Lizza E. Hendriks, MD, PhD

Formal discussant of the ASCEND-7 trial, Lizza E. Hendriks, MD, PhD, of the Maastricht University Medical Center, The Netherlands, said that up to 50% of patients with non–small cell lung cancer (NSCLC) will develop central nervous system (CNS) metastases, and these patients can have poor quality of life and increased health-care costs. Thus, controlling disease progression to the brain is an important goal.

“It is important to know whether we can predict who will develop CNS metastases and thus develop preventive treatments,” Dr. Hendriks said. Factors known to be associated with the development of brain metastases include adenocarcinoma histology, younger age, female sex, and epigenetic alterations.

“Somatic mutations are not associated with CNS metastasis, but several methylation patterns are,” Dr. Hendriks noted. “According to Dr. Fan’s data, 6 independent methylation blocks could differentiate patients with and without CNS metastases in this small series of patients. This work deserves further study, especially whether these methylation blocks can also predict which patients will develop CNS metastases in the future.”

Additional Comments on ASCEND-7

Turning to the ceritinib study, ASCEND-7 showed that penetration of the blood-brain barrier is important in treating patients with NSCLC who have brain metastases. “Disease control rates were high in all treatment arms, and the duration of response, including intracranial response, was substantial. Ceritinib performed as expected, and the trial was well executed,” continued Dr. Hendriks.

“We now know from ASCEND-8 that ceritinib should be taken at 450 mg/d with food, which is better tolerated than the original regimen of 750 mg/d without food. This revised dosing regimen will reduce toxicity associated with ceritinib,” she noted.

Additional trials are needed to optimize the sequence of treatment in patients with NSCLC and brain metastases, including more CNS-specific tyrosine kinase inhibitor trials and studies of concurrent tyrosine kinase inhibitors plus radiation therapy. “It is difficult to compare next-generation tyrosine kinase inhibitors in the absence of head-to-head comparisons, but in general, all appear to be effective in the brain, with a good duration of response,” Dr. Hendriks mentioned. ■

DISCLOSURE: Dr. Hendriks has received research funding from AstraZeneca (institution), Boehringer Ingelheim, and Roche; served on advisory boards for Boehringer, Bristol-Myers Squibb (BMS), and Lilly (institution); has received travel reimbursement from BMS and Roche; has participated in a mentorship program funded by AstraZeneca; and has received fees for educational webinars from Quadia.