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CHMP Issues Positive Opinion for Ixazomib Conditional Approval in Myeloma

Silas Inman @silasinman
Published: Friday, Sep 16, 2016

Philippe Moreau, MD

Philippe Moreau, MD

The Committee for Medicinal Products for Human Use (CHMP) has recommended a conditional approval for ixazomib (Ninlaro) in combination with lenalidomide and dexamethasone as a treatment for patients with multiple myeloma who have received at least 1 prior therapy, based on finding from the phase III TOURMALINE-MM1 study.

Findings from the trial, which were published in The New England Journal of Medicine (NEJM), demonstrated a 26% reduction in the risk of disease progression or death with the ixazomib triplet versus a doublet of lenalidomide and dexamethasone alone. Median progression-free survival (PFS) with the ixazomib triplet was 20.6 months compared with 14.7 months with the doublet (HR, 0.74; 95% CI, 0.59-0.94; P = .01).

“The heterogeneity of multiple myeloma means that it is very important for patients and physicians to have access to a variety of treatment options, and many physicians are now looking forward to the possibility of adding Ninlaro to our treatment armamentarium,” lead investigator Philippe Moreau, MD, Head of the Hematology Department at the University Hospital of Nantes, France, said in a statement.

Earlier this year, the CHMP issued a negative opinion for ixazomib's marketing authorization, due to a paucity of data to support a full authorization, the agency said. In June 2016, Takeda requested a re-examination of the application on the basis of a conditional approval, which led to the newly adopted positive opinion. Under this program, the company will be required to submit additional data from ongoing studies to support continued authorization.

“Today’s positive CHMP opinion for the conditional approval of Ninlaro is an important first step to bringing this treatment to a relapsed and/or refractory patient population where there is a significant unmet need,” Christophe Bianchi, MD, president, Takeda Oncology, said in a statement. “Currently approved proteasome inhibitors are only available through twice-weekly injections and infusions, which can place additional logistical burdens on patients and their caregivers, who already are dealing with a difficult disease. We hope that the efficacy, convenience and manageable safety profile of this innovative treatment may allow for extended duration of treatment, which has the potential to improve patient outcomes.”

The study randomized 722 patients in a 1:1 ratio to receive lenalidomide and dexamethasone with placebo (n = 362) or ixazomib (n = 360). Ixazomib was given orally at 4 mg on days 1, 8, and 15 of a 28-day cycle. Patients received oral lenalidomide at 25 mg on days 1 to 21 and dexamethasone was administered orally at 40 mg on days 1, 8, 15, and 22.

The median age of patients was 66 years, and 12% had ISS stage III disease at baseline. The ECOG PS was primarily 1 or 2 (94%). The median creatinine clearance was 78.4 ml/min (range, 20-233) and 19% of patients had high-risk cytogenetics, including 10% with del17p.

A majority of patients had received 1 prior therapy (61%), with 10% having received 3. Overall, 57% of patients had received prior stem cell transplantation, 77% had relapsed multiple myeloma, and 12% were both relapsed and refractory. Prior therapies included bortezomib (69%), thalidomide (45%), and lenalidomide (12%). Twenty-three percent of patients had disease that was refractory to prior immunomodulatory agents.

The overall response rate was 78.3% with the ixazomib triplet versus 71.5% in the control arm (P = .04). A very good partial response or better was achieved for 48% of those in the ixazomib arm versus 39% in the control (P = .01). The complete response rate with the proteasome inhibitor was 12% versus 7% with placebo (P = .02). The median duration of response was 20.5 months with ixazomib versus 15.0 months in the control arm. The median time to progression was 21.4 months with ixazomib versus 15.7 months in the control arm (P = .007).

In those with high-risk cytogenetics, the median PFS with ixazomib was 21.4 months versus 9.7 months in the control arm (HR, 0.54; 95% CI, 0.32-0.92; P = .02). Specifically for those with del17p (n = 69), the median PFS was 21.4 versus 9.7 months, with and without ixazomib, respectively (HR, 0.60; 95% CI, 0.29-1.24). In patients with t(4;14) without del17p or t(14;16), the median PFS with ixazomib was 18.5 versus 12.0 months in the control (HR, 0.65; 95% CI, 0.25-1.66).

In those previously treated with 1 prior therapy, the median PFS in the ixazomib arm was 20.6 versus 15.9 months with placebo (HR, 0.83). The median PFS in those treated with 2 prior therapies was 17.5 months with ixazomib versus 14.1 months with placebo (HR, 0.75).

The TOURMALINE-MM1 trial was halted upon meeting the primary endpoint of PFS in February 2015. At an analysis conducted in July 2015 after a median of 23 months of follow-up, median overall survival had not yet been reached in either arm.

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