Larotrectinib Induces Promising Response Rate in Patients With Differentiated Thyroid Cancer

Larotrectinib (Vitrakvi) as treatment of patients with TRK fusion-positive thyroid cancer had rapid and durable disease control, with the highest response rates observed in the differentiated thyroid cancer (DTC) population, according to a poster presented during the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.

The overall response rate (ORR) in patients with DTC was 90% and 29% in patients with anaplastic thyroid cancer (ATC). The 18-month progression-free survival (PFS) rate was 86% for those in the DTC arm as well (95% CI, 60-100).

The analysis included patients with thyroid cancer who had an NTRK gene fusion and were treated with larotrectinib in 1 of 2 single-arm clinical trials (NCT02122913 & NCT02576431). Patients had to have locally advanced or metastatic disease and have been previously treated with standard therapy, if available. The primary end point of the study was ORR, and the data cut-off date was July 15, 2019.

The median age of patients was 61.5 years (range, 6.0-8.0), and the majority were female (68%). Overall, 43% had the NTRK1 gene fusion, and 57% had NTRK3. All patients had received prior surgery, while 61% received radiotherapy, 79% received radioactive iodine (RAI), and 57% had prior systemic therapy. The majority of patients (43%) were treated with larotrectinib as their first line of therapy, while 25% each had either 1 or 2 prior lines, and 7% had 3 or more.

Twenty-eight patients with TRK fusion-positive thyroid cancer were identified for this analysis, which included 19 cases of papillary thyroid cancer (PTC), 2 follicular thyroid cancers, and 7 ATCs. At baseline, 4 patients had central nervous system (CNS) metastases, 3 of which had received radiotherapy to the brain. Overall, 9 patients (32%) had received at least 2 lines of systemic therapy.

The ORR was 75% in the overall population (95% CI, 55-89), which included 2 complete responses (CRs), 19 partial responses (PRs), and 3 cases of stable disease (SD), while 3 patients also had progressive disease (PD). In the PTC arm, 2 patients had a CR, 15 had a PR, and 2 had SD. In the ATC arm, 2 had a PR, 1 had SD, and 3 had PD, while both patients in the follicular arm had achieved a PR.

All patients with CNS metastases had a PR at baseline, while 2 had measurable intracranial disease with intracranial reductions of 14% and 46%. Three patients had received radiotherapy around 14 to 15 months prior to the administration of larotrectinib.

The duration of treatment ranges between 0.9 to 45.4+ months, and treatment remained ongoing in 19 patients (68%) at the data cut-off. Three patients (11%) had continued treatment post-progression as well. The median time to a response was 1.9 months (range, 1.6-5.6).

The median duration of response was not estimable (NE; 95% CI, 14.8-NE) after a median follow-up of 10.2 months. The estimated 12-month duration of response was 95% (95% CI, 85-100). Responses lasted between 1.9 and 41.0+ months in the PTC arm, 3.6+ to 14.8 in the follicular thyroid cancer arm, and 3.7 and 10.2+ months in the ATC arm. The patient who achieved SD as their best response progressed after 2.6 months.

The median PFS was also NE (95% CI, 16.6-NE) after median follow-up of 12.8 months, but the estimated PFS rates were 81% at 12 months (95% CI, 67-96) and 70% at 18 months (95% CI, 45–94) in the overall population, although the rate was notably higher in the DTC arm. The median overall survival (OS) was 27.8 months (95% CI, 16.7-NE), and the estimated 12-month OS rate was 92% (95% CI, 82-100). The median OS was 14.1 months (95% CI, 2.6-NE) in the ATC arm and not reached for DTC.

The study authors concluded that larotrectinib had a favorable toxicity profile that was generally well tolerated. Adverse events (AEs) were mostly grades 1/2, and grade 3 AEs occurred in 32% of patients. Grade 3 treatment-related AEs occurred in 7% of the patients as well, while no grade 4 events were observed.

The most common grade 3 treatment-emergent AEs included anemia (14%), lymphocyte count decrease (11%), and diarrhea (7%). One patient (4%) experienced grade 4 treatment-emergent lymphocyte count decrease.

Grade 4/5 AEs were observed in 2 (7%) patients each, but none of these were considered related to treatment with larotrectinib. The grade 5 AEs that were observed were metastatic thyroid cancer in a PTC patient and tracheal hemorrhage in 1 patient with ATC.

Overall, 2 patients (7%) had a dose reduction due to an AE, which included alanine aminotransferase increase and lymphocyte count decrease. However, no patients experienced an AE that led to permanent treatment discontinuation.

In the poster, a case report was shared regarding a 64-year-old woman with a history of chronic obstructive pulmonary disease (COPD) diagnosed with poorly differentiated thyroid cancer that had derived from PTC. She was initially treated with total thyroidectomy and RAI but developed locoregional recurrence and bone metastases 1 year later. A left-neck dissection and partial esophagectomy was conducted, followed by external beam radiation to the neck and stereotactic radiation to multiple levels of the vertebral spine. However, the patient continued to progress and was enrolled to a clinical trial of radiation and immunotherapy, again with no response to treatment.

The patient received larotrectinib at a 100 mg dose twice daily after the ETV6-NTRK3 mutation was detected. She went on to achieve a PR by cycle 3 and 70% tumor reduction by cycle 19. The patient completed 23 cycles of larotrectinib overall, but treatment was held due to COPD complications and pneumonia, which were unrelated to larotrectinib. Disease continued to progress, and the patient died ~3 months later.

These findings indicate that routine testing for NTRK gene fusions should be considered in patients with non-medullary advanced thyroid cancer as this could help physicians select appropriate systemic treatments in the future.

_Reference

_{Cabanillas ME, Drilon A, Farago AF, et al. Larotectinib treatment of advanced TRK fusion thyroid cancer. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 1916P.}