Positive Phase 3 Results Reported for First Oral Proteasome Inhibitor, Ixazomib (Ninlaro)

Combo treatment with lenalidomide and dexamethasone extends progression-free survival

Positive results have been reported from an international, phase 3, randomized, double-blind, placebo-controlled study evaluating once-weekly ixazomib capsules (Ninlaro, Takeda Pharmaceutical Company) plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma. The findings were published in the New England Journal of Medicine.

Ixazomib is the only oral proteasome inhibitor approved by the FDA (in combination with lenalidomide and dexamethasone) for the treatment of patients with multiple myeloma who have received at least one prior therapy.

The TOURMALINE-MM1 trial, which included 722 patients with multiple myeloma, was the first phase 3 study of an oral proteasome inhibitor. The trial results demonstrated a statistically significant 35% extension of progression-free survival (PFS) with ixazomib in combination with lenalidomide and dexamethasone compared with the control group (median PFS: 20.6 months vs. 14.7 months, respectively; P = 0.01) after a median follow-up period of 14.7 months. A benefit in PFS was observed with the ixazomib regimen across prespecified patient subgroups, including patients with a poor prognosis, such as elderly patients; those who have received two or three prior therapies; those with advanced disease; and those with high-risk cytogenetic abnormalities.

The overall response rates were 78% in the ixazomib arm and 72% in the placebo arm. The median period to response was 1.1 months for ixazomib versus 1.9 months for placebo, and median durations of response were 20.5 months versus 15.0 months, respectively.

In the ixazomib and placebo groups, the rates of serious adverse events (47% vs. 49%) and on-study deaths (4% vs. 6%) were similar; 74% and 69% of patients experienced grade-3 or greater adverse events. Grade-3 and grade-4 thrombocytopenia was more frequent in the ixazomib group (12% and 7%) compared with the placebo group (5% and 4%). Rash occurred more often in the ixazomib group than in the placebo group (36% vs. 23%, respectively), as did gastrointestinal adverse events, which were predominantly low grade. The rates of peripheral neuropathy were 27% in the ixazomib group and 22% in the placebo group.

Ixazomib is administered orally once a week as a 4-mg fixed dose on days 1, 8, and 15 of a 28-day treatment cycle in patients with multiple myeloma. The treatment received a breakthrough therapy designation from the FDA for relapsed or refractory systemic light-chain amyloidosis, an ultra-orphan disease related to multiple myeloma, in 2014.

Source: Takeda; April 27, 2016.