Hong Discusses Larotrectinib Efficacy in Thyroid Cancer

David S. Hong, MD

Patients withNTRKfusions who have been treated with larotrectinib (Vitrakvi) have seen significant benefits with the TRK inhibitor. As the agent moves into the community setting, the goal is to best identify which patients fit into this select group, said David S. Hong, MD.

The agent gained FDA approval in November for the treatment of adult and pediatric patients with solid tumors that have anNTRKgene fusion without a known acquired resistance mutation, who are metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or have progressed following treatment. The approval was made based on findings from patients withTRK-positive tumors enrolled across 3 clinical trials, including a phase I adult trial (LOXO-TRK-14001), the phase II NAVIGATE trial, and the phase I/II SCOUT pediatric trial.

Results published in theNew England Journal of Medicinein February 2018 showed larotrectinib induced an objective response rate of 75% by independent review and 80% by investigator assessment in 55 evaluable patients. Patients enrolled across the 3 trials spanned a variety of tumor types, including thyroid cancer.

“Having treated many of these patients with a TRK inhibitor like larotrectinib, you don't forget when a patient has anNTRKfusion and you treat these patients with a drug because the responses are so profound. You don't forget that patient, you don't forget that drug,” Hong said. “My hope is that we will have a thoughtful and a concerted effort as these drugs go into the community to try to identify these patients.”

In an interview withTargeted Oncology, Hong, department of investigational therapeutics, division of cancer medicine, The University of Texas MD Anderson Cancer Center, discussed the use of larotrectinib in patients with thyroid cancer, as well as what is on the horizon with this agent and other TRK inhibitors.

TARGETED ONCOLOGY:What are some of the most recent data we have seen with TRK inhibitors in thyroid cancer?

Hong:The most robust data comes from the larotrectinib trials — the NAVIGATE study and also the data from the SCOUT study. These patients with papillary thyroid cancer who haveNTRKfusions tend to be younger patients who are iodine-refractory and refractory to other small molecules and inhibitors. The response rates in these patients are equivalent to other tumor types, and at least with larotrectinib they respond well. There is an [approximately] 80% response rate in these patients.

TARGETED ONCOLOGY:Now that larotrectinib is approved by the FDA, what are the next steps with this agent?

Hong:Larotrectinib has recently been approved. I think understanding how community doctors are going to both use this drug in the context of their next-generation sequencing I think is important to understand that. I think the next steps beyond that are we don't really know the full prevalence ofNTRKfusions across all tumor types. I think as more patients receive this drug and more patients undergo next-generation sequencing to identify whether or not they haveNTRKfusions, that will be much clearer. There may be other mechanisms of resistance that emerge from either first-generation TRK inhibitors or even LOXO-195, so understanding that will also be important.

TARGETED ONCOLOGY:What are some ongoing trials in this space?

Hong:The NAVIGATE study is still ongoing, and we're going to finish that up very soon. One study, which I also think is very important for this field, is [looking at] LOXO-195. That trial is looking at patients who eventually become resistant to TRK inhibitors, such as larotrectinib and entrectinib, who specifically develop what are called solvent-front or gateway mutations. Initial data, which has been reported by my colleague Alexander Drilon, MD, from Memorial Sloan Kettering Cancer Center, has shown that there definitely seems to be efficacy or benefit in some patients who have these solvent-front mutations or gateway mutations who receive LOXO-195.

TARGETED ONCOLOGY:Are there any other TRK inhibitors that may be promising?

Hong:The current drugs, larotrectinib, is pretty good. There are not only a significant percentage of patients who seem to respond, but the responses appear to be very durable. Our hope is that with LOXO-195 we will also see significant responses and also significant durability, but that is to be determined. After that, just like many of the other small molecules in other diseases like CML, or with BRAF in melanoma, is trying to understand the mechanisms of resistance, if we can develop drugs that are less toxic. With that said, both larotrectinib and entrectinib are relatively non-toxic drugs, but [we can determine if there] are unique side effects we can ameliorate. These are all thoughts and questions and I think many people in the field are trying to explore.

Having treated many of these patients with a TRK inhibitor like larotrectinib, you don't forget when a patient has anNTRKfusion and you treat these patients with a drug because the responses are so profound. You don't forget that patient, you don't forget that drug. My hope is that we will have a thoughtful and a concerted effort as these drugs go into the community to try to identify these patients.

TARGETED ONCOLOGY:What are some of the unanswered questions we still have about TRK inhibitors in thyroid cancer?

Hong:I think the more patients we enroll that haveNTRKfusions, we may be able to differentiate where there are differential responses between papillary versus anaplastic, maybe even follicular thyroid types of cancers. There may be unique mechanisms of resistance with these drugs, particularly in thyroid. The numbers are relatively small at this time, but as they grow, I think some of these further questions will be answered.