Neoadjuvant pembrolizumab in high-risk thyroid cancers (NEPENTHE)

PI: Dott. Salvatore Alfieri 

The incidence of thyroid carcinoma has increased worldwide over recent decades, becoming the most frequent malignant glandular tumor. Although patients with differentiated thyroid carcinoma have a good prognosis (with a 10-year survival rate exceeding 90%), there are specific clinical and pathological factors (e.g. histological variants such as tall cell, incomplete resection, vascular invasion, lymph node involvement, extracapsular growth, BRAF V600E mutation, and distant metastases) that confer a higher risk of disease recurrence/persistence, with a significant impact on patient prognosis. Advanced tumors also show overexpression of PD-L1 (Programmed Death-Ligand 1), which has been associated with a greater risk of recurrence. 

Pembrolizumab is a humanized monoclonal antibody with an anti-PD-L1 mechanism of action, capable of stimulating the immune system to recognize and attack tumor cells. The potential impact of Pembrolizumab has already been demonstrated in previous clinical studies, supporting the biological and clinical rationale for the use of immune checkpoint inhibitors in the pre-surgical setting to reactivate the immune system in patients with advanced thyroid carcinoma and improve their prognosis. 

Specifically, this clinical trial compares the antitumor activity of Pembrolizumab versus standard surgery, evaluating the impact of Pembrolizumab on tumor growth and surgery (rates of complete resection, delay to surgery, complications, etc.). 

The study, conducted in accordance with international ethical guidelines, is considered experimental, as the investigational drug Pembrolizumab has not yet been approved by health authorities for this specific stage of treatment in high-risk thyroid carcinomas. 

The feasibility of patient enrollment in the study depends on: patient characteristics (demographics, oncological history, and comorbidities), laboratory values, and radiological findings, which will be assessed through specific screening examinations prior to starting treatment. These assessments will follow well-defined timelines. 

In addition, it is specified that eligible patients will be those with: 

- a risk > 20% of disease persistence/recurrence 

- primary tumor > 4 cm 

- macroscopic nodal disease 

- multifocal papillary microcarcinoma with extratumoral extension (ETE) and known BRAF V600E mutation; macroscopic invasion of perithyroid soft tissues, extranodal extension 

- expected incomplete tumor resection 

- poorly differentiated thyroid carcinoma or Hürthle cell carcinoma 

- distant metastases at diagnosis. 

The study design provides for assignment to: 

- Arm A: Pembrolizumab, administered by intravenous infusion every 3 weeks, for 2 cycles; 

- Arm B: upfront surgery, in which the patient will not receive any drug but will be referred directly for surgery. 

Assignment to one arm or the other (neoadjuvant Pembrolizumab before surgery versus upfront surgery) will be done through a computerized process called “randomization,” which involves random allocation to treatment without the possibility of choice by either the investigator or the patient. 

Treatment will continue until completion of the 2 Pembrolizumab cycles, but may be discontinued in the event of disease progression, unacceptable toxicity, or—as is always the case in clinical trials—by decision of the investigator and/or the patient (who, however, will continue to have access to medical care and will not forfeit any legal rights or entitled benefits). 

The treatment may induce adverse events, most of which are known, for which the investigators will adopt strategies to reduce their intensity (e.g. with treatment pauses or symptomatic therapies) and to alleviate their manifestations. 

After surgery, metabolic radiotherapy with radioactive iodine may be proposed, according to indications from standard clinical practice. 

The study staff remains available for further information (email: amo@istitutotumori.mi.it).