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Expanding the portfolio of anti-ALK weapons
1Department of Health Sciences, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy.
Abstract:
The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the onset of several malignancies. In particular, ALK is the driving oncogenic lesion in a small but significant fraction of non-small cell lung cancer (NSCLC) patients. ALK+ NSCLCs can be treated with the dual ALK/MET inhibitor crizotinib, with better outcome compared to standard chemotherapy. However, relapses frequently occur, due to various mechanisms, limiting overall efficacy of the treatment. Point mutations within the ALK catalytic domain or ALK gene amplification account for approximately 30-40% of crizotinib-resistant cases, suggesting that the diseases still relies on ALK activity and that more potent inhibitors could be useful in this setting. Ceritinib is a novel selective ALK inhibitor with preclinical activity against crizotinib-resistant ALK mutants. A recent article in the New England Journal of Medicine reports on clinical evaluation of ceritinib. Response rate and progression-free survival (PFS) were comparable to crizotinib, but most importantly, crizotinib-resistant patients were successfully treated, with efficacy similar to crizotinib-naïve patients. The study extends the array of available anti-ALK drugs. Based on these data, ceritinib was approved by FDA in April 2014.
Insights
Ceritinib effectively treats anaplastic lymphoma kinase-positive non-small cell lung cancer, including cases resistant to crizotinib. This novel drug offers a new option for patients with advanced lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK) is a key driver in a subset of non-small cell lung cancer (NSCLC).
- Crizotinib, an ALK inhibitor, is effective but resistance, often due to ALK mutations or amplification, limits long-term outcomes.
- New therapeutic strategies are needed to overcome resistance to existing ALK-targeted therapies.
Purpose of the Study:
- To evaluate the clinical efficacy of ceritinib, a novel selective ALK inhibitor.
- To assess ceritinib's activity in patients with ALK-positive NSCLC, including those who developed resistance to crizotinib.
- To determine if ceritinib offers a viable treatment option for crizotinib-resistant ALK-positive NSCLC.
Main Methods:
- Clinical trial evaluating ceritinib in patients with ALK-positive NSCLC.
- Comparison of response rates and progression-free survival (PFS) between ceritinib and crizotinib.
- Assessment of ceritinib efficacy in both crizotinib-naïve and crizotinib-resistant patient populations.
Main Results:
- Ceritinib demonstrated comparable response rates and PFS to crizotinib in ALK-positive NSCLC.
- Crucially, ceritinib showed significant efficacy in patients who had developed resistance to crizotinib.
- Treatment outcomes in crizotinib-resistant patients were similar to those in crizotinib-naïve patients, highlighting ceritinib's effectiveness against resistant mutations.
Conclusions:
- Ceritinib is an effective treatment for ALK-positive NSCLC.
- Ceritinib provides a valuable therapeutic option for patients who have progressed on or are resistant to crizotinib.
- The study supports ceritinib's role in expanding treatment choices for advanced ALK-driven NSCLC, leading to its FDA approval.