Preclinical studies have demonstrated synergistic antitumor activity when immune checkpoint inhibitors targeting the PD-1/PD-L1 axis were combined with the Bruton’s tyrosine kinase inhibitor, ibrutinib.1 At ASH 2017, the authors reported on the results of a phase 1/2a study evaluating the safety and efficacy of ibrutinib in combination with nivolumab in patients with relapsed or refractory (R/R) high-risk, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and Richter’s transformation (RT).2
The study was initiated with part A to establish the safety of oral ibrutinib administered at the approved doses of 420 mg (CLL, FL, DLBCL) and 560 mg (FL, DLBCL) daily in combination with standard, intravenous nivolumab dosing of 3 mg/kg every 2 weeks. In part B, the efficacy of this combination was examined in 4 expansion cohorts: patients with R/R ibrutinib- and PD-1 inhibitor–naïve CLL and SLL (including deletion 17p and 11q), FL, DLBCL, and RT. Part A demonstrated that the combination of oral ibrutinib (420 or 560 mg daily) and nivolumab (every 14 days) has an acceptable safety profile. In part B, 141 patients were enrolled—36 patients with CLL and SLL, 40 patients with FL, 45 patients with DLBCL, and 20 patients with RT. They were heavily pretreated with a median of 3 prior therapies (range, 1-12).
Among these 141 patients, the incidence of grade 3/4 adverse events was 82%. The most common grade 3/4 events included neutropenia (28%; febrile neutropenia in 4%), anemia (23%), and thrombocytopenia (18%). Grade 3/4 nonhematologic adverse events included rash (10%), pneumonia (9%), increased lipase (6%), hypokalemia (6%), and hyponatremia (5%).
The overall response rate (ORR; complete response + partial response [PR]) was 75% for CLL/SLL (including PR with lymphocytosis), 32% for FL, 36% for DLBCL, and 65% for RT. Median progression-free survival was not reached in patients with CLL/SLL, 9 months for FL, 3 months for DLBCL, and 5 months for RT. Median durations of follow-up for CLL/SLL, FL, DLBCL, and RT were 20, 20, 18, and 9 months, respectively.
The authors concluded that the combination of ibrutinib and nivolumab at full doses resulted in an ORR that was comparable to those observed with single-agent ibrutinib in CLL/SLL, FL, and DLBCL. However, historical results reveal poor outcomes in patients with RT treated with single-agent ibrutinib or with chemotherapy, such that the rate of clinical response observed in patients with RT treated with ibrutinib plus nivolumab supports further clinical evaluation. Biomarker analysis is ongoing to identify patients who may benefit most from this novel therapy.
- Xu-Monette ZY, et al. Blood. 2017 Nov 8. pii: blood-2017-07-740993. doi: 10.1182/blood-2017-07-740993. Epub ahead of print.
- Younes A, et al. ASH 2017. Abstract 833.