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Ibrutinib, nivolumab combination may provide new option in non-Hodgkin lymphoma subtypes
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ATLANTA — Combination therapy with ibrutinib and nivolumab appears safe and effective for several subtypes of relapsed, refractory non-Hodgkin lymphoma, with clinical response rates in Richter’s transformation that “exceeded expectation,” according to findings presented at the ASH Annual Meeting and Exposition.
“This clinical trial was based on preclinical experiments reported by colleagues at Stanford and elsewhere that demonstrated potential synergy between these two agents against a variety of cancers, including lymphoma,” Anas Younes, MD, chief of lymphoma service at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “Because the single-agent response rate of checkpoint inhibitors was somewhat low, it was hoped that the combination would produce higher responses [among] patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia.”
To examine the impact of this combination, Younes and colleagues conducted a two-part study. Part A, which used a modified toxicity probability interval design, focused on establishing the safety of oral ibrutinib when given every day at the standard doses of 420 mg in CLL, follicular lymphoma and DLBCL and 560 mg in follicular lymphoma and DLBCL. Nivolumab 3 mg/kg was administered intravenously every two weeks.
In Part B, the researchers evaluated the combination in four expansion cohorts. The first cohort comprised patients with relapsed or refractory CLL and small lymphocytic lymphoma who had never been treated with ibrutinib or a PD-1 inhibitor and included individuals with deletion of 17p and 11q. The second, third and fourth cohorts included patients with follicular lymphoma; DLBCL — including patients with germinal center B-cell and activated B-cell origin subtypes; and Richter’s transformation. Patients with CLL and small lymphocytic leukemia enrolled in Part B received 420 mg ibrutinib and nivolumab; patients with follicular lymphoma, DLBCL and Richter’s transformation received 560 mg ibrutinib and nivolumab.
The median time on study for 71.4 weeks for patients with CLL, 78.1 weeks for those small lymphocytic leukemia, 65.5 weeks for follicular lymphoma, 19.9 weeks for DLBCL and 12.8 weeks for Richter’s transformation.
Part A included 14 patients. One patient experienced dose-limiting toxicity from grade 3 hyperbilirubinemia that resolved after 5 days. Researchers concluded that the combination of oral ibrutinib 420 mg or 560 mg once daily and intravenous nivolumab every 14 days “displayed an acceptable safety profile.”
The researchers enrolled 127 more patients (median age, 65 years; range, 20-89; 61.7% men) in Part B, for a total study population of 141 patients. Part B included 35 patients with CLL and small lymphocytic leukemia, 35 patients with follicular lymphoma, 37 patients with DLBCL and 20 patients with Richter’s transformation.
The median number of prior therapies was 3 (range, 1-12) and the median time on study was 71.4 weeks for CLL, 78.1 for small lymphocytic leukemia, 65.5 for follicular lymphoma, 19.9 for DLBCL and 12.8 for Richter’s transformation.
Median follow-up was 15.9 months (range, 1.7-25.5) for CLL, 17.02 months (1.9-17.7) for small lymphocytic leukemia, 13.34 months (0.7-21.3) for follicular lymphoma, 14.75 months (0.4-19.2) for DLBCL and 4.6 months (1.4-11.1) for Richter’s transformation.
The overall response rate among patients with CLL was 83.3%, including complete responses, partial responses and partial responses with lymphocytosis. ORR was 66.7% for small lymphocytic leukemia, 30% for follicular lymphoma, 35.6% for DLBCL and 60% for Richter’s transformation.
Initial results suggested that median PFS “was immature and subject to maturation with longer follow-up for CLL [and] not estimable due to lack of events for small lymphocytic leukemia,” according to the researchers. Median PFS was 5.5 months (95% CI, 2.9-12.7) for follicular lymphoma, 3.2 months (95% CI, 2-4.7) for overall DLBCL — 4.1 months (95% CI, 2.1-7.6) for non-transformed DLBCL and 1.9 months (95% CI, .7-4.7) for transformed DLBCL — and 3.6 months (95% CI, 1.4-not estimable) for Richter’s transformation.
Researchers observed a trend toward greater complete response and PFS among patients with DLBCL who had elevated PD-L1 protein staining — 5% or more of tumor cells — by central immunohistochemistry analysis. Among patients with Richter’s transformation, two of eight responders — defined as partial response or better — had raised PD-L1 staining. No other cohorts demonstrated increased PD-L1 staining.
The most commonly reported grade 1 to grade 2 adverse events among all patients included diarrhea (31%), pyrexia and fatigue (23% each). The rate of grade 3 to grade 4 neutropenia ranged from 24% in DLBCL to 56.7% in CLL; febrile neutropenia occurred in 2% of patients with CLL, 5% with Richter’s transformation and 13% with DLBCL. The prevalence of grade 3 to grade 4 anemia ranged from 20% among patients with follicular lymphoma and Richter’s transformation to 24% among patients with DLBCL. Immune-related adverse events occurred in 46.8% of all patients and were commonly grade 1 to grade 2; immune-related adverse events of grade 3 or higher occurred in 13.5% of patients and most commonly included rash and increased alanine aminotransferase.
Adverse events led to treatment discontinuation in 27% of patients and death in 6.4%, although these deaths “were considered unrelated to study drugs,” according to the researchers.
“The combination of ibrutinib and nivolumab at full doses displayed an acceptable safety profile [for] patients in relapsed or refractory non-Hodgkin lymphoma. The ORR was comparable to those observed with single-agent ibrutinib in CLL, small lymphocytic leukemia, follicular lymphoma and DLBCL,” the researchers wrote. “Historical results demonstrate poor outcomes [among] patients with Richter’s transformation treated with single-agent ibrutinib or with chemotherapy. In this study, the rate of clinical response observed [among] patients with Richter’s transformation exceeded expectation and may support further clinical evaluation.”
Biomarker analysis will be used to determine which patients may achieve the greatest benefit from this combination, according to the researchers. – by Julia Ernst, MS
Reference:
Younes A, et al. Abstract 833. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Younes reports a consultant role with Roche; honoraria from Bayer, Bristol-Myers Squibb, Celgene, Incyte, Janssen, Merck, Roche, Sanofi, Seattle Genetics and Millenium/Takeda; research funding from Curis, Johnson & Johnson and Novartis; and providing third-party medical writing assistance that was funded by F. Hoffmann-La Roche Ltd. Please see the abstract for all other authors’ relevant financial disclosures.