Colorectal Cancer, Endometrial Cancer, Solid Tumor, Unspecified, Adult, Triple Negative Breast Cancer
Conditions
Keywords
Breast cancer, Triple negative, Her2-, HR-, ER-, PR-, Her2 negative, HR negative, ER negative, PR negative, TNBC, VEGF, VEGFR, Endometrial cancer, Colon, Rectal, mCRC, Colorectal
Brief summary
This is an open-label, multi-center, non-randomized, Phase 1b/2 study to assess the safety and efficacy of fruquintinib in combination with tislelizumab in patients with locally advanced or metastatic solid tumors. This study will be conducted in 2 parts; a Safety Lead-in Phase (Part 1) and a Dose Expansion Phase (Part 2). The Safety Lead-in Phase, open to any-comer solid tumors, will determine the RP2D. The RP2D will be administered to 3 cohorts of patients in the Dose Expansion Phase. * Cohort A: Advanced or Metastatic Triple Negative Breast Cancer (TNBC) (IO-treated) * Cohort B: Advanced or Metastatic Triple Negative Breast Cancer (TNBC) (IO-Naïve) * Cohort C: Advanced or Metastatic Endometrial Cancer (EC) (IO-Naïve) * Cohort D: Advanced or Metastatic Colorectal Cancer (mCRC) (IO-Naïve)
Interventions
DRUGFruquintinib
Oral VEGFR inhibitor
DRUGTislelizumab
PD-1 inhibitor
Sponsors
BeiGene
Hutchmed
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Willing and able to provide informed consent signed by study patient or legally acceptable representative, as specified by health authorities and institutional guidelines; 2. Age ≥18 years; 3. Histologically or cytologically documented, advanced or metastatic Triple Negative Breast Cancer, histologically or cytologically documented, advanced or metastatic endometrial carcinoma, histologically or cytologically confirmed advanced or metastatic, unresectable adenocarcinoma of the colon or rectum. 4. Tumor tissue (archival or fresh tumor tissues as formalin-fixed paraffin-embedded blocks or approximately 15 unstained slides) for central laboratory assessment. 5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1. 6. At least 1 measurable lesion as defined by RECIST v1.1.
Exclusion criteria
1. Has at screening any central nervous system metastasis and/or leptomeningeal disease. 2. Except for Cohort A, Prior therapy targeting CTLA-4, PD-1, PD-L1 or programmed cell death protein ligand-2 (PD-L2) or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways. 3. Prior treatment with a VEGFR-TKI or anti-VEGFR antibody (eg, ramucirumab). 4. Except for Cohort D, prior treatment with an anti-VEGFR antibody (eg, bevacizumab). 5. Tumor tissue (archival or fresh tumor tissues as formalin-fixed paraffin-embedded blocks or approximately 15 unstained slides) for central laboratory assessment. 6. Active autoimmune diseases or history of autoimmune diseases that may relapse, or history of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases including but not limited to pulmonary fibrosis, acute lung diseases, etc. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Patients With Dose-Limiting Toxicities (DLTs) | From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (cycle duration: 4 weeks) | According to National Cancer Institute Common Terminology Criteria for Adverse Events(AEs) v5.0, DLT was defined as any 1 of following toxicities during DLT assessment window and considered by Investigator to be related to 1 or more study treatments:a)Hematologic: grade(G) 4 neutropenia lasting \>7 days, G ≥3 febrile neutropenia, G 3 thrombocytopenia with clinically significant bleeding, G 4 thrombocytopenia, G ≥4 anemia.b) Non-hematologic:all G ≥3 non-hematologic toxicities except:G 3 endocrinopathy controlled by hormonal replacement with no hospitalization and resolved to G ≤1 within 7 days, G 3 nausea/vomiting or diarrhea for \<72 hours with antiemetic and supportive care, G 3 fatigue for \<1 week, G ≥3 electrolyte abnormality lasting up to 72 hours and resolving with treatment, G 3 rash returning to baseline or G ≤1 within 7 days with treatment,G ≥3 amylase or lipase elevation without symptoms of pancreatitis,G 3 hypertension returning to baseline or G≤1 within 7 days with treatment. |
| Part 1: Recommended Phase 2 Dose (RP2D) of Fruquintinib in Combination With Tislelizumab | From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (cycle duration: 4 weeks) | The RP2D of fruquintinib in combination with tislelizumab based on the safety and tolerability assessments in Part 1 patients. |
| Part 2: Objective Response Rate (ORR) | Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months | The ORR was defined as the percentage of patients with a confirmed best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator using RECIST v1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 millimeters (mm). The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts 1 and 2: Clinical Benefit Rate (CBR) | Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months | The CBR was defined as the percentage of patients with a BOR of CR, PR, or durable SD (i.e., lasting for at least 6 months) as determined by the investigator using RECIST v1.1. Durable SD was SD for at least 6 months. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study. |
| Parts 1 and 2: Duration of Response (DoR) | Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months | The DoR was defined as the time from the first occurrence of PR or CR by RECIST v1.1, whichever came first until PD or death. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The 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 (nadir), including baseline. In addition to the relative increase of 20%, the sum also demonstrated an absolute increase of at least 5 mm. The appearance of 1 or more new lesions was also considered progression. |
| Parts 1 and 2: Overall Survival (OS) | From the first dose of study treatment (Day 1) up to date of death due to any cause, up to a maximum of approximately 34 months | The OS was defined as the time from start of study treatment until the date of death due to any cause. |
| Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Pre-dose on Days 1, 8, 15, 21 of Cycle 1 and on Day 1 of Cycles 2, 4, 7, 13; 2 to 4 hours post-dose on Days 1 and 21 of Cycle 1 (cycle duration: 4 weeks) | Blood samples were collected at the specified timepoints to determine plasma concentrations of fruquintinib and metabolite M11. |
| Part 1: Objective Response Rate | Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months | The ORR was defined as the percentage of patients with a confirmed BOR of CR or PR as determined by the investigator using RECIST v1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. |
| Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab | From the first dose of study treatment (Day 1) up to end of treatment, up to approximately 17 months for Part 1 and 20 months for Part 2 | Blood samples were collected at the specified timepoints to detect ADAs to tislelizumab. Treatment-induced ADA was defined as ADA negative at baseline and ADA positive post-baseline. Treatment-boosted ADA was defined as ADA positive at baseline that was boosted to a 4-fold or higher-level following treatment administration. |
| Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 21 months | An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment, whether or not considered related to the treatment. An AE was considered serious if, in the view of either the investigator or sponsor, it resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, was a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, was an abnormal pregnancy outcome in a child born to a female patient/female partner of a male patient exposed to study treatment or was an important medical event. TEAEs were AEs that started or worsened in severity on or after the first dose of study treatment and up to 30 days after the date of last study treatment administration. |
| Part 2: Change From Baseline in Programmed Death-Ligand 1 (PD-L1) Expression | Baseline (Day 1) up to end of treatment, up to approximately 20 months | Expression of PD-L1 biomarker was planned to be assessed in tumor tissues of the patients. Baseline was defined as the last non-missing assessment prior to the first administration of any study treatment (whichever occurred first), including scheduled and unscheduled visits, unless otherwise specified. |
| Parts 1 and 2: Serum Concentrations of Tislelizumab | Pre-infusion on Day 1 of Cycles 1, 2, 4, 7, 13; at end of infusion on Day 1 of Cycles 1 and 4; on Days 8, 15, and 21 of Cycle 1 (cycle duration: 4 weeks) | Blood samples were collected at the specified timepoints to determine serum concentrations of tislelizumab. |
| Parts 1 and 2: Progression-free Survival (PFS) | Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months | PFS was defined as the time from the start of study treatment until the first radiographic documentation of objective progression as assessed by the investigator using RECIST v1.1, or death from any cause. The 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 (nadir), including baseline. In addition to the relative increase of 20%, the sum also demonstrated an absolute increase of at least 5 mm. The appearance of 1 or more new lesions was also considered progression. |
| Parts 1 and 2: Disease Control Rate (DCR) | Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months | The DCR was defined as the percentage of patients with a BOR of CR, PR, or stable disease (SD) lasting for at least 7 weeks as determined by the investigator using RECIST v1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study. |
Countries
United States
Participant flow
Recruitment details
This phase 1b/2, 2-part, open-label study was conducted in patients with advanced or metastatic solid tumors.
Pre-assignment details
The study consisted of a safety lead-in phase (Part 1) and a dose expansion phase (Part 2). A total of 52 patients were enrolled in this study (6 patients received study treatment in Part 1 and 46 patients received study treatment in Part 2). The study was terminated early based upon the strategic evaluation of clinical development of fruquintinib in the United States. This change was not based on any concern for patient safety or efficacy relative to fruquintinib and/or tislelizumab treatment.
Participants by arm
| Arm | Count |
|---|---|
| Part 2: Cohort A: TNBC (IO-Treated in the Metastatic Setting) Patients with advanced or metastatic TNBC including those with ER or PGR low positive disease who had progressed on at least 1 line, but no more than 3 lines, of cytotoxic therapy in the locally advanced or metastatic setting and had progressed on prior immunotherapy in the metastatic setting were included in this cohort. Patients received fruquintinib 5 mg orally QD for 3 weeks, followed by 1 week off in every 4-week cycle in combination with tislelizumab 300 mg IV infusion Q4W until radiologically determined PD per RECIST v 1.1, unacceptable toxicity, death, or withdrawal from study. | 1 |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) Patients with locally advanced or metastatic TNBC including those with ER or PGR low positive disease who had progressed on at least 1 line, but no more than 3 lines, of cytotoxic therapy in the locally advanced or metastatic setting and had not received prior therapy with an ICI or other immunotherapy in the metastatic setting were included in this cohort. Patients received fruquintinib 5 mg orally QD for 3 weeks, followed by 1 week off in every 4-week cycle in combination with tislelizumab 300 mg IV infusion Q4W until radiologically determined PD per RECIST v 1.1, unacceptable toxicity, death, or withdrawal from study. | 11 |
| Part 2: Cohort C: EC (IO-Naïve) Patients with advanced or metastatic EC who had progressed on 1 prior, platinum-based chemotherapy regimen for EC and had not received prior therapy with an ICI or other immunotherapy were included in this cohort. Patients received fruquintinib 5 mg orally QD for 3 weeks, followed by 1 week off in every 4-week cycle in combination with tislelizumab 300 mg IV infusion Q4W until radiologically determined PD per RECIST v 1.1, unacceptable toxicity, death, or withdrawal from study. | 1 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) Patients with unresectable advanced or metastatic MSS CRC who had failed 2 lines of standard chemotherapies, including fluorouracil, oxaliplatin, irinotecan and had received anti-VEGF (if RAS: wild-type tumor, mutated or status unknown) or EGFR (if RAS wild-type tumor) antibody treatment were included in this cohort. Patients received fruquintinib 5 mg orally QD for 3 weeks, followed by 1 week off in every 4-week cycle in combination with tislelizumab 300 mg IV infusion Q4W until radiologically determined PD per RECIST v 1.1, unacceptable toxicity, death, or withdrawal from study. | 39 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Part 2 | Death | 0 | 1 | 8 | 0 | 20 |
| Part 2 | Investigator decision | 0 | 0 | 0 | 0 | 1 |
| Part 2 | Lost to Follow-up | 0 | 0 | 0 | 0 | 2 |
| Part 2 | Progressive disease | 0 | 0 | 0 | 0 | 2 |
| Part 2 | Sponsor terminated study | 0 | 0 | 3 | 1 | 4 |
| Part 2 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 10 |
Baseline characteristics
| Characteristic | Part 2: Cohort A: TNBC (IO-Treated in the Metastatic Setting) | Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Part 2: Cohort C: EC (IO-Naïve) | Part 2: Cohort D: MSS mCRC (IO-Naïve) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 1 Participants | 7 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 8 Participants | 0 Participants | 32 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 9 Participants | 1 Participants | 32 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) White | 1 Participants | 10 Participants | 1 Participants | 31 Participants | 43 Participants |
| Sex: Female, Male Female | 1 Participants | 11 Participants | 1 Participants | 12 Participants | 25 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 27 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 8 / 11 | 0 / 1 | 20 / 39 |
| other Total, other adverse events | 1 / 1 | 11 / 11 | 1 / 1 | 39 / 39 |
| serious Total, serious adverse events | 0 / 1 | 2 / 11 | 1 / 1 | 20 / 39 |
Outcome results
Primary
Part 1: Number of Patients With Dose-Limiting Toxicities (DLTs)
According to National Cancer Institute Common Terminology Criteria for Adverse Events(AEs) v5.0, DLT was defined as any 1 of following toxicities during DLT assessment window and considered by Investigator to be related to 1 or more study treatments:a)Hematologic: grade(G) 4 neutropenia lasting \>7 days, G ≥3 febrile neutropenia, G 3 thrombocytopenia with clinically significant bleeding, G 4 thrombocytopenia, G ≥4 anemia.b) Non-hematologic:all G ≥3 non-hematologic toxicities except:G 3 endocrinopathy controlled by hormonal replacement with no hospitalization and resolved to G ≤1 within 7 days, G 3 nausea/vomiting or diarrhea for \<72 hours with antiemetic and supportive care, G 3 fatigue for \<1 week, G ≥3 electrolyte abnormality lasting up to 72 hours and resolving with treatment, G 3 rash returning to baseline or G ≤1 within 7 days with treatment,G ≥3 amylase or lipase elevation without symptoms of pancreatitis,G 3 hypertension returning to baseline or G≤1 within 7 days with treatment.
Time frame: From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (cycle duration: 4 weeks)
Population: The DLT-evaluable analysis set included all patients enrolled in Part 1 of the study who received at least 1 dose of fruquintinib or tislelizumab and were considered DLT-evaluable based on the safety review committee review, according to the pre-specified criteria from the protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Part 1: Number of Patients With Dose-Limiting Toxicities (DLTs) | 1 Participants |
Primary
Part 1: Recommended Phase 2 Dose (RP2D) of Fruquintinib in Combination With Tislelizumab
The RP2D of fruquintinib in combination with tislelizumab based on the safety and tolerability assessments in Part 1 patients.
Time frame: From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (cycle duration: 4 weeks)
Population: The SAS included all enrolled patients who received at least 1 dose of fruquintinib or tislelizumab. As pre-specified in SAP, all patients from Part 1 were also included in the relevant Cohorts in Part 2 based on their tumor type.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Part 1: Recommended Phase 2 Dose (RP2D) of Fruquintinib in Combination With Tislelizumab | 5 mg |
Primary
Part 2: Objective Response Rate (ORR)
The ORR was defined as the percentage of patients with a confirmed best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator using RECIST v1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 millimeters (mm). The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
Population: The SAS included all enrolled patients who received at least 1 dose of fruquintinib or tislelizumab. As pre-specified in SAP, all patients from Part 1 were also included in the relevant Cohorts in Part 2 based on their tumor type.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Part 2: Objective Response Rate (ORR) | 0 percentage of patients |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Part 2: Objective Response Rate (ORR) | 27.3 percentage of patients |
| Part 2: Cohort C: EC (IO-Naïve) | Part 2: Objective Response Rate (ORR) | 0 percentage of patients |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Part 2: Objective Response Rate (ORR) | 5.1 percentage of patients |
Secondary
Part 1: Objective Response Rate
The ORR was defined as the percentage of patients with a confirmed BOR of CR or PR as determined by the investigator using RECIST v1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
Population: The SAS included all enrolled patients who received at least 1 dose of fruquintinib or tislelizumab. As pre-specified in SAP, all patients from Part 1 were also included in the relevant Cohorts in Part 2 based on their tumor type.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Part 1: Objective Response Rate | 16.7 percentage of patients |
Secondary
Part 2: Change From Baseline in Programmed Death-Ligand 1 (PD-L1) Expression
Expression of PD-L1 biomarker was planned to be assessed in tumor tissues of the patients. Baseline was defined as the last non-missing assessment prior to the first administration of any study treatment (whichever occurred first), including scheduled and unscheduled visits, unless otherwise specified.
Time frame: Baseline (Day 1) up to end of treatment, up to approximately 20 months
Population: The SAS included all enrolled patients who received at least 1 dose of fruquintinib or tislelizumab. Based upon the strategic evaluation of clinical development of fruquintinib in the United States, the study was early terminated prior to data collection for this outcome measure.
Secondary
Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation
An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment, whether or not considered related to the treatment. An AE was considered serious if, in the view of either the investigator or sponsor, it resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, was a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, was an abnormal pregnancy outcome in a child born to a female patient/female partner of a male patient exposed to study treatment or was an important medical event. TEAEs were AEs that started or worsened in severity on or after the first dose of study treatment and up to 30 days after the date of last study treatment administration.
Time frame: From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 21 months
Population: The SAS included all enrolled patients who received at least 1 dose of fruquintinib or tislelizumab. As pre-specified in SAP, all patients from Part 1 were also included in the relevant Cohorts in Part 2 based on their tumor type.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs | 1 Participants |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TESAEs | 0 Participants |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs leading to fruquintinib treatment discontinuation | 1 Participants |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs leading to tislelizumab treatment discontinuation | 1 Participants |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TESAEs | 2 Participants |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs leading to fruquintinib treatment discontinuation | 1 Participants |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs leading to tislelizumab treatment discontinuation | 1 Participants |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs | 11 Participants |
| Part 2: Cohort C: EC (IO-Naïve) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs leading to fruquintinib treatment discontinuation | 1 Participants |
| Part 2: Cohort C: EC (IO-Naïve) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TESAEs | 1 Participants |
| Part 2: Cohort C: EC (IO-Naïve) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs leading to tislelizumab treatment discontinuation | 0 Participants |
| Part 2: Cohort C: EC (IO-Naïve) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs | 1 Participants |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs leading to tislelizumab treatment discontinuation | 9 Participants |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TESAEs | 20 Participants |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs | 39 Participants |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | TEAEs leading to fruquintinib treatment discontinuation | 9 Participants |
Secondary
Parts 1 and 2: Clinical Benefit Rate (CBR)
The CBR was defined as the percentage of patients with a BOR of CR, PR, or durable SD (i.e., lasting for at least 6 months) as determined by the investigator using RECIST v1.1. Durable SD was SD for at least 6 months. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
Population: The SAS included all enrolled patients who received at least 1 dose of fruquintinib or tislelizumab. As pre-specified in SAP, all patients from Part 1 were also included in the relevant Cohorts in Part 2 based on their tumor type.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Clinical Benefit Rate (CBR) | 16.7 percentage of patients |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Clinical Benefit Rate (CBR) | 0 percentage of patients |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Clinical Benefit Rate (CBR) | 27.3 percentage of patients |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Clinical Benefit Rate (CBR) | 0 percentage of patients |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Clinical Benefit Rate (CBR) | 20.5 percentage of patients |
Secondary
Parts 1 and 2: Disease Control Rate (DCR)
The DCR was defined as the percentage of patients with a BOR of CR, PR, or stable disease (SD) lasting for at least 7 weeks as determined by the investigator using RECIST v1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
Population: The SAS included all enrolled patients who received at least 1 dose of fruquintinib or tislelizumab. As pre-specified in SAP, all patients from Part 1 were also included in the relevant Cohorts in Part 2 based on their tumor type.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Disease Control Rate (DCR) | 50.0 percentage of patients |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Disease Control Rate (DCR) | 0 percentage of patients |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Disease Control Rate (DCR) | 72.7 percentage of patients |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Disease Control Rate (DCR) | 100 percentage of patients |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Disease Control Rate (DCR) | 53.8 percentage of patients |
Secondary
Parts 1 and 2: Duration of Response (DoR)
The DoR was defined as the time from the first occurrence of PR or CR by RECIST v1.1, whichever came first until PD or death. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The 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 (nadir), including baseline. In addition to the relative increase of 20%, the sum also demonstrated an absolute increase of at least 5 mm. The appearance of 1 or more new lesions was also considered progression.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
Population: The SAS included all enrolled patients who received at least 1 dose of fruquintinib or tislelizumab. As pre-specified in SAP, all patients from Part 1 were also included in the relevant Cohorts in Part 2 based on their tumor type. Only those patients with PR or CR (responders) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Duration of Response (DoR) | 14.9 months |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Duration of Response (DoR) | 14.9 months |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Duration of Response (DoR) | NA months |
Secondary
Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab
Blood samples were collected at the specified timepoints to detect ADAs to tislelizumab. Treatment-induced ADA was defined as ADA negative at baseline and ADA positive post-baseline. Treatment-boosted ADA was defined as ADA positive at baseline that was boosted to a 4-fold or higher-level following treatment administration.
Time frame: From the first dose of study treatment (Day 1) up to end of treatment, up to approximately 17 months for Part 1 and 20 months for Part 2
Population: The ADA analysis set included all patients who received at least 1 dose of tislelizumab and had a baseline and at least 1 post-baseline ADA result. As pre-specified in SAP, all patients from Part 1 were also included in the relevant Cohorts in Part 2 based on their tumor type.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab | Treatment-Induced ADA | 2 Participants |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab | Treatment-Induced ADA | 0 Participants |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab | Treatment-Induced ADA | 3 Participants |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab | Treatment-Induced ADA | 0 Participants |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab | Treatment-Induced ADA | 10 Participants |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab | Treatment-Boosted ADA | 2 Participants |
Secondary
Parts 1 and 2: Overall Survival (OS)
The OS was defined as the time from start of study treatment until the date of death due to any cause.
Time frame: From the first dose of study treatment (Day 1) up to date of death due to any cause, up to a maximum of approximately 34 months
Population: The SAS included all enrolled patients who received at least 1 dose of fruquintinib or tislelizumab. As pre-specified in SAP, all patients from Part 1 were also included in the relevant Cohorts in Part 2 based on their tumor type.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Overall Survival (OS) | 16.4 months |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Overall Survival (OS) | 25.8 months |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Overall Survival (OS) | 14.1 months |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Overall Survival (OS) | NA months |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Overall Survival (OS) | 10.2 months |
Secondary
Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11
Blood samples were collected at the specified timepoints to determine plasma concentrations of fruquintinib and metabolite M11.
Time frame: Pre-dose on Days 1, 8, 15, 21 of Cycle 1 and on Day 1 of Cycles 2, 4, 7, 13; 2 to 4 hours post-dose on Days 1 and 21 of Cycle 1 (cycle duration: 4 weeks)
Population: The pharmacokinetic (PK) analysis set included all patients with at least 1 quantifiable plasma or serum concentration of fruquintinib and/or tislelizumab. Only unique patients in Parts 1 and 2 were considered for PK analysis. Cohort A did not enroll any unique patients in Part 2. Only patients who had a quantifiable plasma/serum concentration of fruquintinib at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 1: 2 to 4 hours post-dose | 0 nanograms per milliliter | Standard Deviation 0 |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 21: 2 to 4 hours post-dose | 327 nanograms per milliliter | — |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 1: 2 to 4 hours post-dose | 5.49 nanograms per milliliter | — |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 21: Pre-dose | 148 nanograms per milliliter | — |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 1: Pre-dose | 0 nanograms per milliliter | Standard Deviation 0 |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 21: 2 to 4 hours post-dose | 124 nanograms per milliliter | — |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 21: Pre-dose | 252 nanograms per milliliter | — |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 1: Pre-dose | 0 nanograms per milliliter | Standard Deviation 0 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 15: Pre-dose | 240 nanograms per milliliter | Standard Deviation 72.7 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 21: Pre-dose | 216 nanograms per milliliter | Standard Deviation 59.5 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 21: Pre-dose | 106 nanograms per milliliter | Standard Deviation 40 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 21: 2 to 4 hours post-dose | 327 nanograms per milliliter | — |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 2 Day 1: Pre-dose | 23.2 nanograms per milliliter | Standard Deviation 15.3 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 4 Day 1: Pre-dose | 16.6 nanograms per milliliter | — |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 15: Pre-dose | 87.3 nanograms per milliliter | Standard Deviation 32.4 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 8: Pre-dose | 84.2 nanograms per milliliter | Standard Deviation 53.5 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 4 Day 1: Pre-dose | 5.12 nanograms per milliliter | — |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 1: 2 to 4 hours post-dose | 0.415 nanograms per milliliter | Standard Deviation 0.643 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 1: Pre-dose | 0 nanograms per milliliter | Standard Deviation 0 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 1: 2 to 4 hours post-dose | 56.2 nanograms per milliliter | Standard Deviation 52.9 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 1: Pre-dose | 0 nanograms per milliliter | Standard Deviation 0 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 2 Day 1: Pre-dose | 30.8 nanograms per milliliter | Standard Deviation 12.6 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 8: Pre-dose | 222 nanograms per milliliter | Standard Deviation 29 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 21: 2 to 4 hours post-dose | 124 nanograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 1: 2 to 4 hours post-dose | 2.71 nanograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 1: Pre-dose | 0 nanograms per milliliter | Standard Deviation 0 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 1: 2 to 4 hours post-dose | 125 nanograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 15: Pre-dose | 263 nanograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 2 Day 1: Pre-dose | 15.2 nanograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 1: Pre-dose | 0 nanograms per milliliter | Standard Deviation 0 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 15: Pre-dose | 139 nanograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 2 Day 1: Pre-dose | 40.5 nanograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 1: Pre-dose | 0 nanograms per milliliter | Standard Deviation 0 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 1: 2 to 4 hours post-dose | 0.413 nanograms per milliliter | Standard Deviation 0.766 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 4 Day 1: Pre-dose | 15.3 nanograms per milliliter | Standard Deviation 8.89 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 8: Pre-dose | 60.7 nanograms per milliliter | Standard Deviation 34.7 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 2 Day 1: Pre-dose | 17.0 nanograms per milliliter | Standard Deviation 17.7 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 7 Day 1: Pre-dose | 31.4 nanograms per milliliter | Standard Deviation 8.6 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 15: Pre-dose | 74.6 nanograms per milliliter | Standard Deviation 45.9 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 21: 2 to 4 hours post-dose | 267 nanograms per milliliter | Standard Deviation 66.4 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 21: Pre-dose | 186 nanograms per milliliter | Standard Deviation 51.4 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 21: Pre-dose | 66.1 nanograms per milliliter | Standard Deviation 28 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 15: Pre-dose | 177 nanograms per milliliter | Standard Deviation 37.7 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 8: Pre-dose | 195 nanograms per milliliter | Standard Deviation 57 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 1 Day 21: 2 to 4 hours post-dose | 69.1 nanograms per milliliter | Standard Deviation 25.4 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 1: 2 to 4 hours post-dose | 70.7 nanograms per milliliter | Standard Deviation 34.3 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 13 Day 1: Pre-dose | 11.7 nanograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 2 Day 1: Pre-dose | 20.5 nanograms per milliliter | Standard Deviation 14.4 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 1 Day 1: Pre-dose | 0 nanograms per milliliter | Standard Deviation 0 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | M11: Cycle 4 Day 1: Pre-dose | 19.3 nanograms per milliliter | Standard Deviation 10.4 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 13 Day 1: Pre-dose | 12.3 nanograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 | Fruquintinib: Cycle 7 Day 1: Pre-dose | 28.6 nanograms per milliliter | Standard Deviation 19.1 |
Secondary
Parts 1 and 2: Progression-free Survival (PFS)
PFS was defined as the time from the start of study treatment until the first radiographic documentation of objective progression as assessed by the investigator using RECIST v1.1, or death from any cause. The 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 (nadir), including baseline. In addition to the relative increase of 20%, the sum also demonstrated an absolute increase of at least 5 mm. The appearance of 1 or more new lesions was also considered progression.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
Population: The SAS included all enrolled patients who received at least 1 dose of fruquintinib or tislelizumab. As pre-specified in SAP, all patients from Part 1 were also included in the relevant Cohorts in Part 2 based on their tumor type.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Progression-free Survival (PFS) | 3.8 months |
| Part 2: Cohort B: TNBC (IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Progression-free Survival (PFS) | NA months |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Progression-free Survival (PFS) | 5.0 months |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Progression-free Survival (PFS) | 5.5 months |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Progression-free Survival (PFS) | 3.6 months |
Secondary
Parts 1 and 2: Serum Concentrations of Tislelizumab
Blood samples were collected at the specified timepoints to determine serum concentrations of tislelizumab.
Time frame: Pre-infusion on Day 1 of Cycles 1, 2, 4, 7, 13; at end of infusion on Day 1 of Cycles 1 and 4; on Days 8, 15, and 21 of Cycle 1 (cycle duration: 4 weeks)
Population: The PK analysis set included all patients with at least 1 quantifiable plasma or serum concentration of fruquintinib and/or tislelizumab. Only unique patients in Parts 1 and 2 were considered for PK analysis. Cohort A did not enroll any unique patients in Part 2. Only patients who had a quantifiable plasma/serum concentration of tislelizumab at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 2 Day 1: Pre-infusion | 22.2 micrograms per milliliter | Standard Deviation 8.27 |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 4 Day 1: Pre-infusion | 29.9 micrograms per milliliter | Standard Deviation 11.8 |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 15 | 34.3 micrograms per milliliter | Standard Deviation 11.2 |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 4 Day 1: End of infusion | 158 micrograms per milliliter | Standard Deviation 47.6 |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 21 | 27.3 micrograms per milliliter | Standard Deviation 13.1 |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 1: End of infusion | 105 micrograms per milliliter | Standard Deviation 23.5 |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 8 | 49.5 micrograms per milliliter | Standard Deviation 12.7 |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 13 Day 1: Pre-infusion | 45.9 micrograms per milliliter | — |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 7 Day 1: Pre-infusion | 57.2 micrograms per milliliter | — |
| Part 1: Solid Tumor of Any Type (IO-Treated/IO-Naïve in the Metastatic Setting) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 1: Pre-infusion | 0 micrograms per milliliter | Standard Deviation 0 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 15 | 31.4 micrograms per milliliter | Standard Deviation 7.63 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 4 Day 1: End of infusion | 172 micrograms per milliliter | Standard Deviation 7.78 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 7 Day 1: Pre-infusion | 50.0 micrograms per milliliter | Standard Deviation 31 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 8 | 54.4 micrograms per milliliter | Standard Deviation 15.1 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 13 Day 1: Pre-infusion | 26.0 micrograms per milliliter | — |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 1: Pre-infusion | 0 micrograms per milliliter | Standard Deviation 0 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 21 | 28.1 micrograms per milliliter | Standard Deviation 6.58 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 1: End of infusion | 101 micrograms per milliliter | Standard Deviation 22.7 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 2 Day 1: Pre-infusion | 19.3 micrograms per milliliter | Standard Deviation 10.5 |
| Part 2: Cohort C: EC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 4 Day 1: Pre-infusion | 41.0 micrograms per milliliter | Standard Deviation 15.5 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 4 Day 1: Pre-infusion | 46.6 micrograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 2 Day 1: Pre-infusion | 21.5 micrograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 1: End of infusion | 74.0 micrograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 15 | 36.7 micrograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 4 Day 1: End of infusion | 137 micrograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 1: Pre-infusion | 0 micrograms per milliliter | Standard Deviation 0 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 8 | 45.2 micrograms per milliliter | — |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 13 Day 1: Pre-infusion | 34.9 micrograms per milliliter | Standard Deviation 7.32 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 1: Pre-infusion | 0 micrograms per milliliter | Standard Deviation 0 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 1: End of infusion | 78.3 micrograms per milliliter | Standard Deviation 19.9 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 8 | 39.2 micrograms per milliliter | Standard Deviation 10 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 15 | 27.7 micrograms per milliliter | Standard Deviation 8.72 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 1 Day 21 | 20.3 micrograms per milliliter | Standard Deviation 5.58 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 2 Day 1: Pre-infusion | 15.1 micrograms per milliliter | Standard Deviation 5.14 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 4 Day 1: Pre-infusion | 25.1 micrograms per milliliter | Standard Deviation 8.64 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 4 Day 1: End of infusion | 114 micrograms per milliliter | Standard Deviation 25.4 |
| Part 2: Cohort D: MSS mCRC (IO-Naïve) | Parts 1 and 2: Serum Concentrations of Tislelizumab | Cycle 7 Day 1: Pre-infusion | 35.5 micrograms per milliliter | Standard Deviation 14.4 |