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

Phase 4

Not yet recruiting

• Conditions: Thyroid Neoplasms
• Interventions: Drug: Dabrafenib; Drug: Selpercatinib; Drug: Trametinib; Drug: Pralsetinib; Drug: Larotrectinib; Drug: Lenvatinib; Drug: Pembrolizumab; Drug: Anlotinib; Drug: Sintilimab; Drug: Cabozantinib; Procedure: Conversion Surgery; Drug: Bemosuzumab

• Registration Number: NCT07010393
• Lead Sponsor: Fujian Medical University

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.

Study Timeline

• Status Verified: 2025-01
• Study First Submitted: 2025-05-28
• Study First Submitted QC: 2025-06-01
• Last Update Submitted: 2025-06-01
• Study First Posted: 2025-06-08
• Last Update Posted: 2025-06-08
• Study Start: 2025-07-01
• Primary Completion: 2027-12-31
• Study Completion: 2028-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 335

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BRAF V600E Mutation	Dabrafenib	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.
BRAF V600E Mutation	Trametinib	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.
BRAF V600E Mutation	Lenvatinib	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.
BRAF V600E Mutation	Anlotinib	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.
BRAF V600E Mutation	Cabozantinib	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.
BRAF V600E Mutation	Conversion Surgery	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.
RET Fusion PTC	Selpercatinib	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.
RET Fusion PTC	Pralsetinib	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.
RET Fusion PTC	Lenvatinib	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.
RET Fusion PTC	Anlotinib	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.
RET Fusion PTC	Cabozantinib	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.
RET Fusion PTC	Conversion Surgery	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.
RET Point-Mutation MTC	Selpercatinib	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.
RET Point-Mutation MTC	Lenvatinib	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.
RET Point-Mutation MTC	Anlotinib	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.
RET Point-Mutation MTC	Cabozantinib	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.
RET Point-Mutation MTC	Conversion Surgery	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.
NTRK Fusion	Lenvatinib	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.
NTRK Fusion	Larotrectinib	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.
NTRK Fusion	Anlotinib	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.
NTRK Fusion	Cabozantinib	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.
NTRK Fusion	Conversion Surgery	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.
TERT-Only (MKI)	Lenvatinib	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.
TERT-Only (MKI)	Anlotinib	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.
TERT-Only (MKI)	Pembrolizumab	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.
TERT-Only (MKI)	Sintilimab	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.
TERT-Only (MKI)	Cabozantinib	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.
TERT-Only (MKI)	Bemosuzumab	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.
TERT-Only (MKI)	Conversion Surgery	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.
Triple-Negative (driver-negative) - MKI	Trametinib	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.
Triple-Negative (driver-negative) - MKI	Lenvatinib	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.
Triple-Negative (driver-negative) - MKI	Anlotinib	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.
Triple-Negative (driver-negative) - MKI	Pembrolizumab	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.
Triple-Negative (driver-negative) - MKI	Sintilimab	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.
Triple-Negative (driver-negative) - MKI	Cabozantinib	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.
Triple-Negative (driver-negative) - MKI	Bemosuzumab	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.
Triple-Negative (driver-negative) - MKI	Conversion Surgery	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.
PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI	Lenvatinib	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.
PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI	Anlotinib	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.
PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI	Pembrolizumab	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.
PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI	Sintilimab	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.
PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI	Cabozantinib	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.
PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI	Bemosuzumab	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.
PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI	Conversion Surgery	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Fujian Medical University Union Hospital; 🇨🇳 Fuzhou, Fujian, China