Non Small Cell Lung Cancer
Conditions
Brief summary
This is a randomized, controlled, double-blind, multicenter, phase III clinical study.
Detailed description
This is a randomized, controlled, double-blind, multicenter, phase III clinical trial, evaluating the efficacy and safety of HS-10296 compared to gefitinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor sensitizing mutations (EGFRm+) who have not received systemic therapy. Patients are randomly assigned to an HS-10296 treatment group or a gefitinib treatment group at a ratio of 1:1 and receive a once-daily oral dose of HS-10296 or gefitinib, in order to compare the efficacy and safety of the two different treatment regimens.
Interventions
DRUGHS-10296
Drug: HS-10296 110 mg/55 mg + placebo The initial dose of HS-10296 110 mg once daily can be reduced to 55 mg once daily under specific circumstances. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.
DRUGGefitinib
Drug: Gefitinib 250 mg + placebo The initial dose of Gefitinib 250 mg once daily cannot be reduced. A cycle of treatment is defined as 21 days of once daily treatment. Number of cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.
Sponsors
Jiangsu Hansoh Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion Criteria: Any patient who meets all of the following inclusion criteria will qualify for entry into the study: 1. Provision of informed consent prior to any study specific procedures, sampling and analyses. 2. Male or female, age at least 18 years. 3. Pathologically confirmed locally advanced or metastatic NSCLC (e.g. this may occur systemic recurrence after prior surgery for early stage disease or patients may be newly diagnosed with stage IIIB/IV disease). Patients must be treatment-naïve for locally advanced or metastatic NSCLC. Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents) provided all other entry criteria are satisfied. 4. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either or in combination with other EGFR mutations assessed by central testing using tumour tissue sample or blood sample. 5. A WHO performance status equal to 0-1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks. 6. At least 1 lesion that has not previously been irradiated, that has not been chosen for biopsy during the study screening period, and that can be accurately measured at Baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), whichever is suitable for accurately repeated measurements. If only one measurable lesion exists, it is acceptable to be used (as a target lesion) as long as it has not been previously irradiated and baseline tumour assessment scans are done at least 14days afar the screening biopsy is performed. 7. Females should be using adequate contraceptive measures throughout the study; should not be breastfeeding at the time of screening, during the study and until 3 months after completion of the study; and must have a negative pregnancy test prior to start of dosing if of childbearing potential or must have evidence of non-childbearing potential by fulfilling 1 of the following criteria at Screening: 1. Postmenopausal defined as age more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments. 2. Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more, following cessation of exogenous hormonal treatments, and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory. 3. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not by tubal ligation. 8. Male patients should be willing to use barrier contraception (i.e., condoms). 9. For inclusion in study, patient must provide a written informed consent. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From baseline, then every 6 weeks, until disease progression or discontinuation from study. From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, approximately 2 years. | PFS was defined as the time from the date of first dose until the date of radiological disease progression or until death due to any cause, based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by investigators. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assess the Anti-tumor Activity: Duration of Response (DoR) | From baseline, then every 6 weeks, until disease progression or discontinuation from study. (up to 24 months) | DoR is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression assessed up to 24 months. |
| Assess the Anti-tumor Activity: Disease Control Rate (DCR) | From baseline, then every 6 weeks, until disease progression or discontinuation from study. | The DCR is defined as the proportion of patients with a best overall response of CR, PR, or SD assessed up to 24 months. |
| Assess the Anti-tumor Activity: Depth of Response (DepOR) | From baseline, then every 6 weeks, until disease progression or discontinuation from study.（up to 24 months） | DepOR is defined as the percentage change in tumor shrinkage, based on longest diameter or reconstructed volume, observed at the lowest point (nadir) compared with baseline. |
| Percentage of Participants With Objective Response Rate (ORR) | From baseline, then every 6 weeks, until disease progression or discontinuation from study.（up to 24 months） | ORR is defined as the percentage of patients who have at least 1 response of CR or PR prior to any evidence of progression. Target lesions and assessed by CT per RECIST v1.1 (Complete Response(CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.). |
| Number of Participants With Dose Interruptions | From baseline, then every 6 weeks, until disease progression or discontinuation from study. (up to 24 months) | Participants had at least one delay in planned treatment due to treatment emergent adverse events. |
| Number of Participants With Dose Reductions | From baseline, then every 6 weeks, until disease progression or discontinuation from study. (up to 24 months) | Participants had at least one reduction in planned treatment dosage due to treatment emergent adverse events. Every participant took 2 pills of HS -10296 + 1 pill of placebo(experimental arm) or 2pills of placebo + 1pill of Gefitinib (control arm). When a dose reduction was decided by INV, the set of 2 pills of placebo was decreased resulting in no reduction of active compound in control arm, compliance with dose modification for AEs in Gefitinib's label which includes interruption, discontinuation but reduction. |
| Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) | Continuously throughout the study until 28 days after HS-10296 discontinuation.From first dose of study drug up to 28 days after last dose of study drug taken (up to data cut-off (15 Jan 2021)),approximately 2 years. | Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug. AEs were considered serious (SAEs) if the AE resulted in death, was life threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly, or birth defect or required inpatient hospitalization or led to prolongation of hospitalization. |
Countries
China
Participant flow
Recruitment details
A total of 429 participants were randomized to at 53 study sites.
Participants by arm
| Arm | Count |
|---|---|
| HS-10296 110mg PO once daily
HS-10296: Drug: HS-10296 110 mg/55 mg + placebo The initial dose of HS-10296 110 mg once daily can be reduced to 55 mg once daily under specific circumstances. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria. | 214 |
| Gefitinib 250mg PO once daily
Gefitinib: Drug: Gefitinib 250 mg + placebo The initial dose of Gefitinib 250 mg once daily cannot be reduced. A cycle of treatment is defined as 21 days of once daily treatment. Number of cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria. | 215 |
| Total | 429 |
Baseline characteristics
| Characteristic | HS-10296 | Gefitinib | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 59 Participants | 76 Participants | 135 Participants |
| Age, Categorical Between 18 and 65 years | 155 Participants | 139 Participants | 294 Participants |
| Age, Continuous | 58.1 years STANDARD_DEVIATION 9.59 | 60.6 years STANDARD_DEVIATION 9.72 | 59.3 years STANDARD_DEVIATION 9.72 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 214 Participants | 215 Participants | 429 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 134 Participants | 135 Participants | 269 Participants |
| Sex: Female, Male Male | 80 Participants | 80 Participants | 160 Participants |
| Smoking status Never smoked | 156 Participants | 144 Participants | 300 Participants |
| Smoking status smoked | 58 Participants | 71 Participants | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 54 / 214 | 69 / 215 |
| other Total, other adverse events | 211 / 214 | 213 / 215 |
| serious Total, serious adverse events | 47 / 214 | 46 / 215 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS was defined as the time from the date of first dose until the date of radiological disease progression or until death due to any cause, based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by investigators. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From baseline, then every 6 weeks, until disease progression or discontinuation from study. From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, approximately 2 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HS-10296 | Progression Free Survival (PFS) | 19.3 months |
| Gefitinib | Progression Free Survival (PFS) | 9.9 months |
Secondary
Assess the Anti-tumor Activity: Depth of Response (DepOR)
DepOR is defined as the percentage change in tumor shrinkage, based on longest diameter or reconstructed volume, observed at the lowest point (nadir) compared with baseline.
Time frame: From baseline, then every 6 weeks, until disease progression or discontinuation from study.（up to 24 months）
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HS-10296 | Assess the Anti-tumor Activity: Depth of Response (DepOR) | -44.95 percentage of change from baseline | Standard Deviation 21.961 |
| Gefitinib | Assess the Anti-tumor Activity: Depth of Response (DepOR) | -41.95 percentage of change from baseline | Standard Deviation 19.966 |
Secondary
Assess the Anti-tumor Activity: Disease Control Rate (DCR)
The DCR is defined as the proportion of patients with a best overall response of CR, PR, or SD assessed up to 24 months.
Time frame: From baseline, then every 6 weeks, until disease progression or discontinuation from study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HS-10296 | Assess the Anti-tumor Activity: Disease Control Rate (DCR) | 93.0 percentage |
| Gefitinib | Assess the Anti-tumor Activity: Disease Control Rate (DCR) | 96.7 percentage |
Secondary
Assess the Anti-tumor Activity: Duration of Response (DoR)
DoR is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression assessed up to 24 months.
Time frame: From baseline, then every 6 weeks, until disease progression or discontinuation from study. (up to 24 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HS-10296 | Assess the Anti-tumor Activity: Duration of Response (DoR) | 18.1 months |
| Gefitinib | Assess the Anti-tumor Activity: Duration of Response (DoR) | 8.3 months |
Secondary
Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs)
Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug. AEs were considered serious (SAEs) if the AE resulted in death, was life threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly, or birth defect or required inpatient hospitalization or led to prolongation of hospitalization.
Time frame: Continuously throughout the study until 28 days after HS-10296 discontinuation.From first dose of study drug up to 28 days after last dose of study drug taken (up to data cut-off (15 Jan 2021)),approximately 2 years.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HS-10296 | Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) | 211 Participants |
| Gefitinib | Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) | 213 Participants |
Secondary
Number of Participants With Dose Interruptions
Participants had at least one delay in planned treatment due to treatment emergent adverse events.
Time frame: From baseline, then every 6 weeks, until disease progression or discontinuation from study. (up to 24 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HS-10296 | Number of Participants With Dose Interruptions | 36 Participants |
| Gefitinib | Number of Participants With Dose Interruptions | 53 Participants |
Secondary
Number of Participants With Dose Reductions
Participants had at least one reduction in planned treatment dosage due to treatment emergent adverse events. Every participant took 2 pills of HS -10296 + 1 pill of placebo(experimental arm) or 2pills of placebo + 1pill of Gefitinib (control arm). When a dose reduction was decided by INV, the set of 2 pills of placebo was decreased resulting in no reduction of active compound in control arm, compliance with dose modification for AEs in Gefitinib's label which includes interruption, discontinuation but reduction.
Time frame: From baseline, then every 6 weeks, until disease progression or discontinuation from study. (up to 24 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HS-10296 | Number of Participants With Dose Reductions | 9 Participants |
| Gefitinib | Number of Participants With Dose Reductions | 10 Participants |
Secondary
Percentage of Participants With Objective Response Rate (ORR)
ORR is defined as the percentage of patients who have at least 1 response of CR or PR prior to any evidence of progression. Target lesions and assessed by CT per RECIST v1.1 (Complete Response(CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.).
Time frame: From baseline, then every 6 weeks, until disease progression or discontinuation from study.（up to 24 months）
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HS-10296 | Percentage of Participants With Objective Response Rate (ORR) | 73.8 percentage of participants |
| Gefitinib | Percentage of Participants With Objective Response Rate (ORR) | 72.1 percentage of participants |