Promising phase 1/2 results for entrectinib against ROS1+ non-small cell lung cancer

Robert C. Doebele, MD, PhD

Results of an ongoing global phase II clinical trial of the drug entrectinib against ROS1-positive non-small cell lung cancer (NSCLC) will be presented October 18 at the International Association for the Study of Lung Cancer’s 18th World Conference on Lung Cancer in Yokohama, Japan. As of May 2017, 32 patients were evaluable for response. At a median follow-up of 12 months, 75 percent of patients responded to the drug, including 7 of 11 patients whose disease had metastasized to the brain or elsewhere in the central nervous system. At the time of evaluation, 19 of these 32 patients continued to experience disease control and remained on study. Data from these continuing responders will eventually increase the calculation of progression-free survival, which was seen at this midpoint to be 19.1 months. These data will be updated at the time of presentation.

“In 2016, the drug crizotinib earned FDA approval to treat patients with ROS1-positive non-small cell lung cancer, and now we see very promising results for this potent, CNS-active ROS1 inhibitor, entrectinib,” says Robert C. Doebele, MD, PhD, investigator at the University of Colorado Cancer Center, associate professor of Medical Oncology at the CU School of Medicine, and the trial’s primary investigator.

In fact, laboratory work shows that entrectinib is about 30 times more potent than crizotinib in inhibiting the action of ROS1. The study calls entrectinib “well tolerated” reporting mild (grade 1 or 2) side effects including fatigue, dizziness, weight increase, nausea, constipation and diarrhea.

Importantly, entrectinib can penetrate the blood-brain barrier to act against metastasis of ROS1+ NSCLC in the central nervous system.

“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+ cancer in both the body and the brain,” Doebele says.

ROS1 is a protein called a tyrosine kinase that acts as a kind of on-off switch for various cell functions; in this case ROS1 is altered to continuously signal cells to improperly grow, spread and survive, making the cells act cancerous. ROS1 rearrangements are found in approximately 1-2 percent of lung cancer patients, the majority of whom have never smoked.

The global phase II clinical trial (NCT02568267) continues to enroll patients with solid tumors harboring not only ROS1 rearrangements, but also NTRK rearrangements.

 

About the author: Garth Sundem

In addition to writing for the University of Colorado Cancer Center, Garth is the author of the books The Geeks' Guide to World Domination, Brain Candy, and Geek Logik. Contact him at garth.sundem [at] ucdenver.edu.

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