TRK Fusion Inhibitors in Tumor-Agnostic Clinical Trials

Mark Socinski, MD: I want to turn to Jonathan. Ben gave us a nice overview of larotrectinib, but do you have any other comments with regard to the clinical development of larotrectinib and other end points that might be of interest?

Jonathan Trent, MD, PhD: Larotrectinib certainly is the first NRTK inhibitor that was studied. It has been studied in a number of studies, and researchers have looked at many subsets in this entity. One of the subsets that has been looked at is the sarcoma subset. As I mentioned, in the subset, the most common histology was spindle cell sarcoma or undifferentiated pleomorphic sarcoma. That number makes up a third of the sarcoma patients that have TRK, or adult patients that have TRK trans-locations.

Other patients with different sarcoma subtypes can also harbor these mutations. These subtypes include GISTs [gastrointestinal stromal tumors], MPNSTs [malignant peripheral nerve sheath tumors], chondrosarcomas, and angiosarcomas. We generally have to be on the lookout for the NRTK trans-locations in all our patients with sarcoma. We have treated patients who participated in the larotrectinib study, but entrectinib is equal as active as far as we can tell in patients with sarcoma. I cannot really say if 1 is more appropriate than the other in a given situation, although they seem to be equivalent or reasonably equivalent from the available sarcoma data.

Mark Socinski, MD: What has your experience been like, assuming you have used larotrectinib and entrectinib, in terms of their adverse-effect profile? Do you see any major differences or any issues with this class of drugs?

Jonathan Trent, MD, PhD: I have the most experience with larotrectinib. In my patients with sarcoma, I have not really seen any marked toxicity problems that would preclude me from prescribing either of these medicines. They are both very well tolerated, and we use a lot of TKIs [tyrosine kinase inhibitors] because of my patients with GISTs, who make up about a third of my practice. They are on imatinib, sunitinib, regorafenib, and ripretinib and participate in clinical trials.

We are really used to managing the side effects, so our patients seem to tolerate it pretty well. We aggressively manage the adverse effects. You have to realize that most of our patients with sarcoma had high-doses of doxorubicin or ifosfamide. Some of them have had high doses of methotrexate, so they are moving from this high-dose chemotherapy in certain situations to this treatment, and they tolerate it really reasonably well.

Mark Socinski, MD: Lori, what has your experience been like when treating thyroid, head, and neck cancer to date with these 2 agents?

Lori Wirth, MD: I have not encountered any NRTK fusions in our patients with head and neck cancer with squamous cell carcinoma. In the secretory carcinomas that arise in the salivary glands, we identify them because we are testing. Our surgical pathology group will often do our fusion panel as part of diagnostic testing for salivary gland tumors, and they also look for thyroid cancers. We will often identify these tumors, but they tend to be fairly well behaved. Often, they are treated with surgery. They may have adjuvant radiation but do not need systemic therapy. We have a number of patients with thyroid cancer who have been enrolled in the larotrectinib and entrectinib trials. There certainly is activity. However, my go-to drug to treat my patients with thyroid cancer is larotrectinib at this point. It is just because there are more patients who have been enrolled in the larotrectinib trials with thyroid cancer.

Overall, there were 28 patients with thyroid cancer who have been reported who have received larotrectinib. Maria Cabanillas presented that data at ESMO [European Society for Medical Oncology Congress]. In differentiated thyroid cancer, there is a 90% overall response rate with larotrectinib. How can you not offer it? We do not see quite as high a response rate with anaplastic thyroid cancer, unfortunately. I cannot remember the exact number of patients with anaplastic thyroid cancer treated, but the response rate in those patients was 29%.

One of the other really nifty things with larotrectinib and NRTK-fusion cancers—there was a case report recently in the New England Journal of Medicine on a patient treated in France with larotrectinib harboring an NRTK fusion who had iodine-refractory, widely metastatic, papillary thyroid cancer. They did a whole body radioactive iodine scan in this patient, who was on larotrectinib. They found that, on larotrectinib, the patient was converted from being iodine refractory—they did not take up any radioactive iodine—to taking up radioactive iodine. This suggests that if we block the regulated pathways with an NRTK inhibitor in these patients with NRTK fusion, we may be able to redifferentiate those patients and treat them with a combination of drugs, like larotrectinib and radioactive iodine. You are going to be seeing more case reports emerge along those lines in the future.

Mark Socinski, MD: That is interesting.

Lori Wirth, MD: It is nifty.

Mark Socinski, MD: Has that been a one-off experience to date in this setting? Have there been others?

Lori Wirth, MD: There is a submitted paper, but it is not in print. I have a couple of off-label patients whom I am hoping to treat. I have success, and then I write up their case reports. But unfortunately this is a setting where, right now, it is very difficult to do a clinical trial because of the rarity of the patients and the expense. We would need to do a trial with numerous centers even to get a small number of patients. It is a real challenge in that regard because of feasibility issues.

Mark Socinski, MD: In your sense, you have heard the others weigh in. They have compared and contrasted larotrectinib and entrectinib. Again, I use the Coke and Pepsi analogy. Is that your position?

Lori Wirth, MD: In thyroid cancer treatment, there were so many more patients treated in the larotrectinib trial. We have more robust data. We have experience with entrectinib, including a patient of mine who is enrolled in the trial, but it is such a small handful of patients. It is a big glass of Coke and a smaller glass of Pepsi, perhaps. I do not know if that matters.

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