Safety and Activity of Pembrolizumab in Combination With Rituximab in Patients With Relapsed or Refractory Follicular Lymphoma

Background: Blocking PD-1 enhances the function of anti-tumour T-cells and antibody-dependent cell-mediated cytotoxicity of NK cells. In a single-center, open-label, phase II trial, we tested pembrolizumab, an anti-PD-1 monoclonal antibody, plus rituximab, an anti-CD20 monoclonal antibody that induces antibody-dependent cell-mediated cytotoxicity, as the combination therapy is likely to result in enhanced clinical activity through T- and NK-cell activation in follicular lymphoma (FL). Methods: FL patients with rituximab-sensitive disease relapsing after ≥1 prior therapy were eligible. Pembrolizumab was administered at 200mg IV every 3 weeks for up to 16 cycles starting on day 2 of cycle 1. Rituximab was given at 375mg/m2 IV weekly for 4 weeks in cycle 1 only. The primary endpoint was to assess the overall response rate. Findings: Among the thirty patients treated, the most common grade 3/4 adverse events (AE) were liver enzyme abnormalities (3%), diarrhea (3%), nausea (3%), aseptic meningitis (3%) and pancreatitis (3%). Immune-related AEs were reported for 80% of patients; most were low grade (Grade 3 or 4, 13%) and included diarrhea (43%), liver enzyme abnormalities (33%), thyroid dysfunction (27%), and rash (23%). Treatment-related AEs led to discontinuation in 6 (20%) patients. Overall response rate was 67% and complete response rate was 50%. With a median follow up of 35 months (range 9-49), 7 (23%) patients are still in ongoing remission. Three-year overall survival rate was 97%. Presence of a high CD8+ T-effector score at baseline in the tumour associated with induction of a complete response and improved progression-free survival. Interpretation: The combination of pembrolizumab and rituximab demonstrates promising response rates and is well tolerated in relapsed FL. Trial Registration: The trial is registered at www.clinicaltrials.gov as NCT02446457. Funding Statement: This work is supported by grants from Merck, the Leukemia and Lymphoma Society Quest for Cure Grant (P-QFC-3068-14 to SSN), generous philanthropic contributions to the University of Texas MD Anderson Moon Shots Program, and The University of Texas MD Anderson Cancer Center Support Grant from National Institutes of Health (P30 CA016672). Declaration of Interests: CKC - No conflicts of interest to declare. LJN - has the following disclosures: Honorarium: ADC Therapeutics, Bayer, BMS/Celgene, Epizyme, Genentech, Gilead/KITE, Janssen, MEI, Novartis, Pfizer, TG Therapeutics; Research funding: BMS/Celgene, Epizyme, Genentech, Janssen, Karus Therapeutics, LAM Therapeutics, Merck, Novartis, TG Therapeutics. SSN - has received research support from Kite/Gilead, Cellectis, Poseida, Merck, Acerta, Karus, BMS, Unum Therapeutics, Allogene, and Precision Biosciences; served as consultant and advisory board member for Kite/Gilead, Celgene, Novartis, Unum Therapeutics, Pfizer, Merck, Precision Biosciences, Cell Medica, Incyte, Allogene, Calibr, and Legend Biotech; has royalty income from Takeda Pharmaceuticals; has patents related to cell therapy. All other authors have no conflicts to declare. Ethics Approval Statement: The University of Texas MD Anderson Institutional Review Board approved this study, which was performed in accordance with the Declaration of Helsinki and good clinical practice guidelines. All patients provided written informed consent.