Non-Small Cell Lung Cancer
Conditions
Keywords
Non-Small Cell Lung Cancer, Non small cell lung carcinoma, NSCLC, ALK, LDK378, Ceritinib, crizotinib naïve adult patients, ALK-activated non-small cell lung cancer, treatment of lung cancer after first metastasis, lung cancer, lung adenocarcinoma
Brief summary
A single-arm, open-label, two-stage multicenter, phase II study. Patients were pre-screened for ALK positive status. Treatment with LDK378 at 750 mg qd was continued until the patient experienced unacceptable toxicity that precluded further treatment, discontinued treatment at the discretion of the investigator or patient, started a new anticancer therapy and/or died. LDK378 was continued beyond RECIST defined progressive disease (PD) as assessed by the investigator, if in the judgment of the investigator, there was evidence of clinical benefit. Patients who discontinued the study medication in the absence of progression continued to be followed for tumor assessment until the time of PD as assessed by the investigator. Male and female patients aged 18 or over with ALK-rearranged non-small cell cancer (NSCLC) were screened for eligibility. Patients had to have received no prior crizotinib, and had to be chemotherapy-naïve or been pretreated with cytotoxic chemotherapy (up to three prior lines).
Interventions
DRUGLDK378
LDK378/Ceritinib was supplied as 150 mg hard gelatin capsules and administered orally
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion criteria: * Histologically or cytologically confirmed diagnosis of stage IIIB or IV NSCLC that carried an ALK rearrangement, as per the FDA-approved Vysis ALK break-apart FISH assay (Abbott Molecular Inc.) * Age 18 years or older at the time of informed consent. * Patients must have NSCLC that had progressed during or after the last chemotherapy regimen received prior to the first dose of LDK378, if chemotherapy was received * Patients must have been chemotherapy-naive or had received 1-3 lines of cytotoxic chemotherapy to treat their locally advanced or metastatic NSCLC * Patients must have had a tumor tissue sample available, collected either at the time of diagnosis of NSCLC or any time since. * Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 2, except for patients with grade 2 nausea/vomiting and/or grade 2 diarrhea despite optimal supportive therapy who were not allowed to participate in the study. Key
Exclusion criteria
* Prior treatment with crizotinib, or any other ALK inhibitor investigational agent, for NSCLC * Patients with known hypersensitivity to any of the excipients of LDK378. * Patients with symptomatic central nervous system (CNS) metastases who were neurologically unstable or had required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms. * History of carcinomatous meningitis. * Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years. * Clinically significant, uncontrolled heart disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) by Investigator Assessment | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | ORR per RECIST 1.1 calculated as the percentage of participants with a best overall response (OR) defined as complete response (CR) or partial response (PR) as assessed by the investigator. 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. 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 |
|---|---|---|
| Duration of Response (DOR) as Per Investigator | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to any cause, by investigator assessment per RECIST 1.1. 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. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Duration of Response (DOR) as Per BIRC | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to any cause, by BIRC assessment per RECIST 1.1. 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. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Disease Control Rate (DCR) as Per Investigator and BIRC | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | DCR per RECIST 1.1 is the percentage of participants with best overall response of CR, PR, stable disease (SD) or Non-CR/Non-PD. CR: Disappearance of all non-nodal target lesions. Also, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions that would qualify for PD. PD: At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. |
| Time to Response (TTR) as Per Investigator | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug | TTR, calculated as the time from first dose of LDK378 to first documented response (CR+PR), by investigator. This was only on participants with confirmed CR or PR. 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. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| ORR by Blinded Independent Review Committee (BIRC) | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | ORR per RECIST 1.1 calculated as the percentage of participants with a best overall response (OR) defined as complete response (CR) or partial response (PR) as assessed by BIRC. 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. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Overall Intracranial Response Rate (OIRR) as Per Investigator | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who have measureable disease in the brain at baseline by investigator. |
| Overall Intracranial Response Rate (OIRR) as Per BIRC | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who have measureable disease in the brain at baseline by BIRC. |
| Progression-free Survival (PFS) Per Investigator and BIRC | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | PFS, defined as time from first dose of LDK378 to progression or death due to any cause, as assessed by investigator and BIRC assessments. |
| Overall Survival (OS) | Time from the date of first dose of LDK378 to the date of death due to any cause up to 5 years | OS, defined as time from first dose of LDK378 to death due to any cause |
| Time to Response (TTR) as Per BIRC | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | TTR, calculated as the time from first dose of LDK378 to first documented response (CR+PR), by BIRC assessment. This was only on participants with confirmed CR or PR. 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. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
Countries
Australia, Belgium, Canada, France, Hong Kong, Italy, Japan, New Zealand, Norway, Russia, Singapore, South Korea, Spain, Sweden, Taiwan, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Approximately 105 patients were planned to be enrolled. A total of 124 patients were enrolled and treated with ceritinib.
Participants by arm
| Arm | Count |
|---|---|
| LDK378 (Ceritinib) Participants on this arm took oral LDK378 750 mg once daily. | 124 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 18 |
| Overall Study | Death | 10 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | No longer requires treatment | 1 |
| Overall Study | Physician Decision | 6 |
| Overall Study | Progressive disease | 53 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Subject/guardian decision | 2 |
Baseline characteristics
| Characteristic | LDK378 (Ceritinib) |
|---|---|
| Age, Continuous | 54.8 Years STANDARD_DEVIATION 12.16 |
| Race/Ethnicity, Customized Asian | 74 Participants |
| Race/Ethnicity, Customized Black | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 48 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Sex: Female, Male Female | 74 Participants |
| Sex: Female, Male Male | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 56 / 124 |
| other Total, other adverse events | 123 / 124 |
| serious Total, serious adverse events | 50 / 124 |
Outcome results
Primary
Overall Response Rate (ORR) by Investigator Assessment
ORR per RECIST 1.1 calculated as the percentage of participants with a best overall response (OR) defined as complete response (CR) or partial response (PR) as assessed by the investigator. 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. 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: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
Population: The Full Analysis Set (FAS) consisted of all patients who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDK378 (Ceritinib) | Overall Response Rate (ORR) by Investigator Assessment | 67.7 Percentage of participants |
Secondary
Disease Control Rate (DCR) as Per Investigator and BIRC
DCR per RECIST 1.1 is the percentage of participants with best overall response of CR, PR, stable disease (SD) or Non-CR/Non-PD. CR: Disappearance of all non-nodal target lesions. Also, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions that would qualify for PD. PD: At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm.
Time frame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
Population: The Full Analysis Set (FAS) consisted of all patients who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDK378 (Ceritinib) | Disease Control Rate (DCR) as Per Investigator and BIRC | DCR per Investigator | 90.3 Percentage of participants |
| LDK378 (Ceritinib) | Disease Control Rate (DCR) as Per Investigator and BIRC | DCR per BIRC | 86.3 Percentage of participants |
Secondary
Duration of Response (DOR) as Per BIRC
DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to any cause, by BIRC assessment per RECIST 1.1. 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. 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: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
Population: The set consisted of patients in the Full Analysis Set (FAS) who had confirmed complete response (CR) or partial response (PR) as assessed by BIRC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LDK378 (Ceritinib) | Duration of Response (DOR) as Per BIRC | 27.3 Months |
Secondary
Duration of Response (DOR) as Per Investigator
DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to any cause, by investigator assessment per RECIST 1.1. 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. 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: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
Population: The set consisted of patients in the Full Analysis Set (FAS) who had confirmed complete response (CR) or partial response (PR) by investigator.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LDK378 (Ceritinib) | Duration of Response (DOR) as Per Investigator | 24.0 Months |
Secondary
ORR by Blinded Independent Review Committee (BIRC)
ORR per RECIST 1.1 calculated as the percentage of participants with a best overall response (OR) defined as complete response (CR) or partial response (PR) as assessed by BIRC. 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. 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: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
Population: The Full Analysis Set (FAS) consisted of all patients who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDK378 (Ceritinib) | ORR by Blinded Independent Review Committee (BIRC) | 63.7 Percentage of participants |
Secondary
Overall Intracranial Response Rate (OIRR) as Per BIRC
OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who have measureable disease in the brain at baseline by BIRC.
Time frame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
Population: The set consisted of patients in the Full Analysis Set (FAS) who had measurable target lesions in brain at baseline by BIRC.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDK378 (Ceritinib) | Overall Intracranial Response Rate (OIRR) as Per BIRC | 61.5 Percentage of participants |
Secondary
Overall Intracranial Response Rate (OIRR) as Per Investigator
OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who have measureable disease in the brain at baseline by investigator.
Time frame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
Population: The set consisted of patients in the Full Analysis Set (FAS) who had measurable target lesions in brain at baseline by investigator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDK378 (Ceritinib) | Overall Intracranial Response Rate (OIRR) as Per Investigator | 20.0 Percentage of participants |
Secondary
Overall Survival (OS)
OS, defined as time from first dose of LDK378 to death due to any cause
Time frame: Time from the date of first dose of LDK378 to the date of death due to any cause up to 5 years
Population: The Full Analysis Set (FAS) consisted of all patients who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LDK378 (Ceritinib) | Overall Survival (OS) | 51.3 Months |
Secondary
Progression-free Survival (PFS) Per Investigator and BIRC
PFS, defined as time from first dose of LDK378 to progression or death due to any cause, as assessed by investigator and BIRC assessments.
Time frame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
Population: The Full Analysis Set (FAS) consisted of all patients who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LDK378 (Ceritinib) | Progression-free Survival (PFS) Per Investigator and BIRC | PFS per Investigator | 16.6 Months |
| LDK378 (Ceritinib) | Progression-free Survival (PFS) Per Investigator and BIRC | PFS per BIRC | 19.4 Months |
Secondary
Time to Response (TTR) as Per BIRC
TTR, calculated as the time from first dose of LDK378 to first documented response (CR+PR), by BIRC assessment. This was only on participants with confirmed CR or PR. 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. 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: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
Population: The set consisted of patients in the Full Analysis Set (FAS) who had confirmed complete response (CR) or partial response (PR) as assessed by BIRC.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LDK378 (Ceritinib) | Time to Response (TTR) as Per BIRC | 2.2 Months | Standard Deviation 1.22 |
Secondary
Time to Response (TTR) as Per Investigator
TTR, calculated as the time from first dose of LDK378 to first documented response (CR+PR), by investigator. This was only on participants with confirmed CR or PR. 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. 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: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug
Population: The set consisted of patients in the Full Analysis Set (FAS) who had confirmed complete response (CR) or partial response (PR) by investigator.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LDK378 (Ceritinib) | Time to Response (TTR) as Per Investigator | 2.5 Months | Standard Deviation 2.66 |