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

NCT07010393 | Not Yet Recruiting Phase 4

• 1 other identifier: Real-Neo
• Study Type: interventional
• Target: 335
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Thyroid Neoplasms

Keywords

Locally Advanced; Neoadjuvant Therapy; Real-World Study; BRAF V600E; RET Fusion; VEGF-TKI; Immunotherapy; Conversion Surgery; R0 Resection; Precision Oncology; Real-World Evidence; Conversion Therapy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Real-World Objective Response Rate (rwORR)

  Baseline to first documented response, assessed every 8-12 weeks, up to 24 months

• Pathologic Tumor Regression ≥ 50 %

  At surgery

• R0/1 Resection Rate

  At surgery (≈ 1-5 months after first dose)

• Conversion-to-Surgery Rate

  Up to 12 months from first dose

• Overall Survival (OS)

  Baseline to death from any cause, censored at 36 months

Study Arms (7)

BRAF V600E Mutation

EXPERIMENTAL

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; Drug: Trametinib; Drug: Lenvatinib; Drug: Anlotinib; Drug: Cabozantinib; Procedure: Conversion Surgery

RET Fusion PTC

EXPERIMENTAL

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: Selpercatinib; Drug: Pralsetinib; Drug: Lenvatinib; Drug: Anlotinib; Drug: Cabozantinib; Procedure: Conversion Surgery

RET Point-Mutation MTC

EXPERIMENTAL

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: Selpercatinib; Drug: Lenvatinib; Drug: Anlotinib; Drug: Cabozantinib; Procedure: Conversion Surgery

NTRK Fusion

EXPERIMENTAL

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; Drug: Larotrectinib; Drug: Anlotinib; Drug: Cabozantinib; Procedure: Conversion Surgery

TERT-Only (MKI)

EXPERIMENTAL

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; Drug: Anlotinib; Drug: Pembrolizumab; Drug: Sintilimab; Drug: Cabozantinib; Drug: Bemosuzumab; Procedure: Conversion Surgery

Triple-Negative (driver-negative) - MKI

EXPERIMENTAL

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; Drug: Lenvatinib; Drug: Anlotinib; Drug: Pembrolizumab; Drug: Sintilimab; Drug: Cabozantinib; Drug: Bemosuzumab; Procedure: Conversion Surgery

PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI

EXPERIMENTAL

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; Drug: Anlotinib; Drug: Pembrolizumab; Drug: Sintilimab; Drug: Cabozantinib; Drug: Bemosuzumab; Procedure: Conversion Surgery

Interventions

Dabrafenib DRUG

150 mg orally twice daily; ≤4 × 28-day cycles

BRAF V600E Mutation

Trametinib DRUG

2 mg orally once daily; same duration

BRAF V600E Mutation; Triple-Negative (driver-negative) - MKI

Selpercatinib DRUG

160 mg orally twice daily; ≤4 cycles

RET Fusion PTC; RET Point-Mutation MTC

Pralsetinib DRUG

retrospective, 400 mg orally once daily; ≤4 cycles

RET Fusion PTC

Lenvatinib DRUG

24 mg orally once daily; ≤4 cycles

BRAF V600E Mutation; NTRK Fusion; PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI; RET Fusion PTC; RET Point-Mutation MTC; TERT-Only (MKI); Triple-Negative (driver-negative) - MKI

Larotrectinib DRUG

Larotrectinib 100 mg orally twice daily, continuous 28-day cycles.

NTRK Fusion

Anlotinib DRUG

12 mg orally once daily; 2 weeks on / 1 week off, ≤4 cycles (alternative)

BRAF V600E Mutation; NTRK Fusion; PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI; RET Fusion PTC; RET Point-Mutation MTC; TERT-Only (MKI); Triple-Negative (driver-negative) - MKI

Pembrolizumab DRUG

200 mg IV infusion every 3 weeks; ≤4 cycles

PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI; TERT-Only (MKI); Triple-Negative (driver-negative) - MKI

Sintilimab DRUG

200 mg IV infusion every 3 weeks; ≤4 cycles

PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI; TERT-Only (MKI); Triple-Negative (driver-negative) - MKI

Cabozantinib DRUG

Cabozantinib 60 mg orally once daily, continuous 28-day cycles.

BRAF V600E Mutation; NTRK Fusion; PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI; RET Fusion PTC; RET Point-Mutation MTC; TERT-Only (MKI); Triple-Negative (driver-negative) - MKI

Bemosuzumab DRUG

China PD-L1 antibody bemosuzumab 900 mg IV every 2 weeks (14-day cycle).

PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI; TERT-Only (MKI); Triple-Negative (driver-negative) - MKI

Conversion Surgery PROCEDURE

Conversion Surgery if resectable

BRAF V600E Mutation; NTRK Fusion; PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI; RET Fusion PTC; RET Point-Mutation MTC; TERT-Only (MKI); Triple-Negative (driver-negative) - MKI

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years at enrollment.
• 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.
• Disease judged unresectable or entailing prohibitively high-morbidity surgery at baseline by a multidisciplinary thyroid-oncology board.
• 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).

You may not qualify if:

• Untreated or symptomatic CNS metastases; patients with treated, stable lesions ≥ 4 weeks and off corticosteroids are eligible.
• 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).

Sponsors & Collaborators

• Fujian Medical University: lead

Study Sites (1)

Fujian Medical University Union Hospital

Fuzhou, Fujian, 350001, China

Location

MeSH Terms

Conditions

Thyroid Neoplasms

Interventions

dabrafenib; trametinib; selpercatinib; pralsetinib; lenvatinib; larotrectinib; anlotinib; pembrolizumab; sintilimab; cabozantinib; Conversion to Open Surgery

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Intervention Hierarchy (Ancestors)

Endoscopy; Minimally Invasive Surgical Procedures; Surgical Procedures, Operative

Central Study Contacts

Bo Wang Professor, MD

CONTACT

+13959123550; wangbo@fjmu.edu.cn

Si-si Wang, MD

CONTACT

+8618650064852; WangSiSi@fjmu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: Assignment is open-label, non-randomized; placement into an arm is decided before first dose by a central molecular \& PD-L1 board reviewing NGS/PCR and IHC results. No cross-over permitted.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Head of Thyroid Surgery, Principal Investigator, Clinical Professor

Model Details: Participants are assigned to seven genotype- or immunophenotype-defined, parallel, non-overlapping arms with no planned cross-over: Arm 1 (BRAF V600E) - dabrafenib + trametinib Arm 2 (RET fusion) - selpercatinib Arm 3 (RET point-mutation MTC) - selpercatinib or retrospective cohort on pralsetinib Arm 4 (NTRK fusion) - larotrectinib Arm 5 (TERT-only, driver-negative for BRAF/RET) - lenvatinib, anlotinib, or cabozantinib Arm 6 (Triple-negative, no actionable driver) - investigator-choice MKI (lenvatinib, anlotinib, cabozantinib) Arm 7 (PD-L1 ≥ 1 % or MKI-refractory) - PD-1/PD-L1 blockade (pembrolizumab, sintilimab, or domestic PD-L1 antibody bemosuzumab) ± MKI combination (e.g., pembrolizumab + lenvatinib) per treating physician Assignment is open-label, non-randomized; placement into an arm is decided before first dose by a central molecular \& PD-L1 board reviewing NGS/PCR and IHC results. No cross-over permitted.

Study Record Dates

• First Submitted: May 28, 2025
• First Posted: June 8, 2025
• Study Start: July 1, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028
• Last Updated: June 8, 2025

Record last verified: 2025-01

Locations

CN (1)