Dimopoulos, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Athens, Greece, presented the results at the 2018 ASCO Annual Meeting. The findings were simultaneously published in the New England Journal of Medicine.1,2
The combination reduced the risk for disease progression or death by 80% versus rituximab alone in patients with Waldenström macroglobulinemia. At a median follow-up of 26.5 months, the median progression-free survival (PFS) per independent review was not reached with the ibrutinib combination and was 20.3 months with rituximab alone (HR, 0.20; 95% CI, 0.11-0.38, P <.0001). The 30-month PFS rates were 82% versus 28%, respectively.
Investigators recruited 150 relapsed/refractory or treatment-naïve patients with confirmed symptomatic Waldenström macroglobulinemia into the double-blind, placebo-controlled, parallel assignment, randomized trial. Patients enrolled at 45 sites in 9 countries from July 2014 to January 2016.
Patients received intravenous rituximab at 375 mg/m2 once weekly for 4 straight weeks, followed by another 4-week rituximab course after a 3-month interval. Ibrutinib at 420 mg or placebo were taken once daily continuously. PFS was the primary endpoint, with secondary endpoints including overall response rate (ORR), hematological improvement measured by hemoglobin, time to next treatment, overall survival (OS), and safety.
Based on these findings, the FDA granted a priority review designation in June 2018 to a supplemental new drug application for use of ibrutinib (Imbruvica) in combination with rituximab as a treatment option across all lines of therapy for patients with Waldenström macroglobulinemia.
“With the combination of ibrutinib and rituximab, we were able to abrogate the adverse effect of these mutations,” he said. “We believe now that we have a new standard of care for the treatment of this disease and, in the future, we would like to have further improvements. We would like to increase the depths of response; we only had a minority of patients who achieved very good partial response or complete response.”
In an interview with OncLive, Dimopoulos discussed what he hopes to see in the final analysis of iNNOVATE and the development of future treatments for Waldenström macroglobulinemia.
OncLive: What was the rationale for this trial?
Dimopoulos: Waldenström macroglobulinemia is an unusual, low-grade lymphoplasmacytic lymphoma. Among active treatments for this disease, we have the anti-CD20 monoclonal antibody rituximab, which has been around for 25 years. It is one of the most frequent therapies given as a single agent. Among other agents, we have nucleoside analogues, we have proteasome inhibitors, and in the past few years, there has been a significant interest for treating this disease with BTK inhibitors. The first one was ibrutinib.
Two phase II studies have shown that single-agent ibrutinib is associated with responses in the majority of patients, which appear to be durable. As we know, ibrutinib is given orally on a daily basis without discontinuation.
In the iNNOVATE trial, we wanted to perform a prospective, placebo-controlled, randomized trial—this is a difficult task, because Waldenström’s macroglobulinemia is a rare disease—which would compare the standard of care, which is rituximab, with placebo versus rituximab with ibrutinib. In both arms, patients received rituximab. In one arm, they received placebo. In the other arm, they received ibrutinib [with rituximab].
The primary endpoint of the study was PFS, with secondary endpoints being OS, ORR, safety, and tolerability.
What were the findings?
At the time of the first interim analysis, we observed a highly significant, statistically very important difference in favor of the investigational arm, with a hazard ratio [per investigator assessment] of 0.22. With a median follow-up of 29 months, the median PFS with rituximab and placebo was 22 months, whereas it has not been reached for the investigational arm.
Furthermore, the ORR for patients treated with ibrutinib and rituximab was 92% if one takes into consideration minor responses, as well. Other clinically relevant observations were the abrogation of the IgM flood effect, which we see when patients get only rituximab, the elimination of the rituximab-associated diffusion reactions, and the very significant improvements of the hemoglobin, which occurred in 95% of the patients who were treated.