<p>For the treatment of patients with non–small cell lung cancer (NSCLC) with ROS1 translocations, there are many drugs with positive response rates and extended durations of response. However, the tolerability of ROS1 TKI therapies can vary quite a bit for each individual patient, so the choice of therapy should be highly personalized.</p>

For patients with newly diagnosed ROS1-positive (ROS1+) NSCLC, choosing an initial therapy can be complicated, and I have to look at response rates, durability of response, and tolerability. ROS1 TKIs with multikinase activity are often associated with off-target adverse effects. For example, crizotinib has activity against ALK and MET in addition to ROS1, which means that it can be used for NSCLC with all of those alterations, but the multikinase activity may also contribute to edema and visual changes. Cabozantinib, another multikinase inhibitor and one of the earlier ROS1 inhibitors to be developed, is associated with a lot of toxicity, especially gut toxicity and edema, but it can be tolerated by some patients and can be very effective in later lines. Finally, lorlatinib also targets ROS1 and is active against ALK, but it can be associated with edema, hyperlipidemia, and mental status changes such as depression.

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Newer ROS1 inhibitors such as repotrectinib and taletrectinib penetrate the brain so well that we are seeing more central nervous system adverse effects, including dizziness and, occasionally, altered mental status (eg, depression or, very rarely, psychosis). We also have to watch for gastrointestinal toxicities, and neuropathies can be an issue as well. At the same time, these drugs are some of the most potent treatment options, with very high response rates and long durations of response. Thus, they are now the preferred first-line choices. Other novel medications are in development as well.

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I think that talking through the likelihood of a drug working, how long it might work, and its potential toxicities with patients can help them be part of the decision making. A patient with advanced ROS1+ NSCLC who has a history of mental illness may be much more afraid of the central nervous system penetration of the newer drugs and whether they might exacerbate their mental illness. Others may be unable to tolerate neuropathies that could affect their ability to work or their hobbies, or they may be worried about edema or gastrointestinal toxicity. We do not have a way to know which toxicities a patient is going to have, so part of finding a drug that a patient can tolerate is trial and error.

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Moreover, I think that if one of these agents triggers mental illness in a patient with advanced ROS1+ NSCLC who has a history of serious mental illness, it can sometimes be more immediately life-threatening than the cancer itself. Even though having active cancer in the brain is far worse than having some degree of dizziness or some mild depression for most people, it is all relative, and these risks have to be put into the context of an individual patient to help make the best choice for that patient and to be able to adapt based on the toxicities that develop. As medical oncologists, we are used to recognizing the physical side effects and some of the mental health issues that can come with having a cancer diagnosis. However, for some patients, it is also important to be mindful of novel mental health complications and to have a plan to work with partners, such as a psychiatrist for mental health issues or a dermatologist for skin toxicity. Frequent check-ins are essential as a patient starts treatment to monitor for emerging toxicities and to be aware of how much those can vary across patients.