Evaluating Pembrolizumab in Relapsed/Refractory B-Cell Lymphomas

Pembrolizumab showed clinical benefit in patients with relapsed/refractory B-cell lymphomas following CD19-directed CAR T-cell therapy according to research findings published in Blood.

Patients who responded to pembrolizumab had less exhausted CAR T and non-CAR T cells compared with non-responders. The researchers, led by Elise Chong, MD, of the University of Pennsylvania, suggest this “is likely more easily improved by PD-1 blockade, which may explain a lower threshold for activation of the cells after PD-1 blockade and subsequent higher proliferation.”

This phase I/IIa study enrolled patients with relapsed/refractory B-cell lymphomas who had received a single dose of CAR T-cells that expressed murine or human monoclonal antibody-derived CD19-specific single chain variable fragment.

Patients were treated with intravenous pembrolizumab 200 mg every three weeks for up to a year or until disease progression, therapy-limiting toxicity, or elective protocol discontinuation. Those who achieved complete response (CR) were eligible to discontinue treatment if they had been treated with at least eight pembrolizumab doses and received at least two cycles following CR documentation.

Assessments of response were performed every 12 weeks for up to two years following the initial pembrolizumab dose. While the investigators focused their analysis on safety, the study also examined the best overall response rate (ORR), three-month ORR, progression-free survival (PFS), and overall survival.

The study cohort included 12 patients who previously received CAR T-cells for their disease in two clinical trials. A total of 11 patients had diffuse large B-cell lymphoma, while one patient had follicular lymphoma (FL). The majority of patients (83%) had biopsy-documented lymphoma following CAR T-cells and each patient had a measurable disease following CAR T-cells. Approximately 75% of patients (n=9) had disease that was considered refractory to therapy, while the remaining 25% (n=3) relapsed following responses to CAR T-cells.

Overall, the median PFS following CAR T-cells was 2.8 months. The median duration between infusion to initial dose of pembrolizumab was 3.3 months. In the group of patients who relapsed following CAR T-cells, the median PFS was 26.2 months and the median time to initial pembrolizumab administration was 27.1 months.

The most common grade 3-4 adverse event was neutropenia (25%). Approximately one-quarter of the patients experienced grade 1/2 fever following the first pembrolizumab infusion. Low-grade fatigue was reported in two patients (17%). Only one patient had possibly related hyperbilirubinemia, and this patient was found to have unrelated cytomegalovirus infection and discontinued therapy.

Among the 12 patients who were considered evaluable for response, the best post-pembrolizumab ORR was 25%, which included one CR and two partial responses (PRs). The three-month ORR was 25%. The researchers reported that the three-month clinical benefit rate was 33%, which included one CR, two PRs, and one patient with stable disease. The patient with FL did not experience a response. No difference was observed in ORR or PFS according to prior CAR T-cell response or according to pre-treatment variables including age, lactate dehydrogenase elevation, Eastern Cooperative Oncology Group performance score, number of prior therapies, or absolute lymphocyte count.

Following treatment with pembrolizumab, four patients who had a clinical benefit experienced increased percentage of CAR T-cells by mass cytometry. Three of these patients experienced increases in CAR19 transgene levels. According to deep immune profiling, there was increased CAR T-cell activation and proliferation as well as less T-cell exhaustion in patients who were considered clinical responders.

The investigators concluded that while the study population was small, the findings “suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and non-responders that influence the clinical efficacy of PD-1 blockade administered in this setting.”

Study authors report no relevant conflicts of interest.

Reference

Chong EA, Alanio C, Svoboda J, et al. Pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19-directed CAR T-cell therapy [published online ahead of print, 2021 Sep 9]. Blood. doi: 10.1182/blood.2021012634.