ROS1 Rearrangements in mNSCLC


Jonathan W. Riess, MD: There are a couple of things to keep in mind when looking at the prevalence and natural history of ROS1 rearranged non–small cell lung cancer. The prevalence of ROS1 is about 1.5% to 2% of non–small cell lung cancer adenocarcinoma histology. It is predominantly adenocarcinoma histology and occurs in patients who have never smoked or have a light smoking history, whose age tends to skew younger. They tend to be metastatic, and like with many oncogene-driven lung cancers, there can be a propensity for CNS (central nervous system) metastatic disease.

The prognosis for these patients is generally better than the overall population because we have good targeted therapies we can bring to bear. Crizotinib has been the most extensively studied. It is also an ALK inhibitor, as well as an ROS1inhibitor. It was initially developed as a MET inhibitor. In the most known clinical trial, which was published in The New England Journal of Medicine, response rates were about 70%, with median progression-free survival a bit over 19 months, so it was highly clinically active.

In other studies with crizotinib, progression-free survival was a bit less but still highly active for well over a year. There is entrectinib, which is an ALK and NTRK inhibitor but recently approved for ROS1. Its duration of response in an analysis of patients with ROS1 rearrangement treated in multiple clinical trials with entrectinib was over 20 months. There is also a drug, ceritinib, which is approved as an ALK inhibitor. It's not quite as active as alectinib or brigatinib, and it does have more of a toxicity profile. It does have some activity in ROS1 as well, although it is unclear whether it has any benefit over crizotinib or entrectinib and may have less activity in ROS1 compared with ALK. There are newer drugs that have been studied with activities, such as lorlatinib and repotrectinib. For practicing clinicians, a common question I get is: Can you use alectinib for ROS1 because it's a potent ALK inhibitor? The answer is no.

Alectinib is an ALK inhibitor, and it has some RET inhibitory activity but has no ROS1 inhibitory activity. That's a question I get sometimes. There is a spectrum of drugs in development for this uncommon mutation, but one that we detect frequently in patients who have never smoked or have a light smoking history.

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