Combination of Ibrutinib and Nivolumab Appears Similar to Single-Agent Therapy in Early-Phase Trial

According to results from a phase I/II trial published in Lancet Haematology, treatment with a combination of ibrutinib and the checkpoint inhibitor nivolumab was safe and feasible for patients with relapsed or refractory B-cell malignancies, with notable efficacy in patients with Richter transformation. However, the combination showed similar safety and efficacy to single-agent ibrutinib or nivolumab, questioning the value of added treatment.

“In the present study, the combination of ibrutinib with nivolumab had a safety profile that was consistent with the known profile of each agent alone,” the authors, led by Anas Younes, MD, from Memorial Sloan Kettering Cancer Center in New York, wrote. Also, “the proportion of patients [responding to] ibrutinib in combination with nivolumab was similar to that for single-agent ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).”

This two-part, open-label, phase I/IIa study was conducted in 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the U.S., with a total of 141 patients. Eligible participants had an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2. Diagnoses included: relapsed or refractory high-risk CLL or SLL (n=36), FL (n=40), DLBCL (n=45), and Richter transformation (n=20).

In the dose-escalation cohort (part A), 14 patients received ibrutinib (420 mg or 560 mg once daily) plus nivolumab (3 mg/kg, intravenously infused for 1 hour every 2 weeks) in 14-day treatment cycles. In the dose-expansion cohort (part B), 127 patients received the recommended phase II once-daily dose identified in part A plus nivolumab.

The authors found that the combination of ibrutinib and nivolumab demonstrated “manageable safety.” One dose-limiting toxicity (grade 3 hyperbilirubinemia) occurred at the ibrutinib 420-mg dose in the DLBCL cohort, though this event resolved after five days.

Common all-grade adverse events (AEs) included diarrhea (33%), neutropenia (31%), and fatigue (26%), while common grade 3/4 AEs included neutropenia (28%) and anemia (23%), which the authors noted “were slightly higher in our study than in studies of single-agent ibrutinib or nivolumab in similar patient populations.” They added that “the proportion of treatment discontinuations attributable to AEs in [the CLL/SLL and FL cohorts] was higher with the combination regimen than with single-agent treatments.”

Toxicity profiles differed by disease type; for example, the incidence of grade 3-4 neutropenia was greater in patients with CLL/SLL than patients with DLBCL (53% vs. 18%), while grade 3-4 anemia occurred in a smaller proportion of patients with FL than those with Richter transformation (13% vs. 35%; p values not reported).

A small proportion of patients (n=11; 8%) experienced an AE leading to death (8%), but none were considered related to the study drugs. Overall, the authors wrote, “the safety profile of the combination regimen was consistent with safety data from previous clinical studies of single-agent ibrutinib and nivolumab.”

At a median follow-up of 21.5 months (interquartile range [IQR] = 19.6-22.6 months), the overall response rates were:

  • CLL/SLL: 61%
  • FL: 33%
  • DLBCL: 36%
  • Richter transformation: 65%

Among the entire cohort, the median duration of responses ranged from 19.2 months (IQR=9.4-19.4) in the CLL/SLL cohort to 6.9 months (IQR=1.4 months to not estimable) in the Richter transformation cohort. Median overall survival was not reached in the CLL/SLL or FL cohorts and was 13.5 months in the DLBCL cohort and 10.3 months in the Richter transformation cohort.

Limitations of the study include its small number of participants, the exploratory nature of the analysis, lack of randomized allocation to each protocol, and the relatively short follow-up for most patients.

Overall, the researchers cautioned, “Because of the added toxic effects, the risk-benefit ratio does not favor the combination regimen for [patients with relapsed or refractory B-cell malignancies].” However, the higher efficacy findings in the Richter transformation cohort “warrant further clinical assessment of ibrutinib combined with nivolumab for [this setting].”

The authors report relationships with Bristol-Myers Squibb, the manufacturer of nivolumab, and Janssen, the manufacturer of ibrutinib, which sponsored the trial.


Younes A, Brody J, Carpio C, et al. Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study. Lancet Haematol. 2019;6:e67-e78.