Ceritinib for Patients ALK+ NSCLC With Brain Metastases

In patients with ALK+ non-small cell lung cancer (NSCLC), crizotinib proves to be of favorable efficacy. However, many patients still experience disease activity in the brain or primary site, often due to resistance or lack of activity. 

Therefore, Laura Q. M. Chow, MD, FRCPC, Professor and Associate Chair of Education, Department of Oncology, Dell Medical School, The University of Texas at Austin, and colleagues conducted the ASCEND-7 trial to examine the intracranial effects of ceritinib in patients with ALK-positive NSCLC.

“Early studies with ceritinib and other later-generation ALK inhibitors had demonstrated intracranial activity and reduction in lesions metastatic to the brain, but there was limited formal evaluation of the activity in the brain and no dedicated trial or trial design to evaluate this for targeted agents,” explained Dr Chow.

Although other studies have reported intracranial brain activity, ASCEND-7 is the first documented study to examine the brain activity of a targeted agent in NSCLC. The study included MRIs of all patients and enrolled only those with active brain metastasis.

The ASCEND-7 Phase 2 Study 

The ASCEND-7 study aimed to evaluate the efficacy and safety of oral ceritinib only in patients with ALK-positive NSCLC and active brain metastases. 

Researchers examined whole-body end points—overall response rate (ORR), time to tumor response (TTR), duration of response (DOR), and progression-free survival (PFS)—as well as intracranial responses and extracranial responses.

Results showed durable responses with ceritinib demonstrating activity across all whole-body end points consistent with its known efficacy established in patients with ALK-positive NSCLC with or without brain metastases, crizotinib-pretreated or not. 

Not only did ceritinib yield durable intracranial response across all study arms, but it also worked quickly - with responses evident by two months of therapy. Furthermore, ALK inhibitor naive patients had a higher intracranial response, although the intracranial disease control rate was high across all arms.

According to Dr Chow, there were dose reductions and dose interruptions due to gastrointestinal toxicities for patients treated with ceritinib at 750 mg once daily. The dose adjustments and interruptions were in line with the rest of the ASCEND studies with a ceritinib 750 mg fasted dose. However, a 450-mg fed state proved equivalent to the 750=mg fasted dose and should yield similar activity in the brain with better tolerability. Furthermore, ceritinib did not raise any new or unexpected safety concerns were observed in this study. 

“Based on these data confirming the activity and penetration of ceritinib through the blood-brain barrier into the brain to elicit responses and improve disease control rates and progression-free survival, ceritinib would be ideally an excellent choice for use in patients in ALK-positive NSCLC as first-line therapy or preferential therapy in those who have brain metastases,” explained Dr Chow.

She also mentions that European guidelines now indicate that patients with brain metastases with ALK-positive NSCLC should consider targeted therapy up-front.

Expanding Research with Ceritinib

ASCEND-7 established a basis and design for formally assessing the intracranial activity for all targeted therapies in NSCLC and will be essential for all future studies which assess the formal intracranial activity of targeted agents in NSCLC.

Dr Chow mentions that there are plans to use this design to assess other targeted therapies and their effects on the brain and central nervous system.