Clinical Trials Shows That Entrectinib Performs Well In ROS1 And NTRK Gene Driven Non-Small Cell Lung Cancers
Source: Thailand Medical News Dec 14, 2019 4 years, 11 months, 1 week, 4 hours, 29 minutes ago
Combined analysis of three phase 1 and 2 clinical trials published online ahead of print in the journal Lancet Oncology show that the drug
entrectinib is effective and well-tolerated against advanced
ROS1 and
NTRK fusion-positive
non-small cell lung cancers (
NSCLC). Results of the trials STARTRK-1 (NCT02097810), STARTRK-2 (NCT02568267), and ALKA, show 77 percent response rate to
entrectinib in 53 patients with ROS1+
NSCLC, with a median progression-free survival of 19 months and a median duration of response of 24.6 months. In 54 patients with
NTRK+
NSCLC, 57 percent responded to
entrectinib, with a median progression-free survival of 11.2 months and a median duration of response of 10.4 months. Based on the early promise of these trials, in August 2019 the U.S. Food and Drug Administration granted
entrectinib accelerated approval for the treatment of metastatic
ROS1+
NSCLC and for advanced tumors across cancer types defined by
NTRK fusion. The current journal articles update these findings that led to approval.
Dr Robert C. Doebele, MD, Ph.D., director of the University of Colorado Cancer Center Thoracic Oncology Research Initiative, senior author on the
ROS1 study, and first author on the
NTRK study told
Thailand Medical News, "For a drug to get simultaneous approval for use against two different targets is somewhat unique. I don't know of this ever happening before."
Around 2 percent of
lung cancers are driven by the improper fusion of the gene
ROS1 with one of a handful of possible genetic partners, resulting in a cancer-causing
ROS1 fusion gene. About 1 percent of all solid tumors, including but not limited to
lung cancers, are similarly caused by
NTRK fusion genes. The FDA-approved drug crizotinib can silence the action of
ROS1 fusion genes in some cases, but can't reach cancers that have metastasized to the brain. And, unfortunately, 36 percent of patients with
ROS1+
NSCLC already have brain metastases at the time of advanced disease diagnosis, and many more will go on to develop brain metastases during the course of care.
Dr Doebele added, "For
ROS1+
lung cancer,
entrectinib represents a new and better standard of care due to
entrectinib's effectiveness against
ROS1 in the body and especially due to its activity against
ROS1+ brain metastases. For
NTRK cancers, the picture is a little more complex and I think it depends on an
NTRK+ can
cer's chance of developing brain metastases. Personally, if I were a patient and felt there was any chance of me getting brain mets, I would want this brain-penetrating drug."
Also included in these phase 1 or 2 studies were adults with locally advanced or metastatic
ROS1+ or
NTRK+
NSCLC who had received previous treatment not including other
ROS1 inhibitors. Patients received
entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months follow-up. Doebele describes the drug as "well tolerated with a manageable safety profile," with side effects including weight increase (8%) and neutropenia (4%). Eleven percent of patients had serious treatment-related adverse events, the most common of which were nervous system disorders (3%) and cardiac disorders (2%). No treatment-related deaths occurred.
Dr Doebele concluded, “The genes
ROS1 and
NTRK are on a growing list of known genetic drivers of non-small cell lung cancer. In addition to showing the benefit of
entrectinib against cancers caused by these fusion genes, these results highlight the importance of genetic testing in
NSCLC, especially when patients are diagnosed with the condition in the absence of other risk factors. Only by testing for genes like
ROS1 and
NTRK can we match these genetic drivers of
cancer with drugs like
entrectinib."
Reference : Ulrik Lassen, Entrectinib for ROS1 fusion-positive NSCLC and NTRK fusion-positive solid tumours, The Lancet Oncology (2019). DOI: 10.1016/S1470-2045(19)30789-2
