Trial Outcomes & Findings for A Study of Efficacy and Safety of Fruquintinib (HMPL-013) in Participants With Metastatic Colorectal Cancer (NCT NCT04322539)

Last Updated: 2025-04-04

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

691 participants

Primary outcome timeframe

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

Results posted on

2025-04-04

Participant Flow

The study was conducted at 124 study sites in the United States, Europe region, Japan, and Australia.

A total of 691 participants were randomized and enrolled in this study.

Participant milestones

Participant milestones
Measure	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).	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).
Overall Study STARTED	461	230
Overall Study Safety Population (SP)	456	230
Overall Study Pharmacokinetic (PK) Population	329	2
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	461	230

Reasons for withdrawal

Reasons for withdrawal
Measure	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).	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).
Overall Study Adverse Event	2	0
Overall Study Death	411	203
Overall Study Lost to Follow-up	3	1
Overall Study Withdrawal of consent	14	8
Overall Study Radiological Disease Progression	6	0
Overall Study Sponsor Decision	19	14
Overall Study Other	6	4

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Fruquintinib + BSC Group n=461 Participants 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).	Placebo + BSC Group n=230 Participants 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 n=691 Participants Total of all reporting groups
Age, Continuous	62.2 years STANDARD_DEVIATION 10.41 • n=5 Participants	62.4 years STANDARD_DEVIATION 9.67 • n=7 Participants	62.2 years STANDARD_DEVIATION 10.16 • n=5 Participants
Sex: Female, Male Female	216 Participants n=5 Participants	90 Participants n=7 Participants	306 Participants n=5 Participants
Sex: Female, Male Male	245 Participants n=5 Participants	140 Participants n=7 Participants	385 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	20 Participants n=5 Participants	14 Participants n=7 Participants	34 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	405 Participants n=5 Participants	202 Participants n=7 Participants	607 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	36 Participants n=5 Participants	14 Participants n=7 Participants	50 Participants n=5 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	43 Participants n=5 Participants	18 Participants n=7 Participants	61 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black or African American	13 Participants n=5 Participants	7 Participants n=7 Participants	20 Participants n=5 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Other	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	367 Participants n=5 Participants	192 Participants n=7 Participants	559 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized Race · Multiple races	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Race · Not reported/unknown	28 Participants n=5 Participants	8 Participants n=7 Participants	36 Participants n=5 Participants

PRIMARY outcome

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

Population: ITT population included all randomized participants.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=461 Participants 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).	Placebo + BSC Group n=230 Participants 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 Survival (OS)	7.4 months Interval 6.7 to 8.2	4.8 months Interval 4.0 to 5.8

SECONDARY outcome

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

Population: ITT population included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=461 Participants 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).	Placebo + BSC Group n=230 Participants 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).
Progression Free Survival (PFS), as Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1	3.7 months Interval 3.5 to 3.8	1.8 months Interval 1.8 to 1.9

SECONDARY outcome

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

Population: ITT population included all randomized participants.

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).

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=461 Participants 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).	Placebo + BSC Group n=230 Participants 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).
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	1.5 percentage of participants Interval 0.6 to 3.1	0 percentage of participants Interval 0.0 to 1.6

SECONDARY outcome

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

Population: ITT population included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=461 Participants 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).	Placebo + BSC Group n=230 Participants 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).
Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	55.5 percentage of participants Interval 50.9 to 60.1	16.1 percentage of participants Interval 11.6 to 21.5

SECONDARY outcome

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

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=7 Participants 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).	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).
Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	10.7 months Interval 3.9 to Upper limit of 95% CI was not estimable due to limited number of participants with events.	—

SECONDARY outcome

Timeframe: From start of study drug administration up to approximately 40 months

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

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=456 Participants 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).	Placebo + BSC Group n=230 Participants 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).
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs Participants with TEAEs	451 Participants	214 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs Participants with Serious TEAEs	173 Participants	88 Participants

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=312 Participants 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).	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).
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 1 - 3 hours (Plasma Concentrations of M11)	1.96 nanogram/milliliter (ng/mL) Standard Deviation 9.51	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 1 - 4 hours (Plasma Concentrations of Fruquintinib)	99.7 nanogram/milliliter (ng/mL) Standard Deviation 44.6	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 1 - 4 hours (Plasma Concentrations of M11)	2.71 nanogram/milliliter (ng/mL) Standard Deviation 10.7	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 21 - Pre-dose (Plasma Concentrations of Fruquintinib)	219 nanogram/milliliter (ng/mL) Standard Deviation 82.6	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 21 - Pre-dose (Plasma Concentrations of M11)	94.5 nanogram/milliliter (ng/mL) Standard Deviation 52.6	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 21 - 1 hour (Plasma Concentrations of Fruquintinib)	255 nanogram/milliliter (ng/mL) Standard Deviation 101	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 21 - 1 hour (Plasma Concentrations of M11)	92.0 nanogram/milliliter (ng/mL) Standard Deviation 54.3	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 21 - 2 hours (Plasma Concentrations of Fruquintinib)	279 nanogram/milliliter (ng/mL) Standard Deviation 91.6	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 21 - 2 hours (Plasma Concentrations of M11)	89.9 nanogram/milliliter (ng/mL) Standard Deviation 49.5	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 21 -3 hours (Plasma Concentrations of Fruquintinib)	293 nanogram/milliliter (ng/mL) Standard Deviation 95.2	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 21 - 3 hours (Plasma Concentrations of M11)	88.0 nanogram/milliliter (ng/mL) Standard Deviation 50.4	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 21 - 4 hours (Plasma Concentrations of Fruquintinib)	294 nanogram/milliliter (ng/mL) Standard Deviation 88.0	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 2 Day 21 - Predose (Plasma Concentrations of Fruquintinib)	222 nanogram/milliliter (ng/mL) Standard Deviation 82.0	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 2 Day 21 - Predose (Plasma Concentrations of M11)	97.6 nanogram/milliliter (ng/mL) Standard Deviation 53.7	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 2 Day 21 - 2 hours (Plasma Concentrations of Fruquintinib)	284 nanogram/milliliter (ng/mL) Standard Deviation 95.2	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 2 Day 21 - 2 hours (Plasma Concentrations of M11)	94.2 nanogram/milliliter (ng/mL) Standard Deviation 52.8	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 3 Day 1 - Pre-dose (Plasma Concentrations of Fruquintinib)	16.7 nanogram/milliliter (ng/mL) Standard Deviation 18.9	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 3 Day 1 - Pre-dose (Plasma Concentrations of M11)	22.6 nanogram/milliliter (ng/mL) Standard Deviation 18.2	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 3 Day 21 - Pre-dose (Plasma Concentrations of Fruquintinib)	212 nanogram/milliliter (ng/mL) Standard Deviation 74.6	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 3 Day 21 - Pre-dose (Plasma Concentrations of M11)	90.6 nanogram/milliliter (ng/mL) Standard Deviation 54.1	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 3 Day 21 - 2 hours (Plasma Concentrations of Fruquintinib)	275 nanogram/milliliter (ng/mL) Standard Deviation 78.6	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 3 Day 21 - 2 hours (Plasma Concentrations of M11)	92.8 nanogram/milliliter (ng/mL) Standard Deviation 54.2	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 5 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	16.9 nanogram/milliliter (ng/mL) Standard Deviation 20.5	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 7 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib	18.2 nanogram/milliliter (ng/mL) Standard Deviation 33.0	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 7 Day 1 - Pre-Dose (Plasma Concentrations of M11)	20.1 nanogram/milliliter (ng/mL) Standard Deviation 12.1	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 9 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	12.2 nanogram/milliliter (ng/mL) Standard Deviation 12.6	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 9 Day 1 - Pre-Dose (Plasma Concentrations of M11)	19.1 nanogram/milliliter (ng/mL) Standard Deviation 17.1	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 11 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	13.4 nanogram/milliliter (ng/mL) Standard Deviation 13.4	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 11 Day 1 - Pre-Dose (Plasma Concentrations of M11)	17.1 nanogram/milliliter (ng/mL) Standard Deviation 15.3	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 13 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	15.4 nanogram/milliliter (ng/mL)	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 13 Day 1 - Pre-Dose (Plasma Concentrations of M11)	23.1 nanogram/milliliter (ng/mL)	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 15 Day 1 - Pre-Dose (Plasma Concentrations of M11)	19.2 nanogram/milliliter (ng/mL)	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 17 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	10.6 nanogram/milliliter (ng/mL)	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 17 Day 1 - Pre-Dose (Plasma Concentrations of M11)	15.2 nanogram/milliliter (ng/mL)	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 1 - Pre-dose (Plasma Concentrations of Fruquintinib)	2.90 nanogram/milliliter (ng/mL) Standard Deviation 19.9	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 1 - Pre-dose (Plasma Concentrations of M11)	0.585 nanogram/milliliter (ng/mL) Standard Deviation 6.61	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 1 - 1 hour (Plasma Concentrations of Fruquintinib)	59.9 nanogram/milliliter (ng/mL) Standard Deviation 51.0	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 1 - 1 hour (Plasma Concentrations of M11)	1.06 nanogram/milliliter (ng/mL) Standard Deviation 8.36	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 1 - 2 hours (Plasma Concentrations of Fruquintinib)	91.5 nanogram/milliliter (ng/mL) Standard Deviation 48.2	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 1 - 2 hours (Plasma Concentrations of M11)	1.03 nanogram/milliliter (ng/mL) Standard Deviation 6.81	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 1 - 3 hours (Plasma Concentrations of Fruquintinib)	98.5 nanogram/milliliter (ng/mL) Standard Deviation 47.1	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 Day 21 - 4 hours (Plasma Concentrations of M11)	89.2 nanogram/milliliter (ng/mL) Standard Deviation 49.0	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 5 Day 1 - Pre-Dose (Plasma Concentrations of M11)	23.2 nanogram/milliliter (ng/mL) Standard Deviation 20.9	—
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 15 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)	10.8 nanogram/milliliter (ng/mL)	—

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=272 Participants 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).	Placebo + BSC Group n=131 Participants 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).
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 1 Day 1 - Pre-dose	1.9 millisecond (msec) Standard Deviation 21.33	0.1 millisecond (msec) Standard Deviation 17.95
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 1 Day 1 - 1 hour	-0.1 millisecond (msec) Standard Deviation 19.60	2.5 millisecond (msec) Standard Deviation 19.70
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 1 Day 1 - 2 hours	1.9 millisecond (msec) Standard Deviation 22.58	3.5 millisecond (msec) Standard Deviation 20.13
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 1 Day 1 - 3 hours	2.6 millisecond (msec) Standard Deviation 19.77	3.3 millisecond (msec) Standard Deviation 18.03
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 1 Day 1 - 4 hours	1.2 millisecond (msec) Standard Deviation 20.48	0.9 millisecond (msec) Standard Deviation 17.66
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 1 Day 21 - Pre-dose	3.2 millisecond (msec) Standard Deviation 20.94	-2.2 millisecond (msec) Standard Deviation 20.31
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 1 Day 21 - 1 hour	4.0 millisecond (msec) Standard Deviation 19.56	-0.2 millisecond (msec) Standard Deviation 16.77
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 1 Day 21 - 2 hours	5.0 millisecond (msec) Standard Deviation 20.06	2.8 millisecond (msec) Standard Deviation 18.23
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 1 Day 21 - 3 hours	5.9 millisecond (msec) Standard Deviation 19.46	0.2 millisecond (msec) Standard Deviation 14.70
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 1 Day 21 - 4 hours	3.9 millisecond (msec) Standard Deviation 20.98	-0.6 millisecond (msec) Standard Deviation 18.13
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 2 Day 21 - 2 hours	1.4 millisecond (msec) Standard Deviation 22.41	4.9 millisecond (msec) Standard Deviation 24.28
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Cycle 3 Day 21 - 2 hours	2.6 millisecond (msec) Standard Deviation 31.61	2.0 millisecond (msec) Standard Deviation 20.08

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=258 Participants 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).	Placebo + BSC Group n=122 Participants 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).
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 1 Day 1 - Pre-dose	2.9 msec Standard Deviation 39.49	0.3 msec Standard Deviation 20.55
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 1 Day 1 - 1 hour	-3.1 msec Standard Deviation 23.95	1.9 msec Standard Deviation 20.11
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 2 Day 21 - 2 hours	1.7 msec Standard Deviation 40.61	5.9 msec Standard Deviation 24.96
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 3 Day 21 - 2 hours	4.2 msec Standard Deviation 72.35	1.6 msec Standard Deviation 22.06
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 1 Day 1 - 2 hours	-2.0 msec Standard Deviation 23.95	1.9 msec Standard Deviation 20.11
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 1 Day 1 - 3 hours	-0.9 msec Standard Deviation 24.47	3.9 msec Standard Deviation 19.75
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 1 Day 1 - 4 hours	-1.9 msec Standard Deviation 24.47	2.4 msec Standard Deviation 20.11
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 1 Day 21 - Pre-dose	3.9 msec Standard Deviation 49.99	5.0 msec Standard Deviation 50.43
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 1 Day 21 - 1 hour	-1.3 msec Standard Deviation 25.60	0.9 msec Standard Deviation 20.48
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 1 Day 21 - 2 hours	1.6 msec Standard Deviation 42.28	4.3 msec Standard Deviation 19.57
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 1 Day 21 - 3 hours	1.2 msec Standard Deviation 25.41	2.9 msec Standard Deviation 18.29
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Cycle 1 Day 21 - 4 hours	0.2 msec Standard Deviation 25.91	2.8 msec Standard Deviation 20.13

SECONDARY outcome

Timeframe: Up to 22 months

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=368 Participants 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).	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).
Correlation Between Fruquintinib Exposure (CminSS) and Efficacy Parameters (OS) CminSS Coefficient Based on the Starting Dose for OS Exposure-Response Analyses	0.00193 1/(ng/mL)	—
Correlation Between Fruquintinib Exposure (CminSS) and Efficacy Parameters (OS) CminSS Coefficient Based on the Adjusted RDI for OS Exposure-Response Analyses	0.000407 1/(ng/mL)	—

SECONDARY outcome

Timeframe: Up to 22 months

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=515 Participants 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).	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).
Correlation Between Fruquintinib Exposure (CmaxSS) and Safety Parameters (Any Grade [Gr] and Grade 3+ (Gr3+): Dermatological Toxicity, Proteinuria and Gr Hemorrhage) CmaxSS Coefficient for Gr Dermatological toxicity for Exposure-Response Analyses	0.00134 1/(ng/mL)	—
Correlation Between Fruquintinib Exposure (CmaxSS) and Safety Parameters (Any Grade [Gr] and Grade 3+ (Gr3+): Dermatological Toxicity, Proteinuria and Gr Hemorrhage) CmaxSS Coefficient for Gr3+ Dermatological Toxicity for Exposure-Response Analyses	0.00411 1/(ng/mL)	—
Correlation Between Fruquintinib Exposure (CmaxSS) and Safety Parameters (Any Grade [Gr] and Grade 3+ (Gr3+): Dermatological Toxicity, Proteinuria and Gr Hemorrhage) CmaxSS Coefficient for Gr Proteinuria for Exposure-Response Analyses	-0.00101 1/(ng/mL)	—
Correlation Between Fruquintinib Exposure (CmaxSS) and Safety Parameters (Any Grade [Gr] and Grade 3+ (Gr3+): Dermatological Toxicity, Proteinuria and Gr Hemorrhage) CmaxSS Coefficient for Gr Hemorrhage for Exposure-Response Analyses	0.00180 1/(ng/mL)	—
Correlation Between Fruquintinib Exposure (CmaxSS) and Safety Parameters (Any Grade [Gr] and Grade 3+ (Gr3+): Dermatological Toxicity, Proteinuria and Gr Hemorrhage) CmaxSS Coefficient for Gr3+ Proteinuria for Exposure-Response Analyses	0.00143 1/(ng/mL)	—

SECONDARY outcome

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

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=330 Participants 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).	Placebo + BSC Group n=149 Participants 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).
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 Cycle 2	-2.1 score on a scale Standard Error 1.59	-3.7 score on a scale Standard Error 1.95
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 Cycle 3	-4.5 score on a scale Standard Error 1.69	-6.1 score on a scale Standard Error 2.54
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 Cycle 4	-4.2 score on a scale Standard Error 1.76	-2.1 score on a scale Standard Error 3.03

SECONDARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=388 Participants 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).	Placebo + BSC Group n=230 Participants 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).
Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scale (VAS) Score Cycle 2	-0.3 score on a scale Standard Error 1.38	-0.9 score on a scale Standard Error 1.69
Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scale (VAS) Score Cycle 3	-1.1 score on a scale Standard Error 1.48	-2.5 score on a scale Standard Error 2.22
Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scale (VAS) Score Cycle 4	-4.0 score on a scale Standard Error 1.59	-2.1 score on a scale Standard Error 2.79

SECONDARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=337 Participants 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).	Placebo + BSC Group n=151 Participants 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).
Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Health Utility Index Scores Cycle 2	0.0 score on a scale Standard Error 0.01	0.0 score on a scale Standard Error 0.02
Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Health Utility Index Scores Cycle 3	0.0 score on a scale Standard Error 0.01	0.0 score on a scale Standard Error 0.02
Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Health Utility Index Scores Cycle 4	-0.1 score on a scale Standard Error 0.02	0.0 score on a scale Standard Error 0.03

SECONDARY outcome

Timeframe: From start of study drug administration up to 22 months

Population: ITT population included all randomized 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.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=545 Number of visits 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).	Placebo + BSC Group n=232 Number of visits 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).
Health Care Resource Utilization: Duration of Hospital Visits by Participants	3.3 days per visit Standard Deviation 6.81	4.4 days per visit Standard Deviation 7.53

SECONDARY outcome

Timeframe: From start of study drug administration up to 22 months

Population: ITT population included all randomized participants.

Number of participants with any concomitant medications prescribed were reported.

Outcome measures

Outcome measures
Measure	Fruquintinib + BSC Group n=461 Participants 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).	Placebo + BSC Group n=230 Participants 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).
Health Care Resource Utilization: Number of Participants With Any Concomitant Medications Prescribed	116 Participants	63 Participants

Adverse Events

Fruquintinib + BSC Group

Serious events: 173 serious events

Other events: 446 other events

Deaths: 411 deaths

Placebo + BSC Group

Serious events: 88 serious events

Other events: 205 other events

Deaths: 203 deaths

Serious adverse events

Other adverse events

Additional Information

William Schelman, MD, PhD

HUTCHMED International

Phone: +1-973-306-4490

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place