A combination of pembrolizumab plus rituximab is well-tolerated in relapsed follicular lymphoma, leads to a high overall response rate, and induces a complete response in half of patients, according to a new study (J Clin Oncol 2017; doi:10.1200/JCO.2017.35.15_suppl.7519).
“Immune therapy, specifically with checkpoint inhibitors, appears to be promising for many patients with solid tumors. In the hematologic malignancies, efficacy has been most promising in relapsed/refractory chronic Hodgkin lymphoma. However, our study suggests the combination of rituximab and pembrolizumab in relapsed follicular lymphoma also appears promising. Identifying predictive biomarkers would be a great advancement given the number of treatment options available to these patients,” explained lead author Loretta Nastoupil, MD, Associate Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, in an interview with Oncology Times.
The rationale behind the combination in follicular lymphoma is based on the observation that follicular lymphoma tumors are infiltrated with anti-tumor T cells that may be impaired due to PD-1/PD-L1, explained Nastoupil. “Blocking PD-1 enhances the function of infiltrating antitumor T cells and may enhance the antibody-dependent cell-mediated cytotoxicity effect of natural killer cells. The addition of rituximab, an anti-CD20 antibody, to pembrolizumab was thought to be synergistic through activation of both the innate and adaptive immune systems and result in enhanced clinical activity in follicular lymphoma,” she said.
The researchers evaluated a combination of pembrolizumab and rituximab in an open-label, non-randomized, single-institution, phase II trial of 30 patients. The patients had follicular lymphoma grade 1-3a with an ECOG performance status of 0-1. They had to have relapsed after one or more prior therapies and had rituximab-sensitive disease, defined as a complete or partial response lasting at least 6 months after most recent rituximab-containing therapy.
Among the patients, median age 64 years, about three-quarters had intermediate- or high-risk FLIPI scores, and 50 percent met GELF criteria. They had received a median of two prior therapies and about three-quarters of them had received prior chemotherapy.
The 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.
At the preplanned interim analysis, 20 treated patients had evaluable efficacy data and 30 were evaluable for safety.
After a median follow-up of 8.2 months, the overall response rate was 65 percent, including a complete response rate of 50 percent. The best response was stable disease in three patients and four patients had progressive disease.
Grade 1/2 adverse events occurring in at least 10 percent of patients included fatigue (53%), eye pain/blurry vision (43%), nausea/vomiting and diarrhea (30% each), rash (23%), and dyspnea (13%). Two (7%) patients experienced grade 3 nausea/vomiting, and one (3%) patient had lymphopenia.
Immune-related adverse events included grade 1 diarrhea (20%), rash (10%), transaminitis (10%), and hypothyroidism (3%). Grade 2 immune-related adverse events of diarrhea (10%), rash (13%), pneumonitis (3%), and esophagitis (3%) occurred. There was one patient (3%) with grade 3 aseptic meningitis.
Four patients discontinued treatment due to grade 2 immune-related adverse events, which included diarrhea in two patients and one patient with rash and one patient with pneumonia.
The toxicity profile of the combination was favorable and similar to what has been described with either agent as monotherapy, suggesting no additive toxicity, Nastoupil said. Patients who were discontinued from pembrolizumab due to immune-mediated adverse events were grade 1-2; all had achieved a complete response as well.
“The preliminary results of our single-center, single-arm study of pembrolizumab in combination with rituximab in relapsed follicular lymphoma demonstrate noteworthy efficacy as measured by overall response rate and complete response rates and appears to be well-tolerated with infrequent grade 3 adverse events and no grade 4 or 5 adverse events observed to date,” reported Nastoupil.
She noted some limitations of the study: single-center, single-arm, small study size in a relatively good risk population, and relapsed not refractory follicular lymphoma with a median of two prior lines of therapy.
Nastoupil pointed out that the expression of PD-L1 seems to vary significantly among lymphoma subtypes, and the efficacy of single-agent PD-1 checkpoint inhibitors also varies significantly among these patients. “The response rate of single-agent nivolumab in relapsed follicular lymphoma is 40 percent, which is not good enough with the amount of available therapies for patients with follicular lymphoma,” she noted. “However, for those who responded, the responses were durable, suggesting PD-1 inhibition can be effective in follicular lymphoma, particularly if we can identify biomarkers that predict for response.”
Exploration of Biomarkers
The researchers are actively exploring biomarkers. “Similar to what has been described in follicular lymphoma, PD-L1 expression in pre-treatment tumors was low, 1-8 percent in five of eight tumors tested,” Nastoupil said.
A more robust biomarker may be identification of a favorable pre-existing endogenous anti-tumor T-cell response. “We observed an association with CD8+ T effector score and complete response rate. This work is ongoing with a larger sample size,” she explained. Identifying this predictive biomarker should influence future design of phase III trials, according to Nastoupil.
“Our response rate was notable, and the complete response rate striking and meaningful, particularly since pembrolizumab and nivolumab monotherapy were not impressive in phase I trials in follicular lymphoma,” she continued. “The combination of pembrolizumab and rituximab appears to be synergistic, and provides the rationale for further combination studies.”
The results highlight the promise of a combination with checkpoint inhibitor and CD20 antibody. “Is the combination synergistic or just additive? We need a larger population, randomized study to know,” Nastoupil noted.
A circulating T-cell phenotype may predict for response. “We don't need another effective combination in follicular lymphoma, where many options are already available. We need to identify patients who are more likely to respond to this approach. If we can identify patients who will benefit, then it will be worth developing this combination further,” she concluded.
Mark L. Fuerst is a contributing writer.