ALK-positive Non-small Cell Lung Cancer
Conditions
Keywords
ALK-positive, NSCLC, non-small cell lung cancer, brain metastasis, metastatic to the brain and/or to leptomeninges, ceritinib, LDK378, NSCLC metastatic to the brain, leptomeninges harboring a confirmed ALK rearrangement
Brief summary
This was a phase II, multi-center, open-label, five-arm study in which the efficacy and safety of oral ceritinib treatment was assessed in patients with NSCLC metastatic to the brain and/or to leptomeninges harboring a confirmed ALK rearrangement, using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). If documentation of ALK rearrangement as described above was not locally available, a test to confirm ALK rearrangement was performed by a Novartis designated central laboratory. Patients waited for the central laboratory result of the ALK rearrangement status before initiating treatment with ceritinib.
Detailed description
Approximately 160 patients diagnosed with ALK-positive metastatic NSCLC (according to the 7th edition of the AJCC \[American Joint Committee on Cancer\] Cancer Staging Manual) and active lesions in the brain and/or diagnosed with leptomeningeal carcinomatosis were included in the study, approximately 40 patients in Arm 1 and Arm 2, approximately 30 patients in Arms 3 and Arm 4, and approximately 20 patients in Arm 5. Additional patients were enrolled in Arm 4 to achieve approximately 60 patients in Arms 3 and 4 together (i.e. ALKi naïve patients), if enrollment rate in Arm 3 was slow. * Arm 1 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously treated with radiation to the brain and with prior exposure to an ALKi. * Arm 2 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously untreated with radiation to the brain but with prior exposure to an ALKi. * Arm 3 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously treated with radiation to the brain but with no prior exposure to an ALKi. * Arm 4 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously untreated with radiation to the brain and with no prior exposure to an ALKi * Arm 5 included any patients with leptomeningeal carcinomatosis with or without evidence of active lesion at the baseline Gadolinium-enhanced brain MRI. Note: Previous treatment with ALK inhibitors other than crizotinib was not allowed in Arms 1, 2, and 5. Ceritinib was administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule. The treatment period started on Cycle 1 Day 1. Complete tumor assessments including gadolinium enhanced brain MRI was repeated at Week 8 (on Cycle 3 Day 1) and every 8 weeks (i.e. every 2 cycles) thereafter or earlier if clinically indicated. Safety evaluations included (S)AEs, physical examination, vital signs, ECGs, laboratory parameters and WHO performance status. Blood and CSF samples for PK were also collected.
Interventions
DRUGCeritinib
LDK378 is a gelatin capsule, administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule on an empty stomach.
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
* Histologically or cytologically confirmed diagnosis of metastatic NSCLC according to the 7th edition of the AJCC Cancer Staging Manual. In addition, the NSCLC must harbor an ALK rearrangement, as assessed using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). If documentation of ALK rearrangement as described above was not locally available, a test to confirm ALK rearrangement was to be performed by a Novartis designated central laboratory. Patients had to wait for the central laboratory result of the ALK rearrangement status before initiating treatment with ceritinib * At least one extracranial measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion could only be counted as a target lesion if there was clear sign of progression since the irradiation. * Patients could or could not have neurological symptoms but must have been able to swallow and retain oral medication. * Patients had to be neurologically stable within at least 1 week prior to the first dose of study drug. * Patients could have received prior chemotherapy, crizotinib (other ALK inhibitors were not allowed), biologic therapy or other investigational agents. * Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03). Patients with any grade of alopecia were allowed to enter the study. * Patient had life expectancy ≥ 6 weeks. * Patient had a WHO performance status 0-2. Patients in Arm 1 to 4 had to also meet the following inclusion criteria: \- Patients had to have active brain metastases from NSCLC, confirmed by Gadolinium-enhanced MRI without concomitant leptomeningeal carcinomatosis. Dose of steroids had to be stable for 5 days before the baseline brain MRI. Patients in Arm 5 had to also meet the following inclusion criteria: \- Patients must have been diagnosed with leptomeningeal carcinomatosis.
Exclusion criteria
* Patients who needed whole brain radiation to control the brain metastases. Patients were not eligible unless treated brain lesions were progressive or new brain lesions were observed since the post whole brain radiation therapy MRI. * Planning of any brain local treatment (including but not limited to surgery, stereotactic radiosurgery, whole brain radiation, intrathecal chemotherapy) following the administration of the first dose of study drug. * Patient with a concurrent malignancy or history of a malignant disease other than NSCLC that had been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion included the following: completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type. * Patient had impairment of GI function or GI disease that could significantly alter the absorption of ceritinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome). * Patient was receiving unstable or increasing doses of corticosteroids. * Patient had other severe, acute, or chronic medical conditions including uncontrolled diabetes mellitus or psychiatric conditions or laboratory abnormalities that in the opinion of the investigator could increase the risk associated with study participation, or that could interfere with the interpretation of study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Per Investigator Assessment | 43 months | Overall response rate (ORR) is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by the investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Investigator Assessment | 43 months | OIRR was calculated based on response assessments in the brain for patients having measurable brain metastases at baseline. OIRR was defined as the percentage of participants with a best overall confirmed response of CR or PR in the brain as assessed per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or decreased by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) & non-target lesions are not in progression or in complete response. |
| Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Blinded Independent Review Committee (BIRC) Assessment | 43 months | OIRR was calculated based on response assessments in the brain for patients having measurable brain metastases at baseline. OIRR was defined as the percentage of participants with a best overall confirmed response of CR or PR in the brain as assessed per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or decreased by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) & non-target lesions are not in progression or in complete response. |
| Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 | Week 8 and Week 16 | IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by the Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression. |
| Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment - Overall | 43 months | IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by the Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression. |
| Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 | Week 8 and Week 16 | IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression. |
| Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment - Overall | 43 months | IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression. |
| Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per Investigator Assessment | 43 months | TTIR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at baseline. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per BIRC Assessment | 43 months | TTIR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at baseline. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per Investigator Assessment | 43 months | Defined as the time from the first documented response (PR or CR) in the brain to the date of the first documented disease progression in the brain or death due to any cause, amongst participants with measurable brain metastases at baseline and a confirmed response (PR or CR) in the brain as per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per BIRC Assessment | 43 months | Defined as the time from the first documented response (PR or CR) in the brain to the date of the first documented disease progression in the brain or death due to any cause, amongst participants with measurable brain metastases at baseline and a confirmed response (PR or CR) in the brain as per modified RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment | 43 months | OERR was defined as the percentage of participants with a best overall confirmed response of CR or PR outside of the brain, as assessed per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall | 43 months | EDCR overall was defined as the percentage of participants with a best overall response of CR, PR or SD outside of the brain as assessed per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression. |
| Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | Week 8 and Week 16 | EDCR at weeks 8 & 16: defined as percentage of parts. with CR, PR or SD outside of the brain at Wk 8 & 16 extracranial tumor evaluations respectively, per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression. |
| Disease Control Rate (DCR) Per Investigator Assessment | 43 months | DCR: percentage of parts. with best overall response of CR, PR or stable disease (SD) in the whole body, as assessed per RECIST 1.1 by investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression. |
| Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per BIRC Assessment | 43 months | TTER was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) outside of the brain as assessed per RECIST 1.1 criteria. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Duration of Extracranial Response (DOER) Per RECIST 1.1 Per Investigator Assessment | 43 months | DOER was defined as the time from the first documented response (PR or CR) outside of the brain to the date of the first documented disease progression outside of the brain or death due to any cause, amongst patients with a confirmed response (PR or CR) outside of the brain per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Duration of Extracranial Response (DOER) Per RECIST 1.1 Per BIRC Assessment | 43 months | DOER was defined as the time from the first documented response (PR or CR) outside of the brain to the date of the first documented disease progression outside of the brain or death due to any cause, amongst patients with a confirmed response (PR or CR) outside of the brain per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Overall Response Rate (ORR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 43 months | Overall response rate ORR is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Disease Control Rate (DCR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 43 months | DCR: defined as percentage of participants with a best overall response of CR, PR or stable disease (SD) in the whole body, per RECIST 1.1 by BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression. |
| Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | 43 months | TTR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the whole body as assessed per RECIST 1.1 criteria per Investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 43 months | TTR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the whole body as assessed by RECIST 1.1 criteria per BIRC assessment. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | 43 months | DOR was defined as the time from the first documented response (PR or CR) to the date of the first documented disease progression or death due to any cause, amongst patients with a confirmed response (PR or CR) in the whole body per RECIST 1.1 per Investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 43 months | DOR was defined as the time from the first documented response (PR or CR) to the date of the first documented disease progression or death due to any cause, amongst patients with a confirmed response (PR or CR) in the whole body per RECIST 1.1 per BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
| Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment | 43 months | PFS was defined as the time from the date of the first dose of ceritinib to the date of the first radiologically documented disease progression in the whole body per RECIST 1.1 or death due to any cause. A patient who had not progressed or died at the date of the analysis was censored at the time of the last adequate tumor evaluation on or before the cut-off date. |
| Overall Survival (OS) | 24 weeks | OS was defined as time from the date of first dose of ceritinib to the date of death due to any cause. The OS time for patients who were alive at the end of the study or were lost to follow-up was censored at the date of last contact. |
| Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough) | Cmax: Cycle 2 Day 1 (C2D1); Cmin: C1D1, C1D8, C1D15, C2D1, C3D1, C4D1, C5D1, C6D1 - all 0hr (pre dose) | Cmax is the maximum (peak) concentration of drug in plasma. Cmin is the minimum (trough) concentration of drug in plasma. Sparse blood samples for ceritinib PK evaluation in plasma were collected on C1D1 up to C6D1 from all patients who received at least one dose of investigational study treatment. |
| Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per Investigator Assessment | 43 months | TTER was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) outside of the brain as assessed per RECIST 1.1 criteria. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. |
Countries
Australia, Belgium, Brazil, Canada, France, Germany, Hong Kong, Italy, Netherlands, Russia, Singapore, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total of 156 patients were enrolled and treated with ceritinib. The FAS (N=156) included all patients who received at least one dose of ceritinib with 42, 40, 12, 44 and 18 patients in arms 1 to 5 respectively. The Safety set was identical to full analysis set in this study.
Pre-assignment details
Approximately 160 patients were planned to be enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). | 42 |
| Arm 2 (PrALKi=Y, PrBRad=N) Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). | 40 |
| Arm 3 (PrALKi=N, PrBRad=Y) Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). | 12 |
| Arm 4 (PrALKi=N, PrBRad=N) Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). | 44 |
| Arm 5 (LepDis) Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3. | 18 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 0 | 6 | 4 |
| Overall Study | Death | 6 | 2 | 3 | 6 | 6 |
| Overall Study | Patient/guardian decision | 2 | 4 | 0 | 2 | 1 |
| Overall Study | Physician Decision | 9 | 6 | 7 | 16 | 3 |
| Overall Study | Progressive disease | 23 | 26 | 2 | 14 | 4 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Arm 1 (PrALKi=Y, PrBRad=Y) | Arm 2 (PrALKi=Y, PrBRad=N) | Arm 3 (PrALKi=N, PrBRad=Y) | Arm 4 (PrALKi=N, PrBRad=N) | Arm 5 (LepDis) | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 48.6 years STANDARD_DEVIATION 11.37 | 54.5 years STANDARD_DEVIATION 12.32 | 50.0 years STANDARD_DEVIATION 9.67 | 51.8 years STANDARD_DEVIATION 11.21 | 49.9 years STANDARD_DEVIATION 11.38 | 51.3 years STANDARD_DEVIATION 11.53 |
| Race/Ethnicity, Customized Asian | 18 Participants | 11 Participants | 7 Participants | 8 Participants | 3 Participants | 47 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 24 Participants | 27 Participants | 4 Participants | 32 Participants | 15 Participants | 102 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 21 Participants | 19 Participants | 6 Participants | 27 Participants | 9 Participants | 82 Participants |
| Sex: Female, Male Male | 21 Participants | 21 Participants | 6 Participants | 17 Participants | 9 Participants | 74 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 42 | 5 / 40 | 3 / 12 | 6 / 44 | 9 / 18 | 31 / 156 |
| other Total, other adverse events | 42 / 42 | 40 / 40 | 11 / 12 | 43 / 44 | 18 / 18 | 154 / 156 |
| serious Total, serious adverse events | 28 / 42 | 17 / 40 | 4 / 12 | 15 / 44 | 11 / 18 | 75 / 156 |
Outcome results
Primary
Overall Response Rate (ORR) Per Investigator Assessment
Overall response rate (ORR) is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by the investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Overall Response Rate (ORR) Per Investigator Assessment | 35.7 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Overall Response Rate (ORR) Per Investigator Assessment | 30.0 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Overall Response Rate (ORR) Per Investigator Assessment | 50.0 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Overall Response Rate (ORR) Per Investigator Assessment | 59.1 Percentage of participants |
| Arm 5 (LepDis) | Overall Response Rate (ORR) Per Investigator Assessment | 16.7 Percentage of participants |
Secondary
Disease Control Rate (DCR) Per Investigator Assessment
DCR: percentage of parts. with best overall response of CR, PR or stable disease (SD) in the whole body, as assessed per RECIST 1.1 by investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time frame: 43 months
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Disease Control Rate (DCR) Per Investigator Assessment | 66.7 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Disease Control Rate (DCR) Per Investigator Assessment | 82.5 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Disease Control Rate (DCR) Per Investigator Assessment | 66.7 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Disease Control Rate (DCR) Per Investigator Assessment | 70.5 Percentage of participants |
| Arm 5 (LepDis) | Disease Control Rate (DCR) Per Investigator Assessment | 66.7 Percentage of participants |
Secondary
Disease Control Rate (DCR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
DCR: defined as percentage of participants with a best overall response of CR, PR or stable disease (SD) in the whole body, per RECIST 1.1 by BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time frame: 43 months
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Disease Control Rate (DCR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 61.9 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Disease Control Rate (DCR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 80.0 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Disease Control Rate (DCR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 66.7 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Disease Control Rate (DCR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 68.2 Percentage of participants |
| Arm 5 (LepDis) | Disease Control Rate (DCR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 72.2 Percentage of participants |
Secondary
Duration of Extracranial Response (DOER) Per RECIST 1.1 Per BIRC Assessment
DOER was defined as the time from the first documented response (PR or CR) outside of the brain to the date of the first documented disease progression outside of the brain or death due to any cause, amongst patients with a confirmed response (PR or CR) outside of the brain per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Duration of Extracranial Response (DOER) Per RECIST 1.1 Per BIRC Assessment | NA months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Duration of Extracranial Response (DOER) Per RECIST 1.1 Per BIRC Assessment | 6.0 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Duration of Extracranial Response (DOER) Per RECIST 1.1 Per BIRC Assessment | NA months |
| Arm 4 (PrALKi=N, PrBRad=N) | Duration of Extracranial Response (DOER) Per RECIST 1.1 Per BIRC Assessment | NA months |
| Arm 5 (LepDis) | Duration of Extracranial Response (DOER) Per RECIST 1.1 Per BIRC Assessment | 5.5 months |
Secondary
Duration of Extracranial Response (DOER) Per RECIST 1.1 Per Investigator Assessment
DOER was defined as the time from the first documented response (PR or CR) outside of the brain to the date of the first documented disease progression outside of the brain or death due to any cause, amongst patients with a confirmed response (PR or CR) outside of the brain per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Duration of Extracranial Response (DOER) Per RECIST 1.1 Per Investigator Assessment | 18.4 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Duration of Extracranial Response (DOER) Per RECIST 1.1 Per Investigator Assessment | 19.3 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Duration of Extracranial Response (DOER) Per RECIST 1.1 Per Investigator Assessment | NA months |
| Arm 4 (PrALKi=N, PrBRad=N) | Duration of Extracranial Response (DOER) Per RECIST 1.1 Per Investigator Assessment | NA months |
| Arm 5 (LepDis) | Duration of Extracranial Response (DOER) Per RECIST 1.1 Per Investigator Assessment | 4.6 months |
Secondary
Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per BIRC Assessment
Defined as the time from the first documented response (PR or CR) in the brain to the date of the first documented disease progression in the brain or death due to any cause, amongst participants with measurable brain metastases at baseline and a confirmed response (PR or CR) in the brain as per modified RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline and confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per BIRC Assessment | 11.0 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per BIRC Assessment | 4.6 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per BIRC Assessment | NA months |
| Arm 4 (PrALKi=N, PrBRad=N) | Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per BIRC Assessment | 9.2 months |
| Arm 5 (LepDis) | Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per BIRC Assessment | 3.4 months |
Secondary
Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per Investigator Assessment
Defined as the time from the first documented response (PR or CR) in the brain to the date of the first documented disease progression in the brain or death due to any cause, amongst participants with measurable brain metastases at baseline and a confirmed response (PR or CR) in the brain as per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline and confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per Investigator Assessment | 9.2 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per Investigator Assessment | 10.1 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per Investigator Assessment | NA months |
| Arm 4 (PrALKi=N, PrBRad=N) | Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per Investigator Assessment | 7.5 months |
| Arm 5 (LepDis) | Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per Investigator Assessment | 5.5 months |
Secondary
Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
DOR was defined as the time from the first documented response (PR or CR) to the date of the first documented disease progression or death due to any cause, amongst patients with a confirmed response (PR or CR) in the whole body per RECIST 1.1 per BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 11.0 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 10.6 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | NA months |
| Arm 4 (PrALKi=N, PrBRad=N) | Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 9.2 months |
| Arm 5 (LepDis) | Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 5.7 months |
Secondary
Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment
DOR was defined as the time from the first documented response (PR or CR) to the date of the first documented disease progression or death due to any cause, amongst patients with a confirmed response (PR or CR) in the whole body per RECIST 1.1 per Investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | 10.8 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | 12.8 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | NA months |
| Arm 4 (PrALKi=N, PrBRad=N) | Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | 9.2 months |
| Arm 5 (LepDis) | Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | 5.5 months |
Secondary
Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16
EDCR at weeks 8 & 16: defined as percentage of parts. with CR, PR or SD outside of the brain at Wk 8 & 16 extracranial tumor evaluations respectively, per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time frame: Week 8 and Week 16
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per Investigator @ Week 8 | 69.0 Percentage of participants |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per Investigator @ Week 16 | 57.1 Percentage of participants |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per BIRC @ Week 8 | 66.7 Percentage of participants |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per BIRC @ Week 16 | 54.8 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per Investigator @ Week 8 | 82.5 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per BIRC @ Week 16 | 70.0 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per Investigator @ Week 16 | 82.5 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per BIRC @ Week 8 | 72.5 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per BIRC @ Week 16 | 66.7 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per Investigator @ Week 16 | 66.7 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per BIRC @ Week 8 | 58.3 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per Investigator @ Week 8 | 58.3 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per Investigator @ Week 8 | 63.6 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per Investigator @ Week 16 | 65.9 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per BIRC @ Week 16 | 68.2 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per BIRC @ Week 8 | 61.4 Percentage of participants |
| Arm 5 (LepDis) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per BIRC @ Week 16 | 44.4 Percentage of participants |
| Arm 5 (LepDis) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per BIRC @ Week 8 | 72.2 Percentage of participants |
| Arm 5 (LepDis) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per Investigator @ Week 16 | 50.0 Percentage of participants |
| Arm 5 (LepDis) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 | EDCR per Investigator @ Week 8 | 72.2 Percentage of participants |
Secondary
Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall
EDCR overall was defined as the percentage of participants with a best overall response of CR, PR or SD outside of the brain as assessed per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time frame: 43 months
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall | EDCR per Investigator assessment | 69.0 Percentage of participants |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall | EDCR per BIRC assessment | 64.3 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall | EDCR per Investigator assessment | 92.5 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall | EDCR per BIRC assessment | 80.0 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall | EDCR per Investigator assessment | 66.7 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall | EDCR per BIRC assessment | 66.7 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall | EDCR per BIRC assessment | 68.2 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall | EDCR per Investigator assessment | 72.7 Percentage of participants |
| Arm 5 (LepDis) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall | EDCR per Investigator assessment | 72.2 Percentage of participants |
| Arm 5 (LepDis) | Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall | EDCR per BIRC assessment | 72.2 Percentage of participants |
Secondary
Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16
IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time frame: Week 8 and Week 16
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 | IDCR at 8 weeks | 76.2 Percentage of participants |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 | IDCR at 16 weeks | 69.0 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 | IDCR at 16 weeks | 62.5 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 | IDCR at 8 weeks | 80.0 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 | IDCR at 16 weeks | 58.3 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 | IDCR at 8 weeks | 58.3 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 | IDCR at 8 weeks | 68.2 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 | IDCR at 16 weeks | 68.2 Percentage of participants |
| Arm 5 (LepDis) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 | IDCR at 16 weeks | 38.9 Percentage of participants |
| Arm 5 (LepDis) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 | IDCR at 8 weeks | 66.7 Percentage of participants |
Secondary
Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment - Overall
IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time frame: 43 months
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment - Overall | 73.8 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment - Overall | 85.0 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment - Overall | 66.7 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment - Overall | 75.0 Percentage of participants |
| Arm 5 (LepDis) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment - Overall | 66.7 Percentage of participants |
Secondary
Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16
IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by the Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time frame: Week 8 and Week 16
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 | IDCR at Week 8 | 71.4 Percentage of participants |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 | IDCR at Week 16 | 59.5 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 | IDCR at Week 8 | 75.0 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 | IDCR at Week 16 | 62.5 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 | IDCR at Week 8 | 58.3 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 | IDCR at Week 16 | 58.3 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 | IDCR at Week 16 | 65.9 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 | IDCR at Week 8 | 68.2 Percentage of participants |
| Arm 5 (LepDis) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 | IDCR at Week 8 | 66.7 Percentage of participants |
| Arm 5 (LepDis) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 | IDCR at Week 16 | 50.0 Percentage of participants |
Secondary
Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment - Overall
IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by the Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time frame: 43 months
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment - Overall | 71.4 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment - Overall | 85.0 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment - Overall | 75.0 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment - Overall | 75.0 Percentage of participants |
| Arm 5 (LepDis) | Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment - Overall | 66.7 Percentage of participants |
Secondary
Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment
OERR was defined as the percentage of participants with a best overall confirmed response of CR or PR outside of the brain, as assessed per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment | OERR per Investigator assessment | 31.0 Percentage of participants |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment | OERR per BIRC assessment | 26.2 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment | OERR per Investigator assessment | 42.5 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment | OERR per BIRC assessment | 25.0 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment | OERR per Investigator assessment | 41.7 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment | OERR per BIRC assessment | 50.0 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment | OERR per BIRC assessment | 61.4 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment | OERR per Investigator assessment | 61.4 Percentage of participants |
| Arm 5 (LepDis) | Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment | OERR per Investigator assessment | 22.2 Percentage of participants |
| Arm 5 (LepDis) | Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment | OERR per BIRC assessment | 16.7 Percentage of participants |
Secondary
Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Blinded Independent Review Committee (BIRC) Assessment
OIRR was calculated based on response assessments in the brain for patients having measurable brain metastases at baseline. OIRR was defined as the percentage of participants with a best overall confirmed response of CR or PR in the brain as assessed per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or decreased by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Blinded Independent Review Committee (BIRC) Assessment | 33.3 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Blinded Independent Review Committee (BIRC) Assessment | 24.1 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Blinded Independent Review Committee (BIRC) Assessment | 33.3 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Blinded Independent Review Committee (BIRC) Assessment | 58.8 Percentage of participants |
| Arm 5 (LepDis) | Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Blinded Independent Review Committee (BIRC) Assessment | 20.0 Percentage of participants |
Secondary
Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Investigator Assessment
OIRR was calculated based on response assessments in the brain for patients having measurable brain metastases at baseline. OIRR was defined as the percentage of participants with a best overall confirmed response of CR or PR in the brain as assessed per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or decreased by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Investigator Assessment | 39.3 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Investigator Assessment | 27.6 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Investigator Assessment | 28.6 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Investigator Assessment | 51.5 Percentage of participants |
| Arm 5 (LepDis) | Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Investigator Assessment | 12.5 Percentage of participants |
Secondary
Overall Response Rate (ORR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
Overall response rate ORR is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Overall Response Rate (ORR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 23.8 Percentage of participants |
| Arm 2 (PrALKi=Y, PrBRad=N) | Overall Response Rate (ORR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 15.0 Percentage of participants |
| Arm 3 (PrALKi=N, PrBRad=Y) | Overall Response Rate (ORR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 33.3 Percentage of participants |
| Arm 4 (PrALKi=N, PrBRad=N) | Overall Response Rate (ORR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 61.4 Percentage of participants |
| Arm 5 (LepDis) | Overall Response Rate (ORR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 11.1 Percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as time from the date of first dose of ceritinib to the date of death due to any cause. The OS time for patients who were alive at the end of the study or were lost to follow-up was censored at the date of last contact.
Time frame: 24 weeks
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Overall Survival (OS) | 24.0 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Overall Survival (OS) | NA months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Overall Survival (OS) | NA months |
| Arm 4 (PrALKi=N, PrBRad=N) | Overall Survival (OS) | NA months |
| Arm 5 (LepDis) | Overall Survival (OS) | 7.2 months |
Secondary
Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough)
Cmax is the maximum (peak) concentration of drug in plasma. Cmin is the minimum (trough) concentration of drug in plasma. Sparse blood samples for ceritinib PK evaluation in plasma were collected on C1D1 up to C6D1 from all patients who received at least one dose of investigational study treatment.
Time frame: Cmax: Cycle 2 Day 1 (C2D1); Cmin: C1D1, C1D8, C1D15, C2D1, C3D1, C4D1, C5D1, C6D1 - all 0hr (pre dose)
Population: The Pharmacokinetic Analysis Set (PAS) comprised of all the patients who received at least one (full or partial) dose of ceritinib and provided at least one evaluable PK blood sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough) | Cmin C1D1: 0hr. (pre dose) | 0 ng/mL | Geometric Coefficient of Variation 0 |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough) | Cmin C1D8: 0hr. (pre dose) | 658 ng/mL | Geometric Coefficient of Variation 59.2 |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough) | Cmin C1D15: 0hr. (pre dose) | 846 ng/mL | Geometric Coefficient of Variation 52.9 |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough) | Cmin C2D1: 0hr. (pre dose) | 1000 ng/mL | Geometric Coefficient of Variation 50 |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough) | Cmax C2D1: 4 - 10 hrs. (post dose) | 1100 ng/mL | Geometric Coefficient of Variation 47.8 |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough) | Cmin C3D1: 0hr. (pre dose) | 982 ng/mL | Geometric Coefficient of Variation 59.1 |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough) | Cmin C4D1: 0hr. (pre dose) | 978 ng/mL | Geometric Coefficient of Variation 75.4 |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough) | Cmin C5D1: 0hr. (pre dose) | 885 ng/mL | Geometric Coefficient of Variation 75.5 |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough) | Cmin C6D1: 0hr. (pre dose) | 785 ng/mL | Geometric Coefficient of Variation 120.4 |
Secondary
Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment
PFS was defined as the time from the date of the first dose of ceritinib to the date of the first radiologically documented disease progression in the whole body per RECIST 1.1 or death due to any cause. A patient who had not progressed or died at the date of the analysis was censored at the time of the last adequate tumor evaluation on or before the cut-off date.
Time frame: 43 months
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment | PFS per Investigator assessment | 7.2 months |
| Arm 1 (PrALKi=Y, PrBRad=Y) | Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment | PFS per BIRC assessment | 5.0 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment | PFS per Investigator assessment | 5.6 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment | PFS per BIRC assessment | 5.5 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment | PFS per Investigator assessment | NA months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment | PFS per BIRC assessment | 15.5 months |
| Arm 4 (PrALKi=N, PrBRad=N) | Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment | PFS per BIRC assessment | 7.7 months |
| Arm 4 (PrALKi=N, PrBRad=N) | Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment | PFS per Investigator assessment | 7.9 months |
| Arm 5 (LepDis) | Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment | PFS per Investigator assessment | 5.2 months |
| Arm 5 (LepDis) | Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment | PFS per BIRC assessment | 3.6 months |
Secondary
Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per BIRC Assessment
TTER was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) outside of the brain as assessed per RECIST 1.1 criteria. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per BIRC Assessment | 1.81 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per BIRC Assessment | 1.86 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per BIRC Assessment | 2.66 months |
| Arm 4 (PrALKi=N, PrBRad=N) | Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per BIRC Assessment | 1.77 months |
| Arm 5 (LepDis) | Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per BIRC Assessment | 1.81 months |
Secondary
Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per Investigator Assessment
TTER was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) outside of the brain as assessed per RECIST 1.1 criteria. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per Investigator Assessment | 1.87 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per Investigator Assessment | 1.87 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per Investigator Assessment | 1.81 months |
| Arm 4 (PrALKi=N, PrBRad=N) | Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per Investigator Assessment | 1.77 months |
| Arm 5 (LepDis) | Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per Investigator Assessment | 2.73 months |
Secondary
Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per BIRC Assessment
TTIR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at baseline. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline and confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per BIRC Assessment | 1.91 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per BIRC Assessment | 1.68 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per BIRC Assessment | 6.31 months |
| Arm 4 (PrALKi=N, PrBRad=N) | Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per BIRC Assessment | 1.81 months |
| Arm 5 (LepDis) | Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per BIRC Assessment | 1.22 months |
Secondary
Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per Investigator Assessment
TTIR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at baseline. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline and confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per Investigator Assessment | 1.87 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per Investigator Assessment | 1.84 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per Investigator Assessment | 3.56 months |
| Arm 4 (PrALKi=N, PrBRad=N) | Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per Investigator Assessment | 1.77 months |
| Arm 5 (LepDis) | Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per Investigator Assessment | 1.80 months |
Secondary
Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
TTR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the whole body as assessed by RECIST 1.1 criteria per BIRC assessment. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 2.00 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 1.76 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 1.82 months |
| Arm 4 (PrALKi=N, PrBRad=N) | Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 1.81 months |
| Arm 5 (LepDis) | Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment | 1.86 months |
Secondary
Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment
TTR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the whole body as assessed per RECIST 1.1 criteria per Investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time frame: 43 months
Population: A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (PrALKi=Y, PrBRad=Y) | Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | 1.87 months |
| Arm 2 (PrALKi=Y, PrBRad=N) | Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | 2.00 months |
| Arm 3 (PrALKi=N, PrBRad=Y) | Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | 1.82 months |
| Arm 4 (PrALKi=N, PrBRad=N) | Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | 1.81 months |
| Arm 5 (LepDis) | Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment | 1.91 months |