The tumor microenvironment of follicular lymphoma (FL) is infiltrated with antitumor T-cells, but T-cell function may be impaired by immune checkpoints, such as the PD-1/PD-ligand pathway. In fact, blocking PD-1 enhances the function of antitumor T-cells in FL.1 In addition, blocking PD-1 on natural killer (NK) cells has been shown to enhance the antibody-dependent cell cytotoxicity (ADCC) effect of NK cells.2 Thus, it is reasonable that the combination of pembrolizumab, an anti–PD-1 antibody, and rituximab, an anti-CD20 antibody 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.
At ASH 2017, the authors presented the results of an open-label, nonrandomized, single-institution phase 2 trial evaluating pembrolizumab plus rituximab in patients with FL grade 1 to 3a who were in relapse after ≥1 prior therapies and with rituximab-sensitive disease (defined as a complete response [CR] or partial response [PR] lasting ≥6 months after the most recent rituximab-containing therapy).3 Patients received rituximab (375 mg/m2 intravenously) on days 1, 8, 15, and 22 of cycle 1 and pembrolizumab (200 mg intravenously) every 3 weeks for up to 16 cycles starting on day 2 of cycle 1. The primary end point was overall response rate (ORR).
A total of 32 patients initiated therapy and were evaluable for safety. Thirty patients had ≥8 infusions of pembrolizumab or stopped therapy due to progression or toxicity and were evaluable for efficacy. Adverse events (AEs) regardless of causality were mild, and were mostly grade 1/2. Grade 3/4 AEs included nausea/vomiting, diarrhea, transaminitis, and aseptic meningitis.
After median follow-up of 13.8 months, the ORR was 67% (CR, 50%; PR, 17%) among evaluable patients. Median duration of response was 14.1 months. Median progression-free survival (PFS) was 11.4 months. Of note, PFS was significantly longer among patients whose PFS with prior therapy was ≥1 years compared with patients who progressed within 1 year (13.8 vs 4.1 months, respectively; P = .01).
PD-L1 expression, which was tested in 19 baseline tumor samples, was present in 1% to 8% of tumor cells in 11 samples, but was not associated with response. Immune cell gene signature analysis in baseline tumors in 18 patients showed an association between the presence of high levels of CD8+ T-effector score and induction of a CR.
The authors concluded that pembrolizumab plus rituximab showed promising efficacy in relapsed FL, with meaningful ORR and CR rates. The combination also appears to be well-tolerated. Peripheral blood IFN-gamma gene signature may help identify patients most likely to respond to pembrolizumab plus rituximab, but must be validated.
- Nastoupil LJ, Neelapu SS. Curr Oncol Rep. 2015;17:30.
- Görgün G, et al. Clin Cancer Res. 2015;21:4607-4618.
- Nastoupil L, et al. ASH 2017. Abstract 414.