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

Methods

Study Design and Patients

This was a multicenter, single-arm, open-label, phase II study conducted in accordance with Good Clinical Practice and the Declaration of Helsinki and approved by the institutional review board and independent ethics committee. All patients provided written informed consent before trial enrollment.

Eligibility criteria included age 18 years or older and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had de novo DLBCL or transformed lymphoma (confirmed by biopsy before initiation of the study drug) that had either relapsed after high-dose conditioning chemotherapy and auto-HCT or was relapsed/refractory after two or more prior multiagent chemotherapy regimens if auto-HCT ineligible. Key exclusion criteria included prior therapy with any an antibody or drug specifically targeting T-cell costimulation or checkpoint pathways, prior allogeneic HCT, known CNS lymphoma, and history of interstitial lung disease.

Treatment

Patients received nivolumab 3 mg/kg intravenously over 60 minutes every 2 weeks until disease progression, unacceptable toxicity, or withdrawal from the study. Dose delays were permitted for drug-related adverse events (AEs), but dose escalations or reductions were not. Treatment beyond investigator-assessed disease progression was permitted in patients who did not experience rapid disease progression and who had investigator-determined clinical benefit from nivolumab and stable performance status.

Assessments

Efficacy. Patients were evaluated for tumor response according to the 2007 International Working Group response criteria for malignant lymphoma[22] using spiral computed tomography/magnetic resonance imaging. Evaluation was performed at baseline, beginning at week 9 and continuing every 8 weeks through the first 8 months of treatment, every 12 weeks during months 9 to 24, and then every 6 months thereafter until disease progression or until the patient initiated a preparative regimen for allogeneic or auto-HCT. Tumor assessments via fluorodeoxyglucose–positron emission tomography were performed at baseline and were required to confirm complete remission (CR). Baseline and all subsequent scans were submitted to an independent radiology review committee (IRC) for assessment.

Safety. Safety evaluations included assessment of AEs, clinical laboratory tests, and physical examination with assessment of Eastern Cooperative Oncology Group performance status. Local laboratory assessments were performed within 72 hours before dosing. After discontinuation from the study, safety evaluations were scheduled at the first follow-up visit (35 days from the last dose) and the second follow-up (80 days from the first follow-up visit). Patients were then observed every 3 months for ongoing treatment-related AEs and survival

Biomarkers. In patients with archival tumor biopsies, 9p24.1 genetic alterations were evaluated using a fluorescence in situ hybridization (FISH) assay. Probes encompassed CD274 (PD-L1) or PDCD1LG2 (PD-L2) and included a centromeric control. Copy number alterations were defined as previously described[11,23] on the basis of the target:control signal ratio in 50 analyzed tumor cells per DLBCL. Nuclei with a target:control signal ratio of 3 or more: 1 were defined as coamplified for PD-L1 and PD-L2, and those with a signal ratio of more than 1:1 but less than 3:1 were classified as having relative copy gain. Nuclei with a signal ratio of 1:1 were defined as either polysomic if more than two copies per probe or disomic if there were exactly two copies of the target and control probes.[11] For each patient, we noted the percentage and magnitude of 9p24.1 amplification, copy gain, polysomy, and disomy. Patients were classified by the highest observed level of 9p24.1 genetic alteration. Those with 9p24.1 copy gain lacked amplification and those with 9p polysomy lacked 9p24.1 copy gain or amplification. Chromosomal rearrangements that involved PD-L1 or PD-L2 were also detected with this assay.

We performed dual immunohistochemical staining of PD-L1 (clone 405.9A11)[24] and PAX5 (24/Pax-5; BD Biosciences, San Jose, CA) to delineate PD-L1 expression on tumor biopsies, as previously described.[19,23] H-score (0 to 300) was calculated by multiplying the percentage of malignant (PAX5dim+) cells with PD-L1–positive staining and the average intensity of staining (0 to 3 or more on 50 malignant cells).

Cell-of-origin (COO) assay by gene expression profiling was performed at Bristol-Myers Squibb by targeted expression directly from formalin-fixed, paraffin-embedded sections as previously described.[25] The HTG EdgeSeq DLBCL Cell of Origin Assay comprised probes that targeted 93 genes commonly assessed in lymphomas. Cell Of Origin was assigned using HTG proprietary software (HTG Molecular Diagnostics, Tucson, AZ).

In situ hybridization was performed for EBV-encoded RNA-1 (EBER-1) using formalin-fixed, paraffin-embedded tissue samples. We tested RNA preservation using a nonspecific positive control, and background was assessed with a negative control. Scoring was performed for EBV/EBER if RNA was preserved and score was greater than background. Scores were EBV/EBER positive nuclear staining of any intensity greater than background in tumor cells.

Outcomes

The primary end point was objective response rate (ORR), defined as either partial remission (PR) or CR, as assessed by IRC using the 2007 revised International Working Group criteria. Secondary objectives included duration of response (DOR) on the basis of IRC assessments, IRC-assessed CR rate and duration of CR, IRC-assessed PR rate and duration of PR (DOPR), IRC-assessed progression-free survival (PFS), and investigator-assessed ORR. OS, safety and tolerability, and biomarker assessment were among additional exploratory end points.

Statistical Analyses

Planned sample size was approximately 120 treated patients, divided into two treatment groups on the basis of prior auto-HCT failure (n = 90) or auto-HCT ineligibility (n = 30). The primary analysis population for safety and efficacy was all patients who had received one or more dose of nivolumab. The protocol had an interim analysis that allowed for discontinuation of the study as a result of a lack of efficacy; however, accrual was rapid and the protocol allowed continued enrollment while the interim analysis was performed. This resulted in complete accrual before the interim analysis was concluded. For the auto-HCT–failed cohort, the null hypothesis that the true ORR was 20% or less would be rejected if 25 or more responses were observed in 90 treated patients. For the auto-HCT–ineligible cohort, the sample size of 30 treated patients was determined such that if the observed number of patients with objective response was 10, the true ORR was larger than 17% with 95% confidence.

IRC-assessed ORR, CR, and PR rates, duration of CR, DOPR, and investigator-assessed ORR were summarized for both cohorts separately by binomial response rates and their corresponding two-sided 95% CIs. IRC-assessed DOR, PFS, and OS were analyzed by cohort using the Kaplan-Meier product-limit method with median values and two-sided CI. Survival rate at 6 months was estimated using Kaplan-Meier values from the survival curve. AEs were coded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.[26] All on-study AEs, serious AEs (SAEs), and treatment-related AEs and SAEs were tabulated according to worst grade per National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, by system organ class and Medical Dictionary for Regulatory Activities preferred term.

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