Avelumab combined with R-CHOP [rituximab plus cyclophosphamide, hydroxydaunomycin, oncovin] yielded high rates of complete response with manageable toxicity in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), according to data presented at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.

“Novel strategies are needed to improve upon the 60% cure rate of upfront R-CHOP in advanced DLBCL. Single-agent immune checkpoint inhibition (ICI) has limited efficacy in heavily pre-treated DLBCL (response rate <10%), potentially due to residual immunocompromise from prior therapy. Frontline ICI, given when host immunity is relatively intact, may improve these outcomes,” explained Eliza A Hawkes, FRACP, MD, MBBS, Department of Medical Oncology and Haematology, Eastern Health, Box Hill, Australia, and colleagues.

“Avelumab is an anti-PDL1 monoclonal antibody with antibody-dependent cell cytotoxicity (ADCC) activity which acts synergistically with rituximab in vitro. We report the results of phase II single-arm study assessing safety of 1st line sequential avelumab plus rituximab induction, R-CHOP and avelumab maintenance for DLBCL,” they added.

With this in mind, investigators identified 28 patients over 18 years of age, with an ECOG status of 0-2, untreated stage II-IV DLBCL, and no active autoimmune disease, to participate in their study. Patients received avelumab (20mg/kg IV) plus rituximab (375mg/m2 IV) induction 2 cycles, twice weekly, followed by R-CHOP21 for 6 cycles. If the patient is in complete metabolic response (CMR) post-R-CHOP, they then receive avelumab 10mg for 6 cycles twice weekly. 

The primary endpoint was the rate of grade 3/4 immune-related adverse events (AEs), while secondary end points included overall response rate (ORR), failure-free survival (FFS), overall survival (OS), and overall toxicity. 

The response was determined centrally by PET-CT (Lugano 2014 criteria). The exploratory endpoints were CMR rates by PET-CT post avelumab with rituximab induction and following the second cycle of R-CHOP. Genomic analysis, including next-generation sequencing (NGS) based sequence variant detection, copy number analysis, and structural variant detection, was performed.

The ORR to 2 cycles of induction avelumab plus rituximab was 60% including 6 CMR (21%) across all diagnostic/histologic subgroups (n = 1 PMBCL, n=2 non-GCB DLBCL, n = 3 GCB DLBCL) while ORR post R-CHOP was 89% (all CR). Although 6 patients (21%) progressed during the induction stage (with 1 patient completing only 1 cycle), they all subsequently responded to R-CHOP. After a median follow-up of 16 months, 1-year FFS was 76% and OS 89%.

The study met its pre-specified primary endpoint of G3/4 irAE <30%. Grade 3/4 irAEs included hepatitis (n=1) and rash (n=2) Grades 1 and 2 irAEs occurred in 71% of patients, with the most common being rash 53%, liver dysfunction 26%, hyper/hypothyroidism, 29%, and diarrhea. 79% had grade 3/4 toxicity, the most common being hematologic AEs related to R-CHOP, with 28% of patients experiencing febrile neutropenia/infection. 5 patients had to discontinue treatment early, 2 during R-CHOP due to progressive disease, 3 during avelumab maintenance.

“Sequential avelumab plus rituximab induction, R-CHOP and avelumab maintenance in patients with newly diagnosed DLBCL is feasible with a manageable toxicity profile and a high CR rate. Responses to avelumab plus rituximab alone were higher than expected based on the relapsed/refractory population and may suggest superior efficacy of ICI in the frontline setting,” wrote Dr Hawkes et al. 

“These results support ongoing sequential studies of immune priming with PD1/PDL1 inhibition prior to R-CHOP in DLBCL,” they concluded.—Alexandra Graziano

Eliza A Hawkes, Geoffrey Chong, Charmaine Smit, et al. Safety and Efficacy of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of the Phase II Avr-CHOP Study. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 597.