0/230 (0.00%)
Tachycardia * 1	1/456 (0.22%)	0/230 (0.00%)
Acute myocardial infarction * 1	0/456 (0.00%)	1/230 (0.43%)
Cardiac arrest * 1	0/456 (0.00%)	1/230 (0.43%)
Endocrine disorders
Hypothyroidism * 1	1/456 (0.22%)	0/230 (0.00%)
Gastrointestinal disorders
Abdominal pain * 1	7/456 (1.54%)	2/230 (0.87%)
Intestinal obstruction * 1	7/456 (1.54%)	6/230 (2.61%)
Small intestinal obstruction * 1	5/456 (1.10%)	1/230 (0.43%)
Rectal haemorrhage * 1	4/456 (0.88%)	0/230 (0.00%)
Constipation * 1	3/456 (0.66%)	0/230 (0.00%)
Ileus * 1	3/456 (0.66%)	5/230 (2.17%)
Intestinal perforation * 1	3/456 (0.66%)	0/230 (0.00%)
Vomiting * 1	3/456 (0.66%)	3/230 (1.30%)
Colitis * 1	2/456 (0.44%)	0/230 (0.00%)
Gastrointestinal haemorrhage * 1	2/456 (0.44%)	0/230 (0.00%)
Small intestinal perforation * 1	2/456 (0.44%)	0/230 (0.00%)
Stomatitis * 1	2/456 (0.44%)	1/230 (0.43%)
Subileus * 1	2/456 (0.44%)	2/230 (0.87%)
Abdominal pain upper * 1	1/456 (0.22%)	0/230 (0.00%)
Colonic fistula * 1	1/456 (0.22%)	0/230 (0.00%)
Diarrhoea * 1	1/456 (0.22%)	0/230 (0.00%)
Gastric haemorrhage * 1	1/456 (0.22%)	0/230 (0.00%)
Gastric perforation * 1	1/456 (0.22%)	0/230 (0.00%)
Gastrointestinal perforation * 1	1/456 (0.22%)	0/230 (0.00%)
Haematemesis * 1	1/456 (0.22%)	0/230 (0.00%)
Large intestine perforation * 1	1/456 (0.22%)	0/230 (0.00%)
Nausea * 1	1/456 (0.22%)	0/230 (0.00%)
Oesophageal obstruction * 1	1/456 (0.22%)	0/230 (0.00%)
Oesophagitis * 1	1/456 (0.22%)	0/230 (0.00%)
Pancreatitis * 1	1/456 (0.22%)	0/230 (0.00%)
Pancreatitis acute * 1	1/456 (0.22%)	0/230 (0.00%)
Rectal perforation * 1	1/456 (0.22%)	0/230 (0.00%)
Abdominal distension * 1	0/456 (0.00%)	2/230 (0.87%)
Ascites * 1	0/456 (0.00%)	1/230 (0.43%)
Enterovesical fistula * 1	0/456 (0.00%)	1/230 (0.43%)
Large intestinal obstruction * 1	0/456 (0.00%)	1/230 (0.43%)
Rectal stenosis * 1	0/456 (0.00%)	1/230 (0.43%)
Upper gastrointestinal haemorrhage * 1	0/456 (0.00%)	2/230 (0.87%)
General disorders
Disease progression * 1	27/456 (5.92%)	28/230 (12.17%)
General physical health deterioration * 1	10/456 (2.19%)	5/230 (2.17%)
Asthenia * 1	5/456 (1.10%)	0/230 (0.00%)
Pyrexia * 1	5/456 (1.10%)	2/230 (0.87%)
Condition aggravated * 1	3/456 (0.66%)	2/230 (0.87%)
Non-cardiac chest pain * 1	2/456 (0.44%)	0/230 (0.00%)
Chest pain * 1	1/456 (0.22%)	0/230 (0.00%)
Chills * 1	1/456 (0.22%)	0/230 (0.00%)
Death * 1	1/456 (0.22%)	2/230 (0.87%)
Discomfort * 1	1/456 (0.22%)	0/230 (0.00%)
Malaise * 1	1/456 (0.22%)	0/230 (0.00%)
Multiple organ dysfunction syndrome * 1	1/456 (0.22%)	1/230 (0.43%)
Ulcer * 1	1/456 (0.22%)	0/230 (0.00%)
Generalised oedema * 1	0/456 (0.00%)	1/230 (0.43%)
Pain * 1	0/456 (0.00%)	1/230 (0.43%)
Sudden death * 1	0/456 (0.00%)	1/230 (0.43%)
Hepatobiliary disorders
Biliary obstruction * 1	3/456 (0.66%)	1/230 (0.43%)
Cholangitis * 1	3/456 (0.66%)	1/230 (0.43%)
Hepatic failure * 1	3/456 (0.66%)	2/230 (0.87%)
Cholecystitis * 1	2/456 (0.44%)	0/230 (0.00%)
Bile duct stenosis * 1	1/456 (0.22%)	0/230 (0.00%)
Bile duct stone * 1	1/456 (0.22%)	0/230 (0.00%)
Hepatic function abnormal * 1	1/456 (0.22%)	2/230 (0.87%)
Hypertransaminasaemia * 1	1/456 (0.22%)	0/230 (0.00%)
Jaundice * 1	1/456 (0.22%)	3/230 (1.30%)
Hyperbilirubinaemia * 1	0/456 (0.00%)	1/230 (0.43%)
Immune system disorders
Hypersensitivity * 1	1/456 (0.22%)	0/230 (0.00%)
Infections and infestations
Pneumonia * 1	8/456 (1.75%)	1/230 (0.43%)
Sepsis * 1	5/456 (1.10%)	0/230 (0.00%)
Urinary tract infection * 1	3/456 (0.66%)	3/230 (1.30%)
Abscess limb * 1	1/456 (0.22%)	0/230 (0.00%)
Biliary tract infection * 1	1/456 (0.22%)	0/230 (0.00%)
Bronchitis * 1	1/456 (0.22%)	0/230 (0.00%)
Bronchopulmonary aspergillosis * 1	1/456 (0.22%)	0/230 (0.00%)
COVID-19 pneumonia * 1	1/456 (0.22%)	0/230 (0.00%)
Cellulitis * 1	1/456 (0.22%)	0/230 (0.00%)
Clostridium difficile colitis * 1	1/456 (0.22%)	0/230 (0.00%)
Clostridium difficile infection * 1	1/456 (0.22%)	0/230 (0.00%)
Device related infection * 1	1/456 (0.22%)	0/230 (0.00%)
Empyema * 1	1/456 (0.22%)	1/230 (0.43%)
Fournier's gangrene * 1	1/456 (0.22%)	0/230 (0.00%)
Infection * 1	1/456 (0.22%)	0/230 (0.00%)
Perirectal abscess * 1	1/456 (0.22%)	0/230 (0.00%)
Pyelonephritis * 1	1/456 (0.22%)	0/230 (0.00%)
Septic shock * 1	1/456 (0.22%)	1/230 (0.43%)
COVID-19 * 1	0/456 (0.00%)	3/230 (1.30%)
Coronavirus infection * 1	0/456 (0.00%)	1/230 (0.43%)
Urosepsis * 1	0/456 (0.00%)	1/230 (0.43%)
Wound infection bacterial * 1	0/456 (0.00%)	1/230 (0.43%)
Wound sepsis * 1	0/456 (0.00%)	1/230 (0.43%)
Injury, poisoning and procedural complications
Femur fracture * 1	3/456 (0.66%)	0/230 (0.00%)
Fall * 1	1/456 (0.22%)	0/230 (0.00%)
Joint injury * 1	1/456 (0.22%)	0/230 (0.00%)
Recall phenomenon * 1	1/456 (0.22%)	0/230 (0.00%)
Sternal fracture * 1	1/456 (0.22%)	0/230 (0.00%)
Investigations
Blood bilirubin increased * 1	4/456 (0.88%)	2/230 (0.87%)
Blood creatinine increased * 1	1/456 (0.22%)	0/230 (0.00%)
Alanine aminotransferase increased * 1	0/456 (0.00%)	1/230 (0.43%)
Aspartate aminotransferase increased * 1	0/456 (0.00%)	1/230 (0.43%)
Liver function test abnormal * 1	0/456 (0.00%)	1/230 (0.43%)
SARS-CoV-2 test positive * 1	0/456 (0.00%)	1/230 (0.43%)
Metabolism and nutrition disorders
Hyponatraemia * 1	3/456 (0.66%)	1/230 (0.43%)
Decreased appetite * 1	2/456 (0.44%)	0/230 (0.00%)
Dehydration * 1	2/456 (0.44%)	0/230 (0.00%)
Diabetes mellitus inadequate control * 1	1/456 (0.22%)	0/230 (0.00%)
Hypernatraemia * 1	1/456 (0.22%)	0/230 (0.00%)
Hypoalbuminaemia * 1	1/456 (0.22%)	0/230 (0.00%)
Hypokalaemia * 1	1/456 (0.22%)	0/230 (0.00%)
Hyperglycaemia * 1	0/456 (0.00%)	1/230 (0.43%)
Hypovolaemia * 1	0/456 (0.00%)	1/230 (0.43%)
Musculoskeletal and connective tissue disorders
Back pain * 1	6/456 (1.32%)	1/230 (0.43%)
Fistula * 1	2/456 (0.44%)	0/230 (0.00%)
Muscular weakness * 1	2/456 (0.44%)	0/230 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer metastatic * 1	1/456 (0.22%)	0/230 (0.00%)
Metastases to central nervous system * 1	1/456 (0.22%)	2/230 (0.87%)
Metastases to liver * 1	1/456 (0.22%)	0/230 (0.00%)
Metastases to meninges * 1	1/456 (0.22%)	0/230 (0.00%)
Metastasis * 1	1/456 (0.22%)	0/230 (0.00%)
Tumour invasion * 1	1/456 (0.22%)	0/230 (0.00%)
Tumour pain * 1	1/456 (0.22%)	0/230 (0.00%)
Malignant neoplasm progression * 1	0/456 (0.00%)	1/230 (0.43%)
Neoplasm progression * 1	0/456 (0.00%)	1/230 (0.43%)
Tumour associated fever * 1	0/456 (0.00%)	1/230 (0.43%)
Nervous system disorders
Encephalopathy * 1	2/456 (0.44%)	0/230 (0.00%)
Spinal cord compression * 1	2/456 (0.44%)	1/230 (0.43%)
Cerebral haemorrhage * 1	1/456 (0.22%)	0/230 (0.00%)
Cerebral infarction * 1	1/456 (0.22%)	0/230 (0.00%)
Cerebrovascular accident * 1	1/456 (0.22%)	0/230 (0.00%)
Depressed level of consciousness * 1	1/456 (0.22%)	0/230 (0.00%)
Epilepsy * 1	1/456 (0.22%)	0/230 (0.00%)
Headache * 1	1/456 (0.22%)	1/230 (0.43%)
Hepatic encephalopathy * 1	1/456 (0.22%)	0/230 (0.00%)
Posterior reversible encephalopathy syndrome * 1	1/456 (0.22%)	0/230 (0.00%)
Transient ischaemic attack * 1	1/456 (0.22%)	0/230 (0.00%)
Ischaemic stroke * 1	0/456 (0.00%)	1/230 (0.43%)
Product Issues
Device dislocation * 1	1/456 (0.22%)	0/230 (0.00%)
Psychiatric disorders
Confusional state * 1	2/456 (0.44%)	0/230 (0.00%)
Anxiety * 1	1/456 (0.22%)	0/230 (0.00%)
Renal and urinary disorders
Acute kidney injury * 1	5/456 (1.10%)	1/230 (0.43%)
Urinary tract obstruction * 1	3/456 (0.66%)	0/230 (0.00%)
Hydronephrosis * 1	2/456 (0.44%)	0/230 (0.00%)
Ureteric obstruction * 1	2/456 (0.44%)	0/230 (0.00%)
Haematuria * 1	1/456 (0.22%)	1/230 (0.43%)
Proteinuria * 1	1/456 (0.22%)	0/230 (0.00%)
Renal impairment * 1	1/456 (0.22%)	1/230 (0.43%)
Vesicocutaneous fistula * 1	1/456 (0.22%)	0/230 (0.00%)
Reproductive system and breast disorders
Female genital tract fistula * 1	1/456 (0.22%)	0/230 (0.00%)
Intermenstrual bleeding * 1	1/456 (0.22%)	0/230 (0.00%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea * 1	6/456 (1.32%)	2/230 (0.87%)
Pulmonary embolism * 1	5/456 (1.10%)	0/230 (0.00%)
Acute respiratory distress syndrome * 1	1/456 (0.22%)	0/230 (0.00%)
Bronchospasm * 1	1/456 (0.22%)	0/230 (0.00%)
Epistaxis * 1	1/456 (0.22%)	0/230 (0.00%)
Hydrothorax * 1	1/456 (0.22%)	0/230 (0.00%)
Pleural effusion * 1	1/456 (0.22%)	2/230 (0.87%)
Pneumonitis * 1	1/456 (0.22%)	1/230 (0.43%)
Pneumothorax * 1	1/456 (0.22%)	0/230 (0.00%)
Atelectasis * 1	0/456 (0.00%)	1/230 (0.43%)
Bronchopleural fistula * 1	0/456 (0.00%)	1/230 (0.43%)
Cough * 1	0/456 (0.00%)	1/230 (0.43%)
Interstitial lung disease * 1	0/456 (0.00%)	1/230 (0.43%)
Respiratory distress * 1	0/456 (0.00%)	1/230 (0.43%)
Respiratory failure * 1	0/456 (0.00%)	1/230 (0.43%)
Skin and subcutaneous tissue disorders
Rash * 1	1/456 (0.22%)	0/230 (0.00%)
Skin necrosis * 1	1/456 (0.22%)	0/230 (0.00%)
Vascular disorders
Hypertension * 1	6/456 (1.32%)	0/230 (0.00%)
Hypertensive crisis * 1	2/456 (0.44%)	0/230 (0.00%)
Deep vein thrombosis * 1	1/456 (0.22%)	0/230 (0.00%)
Haemorrhage * 1	0/456 (0.00%)	1/230 (0.43%)
Hypotension * 1	0/456 (0.00%)	1/230 (0.43%)
1 Term from vocabulary, MedDRA 25.0.; * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Fruquintinib + BSC Group	Placebo + BSC Group
	Affected / at Risk (%)	Affected / at Risk (%)
Total	436/456 (95.61%)	185/230 (80.43%)
Blood and lymphatic system disorders
Anaemia * 1	35/456 (7.68%)	28/230 (12.17%)
Thrombocytopenia * 1	30/456 (6.58%)	3/230 (1.30%)
Endocrine disorders
Hypothyroidism * 1	93/456 (20.39%)	1/230 (0.43%)
Gastrointestinal disorders
Oedema peripheral * 1	22/456 (4.82%)	17/230 (7.39%)
Diarrhoea * 1	110/456 (24.12%)	24/230 (10.43%)
Abdominal pain * 1	79/456 (17.32%)	35/230 (15.22%)
Nausea * 1	78/456 (17.11%)	42/230 (18.26%)
Constipation * 1	75/456 (16.45%)	22/230 (9.57%)
Stomatitis * 1	67/456 (14.69%)	7/230 (3.04%)
Vomiting * 1	64/456 (14.04%)	25/230 (10.87%)
Abdominal pain upper * 1	34/456 (7.46%)	8/230 (3.48%)
General disorders
Asthenia * 1	152/456 (33.33%)	52/230 (22.61%)
Fatigue * 1	91/456 (19.96%)	37/230 (16.09%)
Mucosal inflammation * 1	62/456 (13.60%)	6/230 (2.61%)
Pyrexia * 1	42/456 (9.21%)	22/230 (9.57%)
Oedema peripheral * 1	22/456 (4.82%)	17/230 (7.39%)
Investigations
Weight decreased * 1	56/456 (12.28%)	21/230 (9.13%)
Aspartate aminotransferase increased * 1	48/456 (10.53%)	10/230 (4.35%)
Alanine aminotransferase increased * 1	47/456 (10.31%)	8/230 (3.48%)
Blood bilirubin increased * 1	33/456 (7.24%)	10/230 (4.35%)
Blood thyroid stimulating hormone increased * 1	32/456 (7.02%)	3/230 (1.30%)
Platelet count decreased * 1	27/456 (5.92%)	2/230 (0.87%)
Blood alkaline phosphatase increased * 1	24/456 (5.26%)	10/230 (4.35%)
Metabolism and nutrition disorders
Decreased appetite * 1	123/456 (26.97%)	40/230 (17.39%)
Hypokalaemia * 1	28/456 (6.14%)	4/230 (1.74%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	50/456 (10.96%)	10/230 (4.35%)
Back pain * 1	45/456 (9.87%)	17/230 (7.39%)
Pain in extremity * 1	26/456 (5.70%)	5/230 (2.17%)
Nervous system disorders
Headache * 1	40/456 (8.77%)	10/230 (4.35%)
Psychiatric disorders
Insomnia * 1	26/456 (5.70%)	12/230 (5.22%)
Renal and urinary disorders
Proteinuria * 1	79/456 (17.32%)	12/230 (5.22%)
Respiratory, thoracic and mediastinal disorders
Dysphonia * 1	74/456 (16.23%)	12/230 (5.22%)
Cough * 1	38/456 (8.33%)	21/230 (9.13%)
Dyspnoea * 1	38/456 (8.33%)	22/230 (9.57%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome * 1	88/456 (19.30%)	6/230 (2.61%)
Vascular disorders
Hypertension * 1	165/456 (36.18%)	20/230 (8.70%)
1 Term from vocabulary, MedDRA 25.0.; * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: William Schelman, MD, PhD
• Organization: Hutchison MediPharma Limited
• Phone: +1-973-306-4490
• EMail: albertof@hutch-med.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Dasari A, Sobrero A, Yao J, Yoshino T, Schelman W, Yang Z, Chien C, Kania M, Tabernero J, Eng C. FRESCO-2: a global Phase III study investigating the efficacy and safety of fruquintinib in metastatic colorectal cancer. Future Oncol. 2021 Aug;17(24):3151-3162. doi: 10.2217/fon-2021-0202. Epub 2021 May 17.

• Responsible Party: Hutchmed ( Hutchison Medipharma Limited )
• ClinicalTrials.gov Identifier: NCT04322539
• Other Study ID Numbers: 2019-013-GLOB1
• First Submitted: March 24, 2020
• First Posted: March 26, 2020
• Results First Submitted: July 28, 2023
• Results First Posted: September 14, 2023
• Last Update Posted: September 14, 2023