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Real-life experience of ceritinib in crizotinib-pretreated ALK+ advanced non-small cell lung cancer patients

Jacques Cadranel, Alexis B. Cortot, Hervé Lena, Bertrand Mennecier, Pascal Do, Eric Dansin, Julien Mazieres, Christos Chouaid, Maurice Perol, Fabrice Barlesi, Gilles Robinet, Sylvie Friard, Luc Thiberville, Clarisse Audigier-Valette, Alain Vergnenegre, Virginie Westeel, Khemaies Slimane, Alexandru Buturuga, Denis Moro-Sibilot, Benjamin Besse
ERJ Open Research 2018 4: 00058-2017; DOI: 10.1183/23120541.00058-2017
Jacques Cadranel
1Service de Pneumologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris (AP-HP) and Université Pierre-et-Marie-Curie (Paris 6), Paris, France
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  • For correspondence: jacques.cadranel@aphp.fr
Alexis B. Cortot
2Thoracic Oncology, Centre Hospitalier Universitaire (CHU) and Université de Lille, Lille, France
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Hervé Lena
3Pneumologie, CHU and INSERM ERL440-OSS, Rennes, France
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Bertrand Mennecier
4Pneumologie, Nouvel Hôpital Civil, Strasbourg, France
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Pascal Do
5Pathologies Thoraciques, Centre François Baclesse, Caen, France
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Eric Dansin
6Département de cancérologie cervico-faciale et thoracique, CLCC Oscar Lambret, Lille, France
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Julien Mazieres
7Pneumologie, CHU, Toulouse, France
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Christos Chouaid
8Service de Pneumologie, Centre Hospitalier Intercommunal Cretéil (CHIC), Créteil, France
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Maurice Perol
9Cancérologie poumon, tumeurs thoraciques, Centre Léon Bérard, Lyon, France
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Fabrice Barlesi
10Multidisciplinary Oncology & Therapeutic Innovations Dept, Assistance Publique-Hôpitaux de Marseille (AP-HM) and Université Aix-Marseille, Marseille, France
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Gilles Robinet
11Institut de Cancerologie, CHU, Brest, France
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Sylvie Friard
12Pneumologie, Hôpital Foch, Suresnes, France
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Luc Thiberville
13Pneumologie, CHU, Rouen, France
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Clarisse Audigier-Valette
14Pneumologie, Centre Hospitalier Intercommunal (CHI), Toulon, France
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Alain Vergnenegre
15Pneumologie, CHU, Limoges, France
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Virginie Westeel
16Pneumologie, CHU, Besançon, France
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Khemaies Slimane
17Novartis Oncology, Rueil-Malmaison, France
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Alexandru Buturuga
17Novartis Oncology, Rueil-Malmaison, France
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Denis Moro-Sibilot
18Pneumologie, CHU Grenoble-Alpes, Grenoble, France
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Benjamin Besse
19Institut d'Oncologie Thoracique, Institut Gustave Roussy, Villejuif, France
20Université Paris-Sud, Orsay, France
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  • FIGURE 1
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    FIGURE 1

    Patient disposition in the temporary authorisation for use (TAU) programme. ALK+: anaplastic lymphoma kinase positive; ROS1+: ROS proto-oncogene 1 positive; IMT: inflammatory fibroblastic tumour

Tables

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  • Supplementary Materials
  • TABLE 1

    Baseline characteristics of patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC)

    CharacteristicPatients (n=214)
    Age years (n=211)58 (19–90)
    Sex (n=214)
     Female111 (51.9)
    ECOG performance status (n=205)
     0–1145 (70.7)
     ≥260 (28.9)
    Histology (n=207) 
     Adenocarcinoma199 (96.1)
     Undifferentiated carcinoma2 (1.0)
     Other6 (2.9)
    Number of metastatic sites (n=177)
     0–2117 (66.1)
     ≥360 (33.9)
    Metastatic localizations (n=210)
     Brain105 (50.0)
    ALK test method (n=203)
     FISH only107 (52.7)
     IHC only19 (9.4)
     FISH and IHC74 (36.5)
     Other3 (1.5)
    Time from initial diagnosis to inclusion in TAU months (n=206)23.2 (1.7–192.8)
    Prior medication regimens (including crizotinib) (n=213)
     1 (crizotinib only)15 (7.0)
     297 (45.5)
     >2101 (47.4)
     Median2
    Treatment line for crizotinib administration# (n=213)
     127 (12.7)
     2130 (61.0)
     335 (16.4)
     >437 (17.4)
    Crizotinib as last prior regimen# (n=213)
     Yes156 (73.2)
    Duration of crizotinib treatment months (n=208)9.1 (0.1–52.0)
     25%–75%5.0–15.0
    Reason to stop crizotinib# (n=222)
     Disease progression203 (91.4)
     Toxicity16 (7.2)
     Other3 (1.4)

    Data are presented as n (%) or median (range) unless otherwise stated. ECOG: Eastern Cooperative Oncology Group; FISH: fluorescent in situ hybridisation; IHC: immunohistochemistry; TAU: temporary authorisation for use. #: crizotinib could be administered as more than one line/regimen for the same patient.

    • TABLE 2

      Physician-assessed response and treatment duration in patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC)

      Radiological tumour evaluationALK+ NSCLC patients (n=149)
      CR8 (5.4)
      PR70 (47.0)
      SD34 (22.8)
      PD19 (12.8)
      Not realised18 (12.1)
      ORR78 (52.3)
      DCR112 (75.2)
      Duration months (n=182)3.9 (0.4–23.0)

      Data is presented as n (%) or median (range). CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; ORR: overall response rate; DCR: disease control rate.

      • TABLE 3

        Duration of ceritinib treatment according to duration of follow-up in patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC)

        All evaluable ALK+ patients#Patients with follow-up ≥6 monthsPatients with follow-up ≥12 months¶
        Subjects n18213671
        Duration months5.86.88.1
        3.9 (0.4–23.0)5.5 (0.4–23.0)5.5 (0.4–23.0)

        Data are presented as mean or median (range) unless otherwise stated. #: discontinuation of ceritinib was documented for 117 out of 182 patients (64.2%) at the cut-off (64.3% maturity); ¶: 16 out of 71 patients (22.5%) were still receiving ceritinib or were censored at cut-off (77.5% maturity).

        • TABLE 4

          Physician-assessed response and treatment duration in patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) according to subgroups based on Eastern Cooperative Oncology Group (ECOG) performance status and presence of brain metastases

          Radiological tumour evaluationECOG performance statusBrain metastases
          0–1 (n=134)2–4 (n=51)Present (n=97)Absent (n=64)
          Assessed response
           Evaluable subjects109337250
           CR8 (7.3)0 (0.0)2 (2.8)4 (8.0)
           PR52 (47.7)14 (42.4)33 (45.8)26 (52.0)
           SD28 (25.7)4 (12.1)18 (25.0)6 (12.0)
           PD11 (10.1)8 (24.2)8 (11.1)8 (16.0)
           Not realised9 (8.3)6 (18.2)10 (13.9)5 (10.0)
           Not evaluable1 (0.9)1 (3.0)1 (1.4)1 (2.0)
           ORR60 (55.0)14 (42.4)35 (48.6)30 (60.0)
          Treatment duration
           Subjects131439260
           Duration months4.6 (0.4–22.4)2.3 (0.4–19.9)3.3 (0.4–23.0)4.5 (0.4–22.2)

          Data are presented as n, n (%) or median (range) unless otherwise stated. CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; ORR: overall response rate.

          • TABLE 5

            Physician-assessed response in patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) according to subgroups based on the number of previous lines of treatment, the duration of previous treatment with crizotinib and dose reduction

            Radiological tumour evaluationPrevious lines of treatmentDuration of previous crizotinib treatment#Dose reduction¶
            ≤2 lines (n=98)>2 lines (n=94)<Q1 (n=47)Q1−Q2 (n=47)Q2−Q3 (n=46)≥Q3 (n=49)With dose reduction (n=84)Without dose reduction (n=109)
            Assessed response
             Evaluable subjects7276363135437475
             CR5 (6.9)3 (3.9)0 (0.0)4 (12.9)2 (5.7)2 (4.7)5 (6.8)3 (4.0)
             PR35 (48.6)35 (46.1)13 (36.1)12 (38.7)20 (57.1)23 (53.5)36 (48.6)34 (45.3)
             SD18 (25.0)15 (19.7)10 (27.8)5 (16.1)7 (20.0)10 (23.3)17 (23.0)17 (22.7)
             PD10 (13.9)9 (11.8)10 (27.8)3 (9.7)3 (8.6)3 (7.0)8 (10.8)11 (14.7)
             Not realised3 (4.2)13 (17.1)3 (8.3)5 (16.1)3 (8.6)5 (11.6)6 (8.1)10 (13.3)
             Not evaluable1 (1.4)1 (1.3)0 (0.0)2 (6.5)0 (0.0)0 (0.0)2 (2.7)0 (0.0)
             ORR40 (55.5)38 (50.0)13 (36.1)16 (51.6)22 (62.8)25 (58.2)41 (55.4)37 (49.3)
            Treatment duration
             Subjects9190434543478399
             Duration months3.8 (0.4–23.0)3.7 (0.4–22.4)2.3 (0.4–15.9)3.0 (0.4–23.0)5.1 (0.4–19.9)7.6 (0.9–22.2)4.9 (0.4–22.2)2.7 (0.4–23.0)

            Data are presented as n, n (%) or median (range). CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; ORR: overall response rate. #: <Q1 means <5 months of crizotinib, Q1–Q2 means 5 to <9.2 months of crizotinib, Q2–Q3 means 9.2 to <16 months of crizotinib >Q3 means >16 months of crizotinib. ¶: dose reduction is <750 mg·day−1 of ceritinib or a temporary discontinuation in the first 6 months of treatment.

            • TABLE 6

              Summary of adverse events (AEs) suspected of being related to the study drug

              EventAny grade (n=208)Severe (n=208)
              Any AE138 (66.3)105 (50.3)
              Any AE considered to be drug related118 (56.7)74 (35.6)
              Drug reduction and/or interruption67 (32.2)
              Drug discontinuation13 (6.3)
              Most common AEs
               Diarrhoea46 (22.1)12 (5.8)
               Nausea35 (16.8)11 (5.3)
               Vomiting34 (16.3)11 (5.3)
               Hepatic toxicity (ALT/AST-increased or other)41 (19.7)26 (12.5)
               Abdominal pain12 (5.8)1 (0.5)
               Weight decrease12 (5.8)5 (2.4)
               Asthenia10 (4.8)7 (3.4)
               Decreased appetite9 (4.3)5 (2.4)
               Creatinine increase/renal insufficiency14 (6.7)8 (3.8)
               Fatigue6 (2.9)2 (1.0)
               Pericardial tamponade/effusion5 (2.4)3 (1.4)
               Hyperglycaemia3 (1.4)2 (1.0)
               Dyspnoea3 (1.4)3 (1.4)
               Thrombocytopenia4 (1.9)3 (1.4)
               Skin disorders2 (1.0)0 (0.0)
               Dehydration2 (1.0)2 (1.0)

              Data are presented as n (%). ALT: alanine aminotransferase; AST: aspartate aminotransferase.

              • TABLE 7

                Characteristics and outcomes of patients from the French temporary authorisation for use (TAU) ceritinib study with other ceritinib data in crizotinib-pretreated patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC)

                French TAU ceritinib studyASCEND-1 (phase 1)Gainor cohortASCEND-2 (phase 2)ASCEND-5 (phase 3)
                Subjects n21416373#140115
                ECOG %
                 PS 0–170.887.1NA85.792.2
                 PS 2–429.312.9NA14.3¶7.8¶
                Prior lines %
                 1716NA00
                 245.527.6NA43.687.8
                 >247.456.0NA56.411.3+
                Brain metastases %5161NA7156.5
                ORR %52.456.4NA38.639.1
                DCR %75.274.2NA77.176.5
                Median ceritinib duration/exposure months3.9 (all patients)
                5.5 (>12  months follow-up, 78% maturity)
                Median PFS monthsNA6.97.85.75.4
                Median OS monthsNot evaluable or not mature16.749.4 (from diagnosis)
                30.3 (from crizotinib start)
                14.9 (42% maturity)18.1 (∼50% maturity)
                Dose reduction/interruption %32.262 (reduction)
                74 (interruption)
                NA54.380.0
                Discontinuation due to AEs %6.311NA7.95.2

                ECOG: Eastern Cooperative Oncology Group; PS: performance status; NA: not available; ORR: objective response rate; DCR: disease control rate; PFS: progression-free survival; OS: overall survival; AE: adverse event. #: 71 subjects from ASCEND-1; ¶: PS 2; +: three prior lines of therapy.

                Supplementary Materials

                • Figures
                • Tables
                • Supplementary Material

                  C. Audigier-Valette 00058-2017_Audigier-Valette

                  F. Barlesi 00058-2017_Barlesi

                  B. Besse 00058-2017_Besse

                  A. Buturuga 00058-2017_Buturuga

                  J. Cadranel 00058-2017_Cadranel

                  A.B. Cortot 00058-2017_Cortot

                  E. Dansin 00058-2017_Dansin

                  S. Friard 00058-2017_Friard

                  H. Lena 00058-2017_Lena

                  B. Mennecier 00058-2017_Mennecier

                  D. Moro-Sibilot 00058-2017_Moro-Sibilot

                  M. Perol 00058-2017_Perol

                  K. Slimane 00058-2017_Slimane

                  L. Thiberville 00058-2017_Thiberville

                  A. Vergnenegre 00058-2017_Vergnenegre

                  V. Westeel 00058-2017_Westeel

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                Real-life experience of ceritinib in crizotinib-pretreated ALK+ advanced non-small cell lung cancer patients
                Jacques Cadranel, Alexis B. Cortot, Hervé Lena, Bertrand Mennecier, Pascal Do, Eric Dansin, Julien Mazieres, Christos Chouaid, Maurice Perol, Fabrice Barlesi, Gilles Robinet, Sylvie Friard, Luc Thiberville, Clarisse Audigier-Valette, Alain Vergnenegre, Virginie Westeel, Khemaies Slimane, Alexandru Buturuga, Denis Moro-Sibilot, Benjamin Besse
                ERJ Open Research Jan 2018, 4 (1) 00058-2017; DOI: 10.1183/23120541.00058-2017

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                Real-life experience of ceritinib in crizotinib-pretreated ALK+ advanced non-small cell lung cancer patients
                Jacques Cadranel, Alexis B. Cortot, Hervé Lena, Bertrand Mennecier, Pascal Do, Eric Dansin, Julien Mazieres, Christos Chouaid, Maurice Perol, Fabrice Barlesi, Gilles Robinet, Sylvie Friard, Luc Thiberville, Clarisse Audigier-Valette, Alain Vergnenegre, Virginie Westeel, Khemaies Slimane, Alexandru Buturuga, Denis Moro-Sibilot, Benjamin Besse
                ERJ Open Research Jan 2018, 4 (1) 00058-2017; DOI: 10.1183/23120541.00058-2017
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