Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer

ABSTRACT

Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in ALK-positive NSCLC due to the positive results of recently published trials. Unfortunately, resistance inevitably occurs within the first year of treatment. Overcoming resistance is the major challenge in clinical oncology, and novel potent ALK inhibitors are currently under evaluation, including ceritinib. Ceritinib is an oral, potent, second-generation ALK inhibitor demonstrating activity in patients who develop resistance to crizotinib. Recent data also suggested efficacy in ALK-inhibitor-naive population, thus supporting investigation of the drug in front-line setting.

KEYWORDS:

• Ceritinib
• ALK positive NSCLC
• crizotinib
• ALK-inhibitor
• acquired resistance
• oncogene-addicted NSCLC

Financial & competing interests disclosure

F Cuppuzzo declares a consultancy/advisory role for Pfizer. 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.

Key issues

• ALK translocations identify a small group of NSCLC patients with certain clinical characteristics and exquisite sensitivity to ALK inhibitors.

• Crizotinib was the first ALK inhibitor licensed for treatment of ALK-positive NSCLC. Results of clinical trials clearly demonstrated the superiority of crizotinib over standard chemotherapy in both first- and second-line settings.

• Acquired resistance is the inevitable consequence of prolonged exposure to crizotinib, and it generally occurs within the first year of treatment. So far, different mechanisms responsible for acquired resistance have been identified.

• Molecular characterizations of ALK-positive NSCLC at crizotinib progression are crucial in order to understand the changes occurring within the tumor under therapy pressure.

• Ceritinib is a novel and more potent second-generation ALK inhibitor, showing activity in preclinical and clinical models of crizotinib-resistant NSCLC.

• Results of a large phase 1 trial clearly demonstrated that ceritinib produced marked and durable responses in patients with NSCLC refractory to crizotinib as well in those ALK-inhibitor-naïve. However, the majority of patients required dose reduction due to the onset of GI toxicity.

• Although RR could reasonably predict clinical benefit of targeted agents in NSCLC, further trials are currently ongoing in order to confirm the impact of ceritinib and the optimal timing of introducing the drug in the treatment algorithm of ALK-positive NSCLC.

• Additional data will be necessary in order to clarify some issues, including the safety profile of ceritinib, its efficacy in patients with brain metastases or with certain acquired mutations.