Clinical ThyroidologyVol. 35, No. 02 Thyroid CancerFree AccessThe Role of a Neoadjuvant RET Inhibitor in Medullary Thyroid CancerVenessa TsangVenessa TsangDepartment of Endocrinology, Royal North Shore Hospital, Sydney, Australia, and Northern Clinical School, Faculty of Medicine and Health, University of Sydney, AustraliaSearch for more papers by this authorPublished Online:8 Feb 2023https://doi.org/10.1089/ct.2023;35.71-74AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Review of:Contrera KJ, Gule-Monroe M, Hu MI, Cabanillas M, Buisaidy N, Dadu R, Waguespack SG, Wang JR, Maniakas A, Lai SY, Diersing J, Kwon M, Grubbs EG, Subbiah V, Williams MD, Zafereo ME 2022 Neoadjuvant selective RET inhibitor for medullary thyroid cancer: A case series. Thyroid. Epub 2022 Dec 11. PMID: 36503246.SUMMARYBackgroundThere has been a paradigm shift in the management of RET-altered metastatic medullary thyroid carcinoma (MTC) since the publications by Wirth et al. on the use of selpercatinib (1) and Subbiah et al. on pralsetinib (2), both selective RET-targeted tyrosine kinase inhibitors (TKIs). The role of neoadjuvant therapy has been explored in other cancers, including differentiated thyroid carcinoma, with the aim of improving chances of surgical resection. Once metastatic to areas outside the thyroid gland, MTC is usually a noncurable and locoregional disease; it is difficult to control even after thyroidectomy. Primary radiotherapy has been met with mixed results and is usually considered as second-line therapy after surgical resection (9). This article presents the first consecutive case series of 4 patients who received neoadjuvant therapy with selpercatinib that was followed by successful surgical removal (4).MethodsThis article presents a retrospective consecutive series within a single institution (MD Anderson Cancer Center, Houston, Texas) of four patients with somatic RET-mutated MTC who received selpercatinib as neoadjuvant therapy prior to surgery. The timing of subsequent treatment was determined by the treating team.The first primary outcome was Response Evaluation Criteria in Solid Tumours (RECIST) before and after neoadjuvant selpercatinib, defined as the percentage decrease in the longest diameter of target lesion. The second primary outcome was thyroid surgical morbidity score, on a scale of 0 to 4, using as assessed by authors, based on radiological imaging (CT neck) at baseline compared to post neoadjuvant therapy. The secondary outcomes were locoregional disease-free survival from date of surgery, changes in serum calcitonin and carcinoembryonic antigen (CEA) levels, and adverse effects.ResultsThe data from this article are summarized in Table 1. All patients had sporadic RET mutations (2 with M918T mutation); the age range was 20 to 60 years, and 3 of 4 patients were male. Two had previously undergone thyroidectomy but had local recurrence prior to neoadjuvant selpercatinib and further surgery. The decision to start neoadjuvant therapy was due to the likelihood of the need to sacrifice a recurrent laryngeal nerve (RLN) during surgery or a difficult surgical approach to successfully clear the recurrent tumor because of its close proximity to the subclavian artery.Table 1. Summary of Clinical Data adapted from Contrera et al.SubjectAge/SexStageMutationDuration of Treatment Presurgery (days)RECIST ResponseSurgical Risk ScoreSurgical OutcomeFollow-up (years)Locoregional ProgressionAdverse Effects120/MT4bN1bM1Sporadic elY900_S904delisP15655%4 to 2R1 resection, bilateral RNLs preserved3.6Not reachedGrade 1 transaminitis260/MT4aN1bM1Sporadic M918T12032%3 to 2R1 resection, Unilateral RLN loss2.2Not reachedGrade 2 lymphocytopenia (dose reduction), grade 1 xerostomia, leukopenia, thrombocytopenia355/MT1bN1bM1 (1.5 years after initial surgery)Somatic C630R17831%2 to 2Preservation of RLN1.40.6 years: Progression of liver and bone metastases.Grade 2 hypertension (dose reduced)440/FT1bN1bM0 (9 months after initial surgery)Somatic M918T17624%1 to 2Preservation of remaining RLN0.7Not reached.NilRLN = recurrent laryngeal nerveCreated by Venessa Tsang, MBBS, BSc(Med), FRACP, PhDSelpercatinib was given at a median of 168 days (range, 120–178) prior to surgery. The primary outcome showed a median 32% (range, 24–55) reduction via RECIST criteria on the target lesion and improvement in the surgical risk score in 2 of 4 patients. Regarding surgical outcomes, 1 of 5 required the RLN to be sacrificed, and all cases required ongoing locoregional control at the latest follow-up (median, 2 years; range 0.7–3.6). Three patients had distant metastatic progression requiring the restarting of selpercatinib. Serum calcitonin and CEA levels at the latest follow-up had decreased to 4.4% (range, 2.6–60) and 45% (range, 7.6–196) of their pre-selpercatinib treatment levels. Selpercatinib was overall well tolerated, with 1 patient needing dose interruption and 2 needing dose interruption for grade 2 adverse effects (lymphocytopenia and hypertension).ConclusionsIn this case series of 4 patients, neoadjuvant TKI therapy with selpercatinib in patients with locoregional advanced RET-mutated MTC was associated with improvement in local tumor burden, reduction in surgical risk, and tolerable adverse effects. A clinical trial is ongoing to provide further information (10).COMMENTARYMetastatic and locally advanced medullary thyroid carcinoma had been difficult to manage until the advent of the multikinase inhibitors (MKIs) (,5, 9) vandetanib (6) and cabozantinib (7), both of which improved progression-free survival, though at the cost of multiple adverse effects, including significant gastrointestinal symptoms (diarrhea, nausea), weight loss, hypertension, fatigue, and palmar–plantar erythrodysesthesia. The results of two trials on the use of the RET-targeted TKIs selpercatinib (LIBRETTO-001 trial) (1) and pralsetinib (ARROW Trial) (2) has further resulted in an improved response (73% and 71%, respectively) in MKI-naive patients with metastatic RET-mutated MTC after thyroidectomy. Most importantly, these selective agents are much better tolerated than MKIs, as they are associated with fewer off-target effects, and fewer patients need to stop the drug because of adverse effects (only 2% for selpercatinib and 4% for pralsetinib). Similar results have been achieved for other RET-mutated tumors, including RET fusion differentiated thyroid carcinomas. Thus, in this era of precision medicine, it is important to consider the molecular basis of locally advanced and locoregionally progressive disease when considering the use of systemic therapy.The role of selpercatinib as neoadjuvant (presurgical) therapy has been largely untested, with only a single case report (8) in the literature reporting its use. It was not described in the latest version of the American Thyroid Association (ATA) guidelines for medullary thyroid cancer in 2015 (9), though use of MKIs as neoadjuvant therapy was discussed for anaplastic thyroid cancer in the 2021 ATA anaplastic guidelines (3). Their use is an important consideration for advanced thyroid cancer, given that some patients are unable to have surgery owing to significant morbidity, including the possibility of bilateral RLN palsies. However, it is also important to weigh the risks and benefits of these agents. Though well tolerated overall, RET-selective inhibitors have novel adverse effects, including development of novel resistant mutations (11), chylous effusions (12), and small-bowel edema (13).This study is a series of only four cases, and as the authors have discussed, it has not been compared to other methods for local control, including radiotherapy. Nonetheless, it is exciting that there is a suite of novel molecular targeted therapies that may potentially be used in both the neoadjuvant and adjuvant settings. There is a current clinical trial underway (NCT04759911) to assess neoadjuvant selpercatinib treatment for RET-altered MTCs (10).Disclosures: The author has no relevant conflict of interest to declare.