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FDA Approves First Chemotherapy-Free Treatment for Waldenström’s Macroglobulinemia

This morning, August 27, 2018, the US Food and Drug Administration (FDA) approved ibrutinib (IMBRUVICA, AbbVie) in combination with rituximab (RITUXAN) for the treatment of Waldenström’s macroglobulinemia. This combination is the first and only chemotherapy-free treatment option for patients with Waldenström’s macroglobulinemia.

“Ibrutinib/rituximab does potentially become that new standard of care because you can see that rpaid reduction in IGM, that rapid improvement in hemoglobin, and I think that’s important, but you also see a consistent response across all different types of mutation you see in Waldenström’s macroglobulinemia too,” said Mark Wildgust, vice president of Global Medical Affairs Oncology, Janssen, in an exclusive interview to Rare Disease Report ® at the 2018 American Society of Clinical Oncology (ASCO 2018) Annual Meeting. (See video below).

Outcomes from the phase 3 iNNOVATE (PCYC-1127) trial evaluating ibrutinib in combination with rituximab in 150 patients with previously untreated and relapsed/refractory Waldenström’s macroglobulinemia served as the basis for the approval. For the study, patients were randomized to receive 375 mg/m2 once-weekly, intravenously, for the duration of 4 consecutive weeks, followed by a second 4-weekly rituximab course following a 3-month interval. All participants were given either 420 mg of ibrutinib or placebo once daily until criteria for permanent discontinuation were met, AbbVie reports. Progression-free survival served as the trial’s primary endpoint, while secondary endpoints included overall response rate, hematological improvement measured by hemoglobin, time-to-next treatment, overall survival, and number of participants with adverse events within each treatment arm.

The ibrutinib/rituximab combination demonstrated a significant improvement in progression-free survival (PFS) compared with the use of rituximab alone (30-month PFS rates were 82% versus 28%, respectively) at a median follow up of 26.5 months. An 80% reduction in relative risk of disease progression or death compared with those only treated with rituximab (hazard ratio, 0.20; confidence interval: 0.11-0.38, P<0.0001) was also observed in patients who received the combination therapy.

The combination therapy displayed a strong safety profile, as no fatal AEs occurred. Meaningful reductions were also observed in any grade immunoglobin M flare (8% vs 47%) and grade 3 or higher infusion reactions (1% vs 16%).

“Ibrutinib has significantly advanced the treatment of Waldenström’s macroglobulinemia. The approval of ibrutinib and rituximab has added a new option for many Waldenström’s patients,” commented Steven P. Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia at the Dana-Farber Cancer Institute, associate professor at Harvard Medical School, and lead investigator of the IMBRUVICA phase 2 clinical trial in a recent statement.

Regarding data from the phase 2 trial of the combination therapy, investigator Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, Athens, Greece, commented on the treatment’s efficacy and attractive safety profile in an exclusive interview, echoing Dr. Wildgust’s opinion on the combination therapy’s potential top establish a new standard of care.

“There was a significant improvement of the anemia, with increases of the hemoglobin in 95% of the patients treated with the combination. The combination was relatively well tolerated, with the combination of ibrutinib and rituximab we did not see infusion-related reactions that we see with rituximab alone; we did not see an immunoglobulin (IGM) flare, which is an increase of the IGM a few weeks after initiation of treatment. We had some patients who developed hypertension and atrial fibrillation, these are well-established complications associated with the administration of BTK inhibitors.

The combination of ibrutinib and rituximab is becoming a new standard of care that will allow a higher percentage of patients with Waldenström macroglobulinemia to respond to treatment and to have a prolonged progression-free survival. I believe these results are very relevant for the treatment of these patients with this rare disease.”

Previously, ibrutinib in combination with rituximab for the treatment of Waldenström’s Macroglobulinemia was granted a priority review by the FDA.