Non-Small Cell Lung Cancer
Conditions
Keywords
Non-Small Cell Lung Cancer, ALK, LDK378, Non-small cell lung carcinoma (NSCLC), treatment of lung cancer after first metastasis, lung cancer, lung adenocarcinoma, Non small cell lung carcinoma, Non small cell lung cancer, NSCLC, chemotherapy, ALK-positive, ALK-rearranged advanced non-small cell lung cancer, crizotinib
Brief summary
The primary purpose of the study was to compare the antitumor activity of LDK378 vs. chemotherapy in patients previously treated with chemotherapy (platinum doublet) and crizotinib. Patients in the chemotherapy arm were given the option to switch to LDK378 after confirmed progressive disease (PD), while also had the choice to continue with pemetrexed treatment.
Detailed description
A total of 231 patients were randomized to one of the two treatment arms in a 1:1 ratio. Randomization was stratified by World Health Organization (WHO) performance status (0 versus 1-2) and whether the patient had brain metastases at screening. The study was planned to be ended once the final overall survival (OS) analysis was performed (at the earliest of approximately 196 deaths observed or statistical significance reached at earlier OS interim analysis). Following an agreement between Novartis and European Medicines Agency (EMA) in May 2023 to terminate the trial earlier, this study was completed when the total number of deaths was 190. Patients who had Response Evaluation Criteria In Solid Tumors (RECIST)-defined disease progression as confirmed by the Blinded Independent Review Committee (BIRC), but who, in the opinion of the Investigator, had continued clinical benefit from study treatment on either the chemotherapy arm or the ceritinib arm, continued to receive treatment. These patients continued assessments in the treatment phase. In addition, only patients randomized to the chemotherapy arm were allowed to crossover to receive ceritinib therapy (extension treatment \[ET\] phase) after BIRC-confirmed, RECIST-defined disease progression, and provided they met the eligibility requirements.
Interventions
DRUGCeritinib
Ceritinib was the investigational treatment and was provided as 150 mg hard gelatin capsules for oral use. The dose was 750 mg once daily.
DRUGPemetrexed
Pemetrexed was one of the chemotherapy treatments. Pemetrexed, a reconstituted solution, was intravenously administered over 10 minutes at 500 mg/m\^2 every 21 days.
DRUGDocetaxel
Docetaxel was one of the chemotherapy treatments. Docetaxel, a reconstituted solution, was intravenously administered over 1 hour, at 75 mg/m\^2 every 21 days.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
1. Patient has a histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as assessed by the FDA approved Abbott FISH Test. 2. Patient has stage IIIB or IV diagnosis and must have received one or two prior regimens (including platinum- doublet) of cytotoxic chemotherapy for the treatment of locally advanced or metastatic NSCLC. 3. Patient has at least one measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation 4. Patients must have received previous treatment with crizotinib for the treatment of locally advanced or metastatic NSCLC.
Exclusion criteria
1. Patient with known hypersensitivity to any of the excipients of LDK378 (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate) 2. Patient with a history of severe hypersensitivity reaction to pemetrexed or docetaxel or any known excipients of these drugs. 3. Patient with symptomatic central nervous system (CNS) metastases who is neurologically unstable or has required increasing doses of steroids within the 2 weeks prior to screening to manage CNS symptoms.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC) | From the date of randomization to the date of first radiologically documented disease progression or death due to any cause up to approximately 24 months | PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Investigator Assessment | Up to approximately 84 months | PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause. |
| Overall Response Rate (ORR) Per BIRC | Up to approximately 54 months | ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR): (CR+PR) per Response Evaluation Criteria in Solid Tumors (RECIST), v. 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Overall Response Rate (ORR) Per Investigator Assessment | Up to approximately 93 months | ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR): (CR+PR) per Response Evaluation Criteria in Solid Tumors (RECIST), v. 1.1. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Duration of Response (DOR) Per BIRC | Up to approximately 54 months | DOR defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Duration of Response (DOR) Per Investigator Assessment | Up to approximately 93 months | DOR defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Disease Control Rate (DCR) Per BIRC | Up to approximately 54 months | DCR was defined as the percentage of participants with best overall response of CR, PR, or stable disease (SD). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease. |
| Disease Control Rate (DCR) Per Investigator Assessment | Up to approximately 93 months | DCR was defined as the percentage of participants with best overall response of CR, PR, or stable disease (SD). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease. |
| Time to Response (TTR) Per BIRC | Up to approximately 52 weeks | TTR was defined as the time from date of randomization to date of first documented response (CR or PR). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Time to Response (TTR) Per Investigator Assessment | Up to approximately 45 weeks | TTR was defined as the time from date of randomization to date of first documented response (CR or PR). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Overall Intracranial Response Rate (OIRR) Per BIRC | Up to approximately 18 months | OIRR was defined as the ORR based on lesions in brain (target, nontarget lesions (and new lesions, if applicable) and calculated as the percentage of patients with a best overall confirmed response of CR or PR in the brain per modified RECIST 1.1 as assessed by BIRC neuroradiologist. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Intracranial Disease Control Rate (IDCR) Per BIRC | Up to approximately 18 months | IDCR was defined as the DCR based on lesions in brain (target, non-target lesions (and new lesions, if applicable) and calculated as the proportion of patients with a best overall response of CR or PR or SD (or non-CR/nonPD) in the brain per modified RECIST 1.1 as assessed by BIRC neuro-radiologist. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease. |
| Duration of Intracranial Response (DOIR) Per BIRC | Up to approximately 18 months | DOIR was defined as the DOR based on lesions in brain (target, non-target lesions (and new lesions, if applicable) and calculated from the time of first documented response of CR or PR to the date of the first documented disease progression in the brain or death due to any cause per modified RECIST 1.1 as assessed by BIRC neuro-radiologist. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Overall Survival (OS) | Up to approximately 114 months | OS was defined as time from date of randomization to date of death due to any cause. |
| EORTC QLQ-LC13 Time to Definitive Deterioration | Screening and treatment phase up to 92 months | The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) was used in conjunction with the EORTC QLQ-C30 and provided information on an additional 13 items specifically related to lung cancer. The lung cancer module incorporated one multi-item scale to assess dyspnea, and 9 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All of the domain scores ranged from 0 to 100. A high score indicated a high level of symptoms. QLQ-LC13 time to definitive deterioration was defined as the time from randomization to the earliest date a patient shows a 10 point or higher increase from baseline in any of the ALCLC13 scores related to pain in chest, cough, or dyspnea (with no later change below this threshold), or death due to any cause. Each cycle was 21 days. |
| Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Screening and treatment phase up to 92 months | The LCSS patient scale uses a 24-hour recall period and contains nine items: six measuring major symptoms for lung cancer (appetite loss, fatigue, cough, dyspnea, hemoptysis, pain), and three summary items related to total symptom distress, normal activity status, and overall quality of life. The total scale used is a 100 mm visual analog scale to measure the intensity of patient responses, with zero corresponding to the lowest rating (best status) and 100 representing the highest rating (worst status). The total score was calculated as the mean of the 9 items. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data. |
| Least Squares Mean Scores on the EQ-5D-5L Index | Screening and treatment phase up to 92 months | The EQ-5D descriptive classification consists of five dimensions of health: mobility, self-care, usual activities, anxiety/depression and pain/discomfort. Patients are requested to select the statement which best describes their condition on that day for each dimension. EQ-5D-5L index scores can range from -0.59 to 1, where 1 is the best possible health state. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data. |
| Least Squares Mean Scores on the EQ-5D Visual Analogue Scale (VAS) | Screening and treatment phase up to 92 months | The EQ-5D descriptive classification consists of five dimensions of health: mobility, self-care, usual activities, anxiety/depression and pain/discomfort. Patients are requested to select the statement which best describes their condition on that day for each dimension. EQ VAS scores can range from 0 to 100, where 100 is the best possible health state. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data. |
| Cmax for Ceritinib | Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. | The observed maximum plasma concentration following administration |
| Tmax for Ceritinib | Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. | The time to reach peak or maximum concentration |
| Tlast for Ceritinib | Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. | The time to last quantifiable concentration |
| AUC0-24h for Ceritinib | Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. | The area under the plasma concentration-time curve calculated from time zero to 24 hours |
| Mean Accumulation Ratio (Racc) for Ceritinib | Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. | Accumulation ratio calculated using AUC0-24 values obtained from a dosing interval at steady-state (Cycle 2, Day 1) divided by AUC0-24 on Cycle 1, Day 1. |
| Clearance Rate at Steady State (CLss/F) for Ceritinib | Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. | The apparent total body clearance from plasma. CLss/F is calculated from AUC0-24 assuming steady state (CLss/F=Dose/AUC0-24). |
| Post-Hoc: All Collected Deaths | Pre-treatment and on-treatment deaths: Up to approximately 8 years. Post-treatment survival follow-up deaths: Up to an additional 2.5 years. | Pre-treatment deaths: from day of patient's informed consent to the day before first dose of study treatment. On-treatment deaths: from first dose of study treatment to 30 days following the last dose of study treatment at the end of treatment phase. For crossover patients, from first dose of ceritinib at the extension treatment phase to 30 days following the last dose. Survival Follow-up deaths: from Day 31 after last dose of study treatment to the data cut-off date. |
| Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Screening and treatment phase up to 92 months | The EORTC QLQ-C30 questionnaire contained 30 items and was composed of both multi-item scales and single item measures. These included five functional scales (physical, role, emotional, cognitive, and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and a global health status/quality of life (QoL) scale. All of the scales and single items ranged from 0 to 100. A high scale score represented a higher response level. Thus, a high score for a functional scale indicated a high/healthy level of functioning, a high score for the QoL indicated high QoL, but a high score for a symptom scale/single item indicated a high level of symptomatology/problems. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data. |
Countries
Belgium, Canada, France, Germany, Hong Kong, Ireland, Israel, Italy, Japan, Lebanon, Netherlands, Portugal, Russia, Singapore, South Korea, Spain, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled in the following countries (with number of sites): Belgium (4), Canada (1), France (9), Germany (8), Hong Kong (3), Ireland (2), Israel (2), Italy (10), Japan (12), Republic of Korea (5), Lebanon (1), Netherlands (2), Portugal (1), Russia (3), Singapore (2), Spain (11), Switzerland (2), Turkey (3), United Kingdom (5), United States (13).
Pre-assignment details
In the treatment phase, patients were randomized 1:1 to one of the treatment arms (ceritinib or chemotherapy). In the extension treatment phase, only patients randomized to the chemotherapy arm were allowed to crossover to receive ceritinib therapy after BIRC-confirmed, RECIST-defined disease progression.
Participants by arm
| Arm | Count |
|---|---|
| Ceritinib Ceritinib 750 mg | 115 |
| Chemotherapy Chemotherapy as determined by BIRC | 116 |
| Total | 231 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Extension Treatment Phase | Adverse Event | 0 | 0 | 6 |
| Extension Treatment Phase | Death | 0 | 0 | 17 |
| Extension Treatment Phase | Physician Decision | 0 | 0 | 5 |
| Extension Treatment Phase | Progressive disease | 0 | 0 | 46 |
| Extension Treatment Phase | Study terminated by sponsor | 0 | 0 | 1 |
| Extension Treatment Phase | Subject/guardian decision | 0 | 0 | 4 |
| Treatment Phase | Adverse Event | 7 | 8 | 0 |
| Treatment Phase | Death | 9 | 5 | 0 |
| Treatment Phase | No longer required treatment | 0 | 1 | 0 |
| Treatment Phase | Physician Decision | 6 | 7 | 0 |
| Treatment Phase | Pregnancy | 1 | 0 | 0 |
| Treatment Phase | Progressive disease | 79 | 87 | 0 |
| Treatment Phase | Study terminated by sponsor | 1 | 0 | 0 |
| Treatment Phase | Subject/guardian decision | 12 | 8 | 0 |
Baseline characteristics
| Characteristic | Chemotherapy | Total | Ceritinib |
|---|---|---|---|
| Age, Continuous | 54.4 Years STANDARD_DEVIATION 11.61 | 53.7 Years STANDARD_DEVIATION 11.78 | 53.1 Years STANDARD_DEVIATION 11.96 |
| Race/Ethnicity, Customized Asian | 38 Participants | 68 Participants | 30 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 68 Participants | 149 Participants | 81 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 6 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown | 5 Participants | 7 Participants | 2 Participants |
| Sex: Female, Male Female | 61 Participants | 129 Participants | 68 Participants |
| Sex: Female, Male Male | 55 Participants | 102 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 115 | 2 / 116 | 0 / 0 | 16 / 115 | 5 / 113 | 19 / 78 | 86 / 93 | 18 / 23 | 44 / 55 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 114 / 115 | 111 / 113 | 76 / 78 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 57 / 115 | 35 / 113 | 45 / 78 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC)
PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause.
Time frame: From the date of randomization to the date of first radiologically documented disease progression or death due to any cause up to approximately 24 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC) | 5.4 months |
| Chemotherapy | Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC) | 1.6 months |
p-value: <0.00195% CI: [0.36, 0.67]Log Rank
Secondary
AUC0-24h for Ceritinib
The area under the plasma concentration-time curve calculated from time zero to 24 hours
Time frame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
Population: Participants in the pharmacokinetic (PK) analysis set who had extensive PK collection.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ceritinib | AUC0-24h for Ceritinib | Cycle 1, Day 1 n=4,0 | 1470 h*ng/mL | Geometric Coefficient of Variation 65.1 |
| Ceritinib | AUC0-24h for Ceritinib | Cycle 2, Day 1 n=2,0 | 25000 h*ng/mL | Geometric Coefficient of Variation 19 |
Secondary
Clearance Rate at Steady State (CLss/F) for Ceritinib
The apparent total body clearance from plasma. CLss/F is calculated from AUC0-24 assuming steady state (CLss/F=Dose/AUC0-24).
Time frame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
Population: Participants in the pharmacokinetic (PK) analysis set who had extensive PK collection.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ceritinib | Clearance Rate at Steady State (CLss/F) for Ceritinib | Cycle 2, Day 1 n=2,0 | 30 L/h | Geometric Coefficient of Variation 19 |
| Unknown | Clearance Rate at Steady State (CLss/F) for Ceritinib | Cycle 1, Day 1 n=0,0 | — L/h | — |
Secondary
Cmax for Ceritinib
The observed maximum plasma concentration following administration
Time frame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
Population: Participants in the pharmacokinetic (PK) analysis set who had extensive PK collection.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ceritinib | Cmax for Ceritinib | Cycle 1, Day 1 n=4,0 | 90.4 ng/mL | Geometric Coefficient of Variation 49.8 |
| Ceritinib | Cmax for Ceritinib | Cycle 2, Day 1 n=2,0 | 1170 ng/mL | Geometric Coefficient of Variation 17.7 |
Secondary
Disease Control Rate (DCR) Per BIRC
DCR was defined as the percentage of participants with best overall response of CR, PR, or stable disease (SD). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Time frame: Up to approximately 54 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceritinib | Disease Control Rate (DCR) Per BIRC | 76.5 percentage of participants |
| Chemotherapy | Disease Control Rate (DCR) Per BIRC | 37.9 percentage of participants |
Secondary
Disease Control Rate (DCR) Per Investigator Assessment
DCR was defined as the percentage of participants with best overall response of CR, PR, or stable disease (SD). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Time frame: Up to approximately 93 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceritinib | Disease Control Rate (DCR) Per Investigator Assessment | 80.0 percentage of participants |
| Chemotherapy | Disease Control Rate (DCR) Per Investigator Assessment | 39.7 percentage of participants |
Secondary
Duration of Intracranial Response (DOIR) Per BIRC
DOIR was defined as the DOR based on lesions in brain (target, non-target lesions (and new lesions, if applicable) and calculated from the time of first documented response of CR or PR to the date of the first documented disease progression in the brain or death due to any cause per modified RECIST 1.1 as assessed by BIRC neuro-radiologist. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 18 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Patients with measurable and/or nonmeasurable disease in the brain at baseline as per BIRC neuroradiology review. patients with measurable and/or non-measurable disease in the brain at baseline as per BIRC neuro-radiology review, and with confirmed intracranial CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Duration of Intracranial Response (DOIR) Per BIRC | 8.3 months |
| Chemotherapy | Duration of Intracranial Response (DOIR) Per BIRC | 16.7 months |
Secondary
Duration of Response (DOR) Per BIRC
DOR defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 54 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Patients with confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Duration of Response (DOR) Per BIRC | 7.6 months |
| Chemotherapy | Duration of Response (DOR) Per BIRC | 10.4 months |
Secondary
Duration of Response (DOR) Per Investigator Assessment
DOR defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 93 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Data are reported for responders only. Patients with confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Duration of Response (DOR) Per Investigator Assessment | 6.7 months |
| Chemotherapy | Duration of Response (DOR) Per Investigator Assessment | 8.3 months |
Secondary
EORTC QLQ-LC13 Time to Definitive Deterioration
The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) was used in conjunction with the EORTC QLQ-C30 and provided information on an additional 13 items specifically related to lung cancer. The lung cancer module incorporated one multi-item scale to assess dyspnea, and 9 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All of the domain scores ranged from 0 to 100. A high score indicated a high level of symptoms. QLQ-LC13 time to definitive deterioration was defined as the time from randomization to the earliest date a patient shows a 10 point or higher increase from baseline in any of the ALCLC13 scores related to pain in chest, cough, or dyspnea (with no later change below this threshold), or death due to any cause. Each cycle was 21 days.
Time frame: Screening and treatment phase up to 92 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | EORTC QLQ-LC13 Time to Definitive Deterioration | 13.4 months |
| Chemotherapy | EORTC QLQ-LC13 Time to Definitive Deterioration | 2.8 months |
Secondary
Intracranial Disease Control Rate (IDCR) Per BIRC
IDCR was defined as the DCR based on lesions in brain (target, non-target lesions (and new lesions, if applicable) and calculated as the proportion of patients with a best overall response of CR or PR or SD (or non-CR/nonPD) in the brain per modified RECIST 1.1 as assessed by BIRC neuro-radiologist. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Time frame: Up to approximately 18 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Patients with measurable and/or nonmeasurable disease in the brain at baseline as per BIRC neuroradiology review.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceritinib | Intracranial Disease Control Rate (IDCR) Per BIRC | 71.2 percentage of participants |
| Chemotherapy | Intracranial Disease Control Rate (IDCR) Per BIRC | 53.7 percentage of participants |
Secondary
Least Squares Mean Scores on the EQ-5D-5L Index
The EQ-5D descriptive classification consists of five dimensions of health: mobility, self-care, usual activities, anxiety/depression and pain/discomfort. Patients are requested to select the statement which best describes their condition on that day for each dimension. EQ-5D-5L index scores can range from -0.59 to 1, where 1 is the best possible health state. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.
Time frame: Screening and treatment phase up to 92 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ceritinib | Least Squares Mean Scores on the EQ-5D-5L Index | 0.7837 score on a scale | Standard Error 0.01039 |
| Chemotherapy | Least Squares Mean Scores on the EQ-5D-5L Index | 0.7108 score on a scale | Standard Error 0.01533 |
Secondary
Least Squares Mean Scores on the EQ-5D Visual Analogue Scale (VAS)
The EQ-5D descriptive classification consists of five dimensions of health: mobility, self-care, usual activities, anxiety/depression and pain/discomfort. Patients are requested to select the statement which best describes their condition on that day for each dimension. EQ VAS scores can range from 0 to 100, where 100 is the best possible health state. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.
Time frame: Screening and treatment phase up to 92 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ceritinib | Least Squares Mean Scores on the EQ-5D Visual Analogue Scale (VAS) | 71.8 score on a scale | Standard Error 0.98 |
| Chemotherapy | Least Squares Mean Scores on the EQ-5D Visual Analogue Scale (VAS) | 69.0 score on a scale | Standard Error 1.45 |
Secondary
Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30)
The EORTC QLQ-C30 questionnaire contained 30 items and was composed of both multi-item scales and single item measures. These included five functional scales (physical, role, emotional, cognitive, and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and a global health status/quality of life (QoL) scale. All of the scales and single items ranged from 0 to 100. A high scale score represented a higher response level. Thus, a high score for a functional scale indicated a high/healthy level of functioning, a high score for the QoL indicated high QoL, but a high score for a symptom scale/single item indicated a high level of symptomatology/problems. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.
Time frame: Screening and treatment phase up to 92 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Cognitive Functioning n=106,86 | 86.7 score on a scale | Standard Error 0.91 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Pain n=107,86 | 21.4 score on a scale | Standard Error 1.22 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Physical Functioning n=107,86 | 80.5 score on a scale | Standard Error 1.04 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Dyspnea n=107,86 | 17.4 score on a scale | Standard Error 1.03 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Role Functioning n=107,86 | 72.6 score on a scale | Standard Error 1.3 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Insomnia n=107,86 | 18.9 score on a scale | Standard Error 1.33 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Social Functioning n=106,86 | 76.7 score on a scale | Standard Error 1.56 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Appetite Loss n=107,86 | 21.2 score on a scale | Standard Error 1.33 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Fatigue n=107,86 | 31.1 score on a scale | Standard Error 1.1 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Constipation n=107,86 | 15.0 score on a scale | Standard Error 1.31 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Emotional Functioning n=106,86 | 82.4 score on a scale | Standard Error 1.01 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Diarrhea n=106,86 | 29.3 score on a scale | Standard Error 1.29 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Nausea and Vomiting n=107,86 | 17.2 score on a scale | Standard Error 1.08 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Financial Difficulties n=104,85 | 15.5 score on a scale | Standard Error 1.41 |
| Ceritinib | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Global Health Status/QoL n=106,85 | 62.9 score on a scale | Standard Error 1.13 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Financial Difficulties n=104,85 | 19.7 score on a scale | Standard Error 2.1 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Global Health Status/QoL n=106,85 | 63.2 score on a scale | Standard Error 1.74 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Physical Functioning n=107,86 | 75.4 score on a scale | Standard Error 1.52 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Emotional Functioning n=106,86 | 80.7 score on a scale | Standard Error 1.54 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Social Functioning n=106,86 | 71.6 score on a scale | Standard Error 2.31 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Cognitive Functioning n=106,86 | 84.5 score on a scale | Standard Error 1.4 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Role Functioning n=107,86 | 68.7 score on a scale | Standard Error 1.98 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Fatigue n=107,86 | 36.1 score on a scale | Standard Error 1.69 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Nausea and Vomiting n=107,86 | 9.4 score on a scale | Standard Error 1.69 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Pain n=107,86 | 24.2 score on a scale | Standard Error 1.85 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Dyspnea n=107,86 | 24.0 score on a scale | Standard Error 1.62 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Insomnia n=107,86 | 25.6 score on a scale | Standard Error 2.05 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Appetite Loss n=107,86 | 13.9 score on a scale | Standard Error 2.07 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Constipation n=107,86 | 15.0 score on a scale | Standard Error 2 |
| Chemotherapy | Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) | Diarrhea n=106,86 | 11.4 score on a scale | Standard Error 2.02 |
Secondary
Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS)
The LCSS patient scale uses a 24-hour recall period and contains nine items: six measuring major symptoms for lung cancer (appetite loss, fatigue, cough, dyspnea, hemoptysis, pain), and three summary items related to total symptom distress, normal activity status, and overall quality of life. The total scale used is a 100 mm visual analog scale to measure the intensity of patient responses, with zero corresponding to the lowest rating (best status) and 100 representing the highest rating (worst status). The total score was calculated as the mean of the 9 items. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.
Time frame: Screening and treatment phase up to 92 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Total Symptom Distress n=107,85 | 20.7 millimeters | Standard Error 1.26 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | LCSS Total Score n=106,82 | 22.0 millimeters | Standard Error 0.87 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Appetite Loss n=107,85 | 28.0 millimeters | Standard Error 1.26 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Fatigue n=107,84 | 34.6 millimeters | Standard Error 1.33 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Cough n=107,84 | 11.5 millimeters | Standard Error 1.01 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Shortness of Breath n=107,85 | 18.2 millimeters | Standard Error 0.99 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Hemoptysis n=107,85 | 1.8 millimeters | Standard Error 0.34 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Pain n=107,85 | 18.2 millimeters | Standard Error 1.25 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Normal Activity Status n=107,85 | 31.3 millimeters | Standard Error 1.47 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Overall Quality of Life n=106,84 | 33.1 millimeters | Standard Error 1.27 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | LCSS Average Symptom Burden Index n=107,83 | 18.8 millimeters | Standard Error 0.77 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Normal Activity Status n=107,85 | 36.8 millimeters | Standard Error 2.21 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Hemoptysis n=107,85 | 2.2 millimeters | Standard Error 0.55 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | LCSS Total Score n=106,82 | 26.3 millimeters | Standard Error 1.33 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | LCSS Average Symptom Burden Index n=107,83 | 22.9 millimeters | Standard Error 1.2 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Appetite Loss n=107,85 | 26.6 millimeters | Standard Error 1.99 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Pain n=107,85 | 24.3 millimeters | Standard Error 1.92 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Fatigue n=107,84 | 39.2 millimeters | Standard Error 2.06 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Total Symptom Distress n=107,85 | 24.6 millimeters | Standard Error 1.92 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Cough n=107,84 | 18.4 millimeters | Standard Error 1.56 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Overall Quality of Life n=106,84 | 36.4 millimeters | Standard Error 1.94 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Shortness of Breath n=107,85 | 24.8 millimeters | Standard Error 1.56 |
Secondary
Mean Accumulation Ratio (Racc) for Ceritinib
Accumulation ratio calculated using AUC0-24 values obtained from a dosing interval at steady-state (Cycle 2, Day 1) divided by AUC0-24 on Cycle 1, Day 1.
Time frame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
Population: Participants in the pharmacokinetic (PK) analysis set who had extensive PK collection.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ceritinib | Mean Accumulation Ratio (Racc) for Ceritinib | Cycle 2, Day 1 n=1,0 | 15.5 ratio |
| Unknown | Mean Accumulation Ratio (Racc) for Ceritinib | Cycle 1, Day 1 n=0,0 | — ratio |
Secondary
Overall Intracranial Response Rate (OIRR) Per BIRC
OIRR was defined as the ORR based on lesions in brain (target, nontarget lesions (and new lesions, if applicable) and calculated as the percentage of patients with a best overall confirmed response of CR or PR in the brain per modified RECIST 1.1 as assessed by BIRC neuroradiologist. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 18 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Patients with measurable and/or nonmeasurable disease in the brain at baseline as per BIRC neuroradiology review.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceritinib | Overall Intracranial Response Rate (OIRR) Per BIRC | 10.6 percentage of participants |
| Chemotherapy | Overall Intracranial Response Rate (OIRR) Per BIRC | 3.0 percentage of participants |
Secondary
Overall Response Rate (ORR) Per BIRC
ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR): (CR+PR) per Response Evaluation Criteria in Solid Tumors (RECIST), v. 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 54 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceritinib | Overall Response Rate (ORR) Per BIRC | 40.9 percentage of participants |
| Chemotherapy | Overall Response Rate (ORR) Per BIRC | 6.9 percentage of participants |
Secondary
Overall Response Rate (ORR) Per Investigator Assessment
ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR): (CR+PR) per Response Evaluation Criteria in Solid Tumors (RECIST), v. 1.1. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 93 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceritinib | Overall Response Rate (ORR) Per Investigator Assessment | 44.3 percentage of participants |
| Chemotherapy | Overall Response Rate (ORR) Per Investigator Assessment | 6.9 percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as time from date of randomization to date of death due to any cause.
Time frame: Up to approximately 114 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Overall Survival (OS) | 17.7 months |
| Chemotherapy | Overall Survival (OS) | 20.1 months |
Secondary
Post-Hoc: All Collected Deaths
Pre-treatment deaths: from day of patient's informed consent to the day before first dose of study treatment. On-treatment deaths: from first dose of study treatment to 30 days following the last dose of study treatment at the end of treatment phase. For crossover patients, from first dose of ceritinib at the extension treatment phase to 30 days following the last dose. Survival Follow-up deaths: from Day 31 after last dose of study treatment to the data cut-off date.
Time frame: Pre-treatment and on-treatment deaths: Up to approximately 8 years. Post-treatment survival follow-up deaths: Up to an additional 2.5 years.
Population: The analysis included patients who received at least one dose of study drug. For the Chemotherapy/Ceritinib group, the analysis included patients randomized to the chemotherapy arm who crossed over to receive at least one dose of ceritinib in the extension-treatment phase. For pre-treatment deaths, all randomized patients are included.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ceritinib | Post-Hoc: All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Ceritinib | Post-Hoc: All Collected Deaths | On-treatment deaths | 16 Participants |
| Ceritinib | Post-Hoc: All Collected Deaths | Survival follow-up deaths | 86 Participants |
| Ceritinib | Post-Hoc: All Collected Deaths | All deaths | 102 Participants |
| Chemotherapy | Post-Hoc: All Collected Deaths | All deaths | 25 Participants |
| Chemotherapy | Post-Hoc: All Collected Deaths | Pre-treatment deaths | 2 Participants |
| Chemotherapy | Post-Hoc: All Collected Deaths | Survival follow-up deaths | 18 Participants |
| Chemotherapy | Post-Hoc: All Collected Deaths | On-treatment deaths | 5 Participants |
| Chemotherapy/Ceritinib | Post-Hoc: All Collected Deaths | All deaths | 63 Participants |
| Chemotherapy/Ceritinib | Post-Hoc: All Collected Deaths | On-treatment deaths | 19 Participants |
| Chemotherapy/Ceritinib | Post-Hoc: All Collected Deaths | Survival follow-up deaths | 44 Participants |
| Chemotherapy/Ceritinib | Post-Hoc: All Collected Deaths | Pre-treatment deaths | 0 Participants |
Secondary
Progression Free Survival (PFS) Per Investigator Assessment
PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause.
Time frame: Up to approximately 84 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Progression Free Survival (PFS) Per Investigator Assessment | 6.2 months |
| Chemotherapy | Progression Free Survival (PFS) Per Investigator Assessment | 1.6 months |
Secondary
Time to Response (TTR) Per BIRC
TTR was defined as the time from date of randomization to date of first documented response (CR or PR). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 52 weeks
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Patients with confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Time to Response (TTR) Per BIRC | 6.71 weeks |
| Chemotherapy | Time to Response (TTR) Per BIRC | 9.64 weeks |
Secondary
Time to Response (TTR) Per Investigator Assessment
TTR was defined as the time from date of randomization to date of first documented response (CR or PR). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 45 weeks
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Patients with confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Time to Response (TTR) Per Investigator Assessment | 6.43 weeks |
| Chemotherapy | Time to Response (TTR) Per Investigator Assessment | 14.71 weeks |
Secondary
Tlast for Ceritinib
The time to last quantifiable concentration
Time frame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
Population: Participants in the pharmacokinetic (PK) analysis set who had extensive PK collection.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ceritinib | Tlast for Ceritinib | Cycle 1, Day 1 n=4,0 | 24 hours |
| Ceritinib | Tlast for Ceritinib | Cycle 2, Day 1 n=2,0 | 23.9 hours |
Secondary
Tmax for Ceritinib
The time to reach peak or maximum concentration
Time frame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
Population: Participants in the pharmacokinetic (PK) analysis set who had extensive PK collection.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ceritinib | Tmax for Ceritinib | Cycle 2, Day 1 n=2,0 | 7.15 hours |
| Ceritinib | Tmax for Ceritinib | Cycle 1, Day 1 n=4,0 | 6.03 hours |