IN THE LITERATURE
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 lym-
phoma (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 treat-
ment 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 pa-
tient 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
14
Focus on Lymphoid Malignancies
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 previ-
ous 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 partici-
pants, 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 combina-
tion regimen for [patients with relapsed or refractory B-cell ma-
lignancies].” 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.
REFERENCE
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.