Ceritinib in ALK-rearranged non-small-cell lung cancer

Alice T. Shaw, Dong Wan Kim, Ranee Mehra, Daniel S W Tan, Enriqueta Felip, Laura Q M Chow, D. Ross Camidge, Johan Vansteenkiste, Sunil Sharma, Tommaso De Pas, Gregory J. Riely, Benjamin J. Solomon, Juergen Wolf, Michael Thomas, Martin Schuler, Geoffrey Liu, Armando Santoro, Yvonne Y. Lau, Meredith Goldwasser, Anthony L. Boral & 1 others Jeffrey A. Engelman

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. METHODS: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. RESULTS: A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5). CONCLUSIONS: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK.

Original languageEnglish (US)
Pages (from-to)1189-1197
Number of pages9
JournalNew England Journal of Medicine
Volume370
Issue number13
DOIs
StatePublished - 2014
Externally publishedYes

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Non-Small Cell Lung Carcinoma
Genes
Mutation
Maximum Tolerated Dose
Confidence Intervals
anaplastic lymphoma kinase
ceritinib
Disease Progression
Hypophosphatemia
Gene Rearrangement
Poisons
Transaminases
Dehydration
Disease-Free Survival
Vomiting
Diarrhea
Neoplasms
Therapeutics
Pharmacokinetics
crizotinib

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Shaw, A. T., Kim, D. W., Mehra, R., Tan, D. S. W., Felip, E., Chow, L. Q. M., ... Engelman, J. A. (2014). Ceritinib in ALK-rearranged non-small-cell lung cancer. New England Journal of Medicine, 370(13), 1189-1197. https://doi.org/10.1056/NEJMoa1311107

Ceritinib in ALK-rearranged non-small-cell lung cancer. / Shaw, Alice T.; Kim, Dong Wan; Mehra, Ranee; Tan, Daniel S W; Felip, Enriqueta; Chow, Laura Q M; Camidge, D. Ross; Vansteenkiste, Johan; Sharma, Sunil; De Pas, Tommaso; Riely, Gregory J.; Solomon, Benjamin J.; Wolf, Juergen; Thomas, Michael; Schuler, Martin; Liu, Geoffrey; Santoro, Armando; Lau, Yvonne Y.; Goldwasser, Meredith; Boral, Anthony L.; Engelman, Jeffrey A.

In: New England Journal of Medicine, Vol. 370, No. 13, 2014, p. 1189-1197.

Research output: Contribution to journalArticle

Shaw, AT, Kim, DW, Mehra, R, Tan, DSW, Felip, E, Chow, LQM, Camidge, DR, Vansteenkiste, J, Sharma, S, De Pas, T, Riely, GJ, Solomon, BJ, Wolf, J, Thomas, M, Schuler, M, Liu, G, Santoro, A, Lau, YY, Goldwasser, M, Boral, AL & Engelman, JA 2014, 'Ceritinib in ALK-rearranged non-small-cell lung cancer', New England Journal of Medicine, vol. 370, no. 13, pp. 1189-1197. https://doi.org/10.1056/NEJMoa1311107
Shaw AT, Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. New England Journal of Medicine. 2014;370(13):1189-1197. https://doi.org/10.1056/NEJMoa1311107
Shaw, Alice T. ; Kim, Dong Wan ; Mehra, Ranee ; Tan, Daniel S W ; Felip, Enriqueta ; Chow, Laura Q M ; Camidge, D. Ross ; Vansteenkiste, Johan ; Sharma, Sunil ; De Pas, Tommaso ; Riely, Gregory J. ; Solomon, Benjamin J. ; Wolf, Juergen ; Thomas, Michael ; Schuler, Martin ; Liu, Geoffrey ; Santoro, Armando ; Lau, Yvonne Y. ; Goldwasser, Meredith ; Boral, Anthony L. ; Engelman, Jeffrey A. / Ceritinib in ALK-rearranged non-small-cell lung cancer. In: New England Journal of Medicine. 2014 ; Vol. 370, No. 13. pp. 1189-1197.
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abstract = "BACKGROUND: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. METHODS: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. RESULTS: A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58{\%} (95{\%} confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56{\%} (95{\%} CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95{\%} CI, 5.6 to 9.5). CONCLUSIONS: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK.",
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AU - Shaw, Alice T.

AU - Kim, Dong Wan

AU - Mehra, Ranee

AU - Tan, Daniel S W

AU - Felip, Enriqueta

AU - Chow, Laura Q M

AU - Camidge, D. Ross

AU - Vansteenkiste, Johan

AU - Sharma, Sunil

AU - De Pas, Tommaso

AU - Riely, Gregory J.

AU - Solomon, Benjamin J.

AU - Wolf, Juergen

AU - Thomas, Michael

AU - Schuler, Martin

AU - Liu, Geoffrey

AU - Santoro, Armando

AU - Lau, Yvonne Y.

AU - Goldwasser, Meredith

AU - Boral, Anthony L.

AU - Engelman, Jeffrey A.

PY - 2014

Y1 - 2014

N2 - BACKGROUND: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. METHODS: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. RESULTS: A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5). CONCLUSIONS: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK.

AB - BACKGROUND: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. METHODS: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. RESULTS: A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5). CONCLUSIONS: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK.

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