Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma

Steven G Waguespack, Alexander Drilon, Jessica J Lin, Marcia S Brose, Ray McDermott, Mohammed Almubarak, Jessica Bauman, Michela Casanova, Anuradha Krishnamurthy, Shivaani Kummar, Serge Leyvraz, Do-Youn Oh, Keunchil Park, Davendra Sohal, Eric Sherman, Ricarda Norenberg, Josh D Silvertown, Nicoletta Brega, David S Hong, Maria E Cabanillas, Steven G Waguespack, Alexander Drilon, Jessica J Lin, Marcia S Brose, Ray McDermott, Mohammed Almubarak, Jessica Bauman, Michela Casanova, Anuradha Krishnamurthy, Shivaani Kummar, Serge Leyvraz, Do-Youn Oh, Keunchil Park, Davendra Sohal, Eric Sherman, Ricarda Norenberg, Josh D Silvertown, Nicoletta Brega, David S Hong, Maria E Cabanillas

Abstract

Objective: Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC).

Methods: We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020.

Results: Twenty-nine patients (median age: 60; range: 6-80) with TRK fusion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51-87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. ORR was 86% (95% CI: 64-97) for PTC/FTC and 29% (95% CI 4-71) for ATC. Median time to response was 1.87 months (range 1.64-3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adverse events were mainly grades 1-2.

Conclusion: In TRK fusion-positive TC, larotrectinib demonstrates rapid and durable disease control and a favourable safety profile in patients with advanced disease requiring systemic therapy.

Significance statement: NTRK gene fusions are known oncogenic drivers and have been identified in various histologies of thyroid carcinoma, most commonly in papillary thyroid carcinoma. This is the first publication specifically studying a TRK inhibitor in a cohort of TRK fusion-positive thyroid carcinoma patients. In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK fusion-positive thyroid carcinoma. Our findings show that patients with advanced non-medullary thyroid carcinoma who may require systemic therapy could be considered for testing for gene fusions by next-generation sequencing.

Figures

Figure 1
Figure 1
Response to larotrectinib. A waterfall plot of the maximum change in target lesions following treatment with larotrectinib in patients with advanced TRK fusion-positive thyroid carcinoma. The table depicts the overall response in both target and non-target lesions, and the waterfall plot depicts the maximum change in target lesions. *One patient with papillary TC was not evaluable for assessment of tumour response. †Investigator assessment based on RECIST version 1.1. ||Three PDTCs, two in the anaplastic group and one in the papillary group. ¶One patient with anaplastic TC was evaluable, but the response could not be determined because they had clinical disease progression prior to the first tumour response assessment. ATC, anaplastic thyroid carcinoma; FTC, follicular thyroid carcinoma; ORR, objective response rate; PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma; TC, thyroid carcinoma; TRK, tropomyosin receptor kinase. A full colour version of this figure is available at https://doi.org/10.1530/EJE-21-1259.
Figure 2
Figure 2
Treatment duration. A swimmer plot of the treatment duration in patients with advanced TRK fusion-positive thyroid carcinoma treated with larotrectinib. ||Three PDTCs, two in the anaplastic group and one in the papillary group. ATC, anaplastic thyroid carcinoma; FTC, follicular thyroid carcinoma; PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma; TRK, tropomyosin receptor kinase. A full colour version of this figure is available at https://doi.org/10.1530/EJE-21-1259.
Figure 3
Figure 3
Duration of response and survival. Kaplan–Meier curves of (A) duration of response†, (B) progression-free survival‡, and (C) overall survival‡ in patients with advanced TRK fusion-positive thyroid carcinoma treated with larotrectinib. The left panels show data for the entire study group and the right panels show the data based on histology. †Duration of response Kaplan-Meier curve only includes the patients who experienced a response. ATC duration of response Kaplan-Meier curve is not shown due to too few patients. ‡The one patient in the ATC group with a durable response had PDTC. ATC, anaplastic thyroid carcinoma; FTC, follicular thyroid carcinoma; PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma; TRK, tropomyosin receptor kinase. A full colour version of this figure is available at https://doi.org/10.1530/EJE-21-1259.
Figure 4
Figure 4
Case studies of patients with advanced TRK fusion-positive thyroid carcinoma treated with larotrectinib. Contrast-enhanced CT images demonstrating response in target and non-target lesions. (A) An adult female patient was diagnosed with PDTC with an ETV6-NTRK3 gene fusion. The red arrows indicate lung and liver metastases that responded to therapy. (B) An adult male patient was diagnosed with PTC with an ETV6-NTRK3 gene fusion. The red arrows indicate target lesions, and the yellow arrows identify non-target lesions. (C) A paediatric male patient was diagnosed with PTC with an IRF2BP2-NTRK1 gene fusion and a complete response in a lung target lesion (yellow arrows). LN, lymph node; NTRK, neurotrophic tyrosine receptor kinase; PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma; TRK, tropomyosin receptor kinase. A full colour version of this figure is available at https://doi.org/10.1530/EJE-21-1259.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9066591/bin/EJE-21-1259fig4b.jpg

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