Meletios Dimopoulos, MD
Single-agent ibrutinib (Imbruvica) induced a response rate of 90% at a median follow-up of 18.1 months in rituximab-refractory patients with Waldenstrom macroglobulinemia, according to results from an open-label substudy of the ongoing phase III iNNOVATE trial published in The Lancet Oncology
The estimated 18-month progression-free survival (PFS) rate was 86% (95% CI, 66-94), and the
estimated 18-month overall survival (OS) rate was 97% (95% CI, 79-100).
“Patients with disease refractory to rituximab have few options. From a clinical point of view, ibrutinib is the treatment of choice for all pretreated patients with Waldenstrom macroglobulinemia,” lead study author Meletios-Athanassios Dimopoulos, MD, said in an interview with OncLive
“We confirmed the outstanding activity of ibrutinib in Waldenstrom macroglobulinemia and we reported that this agent is equally active in patients with disease refractory to rituximab,” added Dimopoulos, professor and chairman of the Department of Clinical Therapeutics at the University of Athens School of Medicine.
The ongoing, randomized, placebo-controlled phase III iNNOVATE study is examining ibrutinib plus rituximab compared with rituximab plus placebo. This substudy of single-agent ibrutinib was an international, multicenter trial that was conducted at 19 sites in 7 countries.
The study enrolled 31 rituximab-refractory patients with a median age of 67 years (range, 58-74) between August 2014 and 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.
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.
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.