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Alectinib: a selective, next-generation ALK inhibitor for treatment of ALK-rearranged non-small-cell lung cancer
Mariacarmela Santarpia1, Giuseppe Altavilla, Rafael Rosell
1Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy.
Abstract:
Crizotinib was the first clinically available anaplastic lymphoma kinase (ALK) inhibitor, showing remarkable activity against ALK-rearranged non-small-cell lung cancer (NSCLC). Despite initial responses, acquired resistance to crizotinib inevitably develops, with the brain being a common site of relapse. Alectinib is a highly selective, next-generation ALK inhibitor with potent inhibitory activity also against ALK mutations conferring resistance to crizotinib, including the gatekeeper L1196M substitution. In a Phase I/II study from Japan, alectinib was found to be highly active and safe in crizotinib-naïve, ALK-rearranged NSCLC patients. Alectinib also demonstrated promising antitumor activity in crizotinib-resistant patients, including those with CNS metastases. Based on these data, the drug received Breakthrough Therapy Designation by the US FDA and has been recently approved in Japan for the treatment of ALK-positive, advanced NSCLC patients. However, patients may eventually develop resistance to alectinib, highlighting the need for novel therapeutic strategies to further improve the management of ALK-rearranged NSCLC.
Insights
Alectinib shows high activity and safety in ALK-positive non-small-cell lung cancer (NSCLC) patients, including those resistant to crizotinib. Further research is needed as resistance to alectinib can also develop.
Area of Science:
- Oncology
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is initially responsive to crizotinib.
- Acquired resistance to crizotinib is common, often involving central nervous system (CNS) relapse.
Purpose of the Study:
- To evaluate the efficacy and safety of alectinib, a next-generation ALK inhibitor.
- To assess alectinib's activity in both crizotinib-naïve and crizotinib-resistant NSCLC patients, including those with CNS metastases.
Main Methods:
- Phase I/II clinical study conducted in Japan.
- Evaluation of alectinib in patients with ALK-rearranged NSCLC.
Main Results:
- Alectinib demonstrated high activity and a favorable safety profile in crizotinib-naïve patients.
- Promising antitumor activity was observed in crizotinib-resistant patients, including those with CNS metastases.
- Alectinib targets resistance mutations like L1196M.
Conclusions:
- Alectinib is an effective treatment for ALK-positive advanced NSCLC, offering benefits for patients who have progressed on or are resistant to crizotinib.
- The development of resistance to alectinib necessitates ongoing research into new therapeutic strategies for ALK-rearranged NSCLC.
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