Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study

Abstract

Purpose: Cancer cells can exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity. In part, this may occur through overexpression of PD-1 and PD-1 pathway ligands (PD-L1 and PD-L2) in the tumor microenvironment. PD-1 blockade has produced significant antitumor activity in solid tumors, and similar evidence has emerged in hematologic malignancies.

Methods: In this phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma, T-cell lymphoma, and multiple myeloma received the anti-PD-1 monoclonal antibody nivolumab at doses of 1 or 3 mg/kg every 2 weeks. This study aimed to evaluate the safety and efficacy of nivolumab and to assess PD-L1/PD-L2 locus integrity and protein expression.

Results: Eighty-one patients were treated (follicular lymphoma, n = 10; diffuse large B-cell lymphoma, n = 11; other B-cell lymphomas, n = 10; mycosis fungoides, n = 13; peripheral T-cell lymphoma, n = 5; other T-cell lymphomas, n = 5; multiple myeloma, n = 27). Patients had received a median of three (range, one to 12) prior systemic treatments. Drug-related adverse events occurred in 51 (63%) patients, and most were grade 1 or 2. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma, diffuse large B-cell lymphoma, mycosis fungoides, and peripheral T-cell lymphoma, respectively. Median time of follow-up observation was 66.6 weeks (range, 1.6 to 132.0+ weeks). Durations of response in individual patients ranged from 6.0 to 81.6+ weeks.

Conclusion: Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.

Trial registration: ClinicalTrials.gov NCT01592370.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2016 by American Society of Clinical Oncology.

Figures

Fig 1.

Kinetics of response for individual patients with (A) diffuse large B-cell lymphoma (DLBCL), (B) follicular lymphoma (FL), (C) mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL), and (D) peripheral T-cell lymphoma (PTCL) who were treated with nivolumab 3 mg/kg. The horizontal line at –50 indicates the threshold for defining an objective response in DLBCL, FL, MF-CTCL, and PTCL. Most objective responses were sustained. The DLBCL and FL groups had individuals with responses maintained beyond 88 weeks. (closed square) first response; (X) first occurrence of new lesion.

Fig 2.

Immunohistochemical staining for PD-L1 in patient biopsy samples. (A) Orientation of chromosomal probes for fluorescent in situ hybridization. (B) Fluorescent in situ hybridization analysis of MF #1 (left) and disruption of chromosome 9 between PD-L1 and PD-L2 and three copies of chromosome 9 (arrowheads) and of MF #3 (right), which shows disomy 9. (C) Immunohistochemical staining of MF #1 (top and bottom left) and MF #3 (top and bottom right) for PD-L1 (brown = positive staining [top]) and for PD-L2 (brown) and for pSTAT3 (red [bottom]). Images in (B) and (C), magnification ×1,000. Scale bars = 50 μm. MF, mycosis fungoides; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2; pSTAT3, phosphorylated signal transducer and activator of transcription 3.

Fig 3.

Immunohistochemical staining for programmed death ligand 1 (PD-L1; brown) and the B-cell lineage marker PAX5 (red) in three cases of follicular lymphoma (FL) show positive cell membrane expression of PD-L1 among the nonmalignant (PAX5-negative) cells within the tumor microenvironment. Magnification, ×1,000. Scale bars = 50 μm.