CHMP Issues Positive Opinion for Ixazomib Conditional Approval in Myeloma

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.

“The clinical data strongly support the use of Ninlaro in relapsed and/or refractory patients, while also delivering the advantages of an all-oral triplet regimen. In the TOURMALINE-MM1 trial,” Moreau said.

At the 23 month analysis, the most frequently reported all-grade adverse events (AEs) for the ixazomib arm versus the control group, respectively, were diarrhea (45% vs 39%), rash (36% vs 23%), constipation (35% vs 26%), neutropenia (33% vs 31%), thrombocytopenia (31% vs 16%), anemia (29% vs 27%), nausea (29% vs 22%), and back pain (24% vs 17%), vomiting (23% vs 12%).

AEs traditionally associated with proteasome inhibition were generally mild. Peripheral neuropathy occurred in 27% of patients treated with ixazomib versus 22% with placebo; however, the rates of grade 3 AEs were similar in both arms, at 2%. Similar findings were seen for peripheral edema, with an all-grade rate of 28% and 20% and a grade 3 rate of 2% and 1%, with and without ixazomib, respectively.

Fewer cases of acute renal failure were seen with ixazomib (9% vs 11%). Cardiac events were similar between the arms, with heart failure experienced by 4% of patients in both arms. Thromboembolism was less common with ixazomib (8% vs 11%).

“In addition to ixazomib’s efficacy in this relapsed and/or refractory group of patients, its manageable safety profile and oral administration makes ixazomib a very welcome new treatment option for this serious and complex cancer," Eric Low, Chief Executive, Myeloma UK, and Board Member, Myeloma Patients Europe, said in a statement. "It is important that attention is now turned in earnest to the Health Technology Assessment bodies to ensure their approval of ixazomib.’’

The FDA first approved ixazomib in November 2015 for use in combination with lenalidomide and dexamethasone as a treatment for patients with multiple myeloma who received at least one prior therapy.

In addition to the MM1 study, the TOURMALINE clinical trial program contains four other phase III studies that are exploring ixazomib. In the MM2 trial, the combination of ixazomib, lenalidomide, and dexamethasone is being explored in newly diagnosed patients with multiple myeloma. The MM3 and MM4 studies are investigating maintenance therapy with ixazomib in patients who have or have not undergone an autologous stem cell transplant.

The primary completion date for the MM3 study is February 2018 (NCT02181413) and the primary completion date for MM2 is June 2018 (NCT01850524). The MM4 study is still recruiting participants, with an enrollment goal of 761 (NCT02312258).

Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621-1634.