Of 71 lung cancer patients in a trial who had never taken a ROS1-targeted drug, 56 (79%) responded to repotrectinib, and the response lasted at least 18 months. That result sits behind the Food and Drug Administration’s November 2023 approval of the drug, sold as Augtyro, for some advanced lung cancers that carry a ROS1 gene fusion.
The full trial results appeared in the New England Journal of Medicine on January 11, according to the National Cancer Institute.
Who the drug is for
A ROS1 fusion happens when part of the gene breaks off and attaches to another gene. The ROS1 protein that results is overly active, which drives uncontrolled cell growth and tumors. Up to 2% of people diagnosed with non-small cell lung cancer (NSCLC) have these fusions. They turn up mostly in people who have smoked little or never, though heavy smokers have them too.
The approval covers advanced or metastatic NSCLC with ROS1 fusions. Repotrectinib can be used first, or as a second-line treatment for patients who already took another ROS1-targeted drug. Patients take it as a capsule.
What the trial found
The trial, called TRIDENT-1, tested repotrectinib in people with advanced solid tumors. It included 127 participants with ROS1 fusion-positive lung cancer. Bristol Myers Squibb, which makes the drug, paid for it.
Among patients with no earlier ROS1-targeted treatment, the median time before the disease worsened was nearly 36 months. Among the 56 patients who had received crizotinib (Xalkori), entrectinib (Rozlytrek) or a similar drug, 21 (38%) responded, and their median progression-free survival was 9 months. A few patients in both groups saw their cancer disappear entirely.
Brain metastases are common in lung cancer, and the drug appeared to work there as well. Brain tumors shrank in 8 of 9 patients (89%) who had not been treated with a ROS1 drug before, and in 5 of 13 (38%) who had. For many of them the response held for at least a year.
Repotrectinib was also built to work against mutations that make crizotinib and entrectinib stop working. One of them is called G2032R. Ten of 17 participants (59%) whose tumors carried it responded.
“Repotrectinib can lead to long-term responses for patients with ROS1 fusion-positive lung cancers, including those who have and have not received prior targeted therapy,” said Alexander Drilon, M.D., of Memorial Sloan Kettering Cancer Center, who led the study. He added that repotrectinib appears to have the longest progression-free survival of the three approved ROS1-targeted therapies, and that it is the only approved option for patients who have already taken a ROS1 inhibitor.
Side effects
Dizziness was the most common treatment-related side effect. The researchers wrote that lowering the dose or pausing treatment for a time could manage it. Other common effects were a bad taste in the mouth (dysgeusia) and paresthesia, an abnormal burning or prickling sensation with no outside cause. Three percent of participants stopped the drug because of side effects.
Luis Raez, M.D., who directs the Thoracic Oncology Program at Memorial Cancer Institute in Florida and was involved in the study, said the drug “does not seem to have more side effects than other ROS1-targeted drugs,” even though it can overcome resistant mutations that they cannot.
Limits of the evidence
Dr. Raez pointed out that repotrectinib has not been compared head to head with other ROS1 drugs in a randomized phase 3 trial. The trial was also small, largely because ROS1-positive NSCLC is uncommon. Several experts said the next step is research to show doctors how best to use the different ROS1-targeted drugs in individual patients. Until then, Dr. Drilon said, oncologists should weigh how long responses last and how safe each drug is.
