Genotype-Driven Neoadjuvant Therapy for Locally Advanced Thyroid Cancer: A Real-World Cohort Study

A Multicenter Prospective-Retrospective Real-World Study Evaluating Conversion-to-Surgery and Survival After Genotype-Matched Neoadjuvant Systemic Therapy in Locally Advanced Thyroid Carcinoma

This multicenter registry tests whether genomically matched neoadjuvant therapy (1-4 cycles tailored to BRAF V600E, RET fusion/mutation, isolated TERT mutation, triple-negative BRAF/RET/TERT, or ICI ± TKI) can render locally advanced, initially unresectable-or high-morbidity-thyroid cancers operable. The primary endpoint is conversion-to-surgery; key secondaries are R0/1 margin rate and 12-month event-free survival, with propensity-score weighting correcting cohort imbalances. Findings aim to define a precision-guided neoadjuvant standard for down-staging advanced thyroid tumors.

Study Overview

• Status: Not yet recruiting
• Conditions: Thyroid Neoplasms
• Intervention / Treatment: Drug: Dabrafenib; Drug: Trametinib; Drug: Lenvatinib; Drug: Anlotinib; Drug: Cabozantinib; Procedure: Conversion Surgery; Drug: Selpercatinib; Drug: Pralsetinib; Drug: Larotrectinib; Drug: Pembrolizumab; Drug: Sintilimab; Drug: Bemosuzumab

Detailed Description

This multicenter, prospective-retrospective registry will determine whether genotype-matched neoadjuvant systemic therapy can convert locally advanced, initially unresectable or high-morbidity thyroid cancers to successful surgery. Patients receive one to four 28-day cycles of treatment chosen according to actionable genomic alterations-BRAF V600E, RET fusion, RET point mutation, isolated TERT promoter mutation, "BRT triple-negative" (wild-type for BRAF/RET/TERT), or immune-checkpoint blockade ± TKI-before reassessment by a multidisciplinary team.

Primary outcome is the conversion-to-surgery rate. Key secondary outcomes include R0/1 (margin-negative) resection rate and 12-month event-free survival, defined as absence of progression, unresectability at planned surgery, recurrence, or death. Propensity-score weighting will balance baseline differences among cohorts and permit adjusted comparisons. Results will clarify the role of targeted and immunologic agents in down-staging advanced thyroid tumors and may establish a precision-guided neoadjuvant standard of care.

• Study Type: Interventional
• Enrollment (Estimated): 335
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Bo Wang Professor, MD; Phone Number: +13959123550; Email: wangbo@fjmu.edu.cn
• Study Contact Backup: Name: Si-si Wang, MD; Phone Number: +8618650064852; Email: WangSiSi@fjmu.edu.cn

Study Locations

• China
  • Fujian
    • Fuzhou, Fujian, China, 350001
      • Fujian Medical University Union Hospital
      • Contact: Bo Wang Porfessor, MD; Email: wangbo@fjmu.edu.cn
      • Principal Investigator: Bo Wang MD, Principal Investigator

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years at enrollment.

2. Histologically or cytologically confirmed thyroid carcinoma that meets ≥ 1 of the following:

   • Radioactive-iodine-refractory differentiated thyroid carcinoma (DTC)
   • Medullary thyroid carcinoma (MTC)
   • Anaplastic or poorly differentiated thyroid carcinoma (ATC/PDTC)
   • Other locally advanced / metastatic thyroid malignancy deemed incurable by surgery alone.
3. Disease judged unresectable or entailing prohibitively high-morbidity surgery at baseline by a multidisciplinary thyroid-oncology board.

4. Documented molecular or immunophenotype qualifying for ≥ 1 study arm:

   • BRAF V600E mutation
   • RET gene fusion
   • RET activating point mutation (e.g., M918T)
   • NTRK1/2/3 fusion
   • Isolated TERT-promoter mutation with no BRAF/RET/NTRK alterations
   • Driver-negative / VEGFR-wild type ("triple-negative")
   • PD-L1 expression ≥ 1 % OR progression after prior multi-kinase inhibitor (MKI).
5. ECOG Performance Status 0-2.
6. At least one measurable lesion per RECIST v1.1 / iRECIST (MTC with calcitonin/CEA evaluable disease accepted).
7. Written informed consent obtained.

Exclusion Criteria:

1. Untreated or symptomatic CNS metastases; patients with treated, stable lesions ≥ 4 weeks and off corticosteroids are eligible.
2. Pregnant or breastfeeding. Women and men of child-bearing potential must agree to effective contraception during study and for ≥ 120 days after last dose (≥ 180 days for men after dabrafenib/trametinib).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BRAF V600E Mutation; Dabrafenib 150 mg PO BID + trametinib 2 mg PO QD given in 28-day cycles (Day 1-28). After Cycle 4 (Day 112 ± 7) patients undergo imaging review; if previously unresectable disease becomes operable, conversion surgery is scheduled within 3 weeks. Those still unresectable continue treatment until progression/toxicity.	Drug: Dabrafenib; 150 mg orally twice daily; ≤4 × 28-day cycles; Drug: Trametinib; 2 mg orally once daily; same duration; Drug: Lenvatinib; 24 mg orally once daily; ≤4 cycles; Drug: Anlotinib; 12 mg orally once daily; 2 weeks on / 1 week off, ≤4 cycles (alternative); Drug: Cabozantinib; Cabozantinib 60 mg orally once daily, continuous 28-day cycles.; Procedure: Conversion Surgery; Conversion Surgery if resectable
Experimental: RET Fusion PTC; Selpercatinib 160 mg PO BID, continuous 28-day cycles. Surgery conversion assessment at Day 112 (end of Cycle 4). Resectable cases proceed to thyroidectomy ± neck dissection; others maintain therapy per label.	Drug: Lenvatinib; 24 mg orally once daily; ≤4 cycles; Drug: Anlotinib; 12 mg orally once daily; 2 weeks on / 1 week off, ≤4 cycles (alternative); Drug: Cabozantinib; Cabozantinib 60 mg orally once daily, continuous 28-day cycles.; Procedure: Conversion Surgery; Conversion Surgery if resectable; Drug: Selpercatinib; 160 mg orally twice daily; ≤4 cycles; Drug: Pralsetinib; retrospective, 400 mg orally once daily; ≤4 cycles
Experimental: RET Point-Mutation MTC; Prospective cohort: selpercatinib 160 mg PO BID, 28-day cycles; Retrospective sub-cohort: historical pralsetinib 400 mg PO QD (also 28-day cycles). Cycle 4 reassessment (Day 112) for potential curative resection of residual neck disease or distant oligometastases.	Drug: Lenvatinib; 24 mg orally once daily; ≤4 cycles; Drug: Anlotinib; 12 mg orally once daily; 2 weeks on / 1 week off, ≤4 cycles (alternative); Drug: Cabozantinib; Cabozantinib 60 mg orally once daily, continuous 28-day cycles.; Procedure: Conversion Surgery; Conversion Surgery if resectable; Drug: Selpercatinib; 160 mg orally twice daily; ≤4 cycles
Experimental: NTRK Fusion; Larotrectinib 100 mg PO BID in continuous 28-day cycles with multidisciplinary resectability evaluation after 4 cycles (Day 112). Eligible patients undergo surgery; non-eligible continue TRK inhibitor.	Drug: Lenvatinib; 24 mg orally once daily; ≤4 cycles; Drug: Anlotinib; 12 mg orally once daily; 2 weeks on / 1 week off, ≤4 cycles (alternative); Drug: Cabozantinib; Cabozantinib 60 mg orally once daily, continuous 28-day cycles.; Procedure: Conversion Surgery; Conversion Surgery if resectable; Drug: Larotrectinib; Larotrectinib 100 mg orally twice daily, continuous 28-day cycles.
Experimental: TERT-Only (MKI); Investigator-selected MKI: lenvatinib 24 mg PO QD (28-day cycle), anlotinib 12 mg PO d1-14 q21d (21-day cycle; Cycle 4 ends Day 84), or cabozantinib 60 mg PO QD (28-day cycle). Conversion-surgery review: Day 112 for 28-day regimens or Day 84 for anlotinib.	Drug: Lenvatinib; 24 mg orally once daily; ≤4 cycles; Drug: Anlotinib; 12 mg orally once daily; 2 weeks on / 1 week off, ≤4 cycles (alternative); Drug: Cabozantinib; Cabozantinib 60 mg orally once daily, continuous 28-day cycles.; Procedure: Conversion Surgery; Conversion Surgery if resectable; Drug: Pembrolizumab; 200 mg IV infusion every 3 weeks; ≤4 cycles; Drug: Sintilimab; 200 mg IV infusion every 3 weeks; ≤4 cycles; Drug: Bemosuzumab; China PD-L1 antibody bemosuzumab 900 mg IV every 2 weeks (14-day cycle).
Experimental: Triple-Negative (driver-negative) - MKI; Same MKI options/cycle lengths as Arm 5. Cycle 4 resectability check (Day 112 or Day 84 depending on drug). Successful conversions proceed to definitive surgery; others remain on systemic therapy.	Drug: Trametinib; 2 mg orally once daily; same duration; Drug: Lenvatinib; 24 mg orally once daily; ≤4 cycles; Drug: Anlotinib; 12 mg orally once daily; 2 weeks on / 1 week off, ≤4 cycles (alternative); Drug: Cabozantinib; Cabozantinib 60 mg orally once daily, continuous 28-day cycles.; Procedure: Conversion Surgery; Conversion Surgery if resectable; Drug: Pembrolizumab; 200 mg IV infusion every 3 weeks; ≤4 cycles; Drug: Sintilimab; 200 mg IV infusion every 3 weeks; ≤4 cycles; Drug: Bemosuzumab; China PD-L1 antibody bemosuzumab 900 mg IV every 2 weeks (14-day cycle).
Experimental: PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI; Checkpoint agents: pembrolizumab 200 mg IV q3w (21-day cycles), sintilimab 200 mg IV q3w (21 d), or domestic PD-L1 Ab bemosuzumab 900 mg IV q2w (14-day cycles). Combination option: lenvatinib 20 mg PO QD (28-day cycles) added at investigator discretion. Conversion assessment occurs after 4 cycles of the longest component being used (e.g., Day 84 for pembrolizumab; Day 112 if combined with 28-day MKI). Resectable patients undergo surgery; others continue or switch therapy.	Drug: Lenvatinib; 24 mg orally once daily; ≤4 cycles; Drug: Anlotinib; 12 mg orally once daily; 2 weeks on / 1 week off, ≤4 cycles (alternative); Drug: Cabozantinib; Cabozantinib 60 mg orally once daily, continuous 28-day cycles.; Procedure: Conversion Surgery; Conversion Surgery if resectable; Drug: Pembrolizumab; 200 mg IV infusion every 3 weeks; ≤4 cycles; Drug: Sintilimab; 200 mg IV infusion every 3 weeks; ≤4 cycles; Drug: Bemosuzumab; China PD-L1 antibody bemosuzumab 900 mg IV every 2 weeks (14-day cycle).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Real-World Progression-Free Survival (rwPFS)	Time from Cycle 1 Day 1 to the earliest date of disease progression (RECIST/iRECIST) or all-cause death.	Baseline to radiologic/clinical progression or death, whichever occurs first, up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Real-World Objective Response Rate (rwORR)	Percentage of patients with complete or partial response per RECIST v1.1 (or iRECIST for immunotherapy arms) as determined by local radiology.	Baseline to first documented response, assessed every 8-12 weeks, up to 24 months
Pathologic Tumor Regression ≥ 50 %	Proportion of surgical specimens showing ≥ 50 % reduction in viable tumor area compared with baseline imaging estimate.	At surgery
R0/1 Resection Rate	Percentage of resected participants whose final pathology shows microscopically negative (R0) or close (R1 ≤ 1 mm) margins.	At surgery (≈ 1-5 months after first dose)
Conversion-to-Surgery Rate	Proportion of enrolled participants who proceed to the intended curative-intent resection after completion of neoadjuvant therapy.	Up to 12 months from first dose
Overall Survival (OS)	Time from Cycle 1 Day 1 to death; survivors censored at last known follow-up.	Baseline to death from any cause, censored at 36 months
Duration of Response (DoR)	Among responders, time between initial response and subsequent disease progression or death.	From first documented response until progression or death, up to 36 months
Incidence of Grade ≥ 3 Treatment-Related AEs	Number and percentage of participants experiencing Grade 3 or higher adverse events per CTCAE v5.0.	Baseline to 30 days after last dose
Quality-of-Life Change (EORTC QLQ-THY34)	Mean change from baseline in global QoL score.	Baseline, pre-surgery, and 6 months post-surgery
Thyroglobulin Reduction ≥ 90 %	Proportion of differentiated-tumor participants with ≥ 90 % decrease in serum thyroglobulin from baseline.	Pre-surgery (≈ 4 months)

Collaborators and Investigators

• Sponsor: Fujian Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: May 28, 2025
• First Submitted That Met QC Criteria: June 1, 2025
• First Posted (Actual): June 8, 2025

Study Record Updates

• Last Update Posted (Actual): June 8, 2025
• Last Update Submitted That Met QC Criteria: June 1, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Immunotherapy; Locally Advanced; Neoadjuvant Therapy; BRAF V600E; Conversion Therapy; RET Fusion; Real-World Evidence; Precision Oncology; Conversion Surgery; Real-World Study; VEGF-TKI; R0 Resection
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Pralsetinib; Trametinib; Dabrafenib; Pembrolizumab; Lenvatinib
• Other Study ID Numbers: Real-Neo

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: De-identified datasets will be available 6 months after primary publication via institutional repository upon reasonable request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No