Thyroid Neoplasms
Conditions
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
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.
Interventions
DRUGDabrafenib
150 mg orally twice daily; ≤4 × 28-day cycles
DRUGTrametinib
2 mg orally once daily; same duration
DRUGSelpercatinib
160 mg orally twice daily; ≤4 cycles
DRUGPralsetinib
retrospective, 400 mg orally once daily; ≤4 cycles
DRUGLenvatinib
24 mg orally once daily; ≤4 cycles
DRUGLarotrectinib
Larotrectinib 100 mg orally twice daily, continuous 28-day cycles.
DRUGAnlotinib
12 mg orally once daily; 2 weeks on / 1 week off, ≤4 cycles (alternative)
DRUGPembrolizumab
200 mg IV infusion every 3 weeks; ≤4 cycles
DRUGSintilimab
200 mg IV infusion every 3 weeks; ≤4 cycles
DRUGCabozantinib
Cabozantinib 60 mg orally once daily, continuous 28-day cycles.
DRUGBemosuzumab
China PD-L1 antibody bemosuzumab 900 mg IV every 2 weeks (14-day cycle).
PROCEDUREConversion Surgery
Conversion Surgery if resectable
Sponsors
Fujian Medical University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
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.
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Thyroglobulin Reduction ≥ 90 % | Pre-surgery (≈ 4 months) | Proportion of differentiated-tumor participants with ≥ 90 % decrease in serum thyroglobulin from baseline. |
| 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. |
| 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. |
Countries
China
Contacts
Primary ContactBo Wang Professor, MD
Backup ContactSi-si Wang, MD
Outcome results
None listed