After cystectomy (Cy), >40% of patients (pts) with miUBC will develop a recurrence. Neoadjuvant chemotherapy (CT) yields Level 1 evidence in the guidelines, yet it is underutilized worldwide and a small survival improvement is deemed over Cy alone. Pembrolizumab (MK-3475) is a humanized IgG4, high-affinity, anti-PD-1 mAb that has demonstrated significant activity in metastatic UBC. PDL-1 immunohistochemical (IHC) expression can predict drug activity. Our hypothesis was that Pembrolizumab, given neoadjuvantly, could downstage miUBC and reduce recurrence.
Pts with T2-T4a N0 UBC with residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence) will receive 3 cycles of MK-3475 at 200mg 3 weekly prior to surgery (radical Cy). Cy will be planned to be done within 3 weeks of the last dose (accounting for a total of 9 weeks). Computed tomography (CT) scan and fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan will be done during screening and before Cy. After Cy, pts with the evidence of pT3-4 and/or pN+ disease will be managed according to local guidelines. Further anti PD-1 therapy will not be given post-operatively. PD-L1 status will be assessed on TURB specimen using the anti-PD-L1 Ab clone 22C3 and a prototype IHC assay and centralized to Qualtek, Goleta, CA. PD-L1 positivity will be defined as any staining in the stroma or in ≥1% of tumor cells. Pathologic complete response (pCR) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be includes in the ITT analysis. The H1 is pCR ≥20% and H0 pCR ≤ 10%. A 2-stage design will be used to estimate the number of pts required. Out of 90 pts overall, with the first stage of 49 pts, ≥6 pCR will be required in the first stage, and ≥13 pCR in the whole study population (80% power and a 2-sided test of significance at the 10% level). Correlative research on tissue/blood samples will include immune-cell profiling in tumor and blood during Pembrolizumab, cytokine assessment, and molecular profiling of tumor samples (ClinicalTrials.gov NCT02736266).
Clinical trial identification
Legal entity responsible for the study
Fondazione IRCCS Istituto Nazionale dei Tumori
Merck Sharp & Dohme
All authors have declared no conflicts of interest.