MON-LB016 Tyrosine Kinase Inhibitor Induced Hypothyroidism in Pediatric and Young Adult Population: An Institutional Review

Abstract Tyrosine Kinase Inhibitor Induced Hypothyroidism in Pediatric and Young Adult Population: An institutional reviewBackground:Tyrosine kinase inhibitors (TKIs) are a class of molecular targeted therapies approved for the treatment of several hematological and solid tumors in pediatric population. Thyroid dysfunction, most commonly primary hypothyroidism, is a well described adverse effect in adults. There is no available data in the pediatric population regarding the risk of thyroid dysfunction with the use of TKIs.Objective:To document the incidence of hypothyroidism in the pediatric and young adult patients on TKI therapy.Methods:A retrospective chart review including patients’ ≤ 21 years of age who had been treated with at least 1 of 10 predetermined TKIs for malignancy was performed. Demographics, TKI use and duration, thyroid hormone labs, and history of head/neck radiation were collected. We excluded patients with pre-existing thyroid disease prior to start of TKI therapy. Thyroid dysfunction was defined as TSH >5mcIU/mL during TKI therapy. Results:A total of 152 patients who were treated with TKIs for malignancy were identified. The mean age was 12.4 years (SD 6.5). About 20% of patients had therapy with multiple TKI drugs. A total of 24 patients were noted to have TSH elevation >5mcIU/ml of which 19 had a TSH >10 mcIU/mL or low free T4. Fourteen patients were started on levothyroxine. Average duration of TKI therapy prior to development of thyroid dysfunction was 6.7 months but over half developed hypothyroidism within 3 months of initiation of TKI therapy. Cabozantinib and pazopanib were responsible for 70% of TKI associated cases of thyroid dysfunction.Conclusion:This is the first report of incidence of primary hypothyroidism in pediatric and young adult patients treated with TKIs. Thyroid dysfunction can develop in the first few months of therapy and often is clinically significant. Early recognition and treatment of this complication will be important for patient care especially as use of these class of drugs increase.

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Entrectinib: A new Selective Tyrosine Kinase Inhibitor Approved for the Treatment of Pediatric and Adult Patients with NTRK Fusion-positive, Recurrent or Advanced Solid Tumors

Current Medicinal Chemistry ◽

10.2174/0929867328666210914121324 ◽

2021 ◽

Vol 28 ◽

Author(s):

Hind M. Osman ◽

Meral Tuncbilek

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Solid Tumors ◽

Tyrosine Kinases ◽

Kinase Inhibitor ◽

Adult Patients ◽

Advanced Solid Tumors ◽

Synthesis Mechanism ◽

Accelerated Approval ◽

Positive Recurrent

Background: Entrectinib is a highly potent ATP-competitive and selective inhibitor of tyrosine kinases - Trk A B C, ALK, and ROS1. It was developed by Roche and initially approved in Japan in 2019 for the treatment of pediatric and adult patients with NTRK fusion-positive, recurrent, or advanced solid tumors. In August 2019, entrectinib received accelerated approval by the U.S FDA for this indication. It is also the first FDA-approved drug designed to target both NTRK and ROS1. Objective: We aim to summarize recent studies related to the synthesis, mechanism of action, and clinical trials of the newly approved selective tyrosine kinase inhibitor entrectinib. Method: We conduct a literature review of the research studies on the new highly-potent small-molecule entrectinib. Conclusion: Entrectinib, based on three clinical studies (ALKA, STARTRK-1, and STARTRK-2), was well tolerated, with a manageable safety profile. It induced clinically meaningful responses in recurrent or advanced solid tumors associated with NTRK fusion-positive or ROS1+ NSCLC. It demonstrated substantial efficacy in patients with CNS metastases.

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Immunotherapy-induced endocrinopathies: A multi-center experience.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14251 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14251-e14251

Author(s):

Karine Ronan ◽

Elly Hanis Che Othman ◽

Susan McKenna ◽

Cian Anderson ◽

David Sheehan ◽

...

Keyword(s):

Diabetes Mellitus ◽

Risk Factor ◽

Adverse Events ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Thyroid Dysfunction ◽

Kinase Inhibitor ◽

De Novo ◽

Cell Cancer ◽

The Impact

e14251 Background: Endocrinopathies account for approximately 10% of immune-related adverse events.1 Methods: We carried out a retrospective review of 100 patients who received immunotherapy at two hospital sites between 2012 and 2019. Our aim was to ascertain the overall rate of immunotherapy-induced endocrinopathy and assess the impact of immunotherapy on pre-existing diabetes and thyroid dysfunction. Results: 28 out of 100 patients had pre-existing thyroid dysfunction, 36% of these experienced further thyroid dysfunction on immunotherapy. 41 patients had a diagnosis of renal cell cancer, and had treatment with a tyrosine kinase inhibitor prior to treatment with Nivolumab. Eighteen of these patients had a pre-existing thyroid dysfunction. Of these 18 patients, 44% experienced further thyroid dysfunction following immunotherapy. Of the 23 patients who received a tyrosine kinase inhibitor, who had no pre-existing thyroid dysfunction, 17% developed thyroid dysfunction on Nivolumab. 15% of patients without a pre-existing thyroid dysfunction developed a new thyroid dysfunction while on immunotherapy. Seven patients had diabetes mellitus prior to commencing immunotherapy, diabetes control did not disimprove during treatment. One case of diabetes was diagnosed on immunotherapy(1%). One case of adrenalitis(1%) and two cases of hypophysitis(2%) were diagnosed on immunotherapy. The adrenalitis occurred on Nivolumab (1.35%). Both cases of hypophysitis occurred on ipililumab(14%). The overall rate of new immunotherapy-induced endocrinopathy was 15%. Conclusions: The rates of endocrinopathy observed de novo are in line with published rates.1,2,3,4 In this small study, an increased rate of thyroid dysfunction was observed in patients with pre-existing thyroid dysfunction. Prior treatment with a tyrosine kinase inhibitor did not cause an increase in the rate of thyroid dysfunction. Ipilimumab was observed to be a risk factor for development of hypophysitis. [Table: see text]

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