This article was written and published by Lesokhin A et al., from Memorial Sloan Kettering Cancer Centre, New York in the Journal of Clinical Oncology in August 2016; demonstrating data from an open label, phase I, dose escalation, cohort expansion study in patients (n=81) with Relapsed or Refractory B-Cell Lymphoma, T-Cell Lymphoma and Multiple Myeloma who received anti PD-1 monoclonal antibody, nivolumab (1 or 3 mg/kg) every two weeks.
The study objectives were:
To assess the safety and efficacy of nivolumab and to evaluate the PD-L1/PD-L2 locus integrity and protein expression.
The main findings were:
- Patients with follicular lymphoma (FL, n=10), diffuse large B-cell lymphoma (DLBCL, n=11), mycosis fungoides (MF, n=13), peripheral T-cell lymphoma (PTCL, n=5) demonstrated an overall response rate (ORR) of 40%, 36%, 15% and 40% respectively; ORR was not observed in patients (n=10) with other B-cell malignancies.
- Median follow-up observation time was more than 1 year (66.6 weeks) and there were long-lasting responses (range from 6.0 to 81.6+ weeks.
- Biomarker assessment by FISH analysis revealed chromosomal rearrangement involving PD-L2, associated with high level PD-L2 protein expression in malignant cells of a transformed MF (MF#1, results in appendix of the article).
- PD-L1 and to a lesser extent PD-L2 proteins were expressed by non-malignant cells within the microenvironment in non-Hodgkin’s lymphomas (NHL).
- The data in this study also highlights the difference in frequency of 9p24.1 alterations and associated expression of PD-1 ligands in specific lymphoid malignancies.
- Majority of adverse events (AEs) were drug related and of grade 1 or 2; incidence of severe or life threatening drug related AEs was found to be low across the disease cohorts. Most of the AEs were either managed by treatment with corticosteroids or discontinued due to pneumonitis (grade 2, n=1; grade 3, n=1).
Nivolumab showed encouraging results with a manageable toxicity profile in this population of extensively pre-treated patients with R/R B-cell or T-cell lymphomas. Genetic alterations of PD-L1 and PD-L2 were evaluated and found to be rare among NHLs; which is a stark contrast to the frequent 9p24.1 alterations seen in HLs. Studies involving combinations of nivolumab with rituximab, ipilimumab and other immuno-oncology therapies are currently ongoing to determine whether response rates and duration of response achieved in nivolumab monotherapy can be improved, particularly in B-cell lymphoma subtypes.
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.
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.
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.
Nivolumab was well tolerated and exhibited antitumor activity in extensively pre-treated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.
- Lesokhin A et al., Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol 2016 Aug 10:34(23):2698-704. doi: 10.1200/JCO.2015.65.9789. Epub 2016 Jun 6.