Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation

A Single-Arm, Phase II Study

Stephen M. Ansell, MD, PhD; Monique C. Minnema, MD, PhD; Peter Johnson, MD; John M. Timmerman, MD; Philippe Armand, MD, PhD; Margaret A. Shipp, MD; Scott J. Rodig, MD, PhD; Azra H. Ligon, PhD; Margaretha G.M. Roemer, PhD; Nishitha Reddy, MD; Jonathon B. Cohen, MD; Sarit Assouline, MD; Michelle Poon, MD; Manish Sharma, MD; Kazunobu Kato, MD, PhD; Selda Samakoglu, MD, PhD; Anne Sumbul, MS; Andrew Grigg, MD

Disclosures

J Clin Oncol. 2019;37(6):481-489. 

In This Article

Abstract and Introduction

Abstract

Purpose: Treatment options are limited for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Tumor cells can exploit the programmed death-1 checkpoint pathway to evade immune surveillance. In the current study, we evaluated the efficacy and safety of programmed death-1 blockade by nivolumab in patients with relapsed/refractory DLBCL.

Methods: In this phase II, open-label study, patients with relapsed/refractory DLBCL who were ineligible for autologous hematopoietic cell transplantation (auto-HCT) or who had experienced failure with auto-HCT received nivolumab 3 mg/kg every 2 weeks. We assessed the efficacy and safety of nivolumab as well as genetic alterations of 9p24.1.

Results: Among 121 treated patients, patients in the auto-HCT-failed cohort (n = 87) received a median of four nivolumab doses and a median of three doses were administered to those in the auto-HCT—ineligible cohort (n = 34). At a median follow-up of 9 months in the auto-HCT-failed cohort and 6 months in the auto-HCT—ineligible cohort, independently assessed objective response rates were 10% and 3%, and median durations of response were 11 and 8 months, respectively. Median progression-free survival and overall survival were 1.9 and 12.2 months in the auto-HCT-failed cohort and 1.4 and 5.8 months in the auto-HCT—ineligible cohort respectively. All three patients with complete remission—3% of the auto-HCT-failed cohort—had durable response (11 or more, 14 or more, and 17 months). Treatment-related grade 3 and 4 adverse events were reported in 24% of patients. The most common were neutropenia (4%), thrombocytopenia (3%), and increased lipase (3%). Of all evaluable samples for 9p24.1 analysis, 16% exhibited low-level copy gain and 3% had amplification.

Conclusion: Nivolumab monotherapy is associated with a favorable safety profile but a low overall response rate among patients with DLBCL who are ineligible for auto-HCT or who experienced failure with auto-HCT. Genetic alterations of 9p24.1 are infrequent in DLBCL.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma worldwide.[1] With standard front-line therapy, approximately two thirds of adult patients achieve long-term remission and others who experience chemosensitive relapse may benefit from autologous hematopoietic cell transplantation (auto-HCT).[2,3] However, patients with refractory DLBCL or those who are unsuitable for or who have experienced relapse after auto-HCT have limited treatment options,[4] with a median survival of only 6 to 10 months from progression.[3,5] Early results of chimeric antigen receptor T-cell therapy in small numbers of selected patients with refractory DLBCL are promising, but the technology is costly and longterm data are not available.[6] Accessible treatments that provide durable responses and improved outcomes are needed in this setting.

Programmed death-1 (PD-1) and its ligands PD-L1/PD-L2 are immune checkpoints that, in healthy populations, downregulate immune response and are crucial for maintaining self-tolerance and preventing autoimmunity.[7,8] Genes that encode PD-L1/PD-L2 are located on chromosome 9p24.1.[9] Genetic alterations at the locus lead to ligand overexpression, which is common in Hodgkin lymphoma (HL) but are yet to be fully characterized in DLBCL.[10–12] Overexpression of PD-L1 by tumor cells and on tumor-infiltrating nonmalignant cells in the tumor microenvironment has the potential to interact with PD-1–expressing T cells and B cells, which results in the inhibition of antitumor immune response.[7,8] Increased PD-L1 expression has been found in certain defined subtypes of large B-cell lymphoma (LBCL), such as primary mediastinal B-cell lymphoma and Epstein-Barr virus (EBV)–positive and select non–germinal center cell DLBCLs, and is associated with inferior overall survival (OS).[8,10,12,13] Thus, blockade of the PD-1/PD-L1 pathway may have the potential to exert antitumor effects in certain subsets of DLBCL.

Nivolumab is a fully human immunoglobulin G4 anti–PD-1 monoclonal antibody that blocks tumor cell signaling via the PD-1 pathway, which releases T cells from the inhibitory effects of tumor cells and restores T-cell–mediated antitumor immune responses.[14] In clinical trials, nivolumab monotherapy has demonstrated activity in solid tumors, including melanoma, non–small-cell lung cancer, renal cell cancer, and bladder cancer, among others,[15–18] and in relapsed/refractory classic HL (cHL).[19,20] In a phase I doseescalation study of nivolumab monotherapy in patients with relapsed/refractory hematologic malignancies, four of 11 patients with DLBCL demonstrated objective responses.[21] These preliminary results led to this phase II study, which evaluated the efficacy and safety of nivolumab monotherapy in patients with relapsed/refractory DLBCL after auto-HCT or who were not candidates for auto-HCT.

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