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

Official title

A Multicenter Prospective-Retrospective Real-World Study Evaluating Conversion-to-Surgery and Survival After Genotype-Matched Neoadjuvant Systemic Therapy in Locally Advanced Thyroid Carcinoma

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.

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

• Drug Dabrafenib
  150 mg orally twice daily; ≤4 × 28-day cycles
• Drug Trametinib
  2 mg orally once daily; same duration
• Drug Selpercatinib
  160 mg orally twice daily; ≤4 cycles
• Drug Pralsetinib
  retrospective, 400 mg orally once daily; ≤4 cycles
• Drug Lenvatinib
  24 mg orally once daily; ≤4 cycles
• Drug Larotrectinib
  Larotrectinib 100 mg orally twice daily, continuous 28-day cycles.
• Drug Anlotinib
  12 mg orally once daily; 2 weeks on / 1 week off, ≤4 cycles (alternative)
• Drug Pembrolizumab
  200 mg IV infusion every 3 weeks; ≤4 cycles
• Drug Sintilimab
  200 mg IV infusion every 3 weeks; ≤4 cycles
• Drug Cabozantinib
  Cabozantinib 60 mg orally once daily, continuous 28-day cycles.

Primary outcome measures

• Real-World Progression-Free Survival (rwPFS) [Time frame: Baseline to radiologic/clinical progression or death, whichever occurs first, up to 36 months]

Secondary outcome measures (9)

• Real-World Objective Response Rate (rwORR) [Time frame: Baseline to first documented response, assessed every 8-12 weeks, up to 24 months]
• Pathologic Tumor Regression ≥ 50 % [Time frame: At surgery]
• R0/1 Resection Rate [Time frame: At surgery (≈ 1-5 months after first dose)]
• Conversion-to-Surgery Rate [Time frame: Up to 12 months from first dose]
• Overall Survival (OS) [Time frame: Baseline to death from any cause, censored at 36 months]
• Duration of Response (DoR) [Time frame: From first documented response until progression or death, up to 36 months]
• Incidence of Grade ≥ 3 Treatment-Related AEs [Time frame: Baseline to 30 days after last dose]
• Quality-of-Life Change (EORTC QLQ-THY34) [Time frame: Baseline, pre-surgery, and 6 months post-surgery]
• Thyroglobulin Reduction ≥ 90 % [Time frame: Pre-surgery (≈ 4 months)]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years at enrollment.
• 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.
• 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:

• 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).
• 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

• Untreated or symptomatic CNS metastases; patients with treated, stable lesions ≥ 4 weeks and off corticosteroids are eligible.
• 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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Fujian Medical University Union Hospital — Fuzhou

Identifiers

NCT: NCT07010393 · Real-Neo

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗