Entrectinib Encouraging in ROS1-Positive NSCLC

Best Practices in Lung Cancer – November 2018 Vol 9 —November 29, 2018

Entrectinib achieved high response rates as well as durable responses in patients with ROS1-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 as a first-line therapy against ROS1-positive NSCLC,” said lead author Robert Doebele, MD, PhD, University of Colorado, Aurora, CO, who presented study results at the IASLC 19th World Conference on Lung Cancer.

ROS1-mutated lung cancer accounts for about 1% to 2% of all NSCLC. First-line treatment is crizotinib. Entrectinib, an oral, selective inhibitor of ROS1/NTRK/ALK, is more potent than crizotinib. In contrast to crizotinib, entrectinib is central nervous system (CNS)-penetrant. Other ROS1 inhibitors under development include repotrectinib, designed to target the G2032R mutation, and lorlatinib, a third-generation agent that is also CNS-penetrant.

Brain metastasis is common in treatment-naive stage IV NSCLC and is the most common site of first progression in ROS1-positive NSCLC. About 50% of patients who progress on crizotinib have brain metastases.

“We believe patients with ROS1-positive NSCLC may benefit from more potent ROS1 inhibitors that are CNS-penetrant, such as entrectinib, in the first-line setting,” he told the audience.

Pooled Analysis

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

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

The objective response rate was 77.4% for the 53 patients evaluable for response, and the median duration of response was 24.6 months. Twenty patients (37%) enrolled in the 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, median progression-free survival was 19 months. Median progression-free survival was 26.3 months in patients free of brain metastasis at baseline and 13.6 months if baseline brain metastasis was present.

Overall survival is immature, with a median follow-up of 15.5 months. Nine (17%) deaths were reported from the 3 trials.

Entrectinib appeared to have manageable toxicity. Only 3.9% of patients discontinued the drug due to adverse events. Treatment-related adverse events led to dose reduction in 27.3% and dose interruption in 25.4%. The rate of serious adverse events was 8.5%. 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 have 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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