Treatment
TRK inhibitor efficacy and safety data
Clinical data that supported the registration of larotrectinib and entrectinib in all cancers including thyroid cancer, is described in Module 1.
In an analysis reported recently pooling thyroid cancer patient data (cut-off date 20th July 2020) from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687), among 28 evaluable patients, the objective response rate (ORR) was 71% (95% CI: 51–87) with the median time to response being 1.87 months (range 1.64–3.68). [1]. The best responses included complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%) and was undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. The 24-month duration of response, progression free survival and overall survival rates were 81%, 69%, and 76%, respectively. More specifically regarding different thyroid cancer histologies, the ORR was 86% (95% CI 64–97) for PTC/FTC and 29% (95% CI 4–71) for ATC. Treatment-related AEs were mostly grade 1 or 2. Two (7%) patients experienced grade 3 AEs considered related to larotrectinib (anaemia and decreased lymphocyte count).
A real word evidence case series of four patients with NTRK fusion–positive thyroid cancer treated with larotrectinib has been reported [2]. One of these patients with ATC experienced stable disease, one patient with poorly differentiated thyroid cancer showed complete response and two patients with PTC had partial response, as best overall response. At the time of the report, the patient with ATC [harbouring SQSTM1 (intron 6) - NTRK3 (intron 13) fusion], had 16% reduction in tumor burden after 2 months but progressed with enlarging parotid and neck masses after 6 months. One of the PTC patients [harbouring a novel ETV6 (exon 4) - NTRK2 (exon 16) fusion], after receiving stereotactic body radiation to brain metastases and cerebellar resection bed, was treated with larotrectinib, resulting in ongoing partial response in the pleural metastases for more than 18 months without evidence of recurrence in the brain. The second PTC patient [harbouring ETV6 (exon 5) - NTRK3 (exon 14) fusion] developed multiple new bone and pulmonary metastases with a recurrence in the ipsilateral neck, two years after surgery and radiotherapy. He then received larotrectinib and achieved partial response ongoing for 7 months. The patient with the poorly differentiated thyroid cancer [harbouring TPM3-NTRK1 (breakpoint info not available)] started larotrectinib one year after initial surgery and radiotherapy, after developing multiple hilar, mediastinal, and pulmonary metastases. She achieved complete resolution of enlarged lymph nodes and pulmonary nodules consistent with complete response in 2 months and showed radiological response (thyroglobulin rose from 329 to 1,588 ng/mL within 1 month of larotrectinib. It gradually decreased over the next 8 months but remained higher than the baseline before larotrectinib).
Ongoing clinical trials with TRK inhibitors in all cancers, including thyroid cancer are described in Module 1.
References
- Waguespack SG, Drilon A, Lin JJ et al. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. Eur J Endocrinol. 2022 Apr 29;186(6):631-643
- Park JC, Ashok A, Liu C, Kang H. Real-world experience of NTRK fusion-positive thyroid cancer. JCO Precis Oncol. 2022 Feb;6:e2100442.