Clinical trial NCT07010393: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Thyroid Neoplasms
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
Lead sponsor: Fujian Medical University
Sponsor class: OTHER
First posted: 2025-06-08
Enrollment: 335
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Real-World Progression-Free Survival (rwPFS)
timeFrame: Baseline to radiologic/clinical progression or death, whichever occurs first, up to 36 months
Secondary outcomes:
measure: Real-World Objective Response Rate (rwORR)
timeFrame: Baseline to first documented response, assessed every 8-12 weeks, up to 24 months
measure: Pathologic Tumor Regression ≥ 50 %
timeFrame: At surgery
measure: R0/1 Resection Rate
timeFrame: At surgery (≈ 1-5 months after first dose)
measure: Conversion-to-Surgery Rate
timeFrame: Up to 12 months from first dose
measure: Overall Survival (OS)
timeFrame: Baseline to death from any cause, censored at 36 months
measure: Duration of Response (DoR)
timeFrame: From first documented response until progression or death, up to 36 months
measure: Incidence of Grade ≥ 3 Treatment-Related AEs
timeFrame: Baseline to 30 days after last dose
measure: Quality-of-Life Change (EORTC QLQ-THY34)
timeFrame: Baseline, pre-surgery, and 6 months post-surgery
measure: Thyroglobulin Reduction ≥ 90 %
timeFrame: Pre-surgery (≈ 4 months)
Other outcomes:
Locations:
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital
state: Fujian
Study officials:
References: