Entrectinib Active in ROS1-Positive Non–Small-Cell Lung Cancer and Brain Metastases

Entrectinib, a new selective tyro­­sine kinase inhibitor, achieved high response rates as well as durable responses in patients with ROS1 mutation–positive non–small-cell lung cancer (NSCLC), including patients with brain metastases, according to a pooled analysis of phase 1 and 2 trials.

“The data look very exciting. Clinically meaningful, deep, and durable responses were observed, including in patients with baseline brain metastases. The hope is that entrectinib can replace crizotinib [Xalkori] as a first-line therapy against ROS1-positive NSCLC,” said lead investigator Robert C. Doebele, MD, PhD, Director, Thoracic Oncology Research Initiative, University of Colorado Cancer Center, Aurora. He presented the study results at the 2018 International Association for the Study of Lung Cancer World Conference on Lung Cancer.

ROS1 mutation–positive lung cancer, for which crizotinib is the first-line treatment, accounts for approximately 1% to 2% of all NSCLC.

Entrectinib, which is an oral, selective inhibitor of ROS1, NTRK, and ALK mutations, is more potent than crizotinib.

In contrast to crizotinib, entrectinib is central nervous system (CNS)-penetrant. Other ROS1 inhibitors being developed include repotrectinib, which is designed to target the G2032R mutation, and lorlatinib, which is a third-generation CNS-penetrant agent.

Brain metastasis is common in treatment-naïve stage IV NSCLC and is the most common site of first progression in patients with ROS1-positive NSCLC. Approximately 50% of patients whose disease progresses with crizotinib have brain metastases.

“We believe patients with ROS1-positive NSCLC may benefit from more potent ROS1 inhibitors that are central nervous system–penetrant, such as entrectinib, in the first-line setting,” said Dr Doebele at his presentation.

Pooled Analysis of Data from 3 Trials

An integrated analysis of 53 patients with ROS1-positive NSCLC from 3 different clinical trials of entrectinib was conducted, including the phase 2 STARTRK-2 clinical trial (N = 37), and the phase 1 trials STARTRK-1 (N = 7) and ALKA-372-001 (N = 9). The patients were recruited from 150 sites in 15 countries.

“The vast majority of patients in these trials had evidence of tumor regression,” Dr Doebele stated.

The objective response rate was 77.4% for the 53 patients who were evaluable for response, and the me­dian duration of response was 24.6 months. A total of 20 (37%) patients who were enrolled in the pooled-­analysis trial had brain metastases; intracranial response in these patients was 55%, with a median duration of intracranial response of 12.9 months.

At a median follow-up of 15.5 months, the median progression-free survival (PFS) was 19 months. The median PFS was 26.3 months in patients who did not have brain metastases at baseline and 13.6 months if baseline brain metastases were present.

The overall survival results are immature, and the median follow-up is 15.5 months. A total of 9 (17%) deaths were reported from all 3 trials.

The patients who received entrectinib had manageable toxicity. Only 3.9% of patients discontinued the drug because of adverse events. The treatment-related adverse events led to dose reduction in 27.3% of patients and resulted in dose interruption in 25.4% of patients. The rate of serious adverse events was 8.5%, and there were no grade 5 adverse events.

“Previous drugs targeting ROS1, such as crizotinib, have poor CNS penetration and therefore can allow disease progression in the brain even before the cancer becomes resistant to the drug. For these patients, we’ve been using targeted radiation and other strategies to try to control brain metastases while continuing to target ROS1 in the body. We are hopeful that entrectinib will help us control many cases of ROS1-positive cancer in the body and the brain,” Dr Doebele stated in a news release from the University of Colorado.

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