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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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. |
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| 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. |
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| 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dabrafenib | Drug | 150 mg orally twice daily; ≤4 × 28-day cycles |
| |
| 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 |
| 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 % |
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Inclusion Criteria:
Age ≥ 18 years at enrollment.
Histologically or cytologically confirmed thyroid carcinoma that meets ≥ 1 of the following:
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:
ECOG Performance Status 0-2.
At least one measurable lesion per RECIST v1.1 / iRECIST (MTC with calcitonin/CEA evaluable disease accepted).
Written informed consent obtained.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Bo Wang Professor, MD | Contact | +13959123550 | wangbo@fjmu.edu.cn | |
| Si-si Wang, MD | Contact | +8618650064852 | WangSiSi@fjmu.edu.cn |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Fujian Medical University Union Hospital | Fuzhou | Fujian | 350001 | China |
De-identified datasets will be available 6 months after primary publication via institutional repository upon reasonable request
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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.
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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.
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|
| 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. |
|
| 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. |
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| 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. |
|
| Trametinib |
| Drug |
2 mg orally once daily; same duration |
|
| Selpercatinib | Drug | 160 mg orally twice daily; ≤4 cycles |
|
| Pralsetinib | Drug | retrospective, 400 mg orally once daily; ≤4 cycles |
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| Lenvatinib | Drug | 24 mg orally once daily; ≤4 cycles |
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| Larotrectinib | Drug | Larotrectinib 100 mg orally twice daily, continuous 28-day cycles. |
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| Anlotinib | Drug | 12 mg orally once daily; 2 weeks on / 1 week off, ≤4 cycles (alternative) |
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| Pembrolizumab | Drug | 200 mg IV infusion every 3 weeks; ≤4 cycles |
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| Sintilimab | Drug | 200 mg IV infusion every 3 weeks; ≤4 cycles |
|
| Cabozantinib | Drug | Cabozantinib 60 mg orally once daily, continuous 28-day cycles. |
|
| Bemosuzumab | Drug | China PD-L1 antibody bemosuzumab 900 mg IV every 2 weeks (14-day cycle). |
|
| Conversion Surgery | Procedure | Conversion Surgery if resectable |
|
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) |
| ID | Term |
|---|---|
| D013964 | Thyroid Neoplasms |
| ID | Term |
|---|---|
| D004701 | Endocrine Gland Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D006258 | Head and Neck Neoplasms |
| D004700 | Endocrine System Diseases |
| D013959 | Thyroid Diseases |
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| ID | Term |
|---|---|
| C561627 | dabrafenib |
| C560077 | trametinib |
| C000656166 | selpercatinib |
| C000655704 | pralsetinib |
| C531958 | lenvatinib |
| C000609083 | larotrectinib |
| C000625192 | anlotinib |
| C582435 | pembrolizumab |
| C000632826 | sintilimab |
| C558660 | cabozantinib |
| D061887 | Conversion to Open Surgery |
| ID | Term |
|---|---|
| D004724 | Endoscopy |
| D019060 | Minimally Invasive Surgical Procedures |
| D013514 | Surgical Procedures, Operative |
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