Real-world clinical responses to selpercatinib in RET M918T-mutant medullary thyroid carcinoma

Abstract

Background

RET alterations, especially the M918T mutation, contribute to the development of aggressive medullary thyroid carcinoma (MTC). Selective RET inhibition has shown greater efficacy compared to VEGFR-targeting multikinase inhibitors (MKIs). Nevertheless, evidence from real-world settings, particularly involving patients with extensive metastatic burden, concurrent genomic alterations, or disease progression despite MKI therapy, remains scarce. This case series details three patients with metastatic RET-mutant medullary thyroid carcinoma (MTC), all of whom were treated with selpercatinib, including one patient who experienced disease progression on cabozantinib prior to transitioning to selective RET inhibition.

Results

All three patients possessed pathogenic RET M918T mutations. Case 1 also harbored a pathogenic MUTYH variant, whereas Case 3 demonstrated additional alterations, including ARID1A truncation, as well as deletions in MLH1 and CDKN2A. Two patients were treated with selpercatinib as first-line targeted therapy and experienced swift biochemical improvements accompanied by partial radiologic regression of metastases in the liver, lung, and bones. Case 2 exhibited radiologic progression at month 3 while on cabozantinib, subsequently followed by a significant biochemical and radiologic response after transitioning to selpercatinib. Selpercatinib was well tolerated across all cases, with only moderate and transient adverse events.

Conclusion

Selpercatinib produced rapid, durable biochemical and radiologic responses in metastatic RET-mutant MTC, including in a patient with clear progression on VEGFR-directed therapy. These findings support selective RET inhibition as an effective and well-tolerated treatment strategy and emphasize the importance of routine genomic profiling to guide precision therapy in advanced MTC.

Introduction

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor arising from parafollicular C-cells and accounts for approximately 1–2% of all thyroid cancers [1]. Unlike differentiated thyroid cancers, MTC does not concentrate radioactive iodine, making systemic therapy and biomarker monitoring particularly serum calcitonin and carcinoembryonic antigen (CEA) which is essential in advanced disease [2]. Activating alterations in the RET proto-oncogene represent the dominant oncogenic drivers of sporadic MTC, with the RET M918T mutation being the most aggressive variant associated with early metastasis and unfavorable prognosis [3]. RET gene fusions, while more often observed in papillary thyroid carcinoma, further underscore the biological importance of aberrant RET signaling in thyroid tumorigenesis [4].

For over a decade, systemic therapy relied primarily on multikinase inhibitors such as vandetanib and cabozantinib, which inhibit RET indirectly through broader VEGFR-targeting activity. Although these agents improve progression-free survival, their therapeutic impact has been limited by incomplete RET inhibition, off-target toxicities, and high rates of dose reductions [5, 6]. These limitations accelerated the development of highly selective RET inhibitors, particularly selpercatinib, designed to achieve potent, specific RET blockade while minimizing VEGFR-mediated toxicity.

The landmark LIBRETTO-001 trial demonstrated unprecedented efficacy of selpercatinib in RET-mutant MTC, with objective response rates of 69% in previously treated patients and 73% in treatment-naive individuals, accompanied by rapid and durable biochemical responses and a significantly improved safety profile compared to MKIs [7]. The randomized LIBRETTO-531 trial further validated the superior efficacy of selpercatinib compared to vandetanib or cabozantinib as an initial treatment option [8]. Subsequent real-world studies have supported these findings, demonstrating consistent biochemical and radiologic responses, improved symptom control, and favorable tolerability across diverse patient groups [9, 10]. These data collectively highlight the essential role of early molecular profiling—ideally via next-generation sequencing (NGS) in guiding optimal treatment selection for advanced MTC [11].

In this context, real-world documentation continues to be essential, especially for assessing treatment patterns, managing practical toxicity, and determining outcomes in heavily pretreated or clinically complex patients. This case series describes three patients with metastatic RET-mutant medullary thyroid carcinoma (MTC), each receiving selpercatinib, highlighting genomic features, biochemical and radiologic responses, and real-world treatment tolerability.

Case presentations

The clinical characteristics, genomic findings, treatment details, radiologic outcomes, biochemical responses, and duration of response for all three patients are summarized in Table 1.

Table 1.

Clinical, genomic, and treatment characteristics of the three RET M918T–Mutant medullary thyroid carcinoma cases

Variable	Case 1	Case 2	Case 3
Age at diagnosis and sex	38- Female	38- Male	54- Female
Primary site of NGS testing	Thyroid, right lobe (FFPE) – Tempus xT panel	Lung metastasis – FoundationOne® CDx	Thyroid FFPE tissue – ACTOnco®+ panel
RET alteration	RET p.M918T, gain-of-function (VAF 27.3%)	RET p.M918T, activating mutation (VAF 36.4%)	RET p.M918T (VAF 39.3%)
Additional genomic alterations	Pathogenic MUTYH p.G396D (potential germline carrier); VUS in GNAQ, MSH2, SLC26A3, TBC1D12	No additional pathogenic variants reported; MS-stable, TMB 0 muts/Mb	ARID1A K1059* truncating mutation + ARID1A heterozygous deletion; MLH1 and CDKN2A heterozygous deletions
TMB/MSI	TMB-Low (1.6 muts/Mb), MSI-stable	TMB 0 muts/Mb, MSI-stable	TMB 2.6 muts/Mb, MSI-stable
Metastatic sites at targeted therapy start	Liver (miliary pattern), bone (femoral shaft), cervical nodes	Lung, mediastinal and cervical lymph nodes	Lung, liver and multiple bone lesions (femur, sacroiliac, L5)
Targeted therapy	Selpercatinib 160 mg twice daily	Cabozantinib 60 mg once daily	Selpercatinib 160 mg twice daily
Response to initial therapy	Dramatic biochemical & radiologic response	Radiologic progression on cabozantinib (month 3)	Excellent biochemical & radiologic response
Second-line therapy		Selpercatinib 160 mg twice daily
Biochemical response to Selpercatinib	CEA ~ 150 → 27.5 ng/mL; calcitonin > 1800–2900 → 17.7 pg/mL (near-normalization)	CEA 17 → 5–7 ng/mL; calcitonin ~ 2500 → ~126 pg/mL (progressive decline)	Calcitonin 19,555 → 493 pg/mL; CEA 556 to 52 ng/mL (marked decline)
Radiologic response	Partial response in hepatic and bone disease on follow-up imaging; no new lesions	Partial response in cervical and pulmonary metastases on PET-CT; durable stable disease thereafter	Marked regression of pulmonary, hepatic and osseous metastases on PET-CT (excellent response)
Adverse events with selpercatinib	Zosteriform rash (requiring brief drug hold), grade 2 dyspepsia/bloating, transient facial edema – all resolved, no dose reduction	Grade 1 fatigue, no dose reduction needed	No clinically significant adverse events; selpercatinib well tolerated

In all patients, biochemical response assessment (serum calcitonin and CEA) was first performed at week 4 following selpercatinib initiation, in accordance with our institutional clinical practice. Radiologic response evaluation was routinely conducted at week 12 using cross-sectional imaging. In Case 1, early liver MRI was additionally performed at week 6 due to extensive hepatic involvement. Duration of response was defined as the interval from initiation of selpercatinib to the most recent follow-up demonstrating ongoing biochemical and radiologic disease control. As of January 2026, all three patients remained on continuous selpercatinib therapy with sustained responses.

Adverse events were retrospectively assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Overall, selpercatinib was well tolerated across all three patients, with no grade ≥ 3 treatment-related adverse events, no permanent treatment discontinuations, and no requirement for dose reduction. Observed toxicities were mild to moderate and were managed with temporary treatment interruption, supportive care measures—including dietary salt restriction in the setting of edema—and symptomatic treatment. All adverse events resolved or improved, and all patients continued selpercatinib therapy at the full prescribed dose. (Table 2).

Table 2.

Selpercatinib-related adverse events and management

Case	Adverse event	CTCAE v5.0 grade	Time of onset	Management/intervention	Outcome
1	Zosteriform rash	Grade 2	First 2 weeks	Temporary drug interruption (3 days)	Completely resolved
1	Bloating/dyspepsia	Grade 2	Month 5	Temporary treatment interruption (10 days), supportive care	Resolved
1	Facial edema	Grade 1–2	Month 5	Supportive care including dietary salt restriction; treatment interruption (10 days)	Resolved; treatment resumed at same dose
2	Fatigue	Grade 1	Early	No intervention required	Ongoing, mild
3	No clinically significant adverse events	–	–	–	–

Case 1: A 38-year-old female diagnosed with metastatic medullary thyroid carcinoma possessing the RET M918T mutation

A 38-year-old woman initially presented with a palpable mass on the right side of her neck. Baseline CEA was elevated at 67.9 ng/mL, and preoperative calcitonin was significantly elevated at 1842 pg/mL. PET-CT revealed a lesion in the right lobe of the thyroid gland without evidence of distant metastasis. She underwent a total thyroidectomy with bilateral central neck dissection and right lateral neck dissection (April 2021). The tumor was attached to the esophageal wall; however, a R0 resection was accomplished. Pathological examination confirmed medullary thyroid carcinoma (MTC), with 7 out of 14 right cervical lymph nodes exhibiting metastatic involvement, while the left side showed no evidence of disease. She subsequently completed 33 fractions of adjuvant radiotherapy.

Over the subsequent year, serial biomarkers indicated a progressive biochemical progression of the disease, with CEA increasing from 61 to 154 ng/mL and calcitonin rising from 837 to 2938 pg/mL. In March 2022, she experienced a paravertebral cervical recurrence, which was subsequently surgically excised. Following surgical excision of the paravertebral cervical recurrence, the patient demonstrated progressive biochemical disease, with steadily increasing serum calcitonin and CEA levels. However, repeated cross-sectional and functional imaging during this period failed to identify any measurable or targetable lesions. Given the absence of radiologically evident disease and the lack of measurable lesions suitable for response assessment, systemic therapy was deferred and the patient was managed with close biochemical and radiologic surveillance. A cervical ultrasound conducted in September 2024 revealed suspicious lymph nodes, although they appeared radiographically stable relative to previous imaging. In the setting of progressively rising calcitonin and CEA levels, functional imaging was first pursued to identify a potential site of recurrence or metastasis. An 18 F-FDG PET-CT was performed but did not demonstrate any hypermetabolic lesions. Given the neuroendocrine nature of medullary thyroid carcinoma, a subsequent 68Ga-DOTATATE PET-CT was obtained; however, this imaging modality also failed to detect any metabolically active disease. As no lesions were identified with PET-based imaging, whole-body MRI was subsequently performed in November 2024, which revealed a miliary pattern of hepatic metastases along with a metastatic lesion in the left femoral shaft, thereby establishing radiologic evidence of disease progression. Since radiological measurable disease was detected, comprehensive genomic profiling conducted with the Tempus xT (648-gene) assay identified a pathogenic RET p.M918T gain-of-function point mutation with a variant allele frequency of 27.3%, confirming RET activation as the principal oncogenic driver and establishing definitive eligibility for targeted RET inhibition. In addition to the RET alteration, the tumor contained a pathogenic MUTYH p.G396D variant, likely indicative of a germline carrier status, as well as multiple variants of uncertain significance involving GNAQ, MSH2, SLC26A3, and TBC1D12. The tumor mutational burden was low (1.6 mutations/Mb), and the microsatellite status was stable, representing a molecular pattern characteristic of sporadic RET-mutant medullary thyroid carcinoma. Selpercatinib was commenced at a dose of 160 milligrams twice daily following regulatory approval.

During the initial two weeks of therapy, the patient exhibited no systemic toxicities such as lethargy, nausea, or vomiting; however, she developed zosteriform skin eruptions involving the chin, mediastinum, and feet. A three-day interruption of selpercatinib resulted in complete resolution of the rash. In May 2025, she subsequently reported grade 2 bloating and dyspepsia accompanied by a brief episode of facial edema. Selpercatinib was temporarily withheld for 10 days, and supportive care measures—including dietary salt restriction—were implemented. Treatment was then successfully resumed at the same dose without recurrence of symptoms. No persistent or severe adverse events were observed thereafter.

The biochemical response was significant: calcitonin decreased from over 1800 pg/mL to 17.7 pg/mL, and CEA levels fell from approximately 150 ng/mL to 27.5 ng/mL. Follow-up imaging revealed partial radiologic regression, evidenced by a significant decrease in the miliary hepatic metastases and an interval improvement in the femoral bone lesion, with no new metastatic foci observed (Fig. 1). By December 2025, she continued to be clinically stable, with no active adverse events, and maintained selpercatinib with exceptional tolerability and a sustained biochemical and radiologic response for approximately 13 months, without evidence of disease progression.

Fig. 1.

Baseline and post-treatment liver MRI demonstrating regression of miliary hepatic metastases after initiation of selpercatinib. Axial contrast-enhanced liver MRI featuring miliary hepatic metastases at baseline (left) and significant interval regression following selpercatinib therapy (right). The diffusely hyperenhancing metastatic foci demonstrate a notable decrease in size and quantity, indicative of a partial radiologic response.

Case 2: A 38-year-old male with RET M918T–mutant metastatic MTC progressing on cabozantinib and responding to selpercatinib

A 38-year-old male presented with a persistent cough and dyspnea lasting for 2 to 3 months. Imaging demonstrated a thyroid mass, cervical lymphadenopathy, multiple pulmonary metastases, and mediastinal nodal involvement. Family history was significant for maternal papillary thyroid carcinoma.

Thyroid biopsy suggested malignant thyroid carcinoma, and comprehensive genomic profiling performed using the FoundationOne^® CDx assay revealed a pathogenic RET p.M918T activating mutation with a variant allele frequency of 36.4%, supporting a RET-driven oncogenic process consistent with the patient’s aggressive clinical presentation. The tumor exhibited microsatellite stability (MSI-stable) and an ultra-low tumor mutational burden (TMB 0 muts/Mb), a molecular signature characteristic of sporadic RET-mutant MTC. No additional pathogenic single-nucleotide variants, rearrangements, or copy-number alterations were detected, and there was no evidence of alternative driver pathways. The patient underwent total thyroidectomy and cervical lymph node dissection in April 2023.

In the context of metastatic disease, therapy commenced with cabozantinib at a dosage of 60 milligrams daily. During the initial two months, he encountered moderate fatigue, delayed wound healing, and depigmentation of the hair. However, a follow-up scan at three months revealed radiologic progression in pulmonary and nodal disease, accompanied by increasing tumor markers, signifying treatment failure.

He was subsequently transitioned to selpercatinib 160 mg administered twice daily. Within a few weeks, a significant biochemical response was noted, with calcitonin levels decreasing from approximately 2500 pg/mL to 126 pg/mL, and CEA levels showing a downward trend. A PET-CT scan conducted following the initiation of selpercatinib revealed a partial radiologic response, evidenced by regression of pulmonary and cervical lymph node metastases (Fig. 2). The treatment was well tolerated, with no significant adverse effects and no need for dose adjustments. Follow-up in December 2025 verified a stable clinical status, the absence of active symptoms, and continued tolerance of selpercatinib for approximately 32 months, highlighting the durability of selective RET inhibition following progression on cabozantinib. This case illustrates that patients advancing on VEGFR-targeted MKIs can still attain significant biochemical and radiologic responses following a switch to selective RET inhibition.

Fig. 2.

Pretreatment and post-treatment PET-CT showing partial radiologic response in pulmonary and cervical nodal metastases following selpercatinib. Axial FDG PET-CT images demonstrating markedly hypermetabolic pulmonary metastasis at baseline (left) and reduced metabolic activity with interval lesion regression following selpercatinib therapy (right). The findings are consistent with a partial metabolic and radiologic response.

Case 3: A 54-year-old female with widely metastatic RET-mutant MTC treated with selpercatinib

A 54-year-old woman was assessed for worsening bone pain and fatigue. PET-CT (July 2024) demonstrated bilateral pulmonary metastatic nodules, extensive hepatic metastases, and extensive skeletal dissemination affecting the left femur, sacroiliac region, and L5 vertebra. She underwent a total thyroidectomy on 04 July 2024, with pathology confirming the presence of medullary thyroid carcinoma. Baseline calcitonin was markedly elevated at 19,555 pg/mL. Family history was notable for maternal malignancy.

Due to symptomatic bone metastases, she underwent palliative radiotherapy directed at the left femur, sacroiliac joint, and L5. Comprehensive molecular profiling utilizing the ACTOnco^®+ next-generation sequencing panel detected a pathogenic RET p.M918T gain-of-function mutation with a high variant allele frequency (VAF 39.3%), confirming a RET-dependent oncogenic process. Alongside the RET mutation, the tumor exhibited several concurrent alterations linked to aggressive biological behavior, including an ARID1A p.K1059* truncating mutation (VAF 58.6%) in conjunction with ARID1A heterozygous deletion, as well as heterozygous losses in MLH1 and CDKN2A.

The tumor mutational burden was 2.6 mutations per megabase (TMB-low), and the microsatellite stability was MSI-stable, aligning with the classical molecular phenotype of sporadic RET-mutant medullary thyroid carcinoma. This patient presented with de novo widely metastatic disease at initial diagnosis and had not received any prior systemic therapy before selpercatinib initiation. The patient was started on selpercatinib 160 mg twice daily.

At the initial follow-up, she exhibited significant alleviation of bone pain and significant drops in serum tumor markers (CEA and calcitonin). During the visit in December 2024, calcitonin levels decreased to 493 pg/mL, and CEA measured 52.12 ng/mL, indicating a significant biochemical response compared to baseline. The physical examination demonstrated stable vital signs and an absence of toxicities that would limit treatment. A PET-CT performed on 05 December 2024 demonstrated an outstanding radiologic response, with regression of pulmonary, hepatic, and osseous lesions (Fig. 3). Laboratory assessment revealed maintained hematologic and hepatic function. The patient continues selpercatinib therapy with sustained biochemical and radiologic response for approximately 16 months as of January 2026.

Fig. 3.

PET-CT images demonstrating regression of hepatic, pulmonary, and osseous lesions after selpercatinib therapy in a patient with widely metastatic RET-mutant MTC. Coronal and axial PET-CT images illustrating widespread baseline metastatic disease affecting the lungs, liver, and skeletal sites (left panels). Follow-up imaging following selpercatinib (right panels) demonstrates a significant decrease in FDG uptake and tumor burden, indicative of an outstanding radiologic and metabolic response.

Discussion

RET alterations serve as a key oncogenic driver in medullary thyroid carcinoma (MTC), with the M918T mutation associated with notably aggressive biological characteristics and less favorable clinical outcomes [1–3]. Historically, systemic therapy has depended on multikinase inhibitors (MKIs) such as vandetanib and cabozantinib, which indirectly target RET via VEGFR-mediated pathways. Although these agents improve progression-free survival, their therapeutic impact is limited by incomplete RET suppression, frequent off-target toxicities, and high rates of dose reductions [5, 6]. These limitations facilitated the development of selective RET inhibitors, most notably selpercatinib, which offer potent and specific inhibition with significantly enhanced tolerability.

The LIBRETTO-001 trial exhibited unprecedented efficacy with selpercatinib, attaining objective response rates (ORR) of 69% in previously treated patients and 73% in treatment-naïve RET-mutant MTC patients, accompanied by swift biochemical improvement, sustained disease control, and reduced incidence of grade 3 or higher adverse events [7]. The subsequent randomized LIBRETTO-531 trial validated its superiority over vandetanib and cabozantinib in the first-line setting, conclusively establishing selpercatinib as the preferred systemic treatment for RET-driven MTC [8]. Real-world clinical series further substantiate these outcomes, demonstrating consistent biochemical and radiologic responses with favorable safety profiles across diverse and clinically complex patient populations [9, 10].

Our three cases support several of the findings reported in pivotal trials and real-world registries while offering additional practical insights. All three patients carried the pathogenic RET M918T mutation, with two demonstrating additional co-alterations, including pathogenic MUTYH variants and multiple tumor suppressor losses (ARID1A, MLH1, CDKN2A). Despite these unfavorable molecular characteristics, each patient exhibited a pronounced biochemical and radiologic response to selpercatinib, highlighting the potent on-target effectiveness of selective RET inhibition even in genomically complex disease. Beyond corroborating the high response rates observed in registry studies, our cases extend these findings in clinically relevant real-world contexts. Notably, Case 2 illustrates durable disease control with selpercatinib following early radiologic progression on cabozantinib, supporting registry observations that selective RET inhibition remains highly effective despite prior VEGFR-directed multikinase inhibitor exposure. This underscores that progression on MKIs likely reflects insufficient RET pathway suppression rather than true biological resistance. In addition, the sustained responses observed in Cases 1 and 3 suggest that RET M918T remains the dominant oncogenic driver even in the presence of complex co-occurring genomic alterations, reinforcing that selective RET inhibition can override adverse molecular context in routine clinical practice.

Another notable observation is the rapid and profound biochemical response across all three cases. Decreases in calcitonin and CEA were congruent with radiologic regression, supporting the utility of these biomarkers as early predictors of treatment response, as described in earlier clinical studies [2, 7]. Radiologic responses included regression of liver, lung, and extensive skeletal metastases—disease sites where MKIs often show modest or inconsistent efficacy.

Equally important is the favorable tolerability of selpercatinib in our series. Only mild and transient toxicities occurred, none requiring dose reductions. This mirrors the improved safety profile emphasized in prior studies and is particularly relevant in patients with heavy tumor burden or long expected treatment durations [7, 8].

Ultimately, these cases underscore the paramount significance of early implementation of next-generation sequencing (NGS) in informing therapeutic decisions for advanced MTC. All three cases exhibited actionable RET alterations, with one also presenting additional alterations (ARID1A, MLH1, CDKN2A) that may have played a role in promoting aggressive disease biology; however, the presence of these co-alterations did not reduce the efficacy of selpercatinib. These findings endorse guideline recommendations advocating for routine molecular profiling at the time of diagnosis of advanced disease [11].

Conclusion

This study possesses several significant strengths that augment its scientific significance and relevance to current management strategies for RET-driven medullary thyroid carcinoma. First, each case was subjected to extensive next-generation sequencing utilizing three distinct high-resolution genomic platforms (Tempus xT, FoundationOne CDx, and ACTOnco+), enabling a thorough characterization of RET M918T biology and associated genomic co-alterations. This degree of molecular annotation is rare in case-series literature and offers valuable insights into genotypic and phenotypic heterogeneity. Second, the study documents the real-world clinical management of metastatic MTC treated with selpercatinib, including a patient who exhibited evident radiologic progression on cabozantinib prior to showing a robust biochemical and radiologic response following the transition to selective RET inhibition. This underscores the therapeutic limitations of VEGFR-directed MKIs in certain RET-driven tumors and emphasizes the clinical significance of precision-targeted therapy. Ultimately, the findings firmly affirm the importance of routine NGS testing and genotype-guided systemic therapy as fundamental elements of contemporary precision oncology practice in MTC.

This study is constrained by its limited sample size and retrospective methodology, which diminish its generalizability and introduce variability in imaging and follow-up protocols. The follow-up period was relatively brief, limiting the potential to evaluate the long-term durability or late-onset toxicities of selpercatinib.

Author contributions

İ.N.Ö. conceived and designed the study, managed the clinical cases, interpreted the clinical and molecular data, and wrote the main manuscript text. T.B. contributed to data collection, literature review, and manuscript editing. All authors reviewed and approved the final version of the manuscript.

Funding

This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

The genomic data reported in this study were generated as part of routine clinical care using commercially available, clinically validated next-generation sequencing assays (Tempus xT, FoundationOne CDx, and ACTOnco+). Raw sequencing data were not generated or controlled by the authors and therefore cannot be deposited in public repositories. De-identified clinical and molecular data supporting the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and national regulations governing clinical research. Ethical approval for this retrospective study was obtained from the Göztepe Prof. Dr. Süleyman Yalçın Training and Research Hospital Non-Interventional Clinical Research Ethics Committee (Istanbul, Türkiye) (Decision No: 2026/0150, Approval Date: 04 March 2026). Written informed consent was obtained from all adult patients prior to participation in this study.

Consent for publication

Written informed consent was obtained from all adult patients for publication of their clinical details, molecular data, and imaging.

Competing interests

The authors declare no competing interests.