LDK378 Versus Chemotherapy in Previously Untreated Patients With ALK Rearranged Non-small Cell Lung Cancer

A Phase III Multicenter, Randomized Study of Oral LDK378 Versus Standard Chemotherapy in Previously Untreated Adult Patients With ALK Rearranged (ALK-positive), Stage IIIB or IV, Non-squamous Non-small Cell Lung Cancer

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.

Study Overview

• Status: Completed
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Carboplatin; Drug: Ceritinib; Drug: Pemetrexed; Drug: Cisplatin

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).

• Study Type: Interventional
• Enrollment (Actual): 376
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • La Rioja, Argentina, 5300
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1180AAX
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1050AAK
      • Novartis Investigative Site
• Australia
  • Auckland, Australia, 92024
    • Novartis Investigative Site
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Novartis Investigative Site
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Novartis Investigative Site
• Austria
  • Salzburg, Austria, 5020
    • Novartis Investigative Site
  • Wien, Austria, 1210
    • Novartis Investigative Site
• Brazil
  • BA
    • Salvador, BA, Brazil, 40170-110
      • Novartis Investigative Site
  • CE
    • Fortaleza, CE, Brazil, 60336-045
      • Novartis Investigative Site
  • PE
    • Recife, PE, Brazil, 50070-550
      • Novartis Investigative Site
  • RJ
    • Rio De Janiero, RJ, Brazil, 20231-050
      • Novartis Investigative Site
  • RN
    • Natal, RN, Brazil, 59075 740
      • Novartis Investigative Site
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90610-000
      • Novartis Investigative Site
  • SC
    • Itajai, SC, Brazil, 88301-229
      • Novartis Investigative Site
  • SP
    • Barretos, SP, Brazil, 14784 400
      • Novartis Investigative Site
    • Sao Jose do Rio Preto, SP, Brazil, 15090 000
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 01246-000
      • Novartis Investigative Site
• China
  • Beijing, China, 100730
    • Novartis Investigative Site
  • Beijing, China, 101149
    • Novartis Investigative Site
  • Chongqing, China, 400037
    • Novartis Investigative Site
  • Chongqing, China, 400042
    • Novartis Investigative Site
  • Guang Dong Province, China, 510120
    • Novartis Investigative Site
  • Tianjin, China, 300052
    • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Novartis Investigative Site
  • Jilin
    • Chang Chun, Jilin, China, 130021
      • Novartis Investigative Site
    • Changchun, Jilin, China, 130012
      • Novartis Investigative Site
  • Shanghai
    • Shanghai, Shanghai, China, 200433
      • Novartis Investigative Site
  • Shanxi
    • XI An, Shanxi, China, 710038
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Novartis Investigative Site
    • Hangzhou, Zhejiang, China, 310022
      • Novartis Investigative Site
• Colombia
  • Monteria, Colombia, 230004
    • Novartis Investigative Site
  • Cundinamarca
    • Bogota, Cundinamarca, Colombia, 110111
      • Novartis Investigative Site
• Denmark
  • Herlev, Denmark, DK-2730
    • Novartis Investigative Site
  • Odense C, Denmark, DK 5000
    • Novartis Investigative Site
• France
  • Caen, France, 14033
    • Novartis Investigative Site
  • Grenoble, France, 38043
    • Novartis Investigative Site
  • Lille, France, 59037
    • Novartis Investigative Site
  • Paris 10, France, 75475
    • Novartis Investigative Site
  • Pierre Benite, France, 69495
    • Novartis Investigative Site
  • Rennes, France, 35043
    • Novartis Investigative Site
  • Strasbourg Cedex, France, 67091
    • Novartis Investigative Site
  • Villejuif, France, 94800
    • Novartis Investigative Site
  • Haute Vienne
    • Limoges, Haute Vienne, France, 87000
      • Novartis Investigative Site
  • Val De Marne
    • Toulon Cedex 9, Val De Marne, France, 83800
      • Novartis Investigative Site
• Germany
  • Coswig, Germany, 01640
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Gottingen, Germany, 37075
    • Novartis Investigative Site
  • Grosshansdorf, Germany, 22947
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Koeln, Germany, 50937
    • Novartis Investigative Site
  • Oldenburg, Germany, 26121
    • Novartis Investigative Site
  • Tuebingen, Germany, 72076
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
  • Wiesbaden, Germany, D-65199
    • Novartis Investigative Site
• Greece
  • Heraklion Crete, Greece, 71110
    • Novartis Investigative Site
  • GR
    • Athens, GR, Greece, 115 27
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1121
    • Novartis Investigative Site
  • Nyiregyhaza, Hungary, 4400
    • Novartis Investigative Site
  • Veszprem, Hungary, 8200
    • Novartis Investigative Site
  • Zala
    • Zalaegerszeg, Zala, Hungary, 8900
      • Novartis Investigative Site
• India
  • Delhi, India, 110 085
    • Novartis Investigative Site
  • Mumbai, India, 400 012
    • Novartis Investigative Site
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500 034
      • Novartis Investigative Site
  • Delhi
    • New Delhi, Delhi, India, 110076
      • Novartis Investigative Site
  • Karnataka
    • Bangalore, Karnataka, India, 560 095
      • Novartis Investigative Site
  • Kerala
    • Kochi, Kerala, India, 682 041
      • Novartis Investigative Site
  • Maharashtra
    • Nashik, Maharashtra, India, 422 004
      • Novartis Investigative Site
  • Rajasthan
    • Jaipur, Rajasthan, India, 302017
      • Novartis Investigative Site
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632 004
      • Novartis Investigative Site
  • TamilNadu
    • Madurai, TamilNadu, India, 625107
      • Novartis Investigative Site
  • West Bengal
    • Kolkata, West Bengal, India, 700160
      • Novartis Investigative Site
• Ireland
  • Dublin 4, Ireland, DO4
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • AN
    • Ancona, AN, Italy, 60126
      • Novartis Investigative Site
  • BG
    • Bergamo, BG, Italy, 24125
      • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • MB
    • Monza, MB, Italy, 20900
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
    • Milano, MI, Italy, 20141
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
  • PG
    • Perugia, PG, Italy, 06129
      • Novartis Investigative Site
  • PI
    • Pisa, PI, Italy, 56124
      • Novartis Investigative Site
  • PN
    • Aviano, PN, Italy, 33081
      • Novartis Investigative Site
  • PR
    • Parma, PR, Italy, 43100
      • Novartis Investigative Site
  • RE
    • Reggio Emilia, RE, Italy, 42123
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00152
      • Novartis Investigative Site
    • Roma, RM, Italy, 00189
      • Novartis Investigative Site
  • TO
    • Orbassano, TO, Italy, 10043
      • Novartis Investigative Site
  • UD
    • Udine, UD, Italy, 33100
      • Novartis Investigative Site
• Japan
  • Niigata, Japan, 951 8520
    • Novartis Investigative Site
  • Aichi
    • Nagoya, Aichi, Japan, 464 8681
      • Novartis Investigative Site
  • Chiba
    • Kashiwa, Chiba, Japan, 277 8577
      • Novartis Investigative Site
  • Hyogo
    • Akashi, Hyogo, Japan, 673-8558
      • Novartis Investigative Site
  • Osaka
    • Hirakata-city, Osaka, Japan, 573-1191
      • Novartis Investigative Site
    • Osaka-city, Osaka, Japan, 541-8567
      • Novartis Investigative Site
  • Tokyo
    • Koto ku, Tokyo, Japan, 135 8550
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 05505
    • Novartis Investigative Site
  • Gyeonggi Do
    • Bundang Gu, Gyeonggi Do, Korea, Republic of, 13620
      • Novartis Investigative Site
  • Korea
    • Gyeonggi do, Korea, Korea, Republic of, 10408
      • Novartis Investigative Site
• Lebanon
  • Ashrafieh, Lebanon, 166830
    • Novartis Investigative Site
  • Saida, Lebanon, 652
    • Novartis Investigative Site
• Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • Novartis Investigative Site
• Netherlands
  • Amersfroort, Netherlands, 3818 ES
    • Novartis Investigative Site
  • Enschede, Netherlands, 7512 KZ
    • Novartis Investigative Site
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
  • Groningen, Netherlands, 9728 NZ
    • Novartis Investigative Site
  • Maastricht, Netherlands, 6229 HX
    • Novartis Investigative Site
  • Zoetermeer, Netherlands, NL-2722 EP
    • Novartis Investigative Site
  • Zuid Holland
    • Leiden, Zuid Holland, Netherlands, 2333 ZA
      • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0310
    • Novartis Investigative Site
• Poland
  • Szczecin, Poland, 70-891
    • Novartis Investigative Site
  • Warszawa, Poland, 02 781
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 197022
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08041
    • Novartis Investigative Site
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Madrid, Spain, 28033
    • Novartis Investigative Site
  • Madrid, Spain, 28050
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Andalucia
    • Granada, Andalucia, Spain, 18014
      • Novartis Investigative Site
    • Malaga, Andalucia, Spain, 29010
      • Novartis Investigative Site
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
    • Sevilla, Andalucia, Spain, 41014
      • Novartis Investigative Site
  • Asturias
    • Oviedo, Asturias, Spain, 33011
      • Novartis Investigative Site
  • Cataluna
    • Lerida, Cataluna, Spain, 25198
      • Novartis Investigative Site
    • Mataro, Cataluna, Spain, 08301
      • Novartis Investigative Site
    • Reus, Cataluna, Spain, 43201
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08003
      • Novartis Investigative Site
    • Hospitalet de LLobregat, Catalunya, Spain, 08907
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Alicante, Comunidad Valenciana, Spain, 03010
      • Novartis Investigative Site
    • Valencia, Comunidad Valenciana, Spain, 46014
      • Novartis Investigative Site
  • Extremadura
    • Badajoz, Extremadura, Spain, 06080
      • Novartis Investigative Site
  • Galicia
    • La Coruna, Galicia, Spain, 15006
      • Novartis Investigative Site
    • Lugo, Galicia, Spain, 27003
      • Novartis Investigative Site
  • Islas Baleares
    • Palma De Mallorca, Islas Baleares, Spain, 07120
      • Novartis Investigative Site
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Novartis Investigative Site
  • Santa Cruz De Tenerife
    • La Laguna, Santa Cruz De Tenerife, Spain, 38320
      • Novartis Investigative Site
• Sweden
  • Linkoping, Sweden, SE 581 85
    • Novartis Investigative Site
  • Lund, Sweden, 221 85
    • Novartis Investigative Site
  • Stockholm, Sweden, 171 76
    • Novartis Investigative Site
  • Uppsala, Sweden, 751 85
    • Novartis Investigative Site
• Taiwan
  • Kaohsiung, Taiwan, 83301
    • Novartis Investigative Site
  • Taichung, Taiwan, 40447
    • Novartis Investigative Site
  • Taichung, Taiwan, 407219
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
  • Taoyuan, Taiwan, 33305
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • Hat Yai
    • Songkhla, Hat Yai, Thailand, 90110
      • Novartis Investigative Site
  • THA
    • Khon Kaen, THA, Thailand, 40002
      • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06230
    • Novartis Investigative Site
  • Istanbul, Turkey, 35100
    • Novartis Investigative Site
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Novartis Investigative Site
  • London, United Kingdom, NW1 2BU
    • Novartis Investigative Site
  • Manchester, United Kingdom, M20 2BX
    • Novartis Investigative Site
  • Nottingham, United Kingdom, NG5 1PB
    • Novartis Investigative Site
  • Devon
    • Exeter, Devon, United Kingdom, EX2 5DW
      • Novartis Investigative Site
  • West Yorkshire
    • Leeds, West Yorkshire, United Kingdom, LS9 7TF
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ceritinib; Ceritinib administered continuously through oral dosing at a dosage of 750 mg once daily in fasted state.	Drug: Ceritinib; Ceritinib was administered orally once-daily fasted at a dose of 750 mg capsules on a continuous dosing schedule.; Other Names: LDK378
Active Comparator: Chemotherapy; Pemetrexed plus cisplatin or carboplatin (based on Investigator's choice) for 4 cycles (Induction) followed by pemetrexed as single agent (Maintenance)	Drug: Carboplatin; Carboplatin was administered as iv infusion (AUC 5-6) every 21 days up to 4 cycles; Drug: Pemetrexed; Pemetrexed was administered at a dose of 500 mg/m^2 as an intravenous (iv) infusion on Day 1 of each 21-day cycle; Drug: Cisplatin; Cisplatin was administered by iv infusion at a dose of 75 mg/m^2 every 21 days for up to 4 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From date of randomization to date of death due to any cause, up to approximately 120 months
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.	Up to approximately 34 months
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.	Up to approximately 120 months
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.	From first documented response to first documented disease progression or death, assessed up to approximately 34 months
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.	From first documented response to first documented disease progression or death, assessed up to approximately 120 months
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.	Up to approximately 34 months
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.	Up to approximately 120 months
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.	From randomization to date of first documented response, up to approximately 34 months
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	From randomization to date of first documented response, up to approximately 120 months
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.	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
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.	Up to approximately 34 months
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	Up to approximately 34 months
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.	From first documented response to first documented disease progression in the brain or death, assessed up to approximately 34 months
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.	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
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.	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
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	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
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.	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
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.	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
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.	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
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.	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
Cmax of LDK378	The observed maximum plasma concentration following administration	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
Tmax of LDK378	The time to reach peak or maximum concentration (Tmax) was assessed. Actual recorded sampling times were considered for the calculations	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
Tlast of LDK378	The time to last quantifiable concentration. Actual recorded sampling times were considered for the calculations	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
AUC0-24 of LDK378	The area under the plasma concentration-time curve calculated from time zero to 24 hours	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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Lin YT, Yu CJ, Yang JC, Shih JY. Anaplastic Lymphoma Kinase (ALK) Kinase Domain Mutation Following ALK Inhibitor(s) Failure in Advanced ALK Positive Non-Small-Cell Lung Cancer: Analysis and Literature Review. Clin Lung Cancer. 2016 Sep;17(5):e77-e94. doi: 10.1016/j.cllc.2016.03.005. Epub 2016 Mar 30.
• Soria JC, Tan DSW, Chiari R, Wu YL, Paz-Ares L, Wolf J, Geater SL, Orlov S, Cortinovis D, Yu CJ, Hochmair M, Cortot AB, Tsai CM, Moro-Sibilot D, Campelo RG, McCulloch T, Sen P, Dugan M, Pantano S, Branle F, Massacesi C, de Castro G Jr. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017 Mar 4;389(10072):917-929. doi: 10.1016/S0140-6736(17)30123-X. Epub 2017 Jan 24. Erratum In: Lancet. 2017 Mar 4;389(10072):908. doi: 10.1016/S0140-6736(17)30603-7.

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2013
• Primary Completion (Actual): June 24, 2016
• Study Completion (Actual): January 7, 2024

Study Registration Dates

• First Submitted: April 3, 2013
• First Submitted That Met QC Criteria: April 9, 2013
• First Posted (Estimated): April 10, 2013

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 20, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: NSCLC; Non-Small Cell Lung Cancer; lung cancer; lung adenocarcinoma; Non small cell lung cancer; Non-small cell lung carcinoma (NSCLC); treatment of lung cancer after first metastasis; Non small cell lung carcinoma; ALK; LDK378; non-squamous non-small cell lung cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Protein Kinase Inhibitors; Pemetrexed; Carboplatin; Ceritinib
• Other Study ID Numbers: CLDK378A2301; 2013-000319-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No