Anaplastic Thyroid Cancer, Colorectal Cancer, Gastric Cancer, Metastatic Solid Tumor, Neuroendocrine Tumors, Small Cell Lung Cancer, Soft Tissue Sarcoma
Conditions
Keywords
VEGF, PD-1
Brief summary
This open-label, phase Ib/II study of surufatinib in combination with tislelizumab will evaluate the safety, tolerability, PK and efficacy in patients with advanced solid tumors. The study consists of 2 parts - dose finding (Part 1) and dose expansion (Part 2).
Detailed description
This open-label, phase Ib/II study of surufatinib in combination with tislelizumab will evaluate the safety, tolerability, PK and efficacy in patients with advanced solid tumors. The study consists of 2 parts - dose finding (Part 1) and dose expansion (Part 2). Part 1 will be conducted to determine the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) of surufatinib in combination with tislelizumab in patients with advanced or metastatic solid tumors who have progressed on, or are intolerant to standard therapies. Part 2 will be an open-label, multi-cohort design to evaluate the anti-tumor activity of surufatinib in combination with tislelizumab in patients with specific types of advanced or metastatic solid tumors. Patients will receive the RP2D determined in part 1 of this study.
Interventions
DRUGSurufatinib and Tislelizumab _ Part 1
Part 1 (all cohorts): oral surufatinib at a dose based on cohort level and intravenous tislelizumab at a 200-mg dose
DRUGSurufatinib and Tislelizumab _ Part 2
Part 2 (all cohorts): oral surufatinib at the RP2D dose selected in Part 1 and intravenous tislelizumab at a 200-mg dose
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 2. ≥18 years of age 3. Part 1-have evaluable lesions (according to Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST v1.1\]) 4. Part 2-have measurable lesions (according to RECIST v1.1) 5. Have a performance status of 0 or 1 on the ECOG scale 6. For female subjects of childbearing potential and male patients with partners of childbearing potential, agreement to use a highly effective form(s) of contraception Dose Escalation: 7. Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type,. Dose Expansion: 8. Histologically or cytologically documented, locally advanced or metastatic: Cohort A: adenocarcinoma of the colon or rectum that is microsatellite stable. Subjects must have progressed on, or had intolerable toxicity to, at least 3 prior regimens of standard chemotherapy. Cohort B: progressive, low or intermediate grade (grade 1 or grade 2) NETs of thoracic or GEP origins. Subjects must have radiological documentation of progression of disease in the last 6 months and must have progressed on at least one line of standard therapy for metastatic disease. Cohort C: SCLC that has progressed on standard first line chemotherapy treatment. Cohort D: adenocarcinoma of the stomach or gastroesophageal junction and have progressed on at least 2 prior lines of therapy. Tumor stain for PD-L1 by Combined Positive Score (CPS) ≥5%. Cohort E: ASPS or UPS. Subjects must have radiological documentation of disease progression in the last 3 months and have progressed on at least one line of standard therapy or refused standard frontline cytotoxic chemotherapy. Cohort F: Anaplastic thyroid cancer that is considered not curable by resection. Patients with a BRAFV600E mutation must have previously been treated with 1 line of systemic therapy with a BRAF-targeted therapy.
Exclusion criteria
1. Adverse events (AEs) due to previous anti-tumor therapy has not recovered to Common Terminology Criteria for Adverse Event (CTCAE) ≤Grade 1; 2. Part 2 subjects with CRC , NETs and STS any previous treatment with anti-PD-1, anti PD-L1/L2 antibodies, anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) antibody, or any other antibody acting on T cell costimulatory or checkpoint pathway; 3. Previous treatment with surufatinib; 4. Uncontrollable hypertension; 5. History or presence of a serious hemorrhage (\>30 ml within 3 months), hemoptysis (\>5 ml blood within 4 weeks) or life threatening thromboembolic event within 6 months; 6. Clinically significant cardiovascular disease; 7. Any clinically significant active infection, including, but not limited to, known human immunodeficiency virus (HIV) infection; 8. Brain metastases and/or leptomeningeal disease and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of SD for 14 days or longer; subjects requiring steroids within 4 weeks prior to start of study treatment will be excluded; 9. Active autoimmune diseases or history of autoimmune diseases that may relapse with the following exceptions: 1. Controlled Type 1 diabetes 2. Hypothyroidism (provided it is managed with hormone-replacement therapy only) 3. Controlled celiac disease 4. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia) 5. Any other disease that is not expected to recur in the absence of external triggering factors. 10. Arterial thrombosis or thromboembolic events (including stroke and/or transient ischemic attack) within 12 months prior to first dosing; 11. History of deep venous thrombosis within 6 months; 12. Female patients who are pregnant or breastfeeding; 13. Any condition by which investigators judge patients not suitable to participate in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation Phase: Number of Patients With Dose-Limiting Toxicities (DLTs) | From the first dose of study drug (Day 1) up to Day 21 of Cycle 1 (cycle duration: 3 weeks) | According to National Cancer Institute Common Terminology Criteria for Adverse Events(AEs) version (v)5.0,DLT was defined as any of the following AEs during DLT observation period: Nonhematologic toxicities:grade 3 or higher nonhematologic toxicity, except for grade 3 fatigue lasting \<7 days, grade 3 rash returning to baseline or ≤grade 1 within 7 days with treatment, grade 3 hypertension downgraded to ≤grade 1 within 7 days with therapy, grade 3 endocrinopathy controlled by hormonal replacement with no hospitalization and resolving to ≤grade 1 within 7 days, grade 3 or higher amylase or lipase elevation without symptoms of pancreatitis, grade 3 nausea/vomiting or diarrhea for \<72 hours with care, grade 3 or higher electrolyte abnormality lasting up to 72 hours and resolving with treatment. Hematologic toxicities: grade 3 or higher febrile neutropenia, grade 4 neutropenia and grade 4 thrombocytopenia lasting \>7 days, grade 3 thrombocytopenia with severe bleeding, and grade 4 anemia. |
| Dose Escalation Phase: 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 9 months | An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment in humans, 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 a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as 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. |
| Dose Expansion Phase: Objective Response Rate (ORR) | Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 37 months | 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 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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. 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). 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 |
|---|---|---|
| Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR) | Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months | CBR was defined as the percentage of patients with a BOR of CR, PR, or durable SD as determined by the investigator using RECIST v1.1. Durable SD was SD for at least 6 months. 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. 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. 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. 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. |
| Dose Escalation and Dose Expansion Phases: Duration of Response (DoR) | Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months | DoR was defined as the time from the first occurrence of PR or CR by RECIST v1.1, until PD or death, whichever came first. 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. 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. |
| Dose Escalation and Dose Expansion Phases: Time to Response (TTR) | Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months | TTR was defined as the time from start of study treatment until the date of first documented objective response, either CR or PR (whichever status was recorded first), according to RECIST v1.1. 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. 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. |
| Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Pre-dose on Day 1 of Cycles 1, 2, 5, 9, 17 and on Days 8 and 15 of Cycle 1; 2 to 4 hours post-dose on Days 1 and 15 of Cycle 1 (cycle duration: 3 weeks) | Blood samples were collected at the specified timepoints to determine plasma concentration of surufatinib. |
| Dose Escalation Phase: Objective Response Rate | Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months | 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. 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. 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. 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. |
| Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 9 months for dose escalation phase and approximately 33 months for dose expansion phase | Blood samples were collected at the specified timepoints to detect ADAs to tislelizumab. Treatment-boosted ADA was defined as ADA positive at baseline that was boosted to a 4-fold or higher-level following treatment administration. Treatment-induced ADA was defined as ADA negative at baseline and ADA positive post-baseline. |
| Dose Expansion Phase (Cohorts A and F): Overall Survival (OS) | From the first dose of study treatment (Day 1) up to date of death due to any cause, up to approximately 42 months | OS was defined as the time from the start of study treatment until the date of death due to any cause. |
| Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events 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 33 months | An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment in humans, 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 a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as 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. |
| Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Preinfusion on Day 1 of Cycles 1, 2, 5, 9, 17; end of infusion on Day 1 of Cycles 1 and 5; on Days 8 and 15 of Cycle 1 (cycle duration: 3 weeks) | Blood samples were collected at the specified timepoints to determine serum concentration of tislelizumab. |
| Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS) | Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 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. 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 one or more new lesions was also considered progression. |
| Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR) | Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months | 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. 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. 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. 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. 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 solid tumors.
Pre-assignment details
The study consisted of a dose-escalation phase and a dose-expansion phase. A total of 12 patients in dose-escalation phase and 75 patients in dose-expansion phase were enrolled in this study. The study was terminated early based on the strategic re-evaluation of clinical development of surufatinib in the United States and Europe with no safety concerns. No patients were enrolled in Cohort E1 (alveolar soft part sarcoma) in the dose-expansion phase, hence this cohort is not presented in results.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Patients with advanced or metastatic solid tumors of any kind who had progressed on or were intolerant of standard therapies received surufatinib 250 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death. | 6 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Patients with advanced or metastatic solid tumors of any kind who had progressed on or were intolerant of standard therapies received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death. | 6 |
| Dose Expansion Phase: Cohort A: CRC Patients with microsatellite stable, locally advanced or metastatic CRC that was previously treated with at least 3 prior lines of therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death. | 15 |
| Dose Expansion Phase: Cohort B1: Thoracic NETs Patients with thoracic NET who had progressive, locally advanced or metastatic, low-to-intermediate grade (Grade 1 or Grade 2), well-differentiated NETs that progressed on at least 1 line of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death. | 10 |
| Dose Expansion Phase: Cohort B2: GEP NETs Patients with GEP NET who had progressive, locally advanced or metastatic, low-to-intermediate grade (Grade 1 or Grade 2), well-differentiated NETs that progressed on at least 1 line of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death. | 20 |
| Dose Expansion Phase: Cohort C: SCLC Patients with locally advanced or metastatic SCLC that was previously progressed on first-line chemotherapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death. | 15 |
| Dose Expansion Phase: Cohort D: GC Patients with microsatellite stable, PD-L1 ≥5%, locally advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction (GC) and were previously treated with at least 2 lines of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death. | 3 |
| Dose Expansion Phase: Cohort E2: UPS Patients with UPS who progressed on, or had discontinued due to intolerable toxicity to, at least 1 line of standard therapy or were unsuitable for standard frontline cytotoxic chemotherapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death. | 9 |
| Dose Expansion Phase: Cohort F: ATC Patients with locally advanced or metastatic ATC and who had a BRAFV600E mutation were previously treated with 1 line of systemic therapy (not including radiation therapy) with a BRAF-targeted therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death. | 3 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 2 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Death | 4 | 1 | 14 | 3 | 2 | 7 | 0 | 1 | 3 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 2 | 1 | 1 | 1 | 0 | 0 |
| Overall Study | Radiological or Clinical PD | 1 | 4 | 1 | 3 | 9 | 4 | 2 | 2 | 0 |
| Overall Study | Start of New Therapy | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 0 |
| Overall Study | Study Terminated By Sponsor | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 | 2 | 1 | 0 | 3 | 0 |
Baseline characteristics
| Characteristic | Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Expansion Phase: Cohort A: CRC | Dose Expansion Phase: Cohort B1: Thoracic NETs | Dose Expansion Phase: Cohort B2: GEP NETs | Dose Expansion Phase: Cohort C: SCLC | Dose Expansion Phase: Cohort D: GC | Dose Expansion Phase: Cohort E2: UPS | Dose Expansion Phase: Cohort F: ATC | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 62.5 years STANDARD_DEVIATION 14.69 | 68.2 years STANDARD_DEVIATION 9.83 | 53.5 years STANDARD_DEVIATION 11.99 | 58.6 years STANDARD_DEVIATION 9.7 | 63.2 years STANDARD_DEVIATION 9.23 | 58.1 years STANDARD_DEVIATION 14.27 | 60.7 years STANDARD_DEVIATION 5.86 | 59.9 years STANDARD_DEVIATION 13.94 | 63.0 years STANDARD_DEVIATION 19.05 | 60.0 years STANDARD_DEVIATION 12.11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 6 Participants | 15 Participants | 9 Participants | 18 Participants | 13 Participants | 3 Participants | 8 Participants | 2 Participants | 79 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 4 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 10 Participants | 8 Participants | 17 Participants | 12 Participants | 3 Participants | 9 Participants | 3 Participants | 68 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 8 Participants | 4 Participants | 10 Participants | 8 Participants | 0 Participants | 6 Participants | 1 Participants | 40 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 7 Participants | 6 Participants | 10 Participants | 7 Participants | 3 Participants | 3 Participants | 2 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 6 | 1 / 6 | 14 / 15 | 4 / 10 | 2 / 20 | 8 / 15 | 0 / 3 | 1 / 9 | 3 / 3 |
| other Total, other adverse events | 5 / 6 | 6 / 6 | 14 / 15 | 10 / 10 | 20 / 20 | 15 / 15 | 3 / 3 | 8 / 9 | 3 / 3 |
| serious Total, serious adverse events | 5 / 6 | 3 / 6 | 9 / 15 | 5 / 10 | 9 / 20 | 8 / 15 | 0 / 3 | 4 / 9 | 1 / 3 |
Outcome results
Primary
Dose Escalation Phase: Number of Patients With Dose-Limiting Toxicities (DLTs)
According to National Cancer Institute Common Terminology Criteria for Adverse Events(AEs) version (v)5.0,DLT was defined as any of the following AEs during DLT observation period: Nonhematologic toxicities:grade 3 or higher nonhematologic toxicity, except for grade 3 fatigue lasting \<7 days, grade 3 rash returning to baseline or ≤grade 1 within 7 days with treatment, grade 3 hypertension downgraded to ≤grade 1 within 7 days with therapy, grade 3 endocrinopathy controlled by hormonal replacement with no hospitalization and resolving to ≤grade 1 within 7 days, grade 3 or higher amylase or lipase elevation without symptoms of pancreatitis, grade 3 nausea/vomiting or diarrhea for \<72 hours with care, grade 3 or higher electrolyte abnormality lasting up to 72 hours and resolving with treatment. Hematologic toxicities: grade 3 or higher febrile neutropenia, grade 4 neutropenia and grade 4 thrombocytopenia lasting \>7 days, grade 3 thrombocytopenia with severe bleeding, and grade 4 anemia.
Time frame: From the first dose of study drug (Day 1) up to Day 21 of Cycle 1 (cycle duration: 3 weeks)
Population: The DLT-evaluable analysis set included all patients enrolled in dose escalation phase of the study who were evaluable for DLT assessment and received ≥85% of scheduled surufatinib and ≥67% of scheduled tislelizumab administration during the DLT assessment window and/or experienced a DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation Phase: Number of Patients With Dose-Limiting Toxicities (DLTs) | 1 Participants |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation Phase: Number of Patients With Dose-Limiting Toxicities (DLTs) | 2 Participants |
Primary
Dose Escalation Phase: 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 in humans, 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 a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as 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 9 months
Population: The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation Phase: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | Any TEAEs | 6 Participants |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation Phase: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | Any TESAEs | 5 Participants |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation Phase: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to surufatinib treatment discontinuation | 3 Participants |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation Phase: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to tislelizumab treatment discontinuation | 3 Participants |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation Phase: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to tislelizumab treatment discontinuation | 0 Participants |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation Phase: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | Any TEAEs | 6 Participants |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation Phase: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to surufatinib treatment discontinuation | 0 Participants |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation Phase: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation | Any TESAEs | 3 Participants |
Primary
Dose Expansion Phase: Objective Response Rate (ORR)
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 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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. 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). 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 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 37 months
Population: The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Expansion Phase: Objective Response Rate (ORR) | 6.7 percentage of patients |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Expansion Phase: Objective Response Rate (ORR) | 0 percentage of patients |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Expansion Phase: Objective Response Rate (ORR) | 15.0 percentage of patients |
| Dose Expansion Phase: Cohort C: SCLC | Dose Expansion Phase: Objective Response Rate (ORR) | 13.3 percentage of patients |
| Dose Expansion Phase: Cohort D: GC | Dose Expansion Phase: Objective Response Rate (ORR) | 33.3 percentage of patients |
| Dose Expansion Phase: Cohort E2: UPS | Dose Expansion Phase: Objective Response Rate (ORR) | 44.4 percentage of patients |
| Dose Expansion Phase: Cohort F: ATC | Dose Expansion Phase: Objective Response Rate (ORR) | 0 percentage of patients |
Secondary
Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR)
CBR was defined as the percentage of patients with a BOR of CR, PR, or durable SD as determined by the investigator using RECIST v1.1. Durable SD was SD for at least 6 months. 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. 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. 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. 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 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
Population: The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR) | 0 percentage of patients |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR) | 50.0 percentage of patients |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR) | 20.0 percentage of patients |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR) | 20.0 percentage of patients |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR) | 40.0 percentage of patients |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR) | 13.3 percentage of patients |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR) | 33.3 percentage of patients |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR) | 44.4 percentage of patients |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR) | 0 percentage of patients |
Secondary
Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR)
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. 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. 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. 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. 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 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
Population: The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR) | 0 percentage of patients |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR) | 66.7 percentage of patients |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR) | 66.7 percentage of patients |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR) | 50.0 percentage of patients |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR) | 70.0 percentage of patients |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR) | 26.7 percentage of patients |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR) | 66.7 percentage of patients |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR) | 55.6 percentage of patients |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR) | 33.3 percentage of patients |
Secondary
Dose Escalation and Dose Expansion Phases: Duration of Response (DoR)
DoR was defined as the time from the first occurrence of PR or CR by RECIST v1.1, until PD or death, whichever came first. 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. 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 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
Population: The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab. Only those patients with PR or CR (responders) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Duration of Response (DoR) | NA months |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Duration of Response (DoR) | NA months |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Duration of Response (DoR) | 8.3 months |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Duration of Response (DoR) | 11.0 months |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Duration of Response (DoR) | NA months |
Secondary
Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab
Blood samples were collected at the specified timepoints to detect ADAs to tislelizumab. Treatment-boosted ADA was defined as ADA positive at baseline that was boosted to a 4-fold or higher-level following treatment administration. Treatment-induced ADA was defined as ADA negative at baseline and ADA positive post-baseline.
Time frame: From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 9 months for dose escalation phase and approximately 33 months for dose expansion phase
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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Induced ADA | 2 Participants |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Induced ADA | 2 Participants |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Boosted ADA | 2 Participants |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Induced ADA | 5 Participants |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Induced ADA | 3 Participants |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Induced ADA | 5 Participants |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Induced ADA | 1 Participants |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Induced ADA | 0 Participants |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Induced ADA | 5 Participants |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Boosted ADA | 0 Participants |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab | Treatment-Induced ADA | 1 Participants |
Secondary
Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib
Blood samples were collected at the specified timepoints to determine plasma concentration of surufatinib.
Time frame: Pre-dose on Day 1 of Cycles 1, 2, 5, 9, 17 and on Days 8 and 15 of Cycle 1; 2 to 4 hours post-dose on Days 1 and 15 of Cycle 1 (cycle duration: 3 weeks)
Population: The pharmacokinetic (PK) analysis set included all patients with at least 1 quantifiable concentration of surufatinib or tislelizumab. Only patients with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: Pre-dose | 64.36 nanograms per milliliter (ng/mL) | Standard Deviation 15.246 |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: Pre-dose | NA nanograms per milliliter (ng/mL) | — |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 2 Day 1: Pre-dose | 45.82 nanograms per milliliter (ng/mL) | Standard Deviation 27.567 |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: 2 to 4 hours post-dose | 293.03 nanograms per milliliter (ng/mL) | Standard Deviation 244.593 |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 8: Pre-dose | 77.00 nanograms per milliliter (ng/mL) | Standard Deviation 44.023 |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: 2 to 4 hours post-dose | 318.67 nanograms per milliliter (ng/mL) | Standard Deviation 146.77 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: Pre-dose | NA nanograms per milliliter (ng/mL) | — |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: Pre-dose | 181.56 nanograms per milliliter (ng/mL) | Standard Deviation 125.156 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 9 Day 1: Pre-dose | 65.90 nanograms per milliliter (ng/mL) | — |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 5 Day 1: Pre-dose | 55.25 nanograms per milliliter (ng/mL) | Standard Deviation 8.132 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: 2 to 4 hours post-dose | 576.00 nanograms per milliliter (ng/mL) | Standard Deviation 415.108 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 2 Day 1: Pre-dose | 96.80 nanograms per milliliter (ng/mL) | Standard Deviation 38.895 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: 2 to 4 hours post-dose | 757.33 nanograms per milliliter (ng/mL) | Standard Deviation 498.399 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 8: Pre-dose | 189.93 nanograms per milliliter (ng/mL) | Standard Deviation 113.75 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 2 Day 1: Pre-dose | 151.44 nanograms per milliliter (ng/mL) | Standard Deviation 99.521 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: 2 to 4 hours post-dose | 657.54 nanograms per milliliter (ng/mL) | Standard Deviation 369.146 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 8: Pre-dose | 170.33 nanograms per milliliter (ng/mL) | Standard Deviation 131.533 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 5 Day 1: Pre-dose | 141.20 nanograms per milliliter (ng/mL) | Standard Deviation 117.885 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: 2 to 4 hours post-dose | 426.62 nanograms per milliliter (ng/mL) | Standard Deviation 312.209 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: Pre-dose | NA nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: Pre-dose | 135.96 nanograms per milliliter (ng/mL) | Standard Deviation 83.673 |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 2 Day 1: Pre-dose | 89.37 nanograms per milliliter (ng/mL) | Standard Deviation 53.475 |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: Pre-dose | NA nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: 2 to 4 hours post-dose | 276.36 nanograms per milliliter (ng/mL) | Standard Deviation 243.08 |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 8: Pre-dose | 100.12 nanograms per milliliter (ng/mL) | Standard Deviation 71.6 |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: Pre-dose | 159.00 nanograms per milliliter (ng/mL) | Standard Deviation 139.802 |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: 2 to 4 hours post-dose | 354.25 nanograms per milliliter (ng/mL) | Standard Deviation 52.519 |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 5 Day 1: Pre-dose | 41.00 nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: 2 to 4 hours post-dose | 294.13 nanograms per milliliter (ng/mL) | Standard Deviation 292.335 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 9 Day 1: Pre-dose | 87.20 nanograms per milliliter (ng/mL) | Standard Deviation 14.964 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: 2 to 4 hours post-dose | 471.78 nanograms per milliliter (ng/mL) | Standard Deviation 330.598 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: Pre-dose | 84.95 nanograms per milliliter (ng/mL) | Standard Deviation 70.121 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 8: Pre-dose | 92.26 nanograms per milliliter (ng/mL) | Standard Deviation 63.901 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: Pre-dose | NA nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 5 Day 1: Pre-dose | 61.08 nanograms per milliliter (ng/mL) | Standard Deviation 22.279 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 17 Day 1: Pre-dose | 85.10 nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 2 Day 1: Pre-dose | 75.94 nanograms per milliliter (ng/mL) | Standard Deviation 53.028 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 8: Pre-dose | 122.80 nanograms per milliliter (ng/mL) | Standard Deviation 70.875 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: Pre-dose | 96.79 nanograms per milliliter (ng/mL) | Standard Deviation 43.933 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 9 Day 1: Pre-dose | 41.70 nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: 2 to 4 hours post-dose | 425.75 nanograms per milliliter (ng/mL) | Standard Deviation 235.698 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: 2 to 4 hours post-dose | 406.97 nanograms per milliliter (ng/mL) | Standard Deviation 212.791 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 2 Day 1: Pre-dose | 117.68 nanograms per milliliter (ng/mL) | Standard Deviation 79.721 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: Pre-dose | NA nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 5 Day 1: Pre-dose | 105.70 nanograms per milliliter (ng/mL) | Standard Deviation 54.164 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: 2 to 4 hours post-dose | 188.00 nanograms per milliliter (ng/mL) | Standard Deviation 41.012 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: Pre-dose | 111.05 nanograms per milliliter (ng/mL) | Standard Deviation 19.728 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: 2 to 4 hours post-dose | 506.27 nanograms per milliliter (ng/mL) | Standard Deviation 653.616 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 2 Day 1: Pre-dose | 146.50 nanograms per milliliter (ng/mL) | Standard Deviation 26.163 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: Pre-dose | NA nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 8: Pre-dose | 109.10 nanograms per milliliter (ng/mL) | Standard Deviation 18.243 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: Pre-dose | NA nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: 2 to 4 hours post-dose | 518.00 nanograms per milliliter (ng/mL) | Standard Deviation 302.182 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 15: Pre-dose | 118.92 nanograms per milliliter (ng/mL) | Standard Deviation 75.457 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: 2 to 4 hours post-dose | 275.64 nanograms per milliliter (ng/mL) | Standard Deviation 165.937 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 8: Pre-dose | 97.70 nanograms per milliliter (ng/mL) | Standard Deviation 40.471 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 2 Day 1: Pre-dose | 71.95 nanograms per milliliter (ng/mL) | Standard Deviation 9.405 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 8: Pre-dose | 709.00 nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 2 Day 1: Pre-dose | 147.00 nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: Pre-dose | NA nanograms per milliliter (ng/mL) | — |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib | Cycle 1 Day 1: 2 to 4 hours post-dose | 782.50 nanograms per milliliter (ng/mL) | Standard Deviation 463.155 |
Secondary
Dose Escalation and Dose Expansion Phases: 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. 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 one or more new lesions was also considered progression.
Time frame: Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
Population: The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS) | 1.5 months |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS) | 6.0 months |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS) | 4.7 months |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS) | 4.5 months |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS) | 7.4 months |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS) | 1.4 months |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS) | 9.6 months |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS) | NA months |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS) | 2.8 months |
Secondary
Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab
Blood samples were collected at the specified timepoints to determine serum concentration of tislelizumab.
Time frame: Preinfusion on Day 1 of Cycles 1, 2, 5, 9, 17; end of infusion on Day 1 of Cycles 1 and 5; on Days 8 and 15 of Cycle 1 (cycle duration: 3 weeks)
Population: The PK analysis set included all patients with at least 1 quantifiable concentration of surufatinib or tislelizumab. Only patients with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 8 | 16980.0 ng/mL | Standard Deviation 6850.75 |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 2 Day 1: Preinfusion | 9564.0 ng/mL | Standard Deviation 7871.14 |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 15 | 14296.7 ng/mL | Standard Deviation 5945.36 |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: End of Infusion | 44550.0 ng/mL | Standard Deviation 7420.98 |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: Preinfusion | NA ng/mL | — |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 8 | 26216.7 ng/mL | Standard Deviation 7702.32 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: End of Infusion | 87166.7 ng/mL | Standard Deviation 34425.04 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 2 Day 1: Preinfusion | 13804.0 ng/mL | Standard Deviation 4782.16 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: End of Infusion | 62750.0 ng/mL | Standard Deviation 17420.53 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: Preinfusion | 24400.0 ng/mL | Standard Deviation 14028.9 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 9 Day 1: Preinfusion | 22700.0 ng/mL | Standard Deviation 4101.22 |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: Preinfusion | NA ng/mL | — |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 15 | 17900.0 ng/mL | Standard Deviation 5297.55 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 15 | 17414.2 ng/mL | Standard Deviation 4199.94 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 8 | 26446.2 ng/mL | Standard Deviation 6387.83 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 2 Day 1: Preinfusion | 13858.6 ng/mL | Standard Deviation 4730.49 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: End of Infusion | 102500.0 ng/mL | Standard Deviation 26662.02 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: Preinfusion | NA ng/mL | — |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 9 Day 1: Preinfusion | 44800.0 ng/mL | — |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: Preinfusion | 36412.5 ng/mL | Standard Deviation 34947.57 |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: End of Infusion | 57233.3 ng/mL | Standard Deviation 8846.28 |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: Preinfusion | 46400.0 ng/mL | — |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: Preinfusion | NA ng/mL | — |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: End of Infusion | 70990.0 ng/mL | Standard Deviation 41600.73 |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 17 Day 1: Preinfusion | 41300.0 ng/mL | — |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 8 | 29575.0 ng/mL | Standard Deviation 5751.46 |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 9 Day 1: Preinfusion | 50000.0 ng/mL | — |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 15 | 20571.4 ng/mL | Standard Deviation 2817.63 |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 2 Day 1: Preinfusion | 14033.3 ng/mL | Standard Deviation 2436.12 |
| Dose Expansion Phase: Cohort C: SCLC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: End of Infusion | 117500.0 ng/mL | Standard Deviation 6363.96 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: End of Infusion | 61136.8 ng/mL | Standard Deviation 15927.9 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: Preinfusion | 41575.0 ng/mL | Standard Deviation 10065.32 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 2 Day 1: Preinfusion | 18020.0 ng/mL | Standard Deviation 5688.23 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 17 Day 1: Preinfusion | 44766.7 ng/mL | Standard Deviation 12196.86 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: Preinfusion | NA ng/mL | — |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: End of Infusion | 113475.0 ng/mL | Standard Deviation 16286.34 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 15 | 24506.3 ng/mL | Standard Deviation 6403.07 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 8 | 32244.4 ng/mL | Standard Deviation 7253.58 |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 9 Day 1: Preinfusion | 45500.0 ng/mL | Standard Deviation 5384.24 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: Preinfusion | NA ng/mL | — |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 15 | 23783.3 ng/mL | Standard Deviation 4274.2 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: End of Infusion | 66220.0 ng/mL | Standard Deviation 17336.43 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: End of Infusion | 117550.0 ng/mL | Standard Deviation 43800.65 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 17 Day 1: Preinfusion | 51900.0 ng/mL | — |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 9 Day 1: Preinfusion | 41200.0 ng/mL | Standard Deviation 24607.32 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: Preinfusion | 31225.0 ng/mL | Standard Deviation 12388.81 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 2 Day 1: Preinfusion | 17725.0 ng/mL | Standard Deviation 3860.55 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 8 | 35450.0 ng/mL | Standard Deviation 8899.39 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: End of Infusion | 67966.7 ng/mL | Standard Deviation 45015.59 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: Preinfusion | NA ng/mL | — |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 8 | 38233.3 ng/mL | Standard Deviation 35800.33 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 15 | 43950.0 ng/mL | Standard Deviation 40658.64 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 2 Day 1: Preinfusion | 38000.0 ng/mL | Standard Deviation 36910.97 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: Preinfusion | 20100.0 ng/mL | — |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: End of Infusion | 80800.0 ng/mL | — |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 8 | 25475.0 ng/mL | Standard Deviation 6549.1 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: End of Infusion | 103033.3 ng/mL | Standard Deviation 17737.06 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: End of Infusion | 55955.6 ng/mL | Standard Deviation 15499.61 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 9 Day 1: Preinfusion | 41100.0 ng/mL | Standard Deviation 16970.56 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 2 Day 1: Preinfusion | 12161.3 ng/mL | Standard Deviation 4443.93 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: Preinfusion | NA ng/mL | — |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: Preinfusion | 19200.0 ng/mL | Standard Deviation 3143.25 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 15 | 19300.0 ng/mL | Standard Deviation 4755.45 |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 17 Day 1: Preinfusion | 47300.0 ng/mL | — |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: Preinfusion | 22700.0 ng/mL | — |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 2 Day 1: Preinfusion | 7640.0 ng/mL | Standard Deviation 2729.43 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 15 | 10940.0 ng/mL | Standard Deviation 2489.02 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 5 Day 1: End of Infusion | 69000.0 ng/mL | — |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 8 | 16050.0 ng/mL | Standard Deviation 1767.77 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: End of Infusion | 42200.0 ng/mL | Standard Deviation 12727.92 |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab | Cycle 1 Day 1: Preinfusion | NA ng/mL | — |
Secondary
Dose Escalation and Dose Expansion Phases: Time to Response (TTR)
TTR was defined as the time from start of study treatment until the date of first documented objective response, either CR or PR (whichever status was recorded first), according to RECIST v1.1. 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. 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 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
Population: The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab. Only those patients with PR or CR (responders) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Escalation and Dose Expansion Phases: Time to Response (TTR) | 2.7 months |
| Dose Expansion Phase: Cohort D: GC | Dose Escalation and Dose Expansion Phases: Time to Response (TTR) | 3.9 months |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Time to Response (TTR) | 3.5 months |
| Dose Expansion Phase: Cohort F: ATC | Dose Escalation and Dose Expansion Phases: Time to Response (TTR) | 2.7 months |
| Dose Expansion Phase: Cohort E2: UPS | Dose Escalation and Dose Expansion Phases: Time to Response (TTR) | 1.4 months |
Secondary
Dose Escalation Phase: Objective Response Rate
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. 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. 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. 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 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
Population: The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Escalation Phase: Objective Response Rate | 0 percentage of patients |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Escalation Phase: Objective Response Rate | 0 percentage of patients |
Secondary
Dose Expansion Phase (Cohorts A and F): Overall Survival (OS)
OS was defined as the time from the 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 approximately 42 months
Population: The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab. As pre-specified in the protocol and statistical analysis plan (SAP), OS was assessed only in Cohort A (CRC) and Cohort F (ATC) of the dose expansion phase.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Expansion Phase (Cohorts A and F): Overall Survival (OS) | 7.1 months |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Expansion Phase (Cohorts A and F): Overall Survival (OS) | 5.3 months |
Secondary
Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events 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 in humans, 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 a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as 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 33 months
Population: The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs | 14 Participants |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to tislelizumab treatment discontinuation | 6 Participants |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to surufatinib treatment discontinuation | 3 Participants |
| Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TESAEs | 9 Participants |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TESAEs | 5 Participants |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs | 10 Participants |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to tislelizumab treatment discontinuation | 2 Participants |
| Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to surufatinib treatment discontinuation | 2 Participants |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs | 20 Participants |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TESAEs | 9 Participants |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to surufatinib treatment discontinuation | 5 Participants |
| Dose Expansion Phase: Cohort B2: GEP NETs | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to tislelizumab treatment discontinuation | 6 Participants |
| Dose Expansion Phase: Cohort C: SCLC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to tislelizumab treatment discontinuation | 5 Participants |
| Dose Expansion Phase: Cohort C: SCLC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs | 15 Participants |
| Dose Expansion Phase: Cohort C: SCLC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TESAEs | 8 Participants |
| Dose Expansion Phase: Cohort C: SCLC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to surufatinib treatment discontinuation | 5 Participants |
| Dose Expansion Phase: Cohort D: GC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs | 3 Participants |
| Dose Expansion Phase: Cohort D: GC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TESAEs | 0 Participants |
| Dose Expansion Phase: Cohort D: GC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to surufatinib treatment discontinuation | 0 Participants |
| Dose Expansion Phase: Cohort D: GC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to tislelizumab treatment discontinuation | 0 Participants |
| Dose Expansion Phase: Cohort E2: UPS | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to surufatinib treatment discontinuation | 2 Participants |
| Dose Expansion Phase: Cohort E2: UPS | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs | 9 Participants |
| Dose Expansion Phase: Cohort E2: UPS | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TESAEs | 4 Participants |
| Dose Expansion Phase: Cohort E2: UPS | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to tislelizumab treatment discontinuation | 2 Participants |
| Dose Expansion Phase: Cohort F: ATC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to surufatinib treatment discontinuation | 0 Participants |
| Dose Expansion Phase: Cohort F: ATC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs leading to tislelizumab treatment discontinuation | 0 Participants |
| Dose Expansion Phase: Cohort F: ATC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TEAEs | 3 Participants |
| Dose Expansion Phase: Cohort F: ATC | Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation | Any TESAEs | 1 Participants |