NTRK Gene Fusions in NSCLC

Jonathan W. Riess, MD: In terms of NTRK gene fusions in non–small cell lung cancer, as well as its incidence, natural history, and prognosis, NTRK fusions are really rare. Previously, we talked about ROS1 being about 1.5% to 2% of non–small cell lung cancer. NTRK is probably a lot lower, 0.2%, so infrequent. There is a higher frequency in other tumor types and certain salivary gland tumors.

The good thing about finding an NTRK fusion is that when you find it, you have great drugs that are approved with larotrectinib and entrectinib. The TRK family is a kinase domain with a lot of sequence homology, and its standard function is to play a role in neurite outgrowth, pain, and sensory modulation. It’s a low frequency, but 1 of the advantages with raw genomic profiling is that when you find it, you have great drugs you can match to it.

Lyudmila A. Bazhenova, MD: NCCN [National Comprehensive Cancer Network] Guidelines currently list 2 agents that are appropriate for NTRK-rearranged cancers, lung cancers, and others. Those are larotrectinib and entrectinib.

Balazs Halmos, MD: When talking about NTRK–fusion-positive lung cancers, we need to remind ourselves that the tissue-agnostic FDA approval of both larotrectinib and entrectinib NTRK fusions occurs very rarely in many common cancers, including lung cancers, and can occur very commonly in some fairly rare cancers. That includes a number of pediatric malignancies but also certain salivary gland cancers and breast cancers, very specifically the secretory type of breast and salivary gland cancers. Their NTRK fusions are practically pathognomonic, occurring in almost 100% of patients.

In lung cancer per se, NTRK fusions occur maybe in just 0.3%, but in any NTRK–fusion-positive cancer, the presence of this fusion indicates a very high likelihood of response and durable response to these NTRK inhibitors. Identifying these patients is very important. They are a small number, so we have to identify them. When we find them, it benefits these patients so much. I don’t think any of us would want to lose the opportunity for our patients to derive the benefit. This is the beauty of the next-generation sequencing platforms. In just 1 setting, we’d run tests. You can do comprehensive testing. You’re not necessarily looking for NTRK. You’re looking at the overall makeup of the cancer and using that to guide your treatment. If it includes NTRK, and it should, then you’ll be able to identify the NTRK-positive patients and offer them highly effective treatment.

Both larotrectinib and entrectinib seem to have response rates that are very high, 80% or something in that range, with very durable responses. As I mentioned, these are highly tolerable agents that match the need for high quality of life for patients who have survived many years after proper identification of their actionable targets. It’s very important, especially for these patients who will have long survival, to use agents that provide a good quality of life. These drugs do for the majority of patients. As I mentioned beforehand, there are some adverse effects to remember. Besides some organ toxicities that are rare, you want to watch out for liver toxicity. The neurological toxicity very specifically stands out as a class effect of TRK inhibitors. We spoke about it a little beforehand in terms of neuropathies, dizziness, potentially syncopal episodes, polyphagia, weight gain; these are very specific adverse effects that you can see. Rarely is there a significant need for dose reductions, and it is unlikely to guide us in stopping the management of these patients. We should be able to come up with a schedule that patients should tolerate over the long term.

The reality is that both these molecules are highly potent and active in the clinic. I have a very hard time separating them in terms of seeing major benefit with one over the other. We’re lucky to have 2 excellent molecules on the market for our patients. The toxicities seem similar as well, so I cannot pick a champion here. Maybe others can. I’m just glad we have these excellent drugs available to our patients.

Transcript Edited for Clarity