The ALK inhibitor CRZ is effective in ALK+ NSCLC pts, but most develop resistance and progressive disease (PD). Ceritinib showed robust efficacy in CRZ-pretreated pts in phase 1 & 2 studies. This multicenter, open-label phase 3 study (NCT01828112) compared efficacy of ceritinib vs CT in ALK+ NSCLC pts pretreated with CT & CRZ.
ALK+ NSCLC pts pretreated with 1–2 CT regimens & CRZ were randomized to oral ceritinib 750 mg/d or CT (pemetrexed [PEM] 500 mg/m2 or docetaxel [DOC] 75 mg/m2), stratified by WHO PS (0 vs 1–2) & brain metastasis at screening. Pts discontinuing CT due to PD could crossover to ceritinib. Primary endpoint was progression-free survival (PFS), assessed by blinded independent review committee (BIRC) per RECIST v1.1.
Of 231 pts (median age 54 y), 115 were randomized to ceritinib and 116 to CT (PEM, n = 40; DOC, n = 73; 3 not treated). Median treatment exposure was 30.3 wk for ceritinib and 6.3 wk for CT. Median follow-up duration was 16.5 mo. Ceritinib showed statistically significant improvement in PFS (BIRC: median 5.4 vs 1.6 mo, HR = 0.49, P < 0.001) and increased overall response rate [95% CI] (BIRC: 39.1% [30.2, 48.7] vs 6.9% [3.0, 13.1]) vs CT (Table). Of pts discontinuing CT due to PD, 75 crossed over to ceritinib. Most frequent AEs (% any grade [% grade 3/4]) were diarrhoea (72.2 [4.3]), nausea (66.1 [7.8]) & vomiting (52.2 [7.8]) with ceritinib; fatigue (28.3 [4.4]), nausea (23.0 [1.8]), alopecia (21.2 ) & neutropenia (20.4 [15.0]) with CT. 6 (5.2%) ceritinib- and 8 (6.9%) CT-treated pts discontinued due to AEs. Ceritinib significantly improved lung cancer-specific symptoms (LCSS & QLQ-LC13) & overall health status (EQ-5D) vs CT (P < 0.05).
|Ceritinib(n = 115)||CT(n = 116)|
|Median PFS, mo [95% CI]||5.4* [4.1, 6.9]||1.6 [1.4, 2.8]|
|ORR (CR + PR), % [95% CI]||39.1 [30.2, 48.7]||6.9 [3.0, 13.1]|
|DCR (CR + PR + SD), % [95% CI]||76.5 [67.7, 83.9]||36.2[27.5, 45.6]|
|Median PFS, mo [95% CI]||6.7* [4.4, 7.9]||1.6 [1.4, 2.6]|
|ORR (CR + PR), % [95% CI]||42.6 [33.4, 52.2]||6.0 [2.5, 12.0]|
|DCR (CR + PR + SD), % [95% CI]||80.0 [71.5, 86.9]||37.9 [29.1, 47.4]|
|Median OS, mo [95% CI]||18.1† [13.4, 23.9]||20.1[11.9, 25.1]|
*Log-rank P < 0.001 vs CT
†Log-rank P = 0.496 vs CT CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease
Ceritinib showed a clinically meaningful and statistically significant improvement in PFS vs CT in pretreated ALK+ NSCLC.
Clinical trial identification
Legal entity responsible for the study
Novartis Pharmaceutical Corporation
Novartis Pharmaceutical Corporation
G. Scagliotti: Honoraria: Eli Lilly, AZ, Pfizer, Roche, Clovis Oncology Consulting/advisory, Speaker fees: Eli Lilly Travel/accommodation/expenses: Bayer. L. Crinò: Honoraria: Novartis, AstraZeneca, Boheringer Consulting/Advisory: Pfizer, Novartis AstraZeneca G. Liu: Honoraria for advisory board membership: Astra Zeneca, Novartis, Roche, Pfizer. C. Gridelli: Honoraria for advisory board membership: Novartis. S. Novello: Speaker Bureau: Eli Lilly, BMS, MSD, BI, Astra Zeneca. K. Kiura: Corporate-sponsored research: Chugai, AZ, Boehringer, Daiichi-Sankyo, and Shionogi Personal fees (including honoraria): Novartis, Chugai, Pfizer, Lilly, and Taiho. E. Felip: Consulting/Advisory: Lilly, Roche, BI, BMS, Novartis. M. Nishio: Research: Novartis/ONO Pharmaceutical/Chugai Pharmaceutical/BMS/Taiho. Pharmaceutical/Eli Lilly, Pfizer/Astellas Pharma/AstraZeneca Honoraria: Pfizer/BMS/Ono Pharmaceutical/Chugai Pharmaceutical/Eli Lilly/TAIHO pharmaceutical/AstraZeneca. D.R. Spigel: Consulting/Advisory: Novartis, Pfizer, Genentech/Roche; Speaker's bureau: Novartis; Travel/Expenses: Novartis, Pfizer, Genentech/Roche. T.S.K.Mok: Employment: CUHK Stock: Sanomics Ltd Honoraria/Research: AZ, Roche/Genentech, Pfizer, Lilley, BI, Merck Serono, MSD, Jenssen, Clovis Oncology, BioMarin, GSK, Novartis, SFJ, Acta Biosciences, Vertex, Aveo, Biodesix, BMS, GeneDecode. P. Urban, S. Deudon: Employment: Novartis Pharma AG. C. Zheng: Employment: Novartis Pharmaceuticals Corporation. A.T. Shaw: Honoraria: Novartis, Pfizer, Roche Consulting/advisory: Ariad, Daiichi-sankyo, EMD Serono, Genentech, Ignyta, Novartis, Pfizer, Roche, Taiho, Blueprint Medicine Research funding: Genentech/Roche, Pfizer, Novartis. All other authors have declared no conflicts of interest.