Adenocarcinoma Lung Cancer; Squamous Cell Lung Carcinoma
Conditions
Keywords
adenocarcinoma lung cancer,, squamous cell lung carcinoma,, NSCLC
Brief summary
The purpose of this study was to evaluate the anti-tumor activity of single agent BYL719, INC280, LDK378 and MEK162 in advanced NSCLC patients carrying specific molecular alterations. There is a great unmet medical need in NSCLC patients with advanced or metastatic disease. Novel approaches using targeted therapeutic agents for these patient populations with molecular characterization could potentially identify subsets of advanced NSCLC patients who would benefit from targeted kinase inhibition. Study treatments, BYL719, INC280, LDK378 and MEK162, which target PIK3CA, c-MET, ALK/ROS1 and MEK respectively, have shown promising data in either preclinical or clinical lung cancer settings.
Detailed description
To enter the screening phase of the study, the subjects' molecular alterations were determined using locally validated methodologies from a newly obtained tumor sample (preferred) or the most recent archival tumor sample available. Based on the molecular alterations of the tumor, subjects were assigned to one of the treatment arms. Subjects with multiple molecular alterations in epidermal growth factor receptor (EGFR) and the relevant pathways were excluded, except under the conditions described in Inclusion criteria. The treatment period began on Cycle 1 Day 1 and continued in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of informed consent, death or the subject transferred to another Novartis study that could continue to provide the study drug. All subjects were required to be followed up for 30 days for safety after receiving the last dose of study treatment. Subjects who discontinued study treatment for any reason other than disease progression were followed up for progression of disease. All subjects were required to be followed for survival. For subjects transferred to another Novartis study, an end of treatment visit (EOT) was required to be performed and the subject would not enter the follow-up period.
Interventions
DRUGBYL719
BYL719 was dosed as 350 mg once daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to take BYL719 exactly as prescribed.
DRUGINC280
INC280 was dosed as 600 mg (tablet) or 400mg(Capsule) twice daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to takeINC280 exactly as prescribed.
DRUGLDK378
LDK378 was dosed as 750 mg once daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to take LDK378 exactly as prescribed.
DRUGMEK162
MEK162 was dosed as 45 mg twice daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to take MEK162 exactly as prescribed.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Advanced (stage IIIB or stage IV) NSCLC * Must have specific molecular alterations
Exclusion criteria
* Symptomatic central nervous system (CNS) metastases which are neurologically unstable or requiring increasing doses of steroids within the 4 weeks prior to study entry to control their CNS disease * Radiation therapy within ≤ 4 weeks prior to study entry, with the exception of limited field palliative radiotherapy for bone pain relief. * Any other malignancies within the last 5 years before study entry * Major surgery ≤ 2 weeks prior to study entry or who have not recovered from side effects of such therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to 231 weeks | Overall response rate is the proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Progression-free Survival (PFS) | Up to 231 weeks | PFS event is defined as the first documented progression or death due to any cause according to RECIST 1.1 criteria |
| Disease Control Rate (DCR) | Up to 231 weeks | DCR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR) or Stable Disease (SD) according to RECIST 1.1 criteria (DCR: CR+PR+SD) Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD |
| Median Duration of Overall Response (DOR) | Up to 231 weeks | Duration of overall response (DOR) is defined as the time from the first documented CR or PR (confirmed by the subsequent assessment) to the date of the first documented progression or death due to underlying cancer. |
| Median Overall Survival (OS) | Up to 231 weeks | OS is defined as the time from date of randomization/start of treatment to date of death due to any cause. |
| Pharmacokinetics Profile, AUCtau and AUClast | Day 1 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours) and Day 15 (pre dose, 0.5, 1, 2, 4, 6, 8 hours post dose and only for BYL719 350 mg QD and LDK378 750 mg QD arms also at 24 hours post dose) | PK parameters are estimated from each individual plasma concentration-time profile using non-compartmental analysis (Phoenix software version 6.2 and above). AUCtau is the AUC calculated to the end of a dosing interval (tau) (amount x time x volume-1) AUClast is the AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) On Cycle 1 Day 1, PK parameters for only BYL719 350 mg QD arm were analyzed |
| Pharmacokinetics Profile, Cmax | Day 1 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours) and Day 15 (pre dose, 0.5, 1, 2, 4, 6, 8 hours post dose and only for BYL719 350 mg QD and LDK378 750 mg QD arms also at 24 hours post dose) | PK parameters are estimated from each individual plasma concentration-time profile using non-compartmental analysis (Phoenix software version 6.2 and above). Cmax is the maximum (peak) observed plasma concentration (mass x volume-1) On Cycle 1 Day 1, PK parameters for only BYL719 350 mg QD arm were analyzed |
| Pharmacokinetics Profile, Tmax | Day 1 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours) and Day 15 (pre dose, 0.5, 1, 2, 4, 6, 8 hours post dose and only for BYL719 350 mg QD and LDK378 750 mg QD arms also at 24 hours post dose) | PK parameters are estimated from each individual plasma concentration-time profile using non-compartmental analysis (Phoenix software version 6.2 and above). Tmax is the time to reach maximum (peak) plasma concentration (time) On Cycle 1 Day 1, PK parameters for only BYL719 350 mg QD arm were analyzed |
| Number of Participants With Adverse Events | up to 235 weeks | Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to grades 1 - 4, was used. |
Countries
China
Participant flow
Recruitment details
Participants were from China
Pre-assignment details
To enter the screening phase, the subjects' molecular alterations were determined using locally validated methodologies from a newly obtained tumor sample or the most recent archival tumor sample available. Based on the molecular alterations of the tumor, subjects were assigned to one of the treatment arms. Subjects with multiple molecular alterations in epidermal growth factor receptor and the relevant pathways were excluded, except under the conditions described in Inclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| BYL719 350 mg QD Patient's tumor must have molecular alteration of the PIK3CA gene. | 2 |
| INC280 400 mg BID Tab/600 mg BID Cap Patient's tumor must have molecular alteration of the c-MET gene. | 16 |
| LDK378 750 mg QD Patient's tumor must have ALK or ROS1 gene rearrangement. | 26 |
| MEK162 45 mg BID Patient's tumor must have KRAS, NRAS or BRAF mutation. | 22 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 8 | 2 |
| Overall Study | Death | 1 | 0 | 0 | 2 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 |
| Overall Study | Progressive disease | 1 | 13 | 12 | 14 |
| Overall Study | Subject/guardian decision | 0 | 1 | 0 | 3 |
Baseline characteristics
| Characteristic | BYL719 350 mg QD | INC280 400 mg BID Tab/600 mg BID Cap | LDK378 750 mg QD | MEK162 45 mg BID | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.0 years | 58.2 years | 49.4 years | 60.3 years | 55.3 years |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 5 Participants | 15 Participants | 3 Participants | 23 Participants |
| Sex: Female, Male Male | 2 Participants | 11 Participants | 11 Participants | 19 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 4 / 16 | 1 / 26 | 5 / 22 |
| other Total, other adverse events | 2 / 2 | 16 / 16 | 26 / 26 | 22 / 22 |
| serious Total, serious adverse events | 1 / 2 | 12 / 16 | 11 / 26 | 18 / 22 |
Outcome results
Primary
Overall Response Rate (ORR)
Overall response rate is the proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to 231 weeks
Population: Full analysis set: all subjects who received at least one dose of the respective study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BYL719 350 mg QD | Overall Response Rate (ORR) | 0 Participants |
| INC280 400 mg BID Tab/600 mg BID Cap | Overall Response Rate (ORR) | 3 Participants |
| LDK378 750 mg QD | Overall Response Rate (ORR) | 19 Participants |
| MEK162 45 mg BID | Overall Response Rate (ORR) | 2 Participants |
Secondary
Disease Control Rate (DCR)
DCR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR) or Stable Disease (SD) according to RECIST 1.1 criteria (DCR: CR+PR+SD) Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD
Time frame: Up to 231 weeks
Population: Full analysis set: all subjects who received at least one dose of the respective study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BYL719 350 mg QD | Disease Control Rate (DCR) | 50.0 Percentage of participants |
| INC280 400 mg BID Tab/600 mg BID Cap | Disease Control Rate (DCR) | 43.8 Percentage of participants |
| LDK378 750 mg QD | Disease Control Rate (DCR) | 92.3 Percentage of participants |
| MEK162 45 mg BID | Disease Control Rate (DCR) | 59.1 Percentage of participants |
Secondary
Median Duration of Overall Response (DOR)
Duration of overall response (DOR) is defined as the time from the first documented CR or PR (confirmed by the subsequent assessment) to the date of the first documented progression or death due to underlying cancer.
Time frame: Up to 231 weeks
Population: Full analysis set subjects with confirmed complete response (CR) or partial response (PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| INC280 400 mg BID Tab/600 mg BID Cap | Median Duration of Overall Response (DOR) | 3.84 Months |
| LDK378 750 mg QD | Median Duration of Overall Response (DOR) | 34.96 Months |
| MEK162 45 mg BID | Median Duration of Overall Response (DOR) | 5.47 Months |
Secondary
Median Overall Survival (OS)
OS is defined as the time from date of randomization/start of treatment to date of death due to any cause.
Time frame: Up to 231 weeks
Population: Full analysis set: all subjects who received at least one dose of the respective study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BYL719 350 mg QD | Median Overall Survival (OS) | 4.99 Months |
| INC280 400 mg BID Tab/600 mg BID Cap | Median Overall Survival (OS) | 13.26 Months |
| LDK378 750 mg QD | Median Overall Survival (OS) | NA Months |
| MEK162 45 mg BID | Median Overall Survival (OS) | 9.20 Months |
Secondary
Number of Participants With Adverse Events
Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to grades 1 - 4, was used.
Time frame: up to 235 weeks
Population: Safety Set: Includes all patients who received at least one dose of the respective study medication and had at least one valid postbaseline safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BYL719 350 mg QD | Number of Participants With Adverse Events | AE All grades | 2 Participants |
| BYL719 350 mg QD | Number of Participants With Adverse Events | AE Grade 3/4 | 1 Participants |
| BYL719 350 mg QD | Number of Participants With Adverse Events | SAE All grades | 1 Participants |
| BYL719 350 mg QD | Number of Participants With Adverse Events | SAE Grade 3/4 | 1 Participants |
| INC280 400 mg BID Tab/600 mg BID Cap | Number of Participants With Adverse Events | AE Grade 3/4 | 11 Participants |
| INC280 400 mg BID Tab/600 mg BID Cap | Number of Participants With Adverse Events | SAE All grades | 12 Participants |
| INC280 400 mg BID Tab/600 mg BID Cap | Number of Participants With Adverse Events | SAE Grade 3/4 | 7 Participants |
| INC280 400 mg BID Tab/600 mg BID Cap | Number of Participants With Adverse Events | AE All grades | 16 Participants |
| LDK378 750 mg QD | Number of Participants With Adverse Events | SAE All grades | 11 Participants |
| LDK378 750 mg QD | Number of Participants With Adverse Events | AE Grade 3/4 | 23 Participants |
| LDK378 750 mg QD | Number of Participants With Adverse Events | SAE Grade 3/4 | 9 Participants |
| LDK378 750 mg QD | Number of Participants With Adverse Events | AE All grades | 26 Participants |
| MEK162 45 mg BID | Number of Participants With Adverse Events | SAE Grade 3/4 | 15 Participants |
| MEK162 45 mg BID | Number of Participants With Adverse Events | AE Grade 3/4 | 20 Participants |
| MEK162 45 mg BID | Number of Participants With Adverse Events | AE All grades | 22 Participants |
| MEK162 45 mg BID | Number of Participants With Adverse Events | SAE All grades | 18 Participants |
Secondary
Number of Participants With Progression-free Survival (PFS)
PFS event is defined as the first documented progression or death due to any cause according to RECIST 1.1 criteria
Time frame: Up to 231 weeks
Population: Full analysis set: all subjects who received at least one dose of the respective study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BYL719 350 mg QD | Number of Participants With Progression-free Survival (PFS) | 2 Participants |
| INC280 400 mg BID Tab/600 mg BID Cap | Number of Participants With Progression-free Survival (PFS) | 16 Participants |
| LDK378 750 mg QD | Number of Participants With Progression-free Survival (PFS) | 19 Participants |
| MEK162 45 mg BID | Number of Participants With Progression-free Survival (PFS) | 19 Participants |
Secondary
Pharmacokinetics Profile, AUCtau and AUClast
PK parameters are estimated from each individual plasma concentration-time profile using non-compartmental analysis (Phoenix software version 6.2 and above). AUCtau is the AUC calculated to the end of a dosing interval (tau) (amount x time x volume-1) AUClast is the AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) On Cycle 1 Day 1, PK parameters for only BYL719 350 mg QD arm were analyzed
Time frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours) and Day 15 (pre dose, 0.5, 1, 2, 4, 6, 8 hours post dose and only for BYL719 350 mg QD and LDK378 750 mg QD arms also at 24 hours post dose)
Population: PAS: Pharmacokinetic analysis set includes all subjects who have at least one blood sample providing evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BYL719 350 mg QD | Pharmacokinetics Profile, AUCtau and AUClast | AUClast Cycle 1 Day 15 | 23721 ng*h/mL | — |
| BYL719 350 mg QD | Pharmacokinetics Profile, AUCtau and AUClast | AUClast Cycle 1 Day 1 | 20909 ng*h/mL | Standard Deviation 107 |
| BYL719 350 mg QD | Pharmacokinetics Profile, AUCtau and AUClast | AUCtau Cycle 1 Day 15 | 23892 ng*h/mL | — |
| INC280 400 mg BID Tab/600 mg BID Cap | Pharmacokinetics Profile, AUCtau and AUClast | AUClast Cycle 1 Day 15 | 27875 ng*h/mL | Standard Deviation 7629 |
| INC280 400 mg BID Tab/600 mg BID Cap | Pharmacokinetics Profile, AUCtau and AUClast | AUCtau Cycle 1 Day 15 | 32034 ng*h/mL | Standard Deviation 6992 |
| LDK378 750 mg QD | Pharmacokinetics Profile, AUCtau and AUClast | AUCtau Cycle 1 Day 15 | 30361 ng*h/mL | Standard Deviation 3807 |
| LDK378 750 mg QD | Pharmacokinetics Profile, AUCtau and AUClast | AUClast Cycle 1 Day 15 | 28013 ng*h/mL | Standard Deviation 5006 |
| MEK162 45 mg BID | Pharmacokinetics Profile, AUCtau and AUClast | AUClast Cycle 1 Day 15 | 2642 ng*h/mL | Standard Deviation 1026 |
| MEK162 45 mg BID | Pharmacokinetics Profile, AUCtau and AUClast | AUCtau Cycle 1 Day 15 | 2645 ng*h/mL | Standard Deviation 981 |
Secondary
Pharmacokinetics Profile, Cmax
PK parameters are estimated from each individual plasma concentration-time profile using non-compartmental analysis (Phoenix software version 6.2 and above). Cmax is the maximum (peak) observed plasma concentration (mass x volume-1) On Cycle 1 Day 1, PK parameters for only BYL719 350 mg QD arm were analyzed
Time frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours) and Day 15 (pre dose, 0.5, 1, 2, 4, 6, 8 hours post dose and only for BYL719 350 mg QD and LDK378 750 mg QD arms also at 24 hours post dose)
Population: PAS: Pharmacokinetic analysis set includes all subjects who have at least one blood sample providing evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BYL719 350 mg QD | Pharmacokinetics Profile, Cmax | Cmax Cycle 1 Day 1 | 2135 ng/mL | Standard Deviation 700 |
| BYL719 350 mg QD | Pharmacokinetics Profile, Cmax | Cmax Cycle 1 Day 15 | 2630 ng/mL | — |
| INC280 400 mg BID Tab/600 mg BID Cap | Pharmacokinetics Profile, Cmax | Cmax Cycle 1 Day 15 | 8046 ng/mL | Standard Deviation 3550 |
| LDK378 750 mg QD | Pharmacokinetics Profile, Cmax | Cmax Cycle 1 Day 15 | 1362 ng/mL | Standard Deviation 177 |
| MEK162 45 mg BID | Pharmacokinetics Profile, Cmax | Cmax Cycle 1 Day 15 | 587 ng/mL | Standard Deviation 183 |
Secondary
Pharmacokinetics Profile, Tmax
PK parameters are estimated from each individual plasma concentration-time profile using non-compartmental analysis (Phoenix software version 6.2 and above). Tmax is the time to reach maximum (peak) plasma concentration (time) On Cycle 1 Day 1, PK parameters for only BYL719 350 mg QD arm were analyzed
Time frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours) and Day 15 (pre dose, 0.5, 1, 2, 4, 6, 8 hours post dose and only for BYL719 350 mg QD and LDK378 750 mg QD arms also at 24 hours post dose)
Population: PAS: Pharmacokinetic analysis set includes all subjects who have at least one blood sample providing evaluable PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| BYL719 350 mg QD | Pharmacokinetics Profile, Tmax | Tmax Cycle 1 Day 1 | 4.03 hours |
| BYL719 350 mg QD | Pharmacokinetics Profile, Tmax | Tmax Cycle 1 Day 15 | 2.00 hours |
| INC280 400 mg BID Tab/600 mg BID Cap | Pharmacokinetics Profile, Tmax | Tmax Cycle 1 Day 15 | 1.00 hours |
| LDK378 750 mg QD | Pharmacokinetics Profile, Tmax | Tmax Cycle 1 Day 15 | 6.10 hours |
| MEK162 45 mg BID | Pharmacokinetics Profile, Tmax | Tmax Cycle 1 Day 15 | 1.10 hours |