Meletios Dimopoulos, MD
The combination of ibrutinib (Imbruvica) plus rituximab (Rituxan) improved progression-free survival (PFS) versus rituximab alone in patients with Waldenström macroglobulinemia enrolled in the phase III iNNOVATE (PCYC-1127) trial.
Based on these findings, an independent data monitoring committee recommended that the study be unblinded. In a press release, the co-developers of ibrutinib, Pharmacyclics and Janssen, reported that they intend to present the results at an upcoming medical meeting and discuss the findings with regulatory authorities.
"This is a first-of-its-kind prospective randomized trial in Waldenstrom macroglobulinemia [WM]," Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, said in a statement. "The full report of this study will be of important clinical significance regarding the benefits of the combination of ibrutinib with rituximab in patients with WM."
The double-blind, placebo-controlled, randomized phase III iNNOVATE trial included 150 relapsed/refractory or treatment-naïve patients with WM. Patients received IV rituximab at 375 mg/m2
once weekly for 4 straight weeks, followed by another 4-week rituximab course after a 3-month interval. Ibrutinib (420 mg) or placebo were taken once daily continuously. PFS was the primary endpoint, with secondary endpoints including overall response rate, hematological improvement measured by hemoglobin, time-to-next treatment, overall survival (OS), and safety.
Results were previously published for an open-label substudy of iNNOVATE that explored single-agent ibrutinib in WM. The substudy enrolled 31 rituximab-refractory patients with a median age of 67 years (range, 58-74) between August 2014 and February 2015. Thirteen patients (42%) had high-risk disease and the median number of prior therapies was 4 (range, 2-6).
Patients received 420 mg of oral ibrutinib once a day until disease progression, unacceptable toxicity, or withdrawal of consent. After the first occurrence of a drug-related grade 3 or worse adverse event, such as grade 4 neutropenia for more than 7 days or grade 3 or 4 thrombocytopenia, ibrutinib was withheld until resolution of the event to baseline or grade 1 or lower, after which resuming treatment at full dose was permitted.
Efficacy and safety assessments were done every 4 weeks for the first 6 months, and then every 8 weeks by laboratory assessment and physical exam. In addition, all patients had baseline imaging by CT of the neck, chest, abdomen, and pelvis. The patients with evidence of nodal or extranodal disease were followed up with CT scans every 16 weeks for the first 2 years and then every 24 weeks until confirmed disease progression.
CT-identified splenomegaly was reported in 6 of the 31 patients at baseline. Of the 6 patients with splenomegaly, 5 experienced a reduction in splenic enlargement and 1 patient discontinued treatment before response assessment.
The main objectives of this study were overall response, PFS, OS, hematological improvement measured by hemoglobin, time to next treatment, and patient reported outcomes. PFS, which was assessed by investigators, was defined as the duration from the date of treatment initiation to the date of disease progression or death.
The estimated 18-month PFS rate was 86% (95% CI, 66-94), and the estimated 18-month OS rate was 97% (95% CI, 79-100). After 4 weeks, the median baseline IgM of 3920 mg/dL declined by 48% with continued improvement over time. Baseline median hemoglobin of 10.3 g/dL increased to 11.4 g/dL after 4 weeks and reached 12.7 g/dL at week 49.
Common grade 3 adverse events that experienced included neutropenia in 4 patients (13%), hypertension in 3 patients (10%), and anemia, thrombocytopenia, and diarrhea in 2 patients each (6%). There were 10 patients (32%) who experienced serious adverse events, which were most often infections. Overall, 26 patients (84%) continued ibrutinib at the time of the report, while 3 patients discontinued due to progression and 2 discontinued due to adverse events.
The FDA approved single-agent ibrutinib for patients with WM in January 2015, based on results from a phase II study.
Dimopoulos MA, Trotman J, Tedeschi A, et al. Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. The Lancet Oncology. 2017;18(2):241-250. doi:10.1016/s1470-2045(16)30632-5.