Background: Follicular lymphoma (FL) tumors are infiltrated with antitumor T cells, however, their function is impaired by immune checkpoints such as PD-1/PD-ligand pathway. Blocking PD-1 enhances the function of antitumor T cells in FL. In addition, blocking PD-1 on NK cells has been shown to enhance the ADCC effect of NK cells. We reasoned that the combination of pembrolizumab (P), an anti-PD-1 antibody (ab), and rituximab (R), an anti-CD20 ab that induces ADCC, is likely to be synergistic through activation of both the innate and adaptive immune systems and result in enhanced clinical activity in FL. Methods: We evaluated P and R in an open-label, non-randomized, single institution, phase II trial (N=30). Key inclusion criteria included adult (age ≥ 18 years), FL grade 1-3a, ECOG 0-1, in relapse after ≥1 prior therapy (tx) and R sensitive disease, defined as a complete (CR) or partial response lasting at least 6 months (mos) after most recent R-containing therapy. Pts received R (375 mg/m² IV) on days 1, 8, 15, and 22 of cycle 1 and P (200mg IV) q 3 weeks for up to 16 cycles starting on day 2 of cycle 1. Primary endpoint was overall response rate (ORR). Results: 27 pts have initiated therapy, median age 65 (range 42-79), 52% male, 76% had intermediate or high risk FLIPI, 56% met GELF criteria. Median prior tx =1 (range 1-4). Adverse events (AE) regardless of causality were mild, most grade 1-2. Grade 3 AE’s included nausea (N=2), infusion reaction (N=2), aseptic meningitis (N=1), pneumonia (N=1). Immune-related AEs included grade 2 diarrhea (N=2), grade 2 pneumonitis (N=1), grade 2 skin rash (N=1). At the pre-planned interim analysis (N=15), ORR was 80%, CR rate was 60%. With a median follow up of 7 mos (range 0.5-17), median DOR, PFS, and OS has not been reached. PD-L1 expression was tested in 8 baseline tumor samples using PD-L1 22C3 IHC pharmDx and was detected in histiocytes in all 8 tumors, present in only 1-8% of tumor cells in 5 tumors. Additional biomarker analyses are ongoing. Conclusions: The combination of P and R is well tolerated in relapsed FL and is associated with high overall and CR rate. These interim results warrant further investigation of this combination in FL. Clinical trial information: NCT02446457