Response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: Interim results of an on open-label, phase II study.

Abstract

7519 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.

PD-1 expression and clinical PD-1 blockade in B-cell lymphomas

“…111 The combination of pembrolizumab and rituximab showed a high ORR of 80% in relapsed FL. 112 High complete response rates (50% to 65%) have been reported for the combination of nivolumab and brentuximab vedotin in patients with R/R HL in 2 phase 1/2 trials. 113,114 Nivolumab and pembrolizumab showed acceptable safety profiles with low rates of discontinuation resulting from adverse events, although close monitoring is warranted, especially for patients with a history of acute graft-versus-host-disease.…”

“…Across lymphoma entities, anti-PD-1 monotherapy showed the greatest efficacy in R/R cHL. [20][21][22][23]76,[107][108][109][110][111][112][113][114][115] In a phase 1 trial of nivolumab, the objective response rate (ORR) was remarkable (87%). 20 In phase 2 trials, nivolumab and pembrolizumab had similar ORRs (68% and 69%) and OS rates (99%) at 6 months, 22,23 leading to accelerated FDA approval in 2016 for nivolumab and in 2017 for pembrolizumab.…”

“…In R/R FL, the ORR was 40% with nivolumab in a phase 1b trial 107 and 80% with combined pembrolizumab and rituximab in a phase 2 trial (interim results). 112 In R/R DLBCL, the ORR with nivolumab was 36% in a phase Ib trial. 107 In R/R PMBCL, the ORR with pembrolizumab was 41% in a phase 1b trial 109 and 35% in a phase 2 trial (interim results).…”

New developments in immunotherapy for lymphoma

“…Preliminary results from these novel treatment approaches are encouraging, demonstrating improved response rates 102,103 . …”

Cancer Immunotherapy and the Immune Response in Follicular Lymphoma

“…Regarding checkpoint blockade, it can be expected that a combinational approach of passive immunotherapy (anti-CD20) with anti-PD1 antibodies has potential. At the ASH meeting 2017, first data from a trial combining rituximab with pembrolizumab were shown ( 30 ). Here, 30 patients with relapsed FL received rituximab plus pembrolizumab for a total of 16 infusions.…”