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

Fujian Medical University

Status and phase

Not yet enrolling

Phase 4

Conditions

Thyroid Neoplasms

Treatments

Drug: Selpercatinib

Drug: Cabozantinib

Drug: Trametinib

Drug: Dabrafenib

Drug: Pralsetinib

Drug: Bemosuzumab

Drug: Anlotinib

Drug: Pembrolizumab

Drug: Larotrectinib

Drug: Lenvatinib

Drug: Sintilimab

Procedure: Conversion Surgery

Study type

Interventional

Funder types

Other

Identifiers

NCT07010393

Real-Neo

Details and patient eligibility

About

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.

Full 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.

Enrollment

335 estimated patients

Sex

All

Ages

18 to 80 years old

Volunteers

No Healthy Volunteers

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).

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

335 participants in 7 patient groups

BRAF V600E Mutation

Experimental group

Description:

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.

Treatment:

Procedure: Conversion Surgery

Drug: Lenvatinib

Drug: Trametinib

Drug: Dabrafenib

Drug: Anlotinib

Drug: Cabozantinib

RET Fusion PTC

Experimental group

Description:

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.

Treatment:

Procedure: Conversion Surgery

Drug: Lenvatinib

Drug: Anlotinib

Drug: Cabozantinib

Drug: Selpercatinib

Drug: Pralsetinib

RET Point-Mutation MTC

Experimental group

Description:

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.

Treatment:

Procedure: Conversion Surgery

Drug: Lenvatinib

Drug: Anlotinib

Drug: Cabozantinib

Drug: Selpercatinib

NTRK Fusion

Experimental group

Description:

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.

Treatment:

Procedure: Conversion Surgery

Drug: Larotrectinib

Drug: Lenvatinib

Drug: Anlotinib

Drug: Cabozantinib

TERT-Only (MKI)

Experimental group

Description:

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.

Treatment:

Procedure: Conversion Surgery

Drug: Sintilimab

Drug: Pembrolizumab

Drug: Lenvatinib

Drug: Anlotinib

Drug: Bemosuzumab

Drug: Cabozantinib

Triple-Negative (driver-negative) - MKI

Experimental group

Description:

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.

Treatment:

Procedure: Conversion Surgery

Drug: Sintilimab

Drug: Pembrolizumab

Drug: Lenvatinib

Drug: Trametinib

Drug: Anlotinib

Drug: Bemosuzumab

Drug: Cabozantinib

PD-L1 ≥ 1 % / MKI-Refractory - Immunotherapy ± MKI

Experimental group

Description:

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.

Treatment:

Procedure: Conversion Surgery

Drug: Sintilimab

Drug: Pembrolizumab

Drug: Lenvatinib

Drug: Anlotinib

Drug: Bemosuzumab

Drug: Cabozantinib