Non-Small Cell Lung Cancer
Conditions
Keywords
Non-Small Cell Lung Cancer, NSCLC, 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, non-squamous non-small cell lung cancer
Brief summary
To compare the efficacy and safety of ceritinib with standard first-line chemotherapy (pemetrexed plus cisplatin or carboplatin) in patients with stage IIIB (not candidates for definitive multimodality therapy) or stage IV, non-squamous non-small cell lung cancer (NSCLC) harboring a confirmed anaplastic lymphoma kinase (ALK) rearrangement, using the Ventana immunohistochemistry (IHC) test.
Detailed description
This was an open-label, randomized, global, Phase III study that compared the efficacy and safety of ceritinib to standard first-line chemotherapy in patients with advanced (NSCLC) harboring ALK rearrangement. The confirmation of ALK rearrangement was done using the ICH test by a Novartis designated central laboratory. Prior to the study, patients had not received any previous systemic, anti-cancer therapy, including ALK inhibitors, for newly diagnosed advanced non-squamous NSCLC. The patients were randomized in a 1:1 ratio to either receive ceritinib (750 mg once daily, fasted) or chemotherapy. The chemotherapy regimen consisted of a platinum-based doublet with pemetrexed followed by pemetrexed maintenance in patients without progressive disease after 4 cycles. Treatment was continued until the blinded independent review committee (BIRC) confirmed disease progression based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), occurrence of unacceptable toxicity, or meeting other discontinuation criteria. Patients in either arm were permitted to continue the assigned study treatment beyond BIRC-confirmed disease progression in case of continued clinical benefit, as determined by the Investigator. All patients who discontinued treatment during the treatment phase for reasons other than death, lost to follow-up, pregnancy or disease progression entered the post-treatment follow-up period until disease progression, withdrawal of consent or death. In the chemotherapy arm, patients were allowed to switch and receive ceritinib after BIRC-confirmed disease progression (extension-treatment period).
Interventions
DRUGCeritinib
Ceritinib was administered orally once-daily fasted at a dose of 750 mg capsules on a continuous dosing schedule.
DRUGPemetrexed
Pemetrexed was administered at a dose of 500 mg/m\^2 as an intravenous (iv) infusion on Day 1 of each 21-day cycle
DRUGCisplatin
Cisplatin was administered by iv infusion at a dose of 75 mg/m\^2 every 21 days for up to 4 cycles.
DRUGCarboplatin
Carboplatin was administered as iv infusion (AUC 5-6) every 21 days up to 4 cycles
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
Key Inclusion Criteria: 1. The patient had a histologically or cytologically confirmed diagnosis of non-squamous Non-small cell lung cancer (NSCLC) that was Anaplastic lymphoma kinase (ALK) positive as assessed by the Ventana Immunohistochemistry (IHC) test. The test was performed at Novartis designated central laboratories. 2. The patient had a newly diagnosed stage IIIB (who was not a candidate for definitive multimodality therapy) or stage IV NSCLC or relapsed locally advanced or metastatic NSCLC not previously treated with any systemic anti-cancer therapy (e.g. cytotoxic drugs, monoclonal antibody therapy, crizotinib or other ALK inhibitors, or other targeted therapies, either experimental or not), with the exception of neo-adjuvant or adjuvant therapy. 3. The patient had at least one measurable lesion as defined by RECIST 1.1. Key
Exclusion criteria
1. The patient had known hypersensitivity to any of the excipients of LDK378 (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate). 2. The patient had a history of severe hypersensitivity reaction to platinum-containing drugs, pemetrexed, or any known excipients of these drugs. 3. The patient had symptomatic central nervous system (CNS) metastases and was neurologically unstable or had 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) by 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 34 months | PFS is defined as the time from the date of randomization to the date of the first radiologically documented disease progression (as assessed by BIRC per RECIST 1.1) or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or had received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. The distribution of PFS was estimated using the Kaplan-Meier (KM) method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) by BIRC Assessment | Up to approximately 34 months | ORR is defined as the percentage of patients with a best overall response defined as complete response (CR) or or partial response (PR) measured by BIRC per RECIST 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Overall Response Rate (ORR) by Investigator Assessment | Up to approximately 120 months | ORR is defined as the percentage of patients with a best overall response defined as complete response (CR) or or partial response (PR) measured by investigator assessment per RECIST 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Duration of Response (DOR) by BIRC Assessment | From first documented response to first documented disease progression or death, assessed up to approximately 34 months | DOR is defined as the time from date of first documented CR or PR to date of first documented disease progression (measured by BIRC assessment per RECIST 1.1) or death due to any cause. 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. If a patient had not had an event, DOR was censored at the date of last adequate tumor assessment. Patients who had never achieved a best overall response of CR or PR were excluded from the analysis. The distribution function of DOR was estimated using the KM method. |
| Duration of Response (DOR) by Investigator Assessment | From first documented response to first documented disease progression or death, assessed up to approximately 120 months | DOR is defined as the time from date of first documented CR or PR to date of first documented disease progression (measured by investigator assessment per RECIST 1.1) or death due to any cause. 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. If a patient had not had an event, DOR was censored at the date of last adequate tumor assessment. Patients who had never achieved a best overall response of CR or PR were excluded from the analysis. The distribution function of DOR was estimated using the KM method. |
| Disease Control Rate (DCR) by BIRC Assessment | Up to approximately 34 months | DCR is defined as the percentage of patients with best overall response of CR, PR, or stable disease (SD) measured by BIRC assessment per RECIST 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. 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) by Investigator Assessment | Up to approximately 120 months | DCR is defined as the percentage of patients with best overall response of CR, PR, or stable disease (SD) measured by investigator assessment per RECIST 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. 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) by BIRC Assessment | From randomization to date of first documented response, up to approximately 34 months | TTR is defined as the time from date of randomization to date of first documented response (CR or PR) measured by BIRC assessment per RECIST 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. Patients who had not achieved a confirmed CR or PR were censored at the last adequate tumor assessment date when they had not had a PFS event or at maximum follow-up when they had had a PFS event. |
| Time to Response (TTR) by Investigator Assessment | From randomization to date of first documented response, up to approximately 120 months | TTR is defined as the time from date of randomization to date of first documented response (CR or PR) measured by investigator assessment per RECIST 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. Patients who had not achieved a confirmed CR or PR were censored at the last adequate tumor assessment date when they had not had a PFS event or at maximum follow-up when they had had a PFS event |
| PFS by Investigator Assessment | From the date of randomization to the date of first radiologically documented disease progression or death due to any cause, up to approximately 120 months | PFS is defined as the time from the date of randomization to the date of the first radiologically documented disease progression (as assessed by investigator assessment per RECIST 1.1) or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or had received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. The distribution of PFS was estimated using the KM method. |
| Overall Intracranial Response Rate (OIRR) | Up to approximately 34 months | OIRR is defined as the ORR based on lesions in brain (target, non-target 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) | Up to approximately 34 months | IDCR is defined as the DCR based on lesions in brain (target, non-target lesions and new lesions, if applicable) and calculated as the percentage 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 |
| Overall Survival (OS) | From date of randomization to date of death due to any cause, up to approximately 120 months | OS defined as time from date of randomization to date of death due to any cause. If the patient was alive at the date of the analysis cut-off or lost to follow-up, then OS was censored at the last contact date prior to data cut-off date. The distribution of OS was estimated using the KM method. |
| Time to Definitive 10 Point Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ)- Lung Cancer (LC) 13 Questionnaire | Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months | The EORTC QLQ-LC13 complemented the QLQ-C30 and measured disease symptoms and treatment-related adverse effects. 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. Time to definitive symptom deterioration for the composite endpoint was defined as the time from the date of randomization to the earliest date when the patient's score showed a 10 point or higher increase from baseline in any of the symptoms (pain, cough or dyspnea) as per EORTC QLQ-LC13 (with no later change below this threshold i.e., \<10 points was observed or if this increase was observed at the last assessment for the patient) or death due to any cause. |
| Time to Definitive Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the Lung Cancer Symptom Scale (LCSS) | Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months | The LCSS patient scale used a 24-hour recall period and contained 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 LCSS used a 100mm visual analog scale (VAS) to measure the intensity of patient responses, with zero corresponding to the lowest rating (best status) and 100 representing the highest rating (worst status). Time to definitive deterioration for the composite endpoint was defined as the time from the date of randomization to the earliest date when the patient's score showed a 10 point or higher increase from baseline in any of the LCSS scores related to pain in the chest, cough, or dyspnea (with no later change below this threshold i.e., \<10 points was observed or if this increase was observed at the last assessment for the patient) or death due to any cause. |
| Least Squares Mean Scores on the EORTC-QLQ C30 | Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months | The EORTC QLQ-C30 contained 30 items and was of both multi-item scales and single-item measures, including 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and a global health status (GHS)/quality of life (QoL) scale. Items were assessed on a 4- or 7-level Likert scale, ranging from 1=very poor to 7= excellent for GHS items and 1= not at all to 4= very much for all other items. The scores of the scales were averaged from the scores of the component items, transformed, and analyzed on a 0 - 100 scale. A high score represented a higher response level. The scores were analyzed using repeated measurement model for longitudinal data, including terms for visit, treatment, treatment by time interaction, strata and baseline score. Overall mean and standard error were obtained |
| Least Squares Mean Scores on the EORTC QLQ- LC13 | Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months | The 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. Items were scored on a 4-point Likert scale ranging from 1=not at all to 4=very much. For the multi-item scale, the scores were averaged from the scores of the component items, transformed, and then analyzed on a 0 - 100 scale. For the single item scale, raw scores were transformed and analyzed on a 0-100 scale. A high score indicated a high level of symptoms The scores were analyzed using repeated measurement model for longitudinal data, including terms for visit, treatment, treatment by time interaction, strata and baseline score. Overall mean and standard error were obtained. |
| Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months | The LCSS consisted of 9 individual items; 6 measured lung cancer symptoms (appetite, fatigue, cough, dyspnea, hemoptysis, and pain); the remaining 3 items measured general lung cancer symptom distress, interference with daily activities and overall QoL. Each item was scored on a 100-millimeter Visual Analogue Scale (VAS), with scores ranging from 0 to 100 (0 = best outcome). Total score was calculated as the average of the aggregate score of all 9 items. Scores ranged from 0 to 100, with higher total scores indicating a greater overall impact of symptoms on the patient's QoL. The Symptom Burden Index (SBI) was calculated as the average of the six symptom items. It also ranged from 0 to 100, with higher scores indicating greater symptom burden. Scores were analyzed using repeated measurement model for longitudinal data, including terms for visit, treatment, treatment by time interaction, strata and baseline score. Overall mean and standard error were obtained. |
| Least Squares Mean Scores on the EQ-5D-5L Index | Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months | The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of these dimensions, the participant self-assigned a score: from 1 (no problems) to 5 (extreme problems). The 5 digit health states obtained for each dimension was converted into a single mean index value based on the EQ-5D crosswalk value set for the UK using the time trade-off method. This index ranges from -0.594 (worst health) to 1.0 (best health). The scores were analyzed using repeated measurement model for longitudinal data, including terms for visit, treatment, treatment by time interaction, strata and baseline score. Overall mean and standard error were obtained. |
| Least Squares Mean Scores on the EQ-5D-5L Visual Analogue Score (VAS) | Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months | The EQ-5D-5L questionnaire is a standardized measure of health status. The EQ-5D-5L descriptive system comprises of the 5 following dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Along with the five dimensions of health, the EQ-5D-5L includes a VAS where respondents rate their overall health status on a scale from 0 to 100, where 0 represents the worst possible health state and 100 represents the best possible health state. A positive change from baseline indicates improvement. The scores were analyzed using repeated measurement model for longitudinal data, including terms for visit, treatment, treatment by time interaction, strata and baseline score. Overall mean and standard error were obtained. |
| Cmax of LDK378 | Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days | The observed maximum plasma concentration following administration |
| Tmax of LDK378 | Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days | The time to reach peak or maximum concentration (Tmax) was assessed. Actual recorded sampling times were considered for the calculations |
| Tlast of LDK378 | Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days | The time to last quantifiable concentration. Actual recorded sampling times were considered for the calculations |
| AUC0-24 of LDK378 | Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days | The area under the plasma concentration-time curve calculated from time zero to 24 hours |
| Duration of Intracranial Response (DOIR) | From first documented response to first documented disease progression in the brain or death, assessed up to approximately 34 months | DOIR is 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. |
Countries
Argentina, Australia, Austria, Brazil, China, Colombia, Denmark, France, Germany, Greece, Hungary, India, Ireland, Italy, Japan, Lebanon, Mexico, Netherlands, Norway, Poland, Russia, Singapore, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), United Kingdom
Participant flow
Recruitment details
Patients were enrolled in 134 centers across 27 countries.
Pre-assignment details
Participants had to satisfy all the inclusion criteria none of the exclusion criteria prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Ceritinib Ceritinib administered continuously through oral dosing at a dosage of 750 mg once daily in fasted state | 189 |
| Chemotherapy Pemetrexed plus cisplatin or carboplatin (based on Investigator's choice) for 4 cycles (Induction) followed by pemetrexed as single agent (Maintenance) | 187 |
| Total | 376 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension-treatment Phase | Adverse Event | 0 | 17 |
| Extension-treatment Phase | Death | 0 | 11 |
| Extension-treatment Phase | Physician Decision | 0 | 5 |
| Extension-treatment Phase | Progressive disease | 0 | 54 |
| Extension-treatment Phase | Study terminated by sponsor | 0 | 5 |
| Extension-treatment Phase | Subject/guardian decision | 0 | 10 |
| Treatment Period | Adverse Event | 24 | 23 |
| Treatment Period | Death | 10 | 12 |
| Treatment Period | Lost to Follow-up | 2 | 1 |
| Treatment Period | No longer requires treatment | 0 | 1 |
| Treatment Period | Non-compliance with study treatment | 1 | 0 |
| Treatment Period | Physician Decision | 17 | 16 |
| Treatment Period | Progressive disease | 99 | 107 |
| Treatment Period | Protocol deviation | 1 | 0 |
| Treatment Period | Study terminated by Sponsor | 13 | 1 |
| Treatment Period | Subject/guardian decision | 22 | 26 |
Baseline characteristics
| Characteristic | Chemotherapy | Total | Ceritinib |
|---|---|---|---|
| Age, Continuous | 53.3 years STANDARD_DEVIATION 12.49 | 53.9 years STANDARD_DEVIATION 12.62 | 54.5 years STANDARD_DEVIATION 12.76 |
| Race/Ethnicity, Customized Asian | 82 Participants | 158 Participants | 76 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 6 Participants | 3 Participants |
| Race/Ethnicity, Customized Caucasian | 98 Participants | 202 Participants | 104 Participants |
| Race/Ethnicity, Customized Native American | 2 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Female | 114 Participants | 216 Participants | 102 Participants |
| Sex: Female, Male Male | 73 Participants | 160 Participants | 87 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 | 15 / 189 | 10 / 187 | 15 / 100 | 98 / 149 | 38 / 60 | 56 / 83 |
| other Total, other adverse events | 186 / 189 | 166 / 175 | 99 / 100 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 93 / 189 | 64 / 175 | 47 / 100 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Progression Free Survival (PFS) by Blinded Independent Review Committee (BIRC)
PFS is defined as the time from the date of randomization to the date of the first radiologically documented disease progression (as assessed by BIRC per RECIST 1.1) or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or had received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. The distribution of PFS was estimated using the Kaplan-Meier (KM) method.
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 34 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) by Blinded Independent Review Committee (BIRC) | 16.6 Months |
| Chemotherapy | Progression Free Survival (PFS) by Blinded Independent Review Committee (BIRC) | 8.1 Months |
p-value: <0.00195% CI: [0.42, 0.73]Log Rank
Secondary
AUC0-24 of LDK378
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 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days
Population: The Pharmacokinetic Analysis Set (PAS) consisted of all patients who received at least one (full or partial) dose of LDK378 and provided at least one evaluable PK blood sample. Only the subset of participants with extensive PK collection were analyzed
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ceritinib | AUC0-24 of LDK378 | Cycle 1 Day 1 | 2540 hours*ng/mL | Geometric Coefficient of Variation 113.1 |
| Ceritinib | AUC0-24 of LDK378 | Cycle 2 Day 1 | 16600 hours*ng/mL | Geometric Coefficient of Variation 44 |
Secondary
Cmax of LDK378
The observed maximum plasma concentration following administration
Time frame: Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days
Population: The Pharmacokinetic Analysis Set (PAS) consisted of all patients who received at least one (full or partial) dose of LDK378 and provided at least one evaluable pharmacokinetic (PK) blood sample. Only the subset of participants with extensive PK collection were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ceritinib | Cmax of LDK378 | Cycle 1 Day 1 | 162 nanogram (ng) / mililiter (ml) | Geometric Coefficient of Variation 106.9 |
| Ceritinib | Cmax of LDK378 | Cycle 2 Day 1 | 794 nanogram (ng) / mililiter (ml) | Geometric Coefficient of Variation 39.2 |
Secondary
Disease Control Rate (DCR) by BIRC Assessment
DCR is defined as the percentage of patients with best overall response of CR, PR, or stable disease (SD) measured by BIRC assessment per RECIST 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. 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 34 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) by BIRC Assessment | 84.7 Percentage of participants |
| Chemotherapy | Disease Control Rate (DCR) by BIRC Assessment | 73.8 Percentage of participants |
Secondary
Disease Control Rate (DCR) by Investigator Assessment
DCR is defined as the percentage of patients with best overall response of CR, PR, or stable disease (SD) measured by investigator assessment per RECIST 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. 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 120 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) by Investigator Assessment | 89.4 Percentage of participants |
| Chemotherapy | Disease Control Rate (DCR) by Investigator Assessment | 75.9 Percentage of participants |
Secondary
Duration of Intracranial Response (DOIR)
DOIR is 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: From first documented response to first documented disease progression in the brain or death, assessed up to approximately 34 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Patients with measurable brain disease and who had a baseline and at least one post-baseline scan, and a confirmed intracranial CR or PR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Duration of Intracranial Response (DOIR) | 16.6 Months |
| Chemotherapy | Duration of Intracranial Response (DOIR) | NA Months |
Secondary
Duration of Response (DOR) by BIRC Assessment
DOR is defined as the time from date of first documented CR or PR to date of first documented disease progression (measured by BIRC assessment per RECIST 1.1) or death due to any cause. 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. If a patient had not had an event, DOR was censored at the date of last adequate tumor assessment. Patients who had never achieved a best overall response of CR or PR were excluded from the analysis. The distribution function of DOR was estimated using the KM method.
Time frame: From first documented response to first documented disease progression or death, assessed up to approximately 34 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 by BIRC assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Duration of Response (DOR) by BIRC Assessment | 23.9 Months |
| Chemotherapy | Duration of Response (DOR) by BIRC Assessment | 11.1 Months |
Secondary
Duration of Response (DOR) by Investigator Assessment
DOR is defined as the time from date of first documented CR or PR to date of first documented disease progression (measured by investigator assessment per RECIST 1.1) or death due to any cause. 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. If a patient had not had an event, DOR was censored at the date of last adequate tumor assessment. Patients who had never achieved a best overall response of CR or PR were excluded from the analysis. The distribution function of DOR was estimated using the KM method.
Time frame: From first documented response to first documented disease progression or death, assessed up to approximately 120 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 by investigator assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Duration of Response (DOR) by Investigator Assessment | 22.6 Months |
| Chemotherapy | Duration of Response (DOR) by Investigator Assessment | 9.8 Months |
Secondary
Intracranial Disease Control Rate (IDCR)
IDCR is defined as the DCR based on lesions in brain (target, non-target lesions and new lesions, if applicable) and calculated as the percentage 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 34 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Patients with measurable brain disease and who had a baseline and at least one post-baseline scan
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceritinib | Intracranial Disease Control Rate (IDCR) | 86.4 Percentage of participants |
| Chemotherapy | Intracranial Disease Control Rate (IDCR) | 90.9 Percentage of participants |
Secondary
Least Squares Mean Scores on the EORTC-QLQ C30
The EORTC QLQ-C30 contained 30 items and was of both multi-item scales and single-item measures, including 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and a global health status (GHS)/quality of life (QoL) scale. Items were assessed on a 4- or 7-level Likert scale, ranging from 1=very poor to 7= excellent for GHS items and 1= not at all to 4= very much for all other items. The scores of the scales were averaged from the scores of the component items, transformed, and analyzed on a 0 - 100 scale. A high score represented a higher response level. The scores were analyzed using repeated measurement model for longitudinal data, including terms for visit, treatment, treatment by time interaction, strata and baseline score. Overall mean and standard error were obtained
Time frame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Participants with a baseline assessment for at least one of the scales/single items
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Cognitive Functioning | 86.7 Score on a scale | Standard Error 0.68 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Pain | 14.7 Score on a scale | Standard Error 0.75 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Physical Functioning | 83.5 Score on a scale | Standard Error 0.78 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Dyspnea | 15.0 Score on a scale | Standard Error 0.75 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Role Functioning | 79.5 Score on a scale | Standard Error 1.03 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Insomnia | 14.8 Score on a scale | Standard Error 0.78 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Social Functioning | 79.0 Score on a scale | Standard Error 1.01 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Appetite Loss | 15.9 Score on a scale | Standard Error 0.82 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Fatigue | 25.9 Score on a scale | Standard Error 0.84 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Constipation | 8.1 Score on a scale | Standard Error 0.6 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Emotional Functioning | 82.3 Score on a scale | Standard Error 0.7 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Diarrhea | 25.7 Score on a scale | Standard Error 0.8 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Nausea and Vomiting | 11.8 Score on a scale | Standard Error 0.58 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Financial Difficulties | 19.9 Score on a scale | Standard Error 1.19 |
| Ceritinib | Least Squares Mean Scores on the EORTC-QLQ C30 | Global Health Status/QoL | 69.4 Score on a scale | Standard Error 0.71 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Financial Difficulties | 23.8 Score on a scale | Standard Error 1.63 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Global Health Status/QoL | 63.7 Score on a scale | Standard Error 0.98 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Physical Functioning | 77.6 Score on a scale | Standard Error 1.07 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Emotional Functioning | 76.6 Score on a scale | Standard Error 0.97 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Social Functioning | 75.4 Score on a scale | Standard Error 1.38 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Cognitive Functioning | 84.0 Score on a scale | Standard Error 0.94 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Role Functioning | 71.3 Score on a scale | Standard Error 1.44 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Fatigue | 31.4 Score on a scale | Standard Error 1.17 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Nausea and Vomiting | 11.6 Score on a scale | Standard Error 0.82 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Pain | 16.9 Score on a scale | Standard Error 1.05 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Dyspnea | 22.1 Score on a scale | Standard Error 1.05 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Insomnia | 21.1 Score on a scale | Standard Error 1.09 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Appetite Loss | 19.3 Score on a scale | Standard Error 1.15 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Constipation | 13.0 Score on a scale | Standard Error 0.84 |
| Chemotherapy | Least Squares Mean Scores on the EORTC-QLQ C30 | Diarrhea | 4.6 Score on a scale | Standard Error 1.12 |
Secondary
Least Squares Mean Scores on the EORTC QLQ- LC13
The 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. Items were scored on a 4-point Likert scale ranging from 1=not at all to 4=very much. For the multi-item scale, the scores were averaged from the scores of the component items, transformed, and then analyzed on a 0 - 100 scale. For the single item scale, raw scores were transformed and analyzed on a 0-100 scale. A high score indicated a high level of symptoms The scores were analyzed using repeated measurement model for longitudinal data, including terms for visit, treatment, treatment by time interaction, strata and baseline score. Overall mean and standard error were obtained.
Time frame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Participants with a baseline assessment for at least one of the domain scores
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ceritinib | Least Squares Mean Scores on the EORTC QLQ- LC13 | Coughing | 14.7 Score on a scale | Standard Error 0.63 |
| Ceritinib | Least Squares Mean Scores on the EORTC QLQ- LC13 | Dyspnoea | 16.2 Score on a scale | Standard Error 0.74 |
| Ceritinib | Least Squares Mean Scores on the EORTC QLQ- LC13 | Pain in chest | 9.4 Score on a scale | Standard Error 0.59 |
| Ceritinib | Least Squares Mean Scores on the EORTC QLQ- LC13 | Pain in Arm or Shoulder | 10.6 Score on a scale | Standard Error 0.69 |
| Ceritinib | Least Squares Mean Scores on the EORTC QLQ- LC13 | Pain in Other Parts | 12.5 Score on a scale | Standard Error 0.71 |
| Ceritinib | Least Squares Mean Scores on the EORTC QLQ- LC13 | Sore Mouth | 3.0 Score on a scale | Standard Error 0.35 |
| Ceritinib | Least Squares Mean Scores on the EORTC QLQ- LC13 | Dysphagia | 4.1 Score on a scale | Standard Error 0.37 |
| Ceritinib | Least Squares Mean Scores on the EORTC QLQ- LC13 | Peripheral Neuropathy | 9.7 Score on a scale | Standard Error 0.69 |
| Ceritinib | Least Squares Mean Scores on the EORTC QLQ- LC13 | Alopecia | 6.8 Score on a scale | Standard Error 0.7 |
| Ceritinib | Least Squares Mean Scores on the EORTC QLQ- LC13 | Haemoptysis | 0.7 Score on a scale | Standard Error 0.18 |
| Chemotherapy | Least Squares Mean Scores on the EORTC QLQ- LC13 | Peripheral Neuropathy | 16.0 Score on a scale | Standard Error 0.96 |
| Chemotherapy | Least Squares Mean Scores on the EORTC QLQ- LC13 | Sore Mouth | 6.8 Score on a scale | Standard Error 0.49 |
| Chemotherapy | Least Squares Mean Scores on the EORTC QLQ- LC13 | Dyspnoea | 23.3 Score on a scale | Standard Error 1.02 |
| Chemotherapy | Least Squares Mean Scores on the EORTC QLQ- LC13 | Haemoptysis | 1.5 Score on a scale | Standard Error 0.25 |
| Chemotherapy | Least Squares Mean Scores on the EORTC QLQ- LC13 | Pain in chest | 11.8 Score on a scale | Standard Error 0.82 |
| Chemotherapy | Least Squares Mean Scores on the EORTC QLQ- LC13 | Dysphagia | 5.5 Score on a scale | Standard Error 0.52 |
| Chemotherapy | Least Squares Mean Scores on the EORTC QLQ- LC13 | Pain in Arm or Shoulder | 12.3 Score on a scale | Standard Error 0.97 |
| Chemotherapy | Least Squares Mean Scores on the EORTC QLQ- LC13 | Alopecia | 13.3 Score on a scale | Standard Error 0.95 |
| Chemotherapy | Least Squares Mean Scores on the EORTC QLQ- LC13 | Pain in Other Parts | 15.0 Score on a scale | Standard Error 1.01 |
| Chemotherapy | Least Squares Mean Scores on the EORTC QLQ- LC13 | Coughing | 23.0 Score on a scale | Standard Error 0.88 |
Secondary
Least Squares Mean Scores on the EQ-5D-5L Index
The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of these dimensions, the participant self-assigned a score: from 1 (no problems) to 5 (extreme problems). The 5 digit health states obtained for each dimension was converted into a single mean index value based on the EQ-5D crosswalk value set for the UK using the time trade-off method. This index ranges from -0.594 (worst health) to 1.0 (best health). The scores were analyzed using repeated measurement model for longitudinal data, including terms for visit, treatment, treatment by time interaction, strata and baseline score. Overall mean and standard error were obtained.
Time frame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Participants with a baseline assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ceritinib | Least Squares Mean Scores on the EQ-5D-5L Index | 0.80 Score on a Scale | Standard Error 0.01 |
| Chemotherapy | Least Squares Mean Scores on the EQ-5D-5L Index | 0.75 Score on a Scale | Standard Error 0.01 |
Secondary
Least Squares Mean Scores on the EQ-5D-5L Visual Analogue Score (VAS)
The EQ-5D-5L questionnaire is a standardized measure of health status. The EQ-5D-5L descriptive system comprises of the 5 following dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Along with the five dimensions of health, the EQ-5D-5L includes a VAS where respondents rate their overall health status on a scale from 0 to 100, where 0 represents the worst possible health state and 100 represents the best possible health state. A positive change from baseline indicates improvement. The scores were analyzed using repeated measurement model for longitudinal data, including terms for visit, treatment, treatment by time interaction, strata and baseline score. Overall mean and standard error were obtained.
Time frame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Participants with a baseline assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ceritinib | Least Squares Mean Scores on the EQ-5D-5L Visual Analogue Score (VAS) | 77.2 Score on a Scale | Standard Error 0.65 |
| Chemotherapy | Least Squares Mean Scores on the EQ-5D-5L Visual Analogue Score (VAS) | 74.1 Score on a Scale | Standard Error 0.9 |
Secondary
Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS)
The LCSS consisted of 9 individual items; 6 measured lung cancer symptoms (appetite, fatigue, cough, dyspnea, hemoptysis, and pain); the remaining 3 items measured general lung cancer symptom distress, interference with daily activities and overall QoL. Each item was scored on a 100-millimeter Visual Analogue Scale (VAS), with scores ranging from 0 to 100 (0 = best outcome). Total score was calculated as the average of the aggregate score of all 9 items. Scores ranged from 0 to 100, with higher total scores indicating a greater overall impact of symptoms on the patient's QoL. The Symptom Burden Index (SBI) was calculated as the average of the six symptom items. It also ranged from 0 to 100, with higher scores indicating greater symptom burden. Scores were analyzed using repeated measurement model for longitudinal data, including terms for visit, treatment, treatment by time interaction, strata and baseline score. Overall mean and standard error were obtained.
Time frame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Participants with a baseline assessment for at least one of the domain scores
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Shortness of Breath | 18.8 Score on a Scale | Standard Error 1.4 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Total Symptom Distress | 20.5 Score on a Scale | Standard Error 1.75 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Cough | 8.0 Score on a Scale | Standard Error 0.87 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Normal Activity Status | 23.6 Score on a Scale | Standard Error 1.59 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Hemoptysis | 0.7 Score on a Scale | Standard Error 0.37 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Overall Quality of Life | 27.4 Score on a Scale | Standard Error 1.56 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Fatigue | 27.4 Score on a Scale | Standard Error 1.5 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Symptom Burden Index | 14.7 Score on a Scale | Standard Error 0.91 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Pain | 11.6 Score on a Scale | Standard Error 1.16 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Total Score | 19.1 Score on a Scale | Standard Error 1.18 |
| Ceritinib | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Appetite Loss | 20.9 Score on a Scale | Standard Error 1.35 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Total Score | 24.7 Score on a Scale | Standard Error 1.31 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Appetite Loss | 25.1 Score on a Scale | Standard Error 1.58 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Fatigue | 33.9 Score on a Scale | Standard Error 1.74 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Cough | 15.1 Score on a Scale | Standard Error 1.02 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Shortness of Breath | 25.5 Score on a Scale | Standard Error 1.62 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Hemoptysis | 1.9 Score on a Scale | Standard Error 0.44 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Pain | 14.9 Score on a Scale | Standard Error 1.35 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Total Symptom Distress | 29.3 Score on a Scale | Standard Error 2.02 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Normal Activity Status | 33.5 Score on a Scale | Standard Error 1.84 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Overall Quality of Life | 35.3 Score on a Scale | Standard Error 1.75 |
| Chemotherapy | Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) | Symptom Burden Index | 19.4 Score on a Scale | Standard Error 1.05 |
Secondary
Overall Intracranial Response Rate (OIRR)
OIRR is defined as the ORR based on lesions in brain (target, non-target 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 34 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization. Patients with measurable brain disease and who had a baseline and at least one post-baseline scan
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceritinib | Overall Intracranial Response Rate (OIRR) | 72.7 Percentage of participants |
| Chemotherapy | Overall Intracranial Response Rate (OIRR) | 27.3 Percentage of participants |
Secondary
Overall Response Rate (ORR) by BIRC Assessment
ORR is defined as the percentage of patients with a best overall response defined as complete response (CR) or or partial response (PR) measured by BIRC per RECIST 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 34 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) by BIRC Assessment | 72.5 Percentage of participants |
| Chemotherapy | Overall Response Rate (ORR) by BIRC Assessment | 26.7 Percentage of participants |
Secondary
Overall Response Rate (ORR) by Investigator Assessment
ORR is defined as the percentage of patients with a best overall response defined as complete response (CR) or or partial response (PR) measured by investigator assessment per RECIST 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 120 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) by Investigator Assessment | 73.5 Percentage of participants |
| Chemotherapy | Overall Response Rate (ORR) by Investigator Assessment | 33.2 Percentage of participants |
Secondary
Overall Survival (OS)
OS defined as time from date of randomization to date of death due to any cause. If the patient was alive at the date of the analysis cut-off or lost to follow-up, then OS was censored at the last contact date prior to data cut-off date. The distribution of OS was estimated using the KM method.
Time frame: From date of randomization to date of death due to any cause, up to approximately 120 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) | 62.9 Months |
| Chemotherapy | Overall Survival (OS) | 40.7 Months |
Secondary
PFS by Investigator Assessment
PFS is defined as the time from the date of randomization to the date of the first radiologically documented disease progression (as assessed by investigator assessment per RECIST 1.1) or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or had received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. The distribution of PFS was estimated using the KM method.
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 120 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 | PFS by Investigator Assessment | 16.8 Months |
| Chemotherapy | PFS by Investigator Assessment | 7.2 Months |
Secondary
Time to Definitive 10 Point Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ)- Lung Cancer (LC) 13 Questionnaire
The EORTC QLQ-LC13 complemented the QLQ-C30 and measured disease symptoms and treatment-related adverse effects. 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. Time to definitive symptom deterioration for the composite endpoint was defined as the time from the date of randomization to the earliest date when the patient's score showed a 10 point or higher increase from baseline in any of the symptoms (pain, cough or dyspnea) as per EORTC QLQ-LC13 (with no later change below this threshold i.e., \<10 points was observed or if this increase was observed at the last assessment for the patient) or death due to any cause.
Time frame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 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 | Time to Definitive 10 Point Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ)- Lung Cancer (LC) 13 Questionnaire | 76.0 Months |
| Chemotherapy | Time to Definitive 10 Point Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ)- Lung Cancer (LC) 13 Questionnaire | 14.9 Months |
Secondary
Time to Definitive Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the Lung Cancer Symptom Scale (LCSS)
The LCSS patient scale used a 24-hour recall period and contained 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 LCSS used a 100mm visual analog scale (VAS) to measure the intensity of patient responses, with zero corresponding to the lowest rating (best status) and 100 representing the highest rating (worst status). Time to definitive deterioration for the composite endpoint was defined as the time from the date of randomization to the earliest date when the patient's score showed a 10 point or higher increase from baseline in any of the LCSS scores related to pain in the chest, cough, or dyspnea (with no later change below this threshold i.e., \<10 points was observed or if this increase was observed at the last assessment for the patient) or death due to any cause.
Time frame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 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 | Time to Definitive Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the Lung Cancer Symptom Scale (LCSS) | 104.0 Months |
| Chemotherapy | Time to Definitive Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the Lung Cancer Symptom Scale (LCSS) | 36.1 Months |
Secondary
Time to Response (TTR) by BIRC Assessment
TTR is defined as the time from date of randomization to date of first documented response (CR or PR) measured by BIRC assessment per RECIST 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. Patients who had not achieved a confirmed CR or PR were censored at the last adequate tumor assessment date when they had not had a PFS event or at maximum follow-up when they had had a PFS event.
Time frame: From randomization to date of first documented response, up to approximately 34 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 by BIRC assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Time to Response (TTR) by BIRC Assessment | 6.14 Weeks |
| Chemotherapy | Time to Response (TTR) by BIRC Assessment | 13.36 Weeks |
Secondary
Time to Response (TTR) by Investigator Assessment
TTR is defined as the time from date of randomization to date of first documented response (CR or PR) measured by investigator assessment per RECIST 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. Patients who had not achieved a confirmed CR or PR were censored at the last adequate tumor assessment date when they had not had a PFS event or at maximum follow-up when they had had a PFS event
Time frame: From randomization to date of first documented response, up to approximately 120 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 by investigator assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceritinib | Time to Response (TTR) by Investigator Assessment | 6.29 Weeks |
| Chemotherapy | Time to Response (TTR) by Investigator Assessment | 12.71 Weeks |
Secondary
Tlast of LDK378
The time to last quantifiable concentration. Actual recorded sampling times were considered for the calculations
Time frame: Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days
Population: The Pharmacokinetic Analysis Set (PAS) consisted of all patients who received at least one (full or partial) dose of LDK378 and provided at least one evaluable PK blood sample. Only the subset of participants with extensive PK collection were analyzed
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ceritinib | Tlast of LDK378 | Cycle 1 Day 1 | 24.0 Hours |
| Ceritinib | Tlast of LDK378 | Cycle 2 Day 1 | 24.0 Hours |
Secondary
Tmax of LDK378
The time to reach peak or maximum concentration (Tmax) was assessed. Actual recorded sampling times were considered for the calculations
Time frame: Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days
Population: The Pharmacokinetic Analysis Set (PAS) consisted of all patients who received at least one (full or partial) dose of LDK378 and provided at least one evaluable PK blood sample. Only the subset of participants with extensive PK collection were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ceritinib | Tmax of LDK378 | Cycle 1 Day 1 | 6.00 hours |
| Ceritinib | Tmax of LDK378 | Cycle 2 Day 1 | 6.00 hours |
Post Hoc
All Collected Deaths
Pre-treatment: From randomization to start of treatment. On-Treatment: From start of treatment to 30 days post-treatment or start of crossover treatment. Extension-treatment: From start of crossover treatment to 30 days post-crossover treatment. Post-treatment: From 31 days after last dose of treatment to the end of study.
Time frame: Pre-treatment: up to 28 days; On-Treatment: up to approx. 120 months; Extension-treatment: up to approx. 108 months; Post-treatment: up to approx. 120 months
Population: The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned by randomization.~For the Chemotherapy/Ceritinib group, the analysis included patients randomized to the chemotherapy arm who crossed over and received at least one dose of ceritinib
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ceritinib | All Collected Deaths | Pre-treatment | 0 Participants |
| Ceritinib | All Collected Deaths | On-Treatment | 15 Participants |
| Ceritinib | All Collected Deaths | Post-treatment | 98 Participants |
| Ceritinib | All Collected Deaths | All deaths | 113 Participants |
| Chemotherapy | All Collected Deaths | All deaths | 48 Participants |
| Chemotherapy | All Collected Deaths | Pre-treatment | 3 Participants |
| Chemotherapy | All Collected Deaths | Post-treatment | 38 Participants |
| Chemotherapy | All Collected Deaths | On-Treatment | 7 Participants |
| Chemotherapy to Ceritinib | All Collected Deaths | All deaths | 71 Participants |
| Chemotherapy to Ceritinib | All Collected Deaths | On-Treatment | 15 Participants |
| Chemotherapy to Ceritinib | All Collected Deaths | Post-treatment | 56 Participants |
| Chemotherapy to Ceritinib | All Collected Deaths | Pre-treatment | 0 Participants |