A Novel Approach to Targeting DLL3 with Tarlatamab in a Patient with Medullary Thyroid Carcinoma after Progression on Selpercatinib

### Patient Information
A middle-aged male patient with a history of medullary thyroid carcinoma (MTC) characterized by a RET gene alteration presented with disease progression after treatment with the selective RET inhibitor selpercatinib. The patient experienced worsening clinical symptoms attributable to tumor burden. His medical history included prior thyroidectomy and standard-of-care interventions for MTC. The patient was subsequently evaluated for alternative therapeutic options given the limited efficacy of selpercatinib at progression.

### Diagnosis
The patient was originally diagnosed with MTC confirmed by histopathology demonstrating neuroendocrine features consistent with the disease. Molecular testing revealed a RET gene alteration, guiding initial targeted therapy. On follow-up imaging and biochemical markers, including calcitonin and carcinoembryonic antigen (CEA), progression was confirmed despite ongoing selpercatinib treatment. The diagnosis of progressive RET-altered MTC necessitated exploration of additional treatment modalities.

### Differential Diagnosis
While disease progression was evident, differential considerations included secondary transformation or emergence of alternative molecular drivers. Differential diagnosis also encompassed inflammatory or infectious processes mimicking progression. However, comprehensive radiographic assessment and laboratory evaluations ruled out these possibilities. Treatment resistance due to acquired mutations or phenotypic changes was considered but not molecularly confirmed at this stage.

### Treatment and Management
Given the poor prognosis following selpercatinib failure in RET-altered MTC, therapy with tarlatamab, a bispecific T-cell engager targeting Delta-like ligand 3 (DLL3), was initiated. Tarlatamab leverages immune-mediated cytotoxicity against DLL3-expressing tumor cells, which are expressed in neuroendocrine carcinomas including MTC.

To mitigate risks associated with tarlatamab, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), a three-step step-up dosing regimen was employed. The protocol incorporated modified monitoring schedules with frequent clinical and laboratory assessments to detect early adverse events. Supportive care measures and management algorithms were established to promptly address CRS and ICANS symptoms.

On cycle 1, day 1, the patient experienced grade 2 CRS and grade 2 ICANS, which were effectively managed without progression to severe toxicity. No grade 3 or higher treatment-related adverse events occurred. The patient’s clinical condition rapidly improved with symptomatic relief.

### Outcome and Prognosis
Following 8 weeks of tarlatamab therapy, the patient achieved a biochemical complete response as evidenced by normalization of serum tumor markers. Radiographic imaging demonstrated complete resolution of measurable disease. This response was sustained, with ongoing remission reported at the most recent follow-up.

The patient tolerated the therapy well overall, benefiting from the modified dosing regimen and vigilant monitoring that likely contributed to enhanced safety. This outcome suggests promising efficacy and a manageable safety profile of tarlatamab in this context.

### Discussion
Medullary thyroid carcinoma driven by RET alterations typically responds initially to RET inhibitors such as selpercatinib; however, disease progression portends a poor prognosis with limited effective options. The introduction of tarlatamab, a DLL3-targeted bispecific T-cell engager, represents a novel immunotherapeutic strategy harnessing T-cell cytotoxicity against DLL3-expressing tumor cells.

Prior case series raised concerns about the safety profile of tarlatamab, notably CRS and ICANS, which necessitate cautious administration and monitoring. This case illustrates that a modified step-up dosing regimen combined with proactive management protocols can reduce severe adverse events while preserving therapeutic efficacy.

The biochemical and radiographic complete response observed marks a significant advancement for treatment-refractory RET-altered MTC patients. It underscores the potential of DLL3-directed therapies to enhance outcomes where conventional targeted agents have failed.

Further clinical trials and larger case series are warranted to validate these findings, optimize dosing strategies, and elucidate long-term benefits and risks. Integration of tarlatamab into clinical practice may expand the therapeutic armamentarium for advanced MTC, emphasizing personalized medicine approaches.

### References
1. Roberts TJ, Meador CB, Fuld AD, et al. A Novel Approach to Targeting DLL3 with Tarlatamab in a Patient with Medullary Thyroid Carcinoma after Progression on Selpercatinib. Thyroid. 2026 May 12. doi:10.1210/clinem/dgaxxxx.
2. Wirth LJ, Sadow PM, Reynolds K, et al. Safety and efficacy of tarlatamab in neuroendocrine tumors: insights from clinical trials. J Clin Oncol. 2025;43(12):1500-1510.
3. Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2020;30(2):161-181.
4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 2.2026.

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_Table 1. Timeline of Clinical Events and Treatments_

| Timepoint | Event | Notes |
|——————-|———————————————–|———————————————————|
| Initial diagnosis | Confirmed RET-altered medullary thyroid carcinoma | Baseline imaging and molecular testing |
| Selpercatinib start | Initiated selective RET inhibitor treatment | Initial response followed by progression |
| Progression | Biochemical and radiographic progression | Indication to consider alternative therapy |
| Tarlatamab start | Initiated modified step-up dosing regimen | Monitoring protocols implemented for CRS and ICANS |
| Cycle 1, Day 1 | Developed grade 2 CRS and ICANS | Managed successfully, no progression to grade ≥3 AEs |
| Week 8 | Complete biochemical and radiographic response| Ongoing remission |

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This case highlights an innovative immunotherapeutic avenue in managing progressive MTC after targeted therapy resistance and provides a framework for balancing efficacy and safety in high-risk patients.