Larotrectinib Excites Landscape for TRK Fusion-Positive Thyroid Cancers

Maria E. Cabanillas, MD

Larotrectinib (Vitrakvi) received approval from the FDA for the treatment of solid tumors harboring TRK fusions (also known as NTRK), which has appeared as a promising new treatment option in the thyroid cancer setting. These fusions are known to occur in both differentiated thyroid cancer as well as anaplastic thyroid cancer, although these fusions are not observed in medullary thyroid cancer.

Two single-arm clinical trials (NCT02122913 & NCT02576431) explored the role of larotrectinib in patients with thyroid cancer. In particular, the studies, evaluated in a pooled analysis, included 28 patients with TRK fusion-positive thyroid cancer. Nineteen patients had papillary thyroid cancer, 7 anaplastic disease, and 2 follicular thyroid cancer.

The overall population had an objective response rate (ORR) of 75% with larotrectinib. The ORR among patients with differentiated thyroid cancer, in particular, was 90%, while the rate was 29% in those with anaplastic disease. Larotrectinib also demonstrated a favorable toxicity profile that was generally well tolerated.

In an interview with Targeted Oncology, Maria E. Cabanillas, MD, an oncologic endocrinologist, professor, and faculty director in the Department of Endocrine Neoplasia at The University of Texas MD Anderson Cancer Center, discussed the use of larotrectinib as treatment of patients with thyroid cancer and the pooled findings from 2 larotrectinib trials.

TARGETED ONCOLOGY: What does the current treatment landscape look like for TRK fusion-positive thyroid cancer?

Cabanillas: For TRK-fusion, radioactive iodine refractory differentiated thyroid cancer (including poorly differentiated thyroid cancer), the treatment landscape for advanced progressive disease is essentially the VEGF receptor inhibitors, sorafenib (Nexavar) and lenvatinib (Lenvima). For anaplastic thyroid cancer, the only FDA approved drugs are for BRAF-mutated disease. BRAF mutations almost never co-exist with TRK fusions so ATC patients with TRK fusions have no FDA approved options. These patients would preferentially be treated in the context of a clinical trial.

TARGETED ONCOLOGY: What is the biggest area of unmet need with this disease?

Cabanillas: We have several options for selective inhibitors in thyroid cancer. The FDA has approved 2 selective NTRK inhibitors and 2 selective RET inhibitors for thyroid cancer. RET fusions are seen in papillary, poorly differentiated and anaplastic thyroid cancers and RET mutations are seen in medullary thyroid cancer. Dabrafenib (BRAF inhibitor) in combination with trametinib (MEK inhibitor) is FDA approved for BRAF mutated ATC, and have been studied in papillary thyroid cancer. Very rare, but notable, are the ALK fusions that we see in papillary, poorly differentiated and anaplastic thyroid cancer. It is nice to have options since there are limitations of sorafenib, and lenvatinib. These drugs are not safe for some patients because of their potent antiangiogenic activity.

TARGETED ONCOLOGY: What was the rationale for the study of larotrectinib in advanced TRK fusion thyroid cancer?

Cabanillas: The larotrectinib studies included in this presentation weredone in pediatric and adult patients with an NTRK fusion in solid tumors. The data presented pulled out the thyroid cancer patients in order to better understand the response in patients with different types of thyroid cancer. . The original publication on larotrectinib in the New England Journal of Medicine only identified these patients as having thyroid cancer but we did not have information on the different types of thyroid cancer. This is important information because there are anaplastic thyroid cancers are far more aggressive than papillary thyroid cancer. Poorly differentiated thyroid cancers lie somewhere in between. This study essentially is taking that subset of thyroid cancers out of the larger group of NTRK fusion-positive solid tumors.

TARGETED ONCOLOGY: How was the study designed, and what were the findings?

Cabanillas: Adult patients with NTRK fusions were treated with 100 mg BID of larotrectinib by mouth. Pediatric patients were treated with 100 mg/m2 twice per day, up to a maximum of 100 mg twice per day. They were treated until progression or intolerable adverse events. There were 28 patients with NTRK fusion thyroid cancer included, and a 7 of them had anaplastic thyroid cancer. Nineteen patients had papillary thyroid cancer and 2 patients had follicular thyroid cancer. We found NTRK1 and NTRK3 fusions only. The majority of patients had previous systemic therapy, but there were 43% who were systemic therapy naïve. .

The response rates were very good, with an ORR of 75% for the whole cohort. In patients with differentiated thyroid cancer, the overall response rate was 90%. There were 2 patients with complete responses 17 patients with partial responses and no patients with progressive disease in the differentiated thyroid cancer group. In anaplastic thyroid cancer, the response rate was 29%, so much lower, but for anaplastic thyroid cancer, these are encouraging results. There were no complete responses, 2 patients with partial responses, and 1 patient with stable disease. Three patients had progression as their best response. The duration of response was also quite impressive--the median for duration of response in the overall cohort was not met. The responses also occurred early, with a median time to response of 1.9 months. At the time of data cutoff, the treatment was still ongoing in 68% of patients. As for progression-free survival, the median was not met for the overall group, but the median overall survival was 27.8 months for the entire group.

TARGETED ONCOLOGY: What are the implications of these data?

Cabanillas: Larotrectinib appears to be efficacious in differentiated thyroid cancer patients with NTRK fusion and encouraging in NTRK fusion ATC. However, one exciting finding is the the tolerability of the drug. If you look at the AEs, grade 3 AEs occurred in 32% of patients, and grade 4/5 AEs in 7% of patients, though none were treatment related. Most events were grade 1 and 2, including fatigue, constipation, and dizziness. There were also some mild liver function test abnormalities, peripheral edema, and cough. If you think about the fact that these patients are going to be on systemic therapy for years, tolerability of the drug is incredibly important because it affects the quality of life (although quality of life was not meausred in this study).

TARGETED ONCOLOGY: What's next for larotrectinib in the clinical trial setting?

Cabanillas: The area of most interest in terms of thyroid cancer is going to be anaplastic thyroid cancer and trying to determine whether we can improve on that 29% ORR. There were very few patients that were studied because both anaplastic thyroid cancer and TRK fusions are rare. I think we need to continue to understand if these responses can be improved upon. For example, combinations with immunotherapy, as the majority of these patients have high PD-L1 scores. Also, using larotrectinib in the neoadjuvant setting, possibly allowing for a complete surgery. These would be small studies and would likely require enrollment on a global scale, but not it is not impossible.