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Test Your Skills: Medullary Thyroid Cancer

CE / CME

Test Your Skills: Understanding the Current Biomarker Landscape for Patients With Medullary Thyroid Cancer

Physician Assistants/Physician Associates: 0.25 AAPA Category 1 CME credit

Nurses: 0.25 Nursing contact hour

Pharmacists: 0.25 contact hour (0.025 CEUs)

Physicians: maximum of 0.25 AMA PRA Category 1 Credit™

ABIM MOC: maximum of 0.25 Medical Knowledge MOC point

Released: September 17, 2024

Expiration: September 16, 2025

Saad A Khan
Saad A Khan, MD
Laura J. Tafe
Laura J. Tafe, MD
CME/CE Information

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Discussion and Key Research
In this case challenge, our patient has recurrent metastatic MTC. The initial decision was whether to perform additional molecular testing or proceed directly to treatment with a kinase inhibitor. At initial diagnosis, our patient’s tumor was negative for germline RET mutations, but this does not rule out the possibility of a RET-driven MTC. All patients with sporadic recurrent/persistent locoregional or metastatic MTC incurable by surgery should have tumor somatic testing to identify actionable mutations with approved targeted therapies if a germline RET mutation has not been identified.1 Approximately 50% of patients with sporadic MTC will have a somatic RET mutation, which is an actionable genomic alteration with an approved targeted therapy.2

In our patient case, DNA-based and RNA-based NGS was used to identify actionable genomic alterations. NGS can detect a broad range of genetic alterations, including point mutations, indels, and gene rearrangements.3 It is the preferred method for comprehensive genomic profiling in MTC. In our case, RNA-based NGS was negative for NTRK fusion and DNA-based NGS was negative for RAS mutations and positive for the RET M918T mutation. The tumor mutational burden of the thyroid specimen was 5 mut/Mb.

The primary actionable mutation seen with MTC, as seen with this case, is a RET mutation.4 Selpercatinib, a RET inhibitor, is the preferred option for adult and pediatric patients 2 years of age or older with advanced or metastatic MTC with a RET mutation who require systemic therapy.5 Selpercatinib was originally approved for patients 12 years of age or older in this setting based on the LIBRETTO-001 trial where the overall response rate (ORR) for previously treated patients with advanced or metastatic RET-mutant MTC was 69% (95% CI: 55%-81%); 76% of these responding patients had responses lasting 6 months or longer. In patients not previously treated for MTC, the ORR was 73% (95% CI: 62%-82%); 61% of responding patients had responses lasting 6 months or longer.6 The use of selpercatinib in patients 2 years of age or older is supported by the LIBRETTO-121 trial, which studied locally advanced or metastatic RET-activated solid tumors nonresponsive to available therapies or with no standard systemic curative therapy available.7 The confirmed ORR was 48% (95% CI: 28%-69%). Durable responses were observed in these patients with RET-mutant MTC as well (n = 14; ORR: 43%; 95% CI: 18%-71%). As explained in the case, pralsetinib, another RET selective inhibitor, originally received accelerated approval for patients 12 years of age or older with advanced or metastatic RET-mutant MTC who require systemic therapy. However, this indication was withdrawn as the confirmatory trial could not be activated to fulfill the post-marketing requirement.8

Before the availability of selective RET inhibitors, the multikinase inhibitors vandetanib and cabozantinib were widely used for the management of MTC. In our patient case, these inhibitors are feasible treatment options for RET-mutated MTC, but they are not optimal. In the LIBRETTO-531 trial comparing selpercatinib with cabozantinib or vandetanib, selpercatinib resulted in superior PFS (not estimable vs 16.8 months; HR: 0.28; P <.001) when compared with the multikinase inhibitors.9 In addition, there were fewer grade ≥3 treatment-emergent adverse events (53% vs 76%) and lower rates of dose reductions (39% vs 76%) and treatment discontinuation (5% vs 27%).

In our case, pembrolizumab was another suboptimal treatment for this patient. The NCCN guidelines recommends the use of pembrolizumab for metastatic MTC for patients whose tumors has high TMB scores of ≥10 mut/Mb that have disease progression after previous treatment and have no other satisfactory options.1 This patient’s tumor had a TMB score of 5 mut/Mb.