Pembrolizumab (MK-3475) in Combination with Standard RCHOP Therapy for Previously Untreated Diffuse Large B-Cell Lymphoma

Background: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) has served as standard therapy for previously untreated diffuse large B-cell lymphoma (DLBCL) for over a decade. However, a substantial proportion of patients will relapse. Immune checkpoint inhibition with the anti-PD-1 monoclonal antibody pembrolizumab has shown preliminary efficacy in previously treated non-Hodgkin lymphoma patients. Pembrolizumab in the first-line setting, with relatively intact host immunity and coexistence of malignant cells within the tumor microenvironment, may represent a window for effective application of immune checkpoint inhibition in DLBCL. However, the safety of pembrolizumab with chemotherapy in lymphoma, and anthracyclines in particular, remains undefined. We report preliminary results of the first known prospective trial of anti-PD1 therapy with anthracycline chemotherapy in lymphoma.

Methods: Patients age 18 years or older with previously untreated DLBCL, transformed lymphoma and grade 3 B follicular lymphoma of any stage for whom 6-cycle, curative-intent RCHOP is planned are eligible. Key inclusion include measurable disease, adequate organ function, and ECOG 0-2. Key exclusions are prior therapy for DLBCL, steroid administration within 7 days of treatment, and active autoimmune disease or any history of pneumonitis. The study is a phase I design adding pembrolizumab (200 mg IV q 3 weeks x 6) to RCHOP x 6, allowing omission of pembrolizumab doses as indicated and dose reductions of RCHOP per standard practice. A sample size of 20 will allow estimation of an expected 40% incidence of clinically relevant grade 3-5 toxicity, defined as any grade 3-5 toxicity excluding uncomplicated hematologic toxicity, with a +/-21% confidence interval. Exclusion of the upper bound (61%) of such events will suggest tolerability. Study accrual will be suspended if 2/20 patients either die or fail to complete 6 cycles of RCHOP, for any cause other than lymphoma progression. Immune-related adverse events, response rates, and event-free and overall survival data are recorded.

Results: 17 of 20 planned patients have started study therapy; safety data is available for 14 and is presented here. Of these, median age is 62 (range 38-72); NCCN-IPI is low, low-int, and high-int, and high in 2,6,6, and 0 pts respectively. 2/9 tested are double-expressors (MYC IHC >40%, BCL2 IHC>50%), and no pts. have double hit (now high-grade B-cell) lymphoma.

Eleven grade 3-5 clinically significant adverse have occurred, in 7 unique patients (7/14 patients, 50%). Eight serious adverse events occurred in 5 patients; none met criteria for reporting as an unanticipated event. One death occurred in the first accrued patient who had extensive gastric involvement by DLBCL, and died during cycle 1 of RCHOP of bleeding from the responding tumor bed despite maximal inpatient intervention. Two probable immune-related adverse events have been seen: grade 3 rash, resolving with steroid and not recurring on continuation of pembrolizumab and grade 1 hyperthyroidism. No instances of pneumonitis have been observed, and no serious immune-related adverse events were seen.

Ten pts have undergone PET-CT response assessment, and 8 have achieved PET negative complete remission. One pt. had primary refractory disease, and one had residual PET-avid lung nodules (Deauville X) later biopsied, showing a mixed inflammatory lesion with predominant T cells. Excluding the pt who died after cycle 1 due to tumor-associated bleeding, mean anthracycline dose was 96% of planned; two patients had RCHOP dose delays of 1 week; and 97% of planned pembrolizumab doses were given.

Conclusions: Standard RCHOP with pembrolizumab 200 mg q 3 weeks x 6 cycles appears safe, with toxicity so far similar to that expected with RCHOP alone. Mean anthracycline dose and complete remission rates appear favorable. Two immune related adverse events have occurred. These preliminary data suggest chemotherapy with pembrolizumab 200 mg IV q 3 weeks is safe, supporting further study of pembrolizumab with chemotherapy in lymphoid malignancies. Updated response, disease, and survival data will be presented as accrual continues.