Abstract
The discovery of anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved—ceritinib and alectinib—and others that are in development—brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK-positive (ALK+) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for ceritinib penetration across the blood-brain barrier. In clinical trials, ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor–pre-treated and –naïve NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK+ NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK-mutation–driven tumors.
| Original language | English |
|---|---|
| Pages (from-to) | 181-189 |
| Number of pages | 9 |
| Journal | Cancer Treatment Reviews |
| Volume | 55 |
| DOIs | |
| Publication status | Published - Apr 1 2017 |
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Keywords
- Anaplastic lymphoma kinase
- Carcinoma
- Ceritinib
- Drug resistance
- Neoplasm
- Non–small-cell lung
ASJC Scopus subject areas
- Oncology
- Radiology Nuclear Medicine and imaging
Cite this
The accelerated path of ceritinib : Translating pre-clinical development into clinical efficacy. / Mok, Tony S.K.; Crino, Lucio; Felip, Enriqueta; Salgia, Ravi; De Pas, Tommaso; Tan, Daniel S.W.; Chow, Laura Q.M.
In: Cancer Treatment Reviews, Vol. 55, 01.04.2017, p. 181-189.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - The accelerated path of ceritinib
T2 - Translating pre-clinical development into clinical efficacy
AU - Mok, Tony S.K.
AU - Crino, Lucio
AU - Felip, Enriqueta
AU - Salgia, Ravi
AU - De Pas, Tommaso
AU - Tan, Daniel S.W.
AU - Chow, Laura Q.M.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - The discovery of anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved—ceritinib and alectinib—and others that are in development—brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK-positive (ALK+) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for ceritinib penetration across the blood-brain barrier. In clinical trials, ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor–pre-treated and –naïve NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK+ NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK-mutation–driven tumors.
AB - The discovery of anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved—ceritinib and alectinib—and others that are in development—brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK-positive (ALK+) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for ceritinib penetration across the blood-brain barrier. In clinical trials, ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor–pre-treated and –naïve NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK+ NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK-mutation–driven tumors.
KW - Anaplastic lymphoma kinase
KW - Carcinoma
KW - Ceritinib
KW - Drug resistance
KW - Neoplasm
KW - Non–small-cell lung
UR - http://www.scopus.com/inward/record.url?scp=85018318057&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018318057&partnerID=8YFLogxK
U2 - 10.1016/j.ctrv.2017.03.006
DO - 10.1016/j.ctrv.2017.03.006
M3 - Review article
VL - 55
SP - 181
EP - 189
JO - Cancer Treatment Reviews
JF - Cancer Treatment Reviews
SN - 0305-7372
ER -