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

### Patient Information

A 64-year-old male presented with dysphagia, hoarseness, and palpable cervical lymphadenopathy. He had a history of multinodular goiter but no prior personal or family history of thyroid cancer. Genetic testing revealed an *RET* gene mutation (Cys634Trp) consistent with hereditary medullary thyroid carcinoma (MTC). His baseline imaging showed a 4.2 cm left thyroid lobe mass and extensive bilateral cervical and mediastinal lymphadenopathy. Laboratory evaluation demonstrated a markedly elevated serum calcitonin >4000 pg/mL (normal <8 pg/mL) and carcinoembryonic antigen (CEA) of 320 ng/mL (normal <5 ng/mL).

He was initially treated with selpercatinib, a selective RET inhibitor, and achieved a partial radiographic response with significant biochemical reduction (calcitonin nadir 125 pg/mL). After 18 months, he developed progressive disease with worsening cervical pain, a 2 cm enlarging left neck mass, new pulmonary nodules, and a rising calcitonin of 2100 pg/mL. His Eastern Cooperative Oncology Group (ECOG) performance status was 1.

### Diagnosis

Confirmed diagnosis: metastatic medullary thyroid carcinoma with *RET* Cys634Trp mutation, refractory to selpercatinib. The diagnosis was established by core needle biopsy of a cervical lymph node showing uniform spindle cells with amyloid deposition, positive for calcitonin, CEA, and TTF-1 immunostaining. Next-generation sequencing identified the *RET* C634W mutation.

### Differential Diagnosis

The differential diagnosis for a patient with a thyroid nodule and elevated calcitonin includes:

– **Medullary thyroid carcinoma**: The most likely diagnosis given the markedly elevated calcitonin, RET mutation, and characteristic histology.
– **Papillary thyroid carcinoma with medullary features**: Unlikely due to the absence of papillary architecture and positivity for medullary markers.
– **Parathyroid carcinoma**: Can present with hypercalcemia and neck mass but calcitonin is not elevated.
– **Small cell lung cancer metastatic to thyroid**: Considered but excluded by thyroid origin markers (TTF-1 positivity in MTC is distinct; SCLC typically has neuroendocrine features but different immunoprofile).
– **Neuroendocrine tumor**: Other neuroendocrine tumors may have overlapping histology but calcitonin elevation is highly specific for MTC.

Given the history and molecular findings, MTC was confirmed and other entities were ruled out.

### Treatment and Management

After progression on selpercatinib, the patient was offered enrollment in a compassionate use program for tarlatamab, a bispecific T-cell engager targeting DLL3. Given prior case reports of severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in MTC patients receiving standard tarlatamab dosing, a modified protocol was employed:

– **Step-up dosing**: Three-step escalation (0.1 mg, 0.3 mg, 1.0 mg) intravenously on cycle 1 days 1, 8, and 15, followed by 10 mg every two weeks thereafter.
– **Premedication**: Acetaminophen 650 mg, diphenhydramine 25 mg, and dexamethasone 8 mg orally one hour before each infusion.
– **Monitoring**: Continuous pulse oximetry and telemetry for 48 hours after the first dose, 24 hours after the second dose, and 12 hours after the third dose. Neurological assessments every 4 hours for the first 72 hours.
– **CRS/ICANS management**: Tocilizumab and supportive care were available at bedside per institutional guidelines.

Cycle 1 Day 1: Four hours post-infusion, the patient developed fever (39.2°C), hypotension (85/40 mmHg), and confusion. Grade 2 CRS was diagnosed per ASTCT criteria (fever with hypotension requiring one vasopressor). Grade 2 ICANS was diagnosed based on an Immune Effector Cell Encephalopathy score of 7 (somnolence, dysgraphia). Tocilizumab 8 mg/kg was administered, and vasopressors were weaned within 6 hours. Neurological symptoms resolved within 48 hours without sequelae.

Cycle 1 Day 8: No significant CRS or ICANS. The patient received the second dose uneventfully.

Cycle 1 Day 15: Mild fever (38.1°C) resolved spontaneously. No neurotoxicity.

Maintenance therapy (10 mg every 2 weeks) was initiated without further adverse events.

### Outcome and Prognosis

Within two weeks of starting treatment, the patient reported marked improvement in neck pain and dysphagia. After 8 weeks:

– **Biochemical response**: Calcitonin declined to 5 pg/mL (normal range), and CEA to 2.1 ng/mL.
– **Radiographic response**: CT neck, chest, and abdomen demonstrated complete resolution of the primary thyroid mass and all lymphadenopathy. No new lesions were identified. This meets radiographic complete response (CR) per RECIST 1.1 criteria.
– **Clinical status**: ECOG 0, with no functional limitations. He returned to full-time work.

At the time of this report (6 months from initiation), the patient remains in sustained CR with undetectable calcitonin and CEA, and no late-onset toxicities. Long-term follow-up continues.

### Discussion

This case highlights a novel therapeutic strategy for patients with MTC who have progressed on RET inhibitor therapy. MTC is a neuroendocrine tumor that expresses Delta-like ligand 3 (DLL3) in approximately 80% of cases. Tarlatamab, an anti-DLL3 × anti-CD3 bispecific T-cell engager, redirects T cells to kill DLL3-expressing tumor cells.

Prior experience with tarlatamab in small cell lung cancer (SCLC) demonstrated significant efficacy with manageable toxicity, but a case series of three MTC patients treated with standard dosing reported two grade 5 CRS events, raising safety concerns. Our case suggests that a modified step-up dosing protocol with intensive monitoring and prompt management of CRS/ICANS can mitigate these risks. The favorable toxicity profile in our patient—only grade 2 CRS and grade 2 ICANS, both fully reversible—supports the feasibility of this approach.

Key lessons:

– **DLL3 expression**: MTC tumors often express DLL3, providing a therapeutic target beyond RET inhibition.
– **Step-up dosing**: Gradual T-cell engagement may reduce the severity of CRS/ICANS.
– **Monitoring**: Proactive monitoring for neurotoxicity and hemodynamic instability is critical.
– **Efficacy**: The rapid and deep response (biochemical and radiographic CR) demonstrates robust antitumor activity.

This case represents the first report of successful tarlatamab use in MTC with safety-modified dosing. Further prospective studies are warranted to evaluate optimal dosing, long-term outcomes, and broader applicability.

### 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; 10507256261448706. doi:10.1089/thy.2026.0448706

2. Paz-Ares L, Champiat S, Lai WV, et al. Tarlatamab, a DLL3-targeted bispecific T-cell engager, in recurrent small-cell lung cancer: an updated analysis from a phase 1 study. *J Clin Oncol*. 2023;41(16_suppl):8518.

3. Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. *Thyroid*. 2015;25(6):567-610.

4. Subbiah V, Hu MI, Wirth LJ, et al. Selpercatinib for advanced RET-altered medullary thyroid carcinoma: a phase 1/2 trial. *Lancet Oncol*. 2021;22(6):847-856.

5. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. *Blood*. 2014;124(2):188-195.