Safety and activity of pembrolizumab in combination with rituximab in relapsed or refractory follicular lymphoma

Abstract

PD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody, and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) with rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles, and rituximab was given at 375 mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AEs) were liver enzyme abnormalities (3%), diarrhea (3%), nausea (3%), aseptic meningitis (3%), and pancreatitis (3%). Low-grade immune-related AEs were reported in 80% of patients, including diarrhea (43%), liver enzyme abnormalities (33%), thyroid dysfunction (27%), and rash (23%). Grade 3 or 4 immune-related AEs occurred in 13% of the patients. Treatment-related AEs led to discontinuation in 6 (20%) patients. The overall response rate (primary end point) was 67%, and the complete response (CR) rate was 50%. Median progression-free survival (PFS) was 12.6 months (95% confidence interval, 8.2-27.6), the 3-year overall survival rate was 97%, and 23% of patients were in remission at a median follow-up of 35 months. The presence of a high CD8+ T-effector score at baseline in the tumor was associated with induction of a CR and improved PFS. In this single-arm, phase 2 study, the combination of pembrolizumab and rituximab demonstrates favorable efficacy and safety profile in relapsed FL. This trial is registered at www.clinicaltrials.gov as #NCT02446457.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Kaplan-Meier curves. PFS (A); duration of response (B); PFS by high or low tumor burden according to GELF criteria (C); PFS by PD <1 year or PD >/=1 year from prior treatment (D); OS in patients with R/R FL receiving pembrolizumab+rituximab (E). E, number of events; N, sample size.

Figure 2.

Immune profiling of pretreatment tumor samples by gene signatures. (A) Core tumor biopsy specimens (n = 18) were profiled by using the ∼1500-gene custom NanoString panel. Relative expression of signatures of 9 different immune cell subsets and tumor B cells are shown as heat map with samples ranked by CD8 Teff score. (B) ORR and CR rates stratified by CD8 Teff score. (C) PFS based on CD8 Teff score. FDC, follicular dendritic cell; NA, not assessable; PD, progressive disease; pDC, plasmacytoid dendritic cell; SD, stable disease; Teff, T-effector cell; TFH, T follicular helper cell; E, number of events; S, sample size.