Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib.
OBJECTIVE
Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non-small cell lung cancer (NSCLC) that confer sensitivity to the ALK inhibitors crizotinib and ceritinib. To determine the outcome of sequential treatment with crizotinb and ceritinib, we retrospectively evaluated a cohort of ALK-positive patients treated with both agents.


METHODS
We identified 73 ALK-positive NSCLC patients treated with crizotinib followed by ceritinib at four institutions. Medical records were reviewed to determine overall survival (OS) and progression-free survival (PFS) on crizotinib and ceritinib.


RESULTS
Among 73 ALK-positive patients, the median PFS (mPFS) on crizotinib was 8.2 months [95% confidence interval (CI), 7.4-10.6]. The median interval from crizotinib discontinuation to initiation of ceritinib was 25 days (range, 1-694). The mPFS on ceritinib was 7.8 months (6.5-9.1). Among 53 patients with no interval therapies between crizotinib and ceritinib, the mPFS on ceritinib was similar at 7.8 months (5.4-9.8). The median combined PFS for sequential treatment with crizotinib and ceritinib was 17.4 months (15.5-19.4). Among 23 patients who underwent post-crizotinib/pre-ceritinib biopsies, there was no difference in PFS on ceritinib between patients with or without ALK resistance mutations (mPFS 5.8 vs. 6.5 months, respectively; P = 0.510). In the overall study population, median OS was 49.4 months (35.5-63.1).


CONCLUSIONS
Ceritinib has significant antitumor activity in ALK-positive NSCLC-even when crizotinib immediately precedes treatment with ceritinib (median combined PFS 17.0 months). Additional studies are necessary to further define the impact of specific ALK resistance mutations on duration of response to ceritinib.
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Justin F
JF
Gainor
Division of Medical Oncology, National Cancer Center and Genome Institute of Singapore, Singapore, Singapore.
Daniel S W
DS
Tan
Department of Medicine, Istituto Europeo di Oncologia, Milan, Italy.
Tomasso
T
De Pas
Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Australia.
Benjamin J
BJ
Solomon
Division of Medical Oncology, National Cancer Center and Genome Institute of Singapore, Singapore, Singapore.
Aziah
A
Ahmad
Department of Medicine, Istituto Europeo di Oncologia, Milan, Italy.
Chiara
C
Lazzari
Department of Medicine, Istituto Europeo di Oncologia, Milan, Italy.
Filippo
F
de Marinis
Department of Medicine, Istituto Europeo di Oncologia, Milan, Italy.
Gianluca
G
Spitaleri
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Katherine
K
Schultz
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Luc
L
Friboulet
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Beow Y
BY
Yeap
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Jeffrey A
JA
Engelman
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. ashaw1@partners.org.
Alice T
AT
Shaw
D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D000077547:Crizotinib; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib