1941TiP - Neoadjuvant pembrolizumab in high-risk thyroid cancer (NePenTHe)

Background

Even if outcome of thyroid cancer (TC) is generally good, high-risk cases (e.g. tall cell histological variant; incomplete resection; vascular invasion; lymph node involvement; extracapsular spread; BRAFV600E; distant metastasis) have a 20-30% probability of relapse despite surgery and adjuvant radioiodine (RAI). PD-1 is a T-cell coreceptor and an important member of the immunoregulatory molecule family. PD-L1 overexpression is more common in advanced TC (pT4; pN+) and in histotypes such as differentiated and anaplastic cancer. We hypothesize that pembrolizumab (anti PD-1) increases the frequency of tumor-specific T-cell clones in the tumor and in peripheral blood contributing to the enhancement of adaptative anti-tumor response and reactivation of exhausted T cells.

Trial design

This is a prospective window of opportunity trial that will start in Q3 2024 and will be completed in 3 years. Primary aim of this trial is to investigate if pembrolizumab might reverse immunosuppressive behavior in high-risk TC. Spatial-transcriptomic sequencing will be performed in tumor tissues and will be paired to single-cell maps at peripheral level before and after pembrolizumab. To fulfill the translational endpoint and detect changes in immune exhaustion by single-cell sequencing, we should consider sample size both for identifying cell subpopulation in single-cell RNA-seq and for the clinical study. We impose to sequence >10000 cells with a frequency of 0.005 for the rarest subpopulation. Under these assumptions, we expect a probability of 0.95 of sequencing these cells from each subpopulation. We assume to reduce immune exhaustion level at least by 25% in the experimental arm. Following a one-stage Hern design to the pembrolizumab arm and with 80% power and 5% Type I error, 25 patients will be enrolled and randomized 4:1 to receive pembrolizumab ev 200mg Q3W for 2 courses (20 patients, experimental arm A) versus surgery upfront (5 patients, control group B). Adjuvant RAI administration will be provided as clinical practice.

Clinical trial identification

EudraCT 2021-003524-32 NCT05852223.

Editorial acknowledgement

Legal entity responsible for the study

Istituti Clinici Scientifici Maugeri IRCCS.

Funding

MSD.

Disclosure

S. Alfieri: Financial Interests, Personal, Advisory Board: Eisai. C. Durante: Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Invited Speaker: Eisai, Lilly. M. Raffaelli: Financial Interests, Other: Medtronic, Intuitive/Ab Medica, J&J. L.D. Locati: Financial Interests, Personal, Invited Speaker: Eisai, Ipsen, SunPharma, Bayer, Novartis, Seagen; Financial Interests, Personal, Advisory Board: MSD, Merck Serono, Eli Lilly, Roche; Financial Interests, Personal, Other, Scientific consultant: Istituto Gentili Srl; Financial Interests, Institutional, Local PI: Eisai; Financial Interests, Institutional, Funding: Pfizer; Non-Financial Interests, Leadership Role, Endocrine Tumor Group: EORTC; Non-Financial Interests, Advisory Board: AIOM (Italian Association of Medical Oncology), MSGS (Multidisciplinary Salivary Glands Society); Non-Financial Interests, Advisory Role: AIOCC (Associazione Italiana Oncologia Cervico Cefalica). All other authors have declared no conflicts of interest.