Background
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.
Methods
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.
Results
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 [0]) & 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) |
| By BIRC |
|
|
| 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] |
| By Investigator |
|
|
| 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
Conclusions
Ceritinib showed a clinically meaningful and statistically significant improvement in PFS vs CT in pretreated ALK+ NSCLC.
Clinical trial identification
NCT01828112
Legal entity responsible for the study
Novartis Pharmaceutical Corporation
Funding
Novartis Pharmaceutical Corporation
Disclosure
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.
