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

NCT ID: NCT07010393

Last Updated: 2025-06-08

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 335 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-07-01
• Study Completion Date: 2028-12-31

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.

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.

Conditions

Thyroid Neoplasms

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Dabrafenib

Intervention Type: DRUG

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

Trametinib

Intervention Type: DRUG

2 mg orally once daily; same duration

Lenvatinib

Intervention Type: DRUG

24 mg orally once daily; ≤4 cycles

Anlotinib

Intervention Type: DRUG

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

Cabozantinib

Intervention Type: DRUG

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

Conversion Surgery

Intervention Type: PROCEDURE

Conversion Surgery if resectable

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.

Group Type: EXPERIMENTAL

Selpercatinib

Intervention Type: DRUG

160 mg orally twice daily; ≤4 cycles

Pralsetinib

Intervention Type: DRUG

retrospective, 400 mg orally once daily; ≤4 cycles

Lenvatinib

Intervention Type: DRUG

24 mg orally once daily; ≤4 cycles

Anlotinib

Intervention Type: DRUG

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

Cabozantinib

Intervention Type: DRUG

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

Conversion Surgery

Intervention Type: PROCEDURE

Conversion Surgery if resectable

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.

Group Type: EXPERIMENTAL

Selpercatinib

Intervention Type: DRUG

160 mg orally twice daily; ≤4 cycles

Lenvatinib

Intervention Type: DRUG

24 mg orally once daily; ≤4 cycles

Anlotinib

Intervention Type: DRUG

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

Cabozantinib

Intervention Type: DRUG

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

Conversion Surgery

Intervention Type: PROCEDURE

Conversion Surgery if resectable

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.

Group Type: EXPERIMENTAL

Lenvatinib

Intervention Type: DRUG

24 mg orally once daily; ≤4 cycles

Larotrectinib

Intervention Type: DRUG

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

Anlotinib

Intervention Type: DRUG

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

Cabozantinib

Intervention Type: DRUG

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

Conversion Surgery

Intervention Type: PROCEDURE

Conversion Surgery if resectable

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.

Group Type: EXPERIMENTAL

Lenvatinib

Intervention Type: DRUG

24 mg orally once daily; ≤4 cycles

Anlotinib

Intervention Type: DRUG

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

Pembrolizumab

Intervention Type: DRUG

200 mg IV infusion every 3 weeks; ≤4 cycles

Sintilimab

Intervention Type: DRUG

200 mg IV infusion every 3 weeks; ≤4 cycles

Cabozantinib

Intervention Type: DRUG

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

Bemosuzumab

Intervention Type: DRUG

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

Conversion Surgery

Intervention Type: PROCEDURE

Conversion Surgery if resectable

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.

Group Type: EXPERIMENTAL

Trametinib

Intervention Type: DRUG

2 mg orally once daily; same duration

Lenvatinib

Intervention Type: DRUG

24 mg orally once daily; ≤4 cycles

Anlotinib

Intervention Type: DRUG

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

Pembrolizumab

Intervention Type: DRUG

200 mg IV infusion every 3 weeks; ≤4 cycles

Sintilimab

Intervention Type: DRUG

200 mg IV infusion every 3 weeks; ≤4 cycles

Cabozantinib

Intervention Type: DRUG

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

Bemosuzumab

Intervention Type: DRUG

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

Conversion Surgery

Intervention Type: PROCEDURE

Conversion Surgery if resectable

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.

Group Type: EXPERIMENTAL

Lenvatinib

Intervention Type: DRUG

24 mg orally once daily; ≤4 cycles

Anlotinib

Intervention Type: DRUG

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

Pembrolizumab

Intervention Type: DRUG

200 mg IV infusion every 3 weeks; ≤4 cycles

Sintilimab

Intervention Type: DRUG

200 mg IV infusion every 3 weeks; ≤4 cycles

Cabozantinib

Intervention Type: DRUG

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

Bemosuzumab

Intervention Type: DRUG

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

Conversion Surgery

Intervention Type: PROCEDURE

Conversion Surgery if resectable

Interventions

Dabrafenib

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

Intervention Type: DRUG

Trametinib

2 mg orally once daily; same duration

Intervention Type: DRUG

Selpercatinib

160 mg orally twice daily; ≤4 cycles

Intervention Type: DRUG

Pralsetinib

retrospective, 400 mg orally once daily; ≤4 cycles

Intervention Type: DRUG

Lenvatinib

24 mg orally once daily; ≤4 cycles

Intervention Type: DRUG

Larotrectinib

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

Intervention Type: DRUG

Anlotinib

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

Intervention Type: DRUG

Pembrolizumab

200 mg IV infusion every 3 weeks; ≤4 cycles

Intervention Type: DRUG

Sintilimab

200 mg IV infusion every 3 weeks; ≤4 cycles

Intervention Type: DRUG

Cabozantinib

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

Intervention Type: DRUG

Bemosuzumab

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

Intervention Type: DRUG

Conversion Surgery

Conversion Surgery if resectable

Intervention Type: PROCEDURE

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fujian Medical University

OTHER

Sponsor Role: lead

Responsible Party

Bo Wang,MD

Director, Head of Thyroid Surgery, Principal Investigator, Clinical Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Fujian Medical University Union Hospital

Fuzhou, Fujian, China

Countries

China

Central Contacts

Bo Wang Professor, MD

Role: CONTACT

wangbo@fjmu.edu.cn

+13959123550

Si-si Wang, MD

Role: CONTACT

WangSiSi@fjmu.edu.cn

+8618650064852

Facility Contacts

Bo Wang Porfessor, MD

Role: primary

wangbo@fjmu.edu.cn

Other Identifiers

Real-Neo

Identifier Type: -

Identifier Source: org_study_id