Phase 3 TOURMALINE-MM2 Fails to Meet Primary End Point of PFS

The phase 3 TOURMALINE-MM2 trialevaluating the addition of ixazomib (Ninlaro) to lenalidomide (Revlimid) and dexamethasone (Ozurdex) versus lenalidomide and dexamethasone plus placebo in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant did not meet its primary end point of progression-free survival (PFS), according to Takeda, the developer of the agent.

The data were presented at the virtual scientific meeting of the Society of Hematologic Oncology (SOHO) on September 9, 2020.

“There is a specific need in newly diagnosed multiple myeloma, given there are currently no approved all-oral, proteasome inhibitor-based treatment options,” principle investigator and lead author of the study Thierry Facon, MD, from Lille University Hospital, said in a press release. “Findings from the TOURMALINE-MM2 trial are important overall for this patient population as well as across multiple subgroups including patients with high-risk cytogenetics. We hope these data will help inform future research and further progress for the multiple myeloma community.”

The international, randomized, double-blind, multicenter, placebo-controlled phase 3 trial was designed to evaluate ixazomib plus lenalidomide and dexamethasone compared to placebo plus lenalidomide and dexamethasone in 705 adult patients with newly diagnosed multiple myeloma who were not candidates for transplant. The study’s primary end point was PFS and key secondary end points included rate of complete response (CR), pain response, and overall survival (OS).

The study found the addition of ixazomib to lenalidomide and dexamethasone, compared with placebo, led to a 13.5-month increase in median PFS (35.3 months vs 21.8 months; HR, 0.830; P = .073). The trial did not meet the threshold for statistical significance and therefore the primary endpoint of PFS was not met. In addition, after a median follow up of 57.8 months in the ixazomib arm versus 58.6 months in the placebo arm for OS, the median OS was not reached in either arm (HR, 0.998).

Notably, the rate of CR was 26% in the ixazomib arm versus 14% in the placebo arm. Moreover, the median time to progression was longer with the ixazomib combination versus placebo, at 45.8 months in the ixazomib arm versus 26.8 months in the placebo arm (HR, 0.738).

Overall, the safety profile associated with ixazomib from the trial was generally consistent with the existing prescribing information. Treatment emergent adverse events (TEAEs) were reported in 96.6% of patients receiving ixazomib plus lenalidomide and dexamethasone compared to 92.6% of patients receiving placebo plus lenalidomide and dexamethasone. The most common TEAEs of clinical importance in the ixazomib arm were diarrhea, rash, peripheral edema, constipation, and nausea.

Further, TEAEs of grade 3 or greater were experienced by 88.1% of patients receiving ixazomib versus 81.4% receiving placebo. Most of the TEAEs observed were managed without discontinuation, with TEAEs resulting in 35% regimen discontinuation in the ixazomib arm and 26.9% in the placebo arm. However, the rate of on-study deaths was 7.6% in the ixazomib arm and 6.3% in the placebo arm.

“Insights from studies like TOURMALINE-MM2 are important, especially to those patients who may benefit from the convenience of treatment options that can be taken at home,” Paul Giusti, president and chief executive officer for the Multiple Myeloma Research Foundation, said in the release. “These critical learnings enable the community to comprehensively assess the different treatment combinations available for patients and physicians.”

Ixazomib was first approved by the FDA in November 2015 and is indicated for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. Currently, the oral proteasome inhibitor is approved in more than 65 countries, with 9 regulatory filings currently under review. In Japan, ixazomib is approved as a maintenance therapy in patients with multiple myeloma who have undergone autologous stem cell transplant and has been filed for maintenance therapy in patients who are not eligible for stem cell transplant.

Reference:

Takeda Announces Results from Phase 3 Clinical Trial Evaluating NINLARO™ (ixazomib) in Newly Diagnosed Multiple Myeloma [news release]. Cambridge, Massachusetts and Osaka, Japan. Published September 9, 2020. Accessed September 10, 2020.