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ROS1+ Non-Small Cell Lung Cancer: Entrectinib Shows Promise

Robert Doebele, MD, PhD. Credit: University of Colorado Cancer Center

Results have been strong for phase 1 and 2 clinical trials of entrectinib (RXDX-101), an orally available selective tyrosine kinase inhibitor, in treatment of patients with ROS1-positive non-small cell lung cancer (NSCLC).

A ROS1 rearrangement is a chromosomal abnormality where ROS1 has mutated so that it signals cells to continuously survive and multiply, thereby causing cancer. ROS1-positive NSCLC is a distinct molecular subset of NSCLC that occurs in 1% to 2% of lung cancer cases. Compared with other patients with lung cancer, those with ROS1-positive NSCLC tend to be younger at diagnosis, with a median age of 50.5 versus 72, and are more likely to be female (64.5%). ROS1-positive NSCLC occurs most frequently in never-smokers with adenocarcinoma who have an EGFR mutation and ALK receptor tyrosine kinase gene wild type.

In 53 ROS1-positive NSCLC patients, including patients with untreated and treated brain metastases at baseline, entrectinib led to a response rate of 77.4%, with a median response duration of 24.6 months. In the 20 patients with central nervous system (CNS) involvement, entrectinib produced a 55% response rate for brain metastases. The 30 patients with no brain metastases at baseline experienced a median progression-free survival of 26.3 months, compared with 13.6 months for those with initial brain metastases. These results were presented by researchers from the University of Colorado Cancer Center at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer.

"The data look very exciting. The hope is that entrectinib could replace crizotinib as a first-line therapy against ROS1-positive NSCLC," commented Robert C. Doebele, MD, PhD, director of the University of Colorado Cancer Center Thoracic Oncology Research Initiative and the clinical trials' principal investigator.

Entrectinib differs from crizotinib (Xalkori®, Pfizer), which is FDA-approved for some NSCLCs, in its powerful CNS activity. In contrast, crizotinib is typically unable to penetrate the blood-brain barrier. "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," explained Dr. Doebele. "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."

In a safety study involving 355 adult patients treated with a wide variety of solid tumors, entrectinib demonstrated tolerability with a manageable safety profile. Most patients reported only mild (grade 1 or 2) adverse events, including fatigue, dizziness, weight gain, nausea, constipation, and diarrhea. Thirty-one percent experienced grade 3 adverse events, and only 3.9% discontinued treatment.

The phase 1 trial is active but not recruiting. The phase 2 trial is still recruiting patients with various types of solid tumors harboring ROS1, ALK, and NTRK gene rearrangements.

According to Dr. Doebele, results thus far hold great promise: "This trial includes generally poorer-prognosis patients than in previous trials of ROS1-directed therapies, given the high percentage of patients with brain metastases and the inclusion of patients with an ECOG [Eastern Cooperative Oncology Group] performance status of 2. And yet despite treating a sicker population, entrectinib results remain very competitive with those of previous trials."

For More Information

Clinicaltrials.gov (2018). Study of oral RXDX-101 in adult patients with locally advanced or metastatic cancer targeting NTRK1, NTRK2, NTRK3, ROS1, or ALK molecular alterations. (STARTRK-1). NLM identifier: NCT02097810.

Clinicaltrials.gov (2018). Basket study of entrectinib (RXDX-101) for the treatment of patients with solid tumors harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK gene rearrangements (fusions) (STARTRK-2). NLM identifier: NCT02568267.

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