TRK Fusion Inhibitors in Clinical Practice

Mark Socinski, MD: Dr Patel, you I think said early on that you had a handful of these patients with NTRK fusion-positive lung cancer. I wonder if you could tell us about your experience.

Jyoti Patel, MD, FASCO: Primarily, I am prescribing more larotrectinib, but that is primarily because of my familiarity with the trial. I am also using a lot of entrectinib to treat patients with ROS1 fusions. There are different types, but I am looking at the toxicity profile. These drugs are well tolerated, as Ben mentioned. There is perhaps a little more fluid retention for patients who take entrectinib, but generally our patients have done really well. One thing that is interesting is how quickly we have understood resistance in these patients; researchers identified where resistance would develop even before it was clinically detected for larotrectinib. It may be that most patients have a good duration of response, but for patients who do develop resistance, it will be interesting in the long run to see if there are any differences in the mutational profiles of patients taking larotrectinib and those taking entrectinib.

Mark Socinski, MD: Going back to Jonathan, I think Jonathan raised some of those issues regarding resistance. I wonder if you could give us your comments on what you have seen in the sarcoma population, in terms of the acquired resistance to these agents.

Jonathan Trent, MD, PhD: I have really only found 1 patient so far who has acquired resistance, and that seemed to be the result of a mutation in the ATP [adenosine triphosphate] binding pocket of the kinase. This is similar to what we have seen in patients with KIT mutations and patients with GISTs [gastrointestinal stromal tumors] who become resistant to imatinib. That is the only patient with acquired resistance I have seen. It is going to be interesting to see whether newer agents, newer generations of TRK inhibitors can overcome this type of resistance.

Mark Socinski, MD: I will open it up to the panel. Is there anything we have not discussed in the NTRK space that we should mention to our audience? I cannot think of anything off the top of my head, but I will give people a moment. If something comes to mind before we transition to our next session, please say so. I think it is important for our audience to remember that this should be on our list of biomarkers that are routinely tested. It is seen across a broad base of solid tumors. We talked about many of them here today, but again, they should be on the list, and you should know the NTRK status of all your patients. Remember it is the fusions we want to identify and not necessarily the mutations.

Jyoti Patel, MD, FASCO: I would add one thing. Ben mentioned that many of these patients have a proclivity for developing CNS [central nervous system] metastasis. Certainly, NTRK, when it was first presented, was presented with CNS data. Larotrectinib also has CNS data available. Many of these patients will do well for a long time, and so when I am able, I always prioritize a TKI [tyrosine kinase inhibitor] before brain-directed therapy. I think with radiation, the cognitive and quality-of-life deficits, over time, can certainly add up for these patients. Again, understanding the mutation status is important; if you have the time to wait a little longer until you have that firmed up, I think that has implications for how they do.

Mark Socinski, MD: When treating lung cancer historically, we have had the reflex of pursuing radiotherapy initially. I think we now know that in many of these oncogenic driver subsets, these TKIs can be highly effective. Is the issue of brain metastases a lung cancer issue? I’ll ask Lori and Jonathan to weigh in. Is there something specific about NTRK across all tumors? We in the lung cancer field are used to having a high incidence, particularly in many driver situations, ALK is like the poster child, for the most part, of brain metastases. Is it true? Are you seeing that in other populations with these drivers, or is it mostly more of a lung cancer phenomenon?

Lori Wirth, MD: We see brain metastases in patients with advanced thyroid cancers. Anaplastic thyroid cancer goes anywhere, including the brain, and so we routinely rule out brain metastases in all patients with newly diagnosed anaplastic thyroid cancer. For patients with other advanced thyroid cancers—differentiated thyroid cancer or poorly differentiated thyroid cancer, medullary thyroid cancer—we see about 10% of patients harboring brain metastases. I do not know that we see them more commonly with the NTRK- or RET-fusion driven cancers. But I think it is an underappreciated phenomenon. I now, knowing that, routinely rule out brain metastases in all patients with advanced thyroid cancer who need systemic therapy.

Mark Socinski, MD: Jonathan, what are your thoughts?

Jonathan Trent, MD, PhD: It is an important topic. If you consider sarcomas in general, we rarely see brain metastases. Less than a fraction of a percentage of patients will ever get brain metastases. However, each subset is different; for instance, when considering patients with TFE-translocated alveolar soft part sarcoma, some people would say 100% of patients will eventually develop brain metastases. It is very common in that entity. Every patient gets an MRI of the brain at diagnosis. With the other sarcomas, it is so rare that we do not generally do a brain scan. It is not surprising that, in the presentation at the CTOS [Connective Tissue Oncology Society] conference in 2020 given by Sant P. Chawla, MD, which addressed the sarcoma subset from the larotrectinib trial, there were not any patients who had brain metastases in that study.

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