Alectinib: a selective, next-generation ALK inhibitor for treatment of ALK-rearranged non-small-cell lung cancer

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.

Keywords:

• alectinib
• anaplastic lymphoma kinase
• non-small-cell lung cancer
• personalized treatment

Financial & competing interests disclosure

Work in Dr Rosell’s laboratory is partially supported by a grant from Fundación La Caixa. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Anaplastic lymphoma kinase (ALK) rearrangements function as potent ‘oncogenic drivers’ and confer high sensitivity to therapeutic ALK kinase inhibition.

• Alectinib is a potent, selective and orally available ALK inhibitor, with a IC₅₀ for ALK activity of 1.9 nM.

• Alectinib has also been demonstrated to inhibit RET kinase activity and the growth of RET fusion-positive cells in vitro and in vivo.

• In contrast to crizotinib, alectinib also has substantial inhibitory activity against ALK with secondary resistance mutations, including the gatekeeper L1196M substitution, both in vitro and in vivo.

• The high potency and selectivity of alectinib is considered to be related to its unique benzo[b]carbazole scaffold that maintains a crucial hydrogen-bonding network even in the presence of ALK secondary mutations.

• In a Phase I/II first-in-human study (AF-001JP) conducted in Japan, alectinib was found to be highly effective and safe in crizotinib-naïve, ALK rearranged non-small-cell lung cancer (NSCLC) patients, with 93.5% of patients achieving an objective response.

• Results from the Phase I portion of the Phase I/II study (AF-002JG) conducted in the USA have demonstrated that alectinib was also highly active in ALK-rearranged NSCLC patients who progressed on or were intolerant to crizotinib. In this study, alectinib also showed promising activity in patients with CNS metastases at baseline. Phase II portion results from this study are awaited to further confirm the systemic and CNS activity of alectinib in this crizotinib-pretreated patient population.

• Based on this promising activity, the US FDA granted Breakthrough Therapy Designation for alectinib, which has been recently approved in Japan for ALK fusion gene-positive unresectable, advanced NSCLC.

• Phase II and III studies are ongoing to test alectinib in ALK rearranged NSCLC patients after crizotinib failure or as first-line treatment compared with crizotinib in treatment-naïve NSCLC patients.

• As with crizotinib, acquired resistance to alectinib may ultimately develop, limiting its efficacy. Secondary mutations in the ALK gene have been reported in tumor samples of patients or tumor cell lines resistant to alectinib, including ALK G1202R, V1180L and the I1171T mutation.

• Novel therapeutic strategies are needed to overcome resistance to next-generation ALK inhibitors.