Ianalumab plus ibrutinib showed promising efficacy and uMRD rates with manageable safety in a phase 1b study of patients with CLL.
The addition of ianalumab to ibrutinib (Imbruvica) led to an overall response rate (ORR) of 59% at cycle 9 in 39 patients with ibrutinib (Imbruvica)–pretreated chronic lymphocytic leukemia (CLL), according to findings from a phase 1b trial (NCT03400176) published in Clinical Cancer Research.1
Among efficacy-evaluable patients (n = 39), the complete response (CR) rate was 35.9%, the CR with incomplete marrow recovery (CRi) rate was 2.6%, and the partial response (PR) rate was 20.5%. Stable disease (SD) and progressive disease (PD) occurred in 30.8% and 10.3% of patients, respectively.
In dose escalation (n = 15), the ORR was 40% (90% CI, 19.1%-64%). Six (40%) patients achieved CR, 6 (40%) achieved SD, and 6 (20%) had PD. The ORR during dose expansion (n = 24) was 70.8% (90% CI, 52.1%-85.4%). Eight (33.3%) achieved CR, 4.2% achieved CRi, 8 (33.3%) achieved PR, 6 (25%) achieved SD, and 4.2% had PD.
“In this phase 1b study, the combination of ianalumab and ibrutinib was well tolerated and resulted in almost half the patients achieving undetectable minimal residual disease [uMRD] status in blood or bone marrow. The present results suggest that adding ianalumab to ibrutinib for the treatment of patients with CLL may be a viable strategy to reduce the duration of BTK inhibitor therapy. However, a larger study is necessary to confirm this therapeutic hypothesis,” Kerry A. Rogers, MD, associate professor of internal medicine in the Division of Hematology at The Ohio State University Comprehensive Cancer Center–James in Columbus, and coauthors wrote in the discussion section of the publication.
Ianalumab is a human monoclonal antibody designed to deplete BAFF-R–positive B cells via antibody dependent cell–mediated cytotoxicity. Through its multimodal mechanism of action, ianalumab has shown better antileukemic activity than that of anti-CD20 monoclonal antibodies in preclinical models. Because ianalumab activates alternative NF-κB–dependent survival signaling than BTK inhibitors such as ibrutinib, investigators theorized the combination could show synergistic activity.
With this rationale in mind, investigators launched a phase 1b, open-label, multicenter, dose-escalation and dose-expansion trial that evaluated the safety, tolerability, and antitumor activity of ianalumab plus ibrutinib in adult patients with CLL. The recommended phase 2 dose (RP2D) as well as the pharmacokinetic and pharmacodynamic profiles of the combination were also defined.
During dose escalation, patients received the approved dose of 420 mg of oral ibrutinib once daily, plus either 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, and 9.0 mg/kg of intravenous (IV) ianalumab once every 2 weeks for up to eight, 28-day cycles. The 3.0-mg/kg dose level was selected as the RP2D for expansion. In the expansion phase, patients received 3.0 mg/kg of IV ianalumab once every 2 weeks in 1 of 2 cohorts: patients with (arm B) and without ibrutinib resistance at enrollment (arm A). After 6 cycles of therapy, patients with a CR discontinued ianalumab, continuing ibrutinib for another 2 cycles. Patients without a CR after 6 cycles of therapy continued both agents for the remaining 2 cycles.
The study included adult patients with a diagnosis of CLL per World Health Organization classification of hematologic disorders or International Working Group CLL guidelines.1,2 Patients must have received ibrutinib in the first line or after relapse and either not experienced a CR after more than 1 year of ibrutinib exposure or acquired a resistance mutation to ibrutinib. Also required was an ECOG performance status between 0 and 2 and platelet levels measuring at least 25 × 109/L without transfusion support within 7 days of the first dose of ianalumab.
Dose-limiting toxicity (DLT) within the first 28 days of therapy, as well as the incidence and severity of adverse effects (AEs) and serious AEs were the primary safety end points during dose escalation. The latter 2 end points were also assessed in dose expansion in conjunction with the rate of dose interruption, reduction, and dose intensity. Secondary end points during dose expansion included the rate of CR/CRi at the beginning of cycle 9, ORR, and clearance of ibrutinib resistance mutations.
Thirty-nine patients were enrolled in the escalation (n = 15) and expansion (n = 24) phases of the trial. During dose expansion, 19 patients were included in arm A and 5 patients were included in arm B.
With respect to all-comers, the median age was 65 years (range, 39-82), and 92.3% of patients had an ECOG performance status of 0.1 Twelve patients (30.8%), all of whom were enrolled in the ianalumab 3.0 mg/kg plus 420 mg ibrutinib expansion cohort (n = 27), had only received ibrutinib before enrollment. The median number of prior lines of therapy excluding ibrutinib was 1 (range, 0-14). A total of 8 patients (20.5%) had BTK C481S mutations, 4 (10.3%) had PLCc2 mutations, and 3 (7.7%) had BTK C481S and PLCc2 comutations. Six patients (15.4%) had 17p deletion, 32 (82.1%) had unmutated IGHV, and 20 patients (51.3%) had a complex karyotype. The median absolute lymphocyte count was 5.45 × 109/L (range, 0.47-202.16).
The median duration of exposure to ianalumab and ibrutinib was 5.52 months (range, 1.8-7.8 months) and 7.39 months (range, 1.8-8.5 months), respectively. A total of 32 patients (82.0%) completed the full duration of ianalumab exposure, having completed the sixth cycle of treatment. The primary reason for early discontinuation (18.0%) was PD (10.3%), followed by an AE, patient decision, and physician decision. Thirty patients (76.9%) completed the entire course of ibrutinib, having received all 8 cycles of therapy; 23.1% of patients discontinued early because of PD (12.8%).
Eleven patients (28.2%) received the additional 2 cycles of ianalumab, 10 of whom completed them in entirety.
In the expansion phase, the CR/CRi rate was 37.5% (90% CI, 21.2%-56.3%), which included 8 (33.3%) CRs, 1 (4.2%) CRi, 6 (25%) PRs, and 3 (12.5%) cases of SD. When looking at arm A, 47.4% of patients achieved CR/CRi; none in arm B experienced CR/CRi.
Approximately half (n = 17; 43.6%) of patients who chose to discontinue ibrutinib at or after the ninth cycle of treatment after achieving CR and/or uMRD were able to stay off therapy between 12.1 and 24.5 months.
During cycle nine, 17 patients (43.6%) had uMRD at the threshold of 10–4 in the blood or bone marrow. Thirteen patients (33%) had uMRD in their bone marrow and blood, and 4 patients achieved uMRD in the blood only.
In all patients, the median best percentage change from baseline to cycle 9 in blood and bone marrow MRD was –99.16% (range, –100.0% to –16.7%) and –99.98% (range, –100.0% to –1,346.3%), respectively.
No DLTs occurred in any dose level. Any-grade AEs occurred in all patients. Hyperglycemia was common, occurring in 41.0% of those in the first cycle, but was attributed to steroid premedication.
Grade 3 or greater AEs were experienced by 41.0% of patients, the most frequent being neutropenia/decrease in neutrophil count (15.4%), an increase in lipase levels (10.3%), hypophosphatemia (7.7%), decrease in lymphocyte count (5.1%), and an increase in amylase levels (5.1%).
Serious AEs were documented in 2 patients: 1 case of suspected treatment-related, grade 4 neutropenia/decrease in neutrophil count and grade 3 noncardiac chest pain deemed unrelated to treatment in the ianalumab 3.0 mg/kg plus ibrutinib 420 mg group, and 1 case of suspected treatment-related, grade 4 neutropenia/decrease in neutrophil count in the ianalumab 1.0 mg/kg plus ibrutinib 420 mg group.
Three patients received growth factor support, and no instances of neutropenia or decreased neutrophil count required treatment discontinuation. Moreover, no on-treatment deaths were reported during the study period.
“The addition of ianalumab to covalent BTK inhibition in the treatment of [patients with] CLL holds potential. The combination could offer a safer therapeutic option with improved selectivity and reduced [AEs] and possibly allow some patients to discontinue BTK inhibition after achieving uMRD, resulting in shorter treatment duration and lower toxicity,” the study authors concluded.
