Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Shaw AT, Kim D-W, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368: DOI: /NEJMoa

2 SUPPLEMENTARY APPENDIX Supplement to: Shaw et al. A Randomized Trial of Crizotinib or Chemotherapy in Advanced, Previously Treated Lung Cancer with ALK Rearrangement Contents Page PROFILE 1007 Investigators 2 PROFILE 1007 Steering Committee 2 Table S1. Baseline Clinical Characteristics of the Patients by Type of 3 Chemotherapy (As-Treated Population). Table S2. Treatment Status in Chemotherapy Arm at Data Cutoff. 4 Table S3. Grade 3 or 4 Adverse Events of Any Cause in 3% of Patients. 5 Table S4. Grade 5 Adverse Events of Any Cause on Study. 6 Table S5. Incidence of AEs of Any Cause Occurring During Entire Study or Until 7 RECIST-Defined PD. Table S6. Baseline Scores for EORTC QLQ-C30 and LC-13 Scales. 8 Figure S1. Patient Disposition. 9 Figure S2. Treatment Effect on Progression-free Survival in Selected Subgroups. 10 Figure S3. Summary of Best Responses in Patients Treated with Crizotinib, 11 Pemetrexed, or Docetaxel. Figure S4. Interim Analysis of Overall Survival. 12 Figure S5. Overall Change from Baseline in Functioning Domains. 13

3 PROFILE 1007 INVESTIGATORS Australia: M Boyer, M Brown, A Hasani, B Solomon Brazil: C Barrios, C da Silva, G de Castro, V de Lima, C Ferreira, F Franke, C Mathias, J Segalla, M Zereu Bulgaria: K Dimitrov, A Dimitrova, Z Milanova, V Taskova, C Timcheva Canada: A Benjelloun, N Blais, D Hao, V Hirsh, A Joy, G Nicholas, R Wierzbicki China: C Bai, B Han, X Liu, S Lu, S Qin, Y Shi, Y-L Wu, L Zhang, C Zhou France: F Barlesi, B Besse, J Cadranel, B Coudert, R Gervais, F Goldwasser, J Louridi, D Moro-Sibilot, M Poudenx Germany: W Eberhardt, N Frickhofen, F Griesinger, R Huber, H-E Laack, M Reck, J Stoehlmacher-Williams, M Thomas, J Wolf Greece: V Georgoulias, K Syrigos, K Zarogoulidis Hong Kong: J Ho, T Mok, W-Y Ng Hungary: G Losonczy, Z Mark, B Medgyasszay, Z Papai, J Strausz, M Szilasi Ireland: P Donnellan, K O'Byrne Italy: D Amoroso, E Baldini, P Bidoli, L Ciuffreda, L Crinó, F De Marinis, T de Pas, F Di Costanzo, L Gianni, C Gridelli, F Grossi, G Scagliotti, S Siena Japan: M Harada, T Hida, K Kiura, K Nakagawa, M Nishio, H Nokihara, Y Ohe, M Satouchi, T Seto, N Yamamoto Korea, Republic of: M-J Ahn, J-Y Han, D-W Kim Netherlands: H Groen Poland: J Jassem, A Kazarnowicz, R Ramlau, A Szczesna Russian Federation: A Kuzmin, M Lichinitser, G Manikhas, S Orlov, D Udovitsa Spain: E Carcereny Costa, F Cardenal Alemany, J De Castro Carpeño, E Felip Font, R Garcia Campelo, Y Garcia Garcia, M Lopez-Brea Piqueras, B Hernandez Marin, L Paz-Ares Rodriguez, A Taus Garcia, N Villanueva Palicio Sweden: S Friesland Taiwan: W-C Su, C-M Tsai, P-C Yang United Kingdom: F Blackhall, E Boleti, C Ottensmeier, S Popat, J Spicer, D Talbot United States: I Anderson, V Armenio, M Batus, L Bazhenova, C Belani, D Camidge, A Chiappori, J Cho, T Evans, S Gadgeel, D Gandara, E Garon, S Gettinger, R Govindan, S Graziano, B Halmos, S Hamburg, N Hanna, L Horn, P Jänne, F Johnson, M Kozloff, R Martins, R Mehra, A Menter, R Mudad, G Otterson, S-H Ou, R Patel, N Pennell, H Raftopoulos, G Riely, J Rigas, C Rudin, S Sakkarai, M Saleh, R Salgia, A Sandler, A Schwarzberg, A Shaw, M Socinski, D Spigel, T Stinchcombe, H Wakelee, H West PROFILE 1007 STEERING COMMITTEE Fiona Blackhall, D. Ross Camidge, Vera Hirsh, Pasi Jänne, Dong-Wan Kim, Tony Mok, Alice Shaw, Benjamin Solomon, Jean-Charles Soria 2

4 Table S1. Baseline Clinical Characteristics of the Patients by Type of Chemotherapy (As-Treated Population).* Characteristic Crizotinib (N=172) Pemetrexed (N=99) Docetaxel (N=72) Age Median (range) yr 51 (22 81) 50 (26 85) 49 (24 71) <65 yr no. (%) 145 (84) 82 (83) 66 (92) 65 yr no. (%) 27 (16) 17 (17) 6 (8) Male sex no. (%) 75 (44) 46 (46) 31 (43) Race no. (%) Caucasian 89 (52) 47 (47) 42 (58) Asian 79 (46) 50 (51) 27 (38) Other 4 (2) 2 (2) 3 (4) Smoking no. (%) Never smoker 108 (63) 59 (60) 49 (68) Ex-smoker 59 (34) 33 (33) 21 (29) Current smoker 5 (3) 7 (7) 2 (3) Histology no. (%) Adenocarcinoma 164 (95) 94 (95) 68 (94) Non-adenocarcinoma 5 (3) 3 (3) 3 (4) ECOG performance status no. (%) 0 72 (42) 34 (34) 30 (42) 1 84 (49) 57 (58) 37 (51) 2 16 (9) 8 (8) 5 (7) Extent of disease no. (%) Locally advanced 7 (4) 11 (11) 5 (7) Metastatic 165 (96) 88 (89) 67 (93) Brain metastases no. (%) 60 (35) 31 (31) 28 (39) * ECOG denotes Eastern Cooperative Oncology Group. Data missing for 6 patients (crizotinib, N=3; pemetrexed, N=2; docetaxel, N=1). 3

5 Table S2. Treatment Status in Chemotherapy Arm at Data Cutoff.* Chemotherapy Status (N=174) number of patients Still receiving chemotherapy 28 Discontinued chemotherapy and crossed over to receive crizotinib 112 Discontinued chemotherapy without crossover to crizotinib 34 Died on chemotherapy or before starting follow-up therapy 13 No follow-up therapy recorded after discontinuation of 10 chemotherapy Discontinued chemotherapy for reason other than disease 6 progression and were in follow-up for confirmation of disease progression Refused further follow-up 3 Received follow-up therapy other than crizotinib 2 * March 30, One each erlotinib and an investigational agent. 4

6 Table S3. Grade 3 or 4 Adverse Events of Any Cause in 3% of Patients. Adverse Events Crizotinib (N=172) Chemotherapy (N=171) number of patients (percent) Incidence higher in crizotinib arm Elevated transaminases* 27 (16) 4 (2) Pulmonary embolism* 9 (5) 3 (2) Dyspnea* 7 (4) 5 (3) Pneumonia 6 (4) 3 (2) Hypokalemia 6 (4) 0 Electrocardiogram QTc prolonged 6 (4) 0 Incidence higher in chemotherapy arm Neutropenia* 23 (13) 33 (19) Febrile neutropenia 1 (1) 16 (9) Anemia* 4 (2) 9 (5) White blood cells decreased 2 (1) 8 (5) Fatigue 4 (2) 7 (4) * Clustered term. No on-treatment assessments. 5

7 Table S4. Grade 5 Adverse Events of Any Cause on Study. Adverse Events Crizotinib (N=172) Chemotherapy (N=171) number of patients (percent) Disease progression* 14 (8) 3 (2) Study-treatment-related Arrhythmia 1 (1) 0 Interstitial lung disease or pneumonitis 2 (1) 0 Sepsis 0 1 (1) Other Acute respiratory distress syndrome 1 (1) 0 Cognitive disorder 1 (1) 0 Dyspnea 1 (1) 1 (1) Pericardial effusion 0 1 (1) Pneumonia 1 (1) 0 Pulmonary embolism 1 (1) 0 Respiratory failure 1 (1) 0 Sepsis 1 (1) 0 Sudden death 1 (1) 0 Tumor hemorrhage 0 1 (1) Unknown 1 (1) 0 Total events 25 (15) 7 (4) * Includes all disease-progression events with "disease under study" as the causality. The causality of this event was reported to be "infection." The causality of this event was reported to be "disease under study." The causality of this event was reported to be "sputum block." One death was attributed to both acute respiratory distress syndrome and sepsis. 6

8 Table S5. Incidence of AEs of Any Cause Occurring During Entire Study or Until RECIST- Defined PD.* Crizotinib (N=172) Chemotherapy (N=171) Entire study Until PD Entire study Until PD Number of AEs Patients with AEs no. (%) 172 (100) 172 (100) 168 (98) 164 (96) Patients with SAEs no. (%) 64 (37) 46 (27) 40 (23) 35 (21) Patients with grade 3 or 4 AEs no. (%) 97 (56) 83 (48) 78 (46) 68 (40) Patients with grade 5 AEs no. (%) 25 (15) 16 (9) 7 (4) 4 (2) *AEs denotes adverse events; PD progressive disease; RECIST Response Evaluation Criteria in Solid Tumors; and SAEs serious AEs. 7

9 Table S6. Baseline Scores for EORTC QLQ-C30 and LC-13 Scales.* Domain Crizotinib (N=173) Chemotherapy (N=174) mean ± standard deviation Global quality of life (QLQ-C30) 57.2± ±22.2 Functioning (QLQ-C30) Physical 76.3± ±21.9 Social 68.0± ±29.0 Role 69.3± ±30.2 Cognitive 85.6± ±22.3 Emotional 74.5± ±20.7 Symptoms (QLQ-C30) Fatigue 38.3± ±25.3 Nausea and vomiting 8.4± ±18.0 Pain 23.9± ±27.3 Dyspnea 31.1± ±28.2 Insomnia 22.6± ±27.3 Appetite loss 24.4± ±28.2 Constipation 14.8± ±25.0 Diarrhea 9.7± ±16.0 Symptoms (QLQ-LC13) Dyspnea 27.2± ±23.4 Cough 38.2± ±31.3 Hemoptysis 2.4± ±12.3 Sore mouth 5.5± ±18.4 Dysphagia 7.1± ±20.9 Peripheral neuropathy 14.0± ±27.3 Alopecia 17.4± ±29.8 Pain in chest 18.8± ±27.5 Pain in arm or shoulder 16.3± ±28.0 Pain in other parts 23.1± ±30.4 * EORTC denotes European Organisation for Research and Treatment of Cancer. 8

10 9

11 10

12 11

13 12

14 13