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

Phase 4Not Yet RecruitingNCT07010393

Fujian Medical University335 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

335

Interventions

DabrafenibDRUG

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

TrametinibDRUG

2 mg orally once daily; same duration

SelpercatinibDRUG

160 mg orally twice daily; ≤4 cycles

PralsetinibDRUG

retrospective, 400 mg orally once daily; ≤4 cycles

LenvatinibDRUG

24 mg orally once daily; ≤4 cycles

LarotrectinibDRUG

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

AnlotinibDRUG

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

PembrolizumabDRUG

200 mg IV infusion every 3 weeks; ≤4 cycles

SintilimabDRUG

200 mg IV infusion every 3 weeks; ≤4 cycles

CabozantinibDRUG

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

BemosuzumabDRUG

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

Conversion SurgeryPROCEDURE

Conversion Surgery if resectable

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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).

Outcomes

Primary Outcomes

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.

Time frame: Baseline to radiologic/clinical progression or death, whichever occurs first, up to 36 months

Secondary Outcomes

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.

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

Pathologic Tumor Regression ≥ 50 %

Proportion of surgical specimens showing ≥ 50 % reduction in viable tumor area compared with baseline imaging estimate.

Time frame: At surgery

R0/1 Resection Rate

Percentage of resected participants whose final pathology shows microscopically negative (R0) or close (R1 ≤ 1 mm) margins.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline to 30 days after last dose

Quality-of-Life Change (EORTC QLQ-THY34)

Mean change from baseline in global QoL score.

Time frame: Baseline, pre-surgery, and 6 months post-surgery

Thyroglobulin Reduction ≥ 90 %

Proportion of differentiated-tumor participants with ≥ 90 % decrease in serum thyroglobulin from baseline.

Time frame: Pre-surgery (≈ 4 months)