Drug Duo Granted Priority Review to Treat Waldenstrom Macroglobulinemia

The FDA has granted a priority review to a supplemental new drug application (sNDA) Imbruvica (ibrutinib) for use in combination with Rituxan (rituximab) as a treatment option across all lines of therapy for patients with Waldenström macroglobulinemia, according Pharmacyclics (AbbVie) and Janssen Biotech, the codevelopers of Imbruvica.

The sNDA is based on findings from the phase 3 iNNOVATE (PCYC-1127) trial presented at the 2018 ASCO Annual Meeting and published in the New England Journal of Medicine.^1,2 In the study the Imbruvica / Rituxan combination lowered the risk of disease progression or death by 80 percent versus Rituxan alone in patients with Waldenström macroglobulinemia.

At a median follow-up of 26.5 months, the median progression-free survival (PFS) was not reached with the Imbruvica combination and was 20.3 months with Rituxan alone. The 30-months PFS rates were 82 percent versus 28 percent, respectively.

"We are excited about the data from the Phase 3 iNNOVATE study, which indicate that Imbruvica plus rituximab was able to improve progression-free survival, versus rituximab alone, across all lines of therapy and Waldenström's macroglobulinemia patient subgroups that were studied," Thorsten Graef, M.D., Ph.D., Head of Clinical Development at Pharmacyclics said in a statement.

"These promising findings build on our commitment to exploring the full potential of Imbruvica alone and in combination with other treatments. If approved, this chemotherapy-free combination will provide another treatment opportunity for patients living with this rare disease, which continues to have very limited treatment options," Graef added.

The double-blind, placebo-controlled, parallel assignment, randomized phase 3 iNNOVATE trial included 150 relapsed/refractory or treatment-naïve patients with confirmed symptomatic Waldenström macroglobulinemia. Patients were enrolled at 45 sites in nine countries between July 2014 and January 2016.

The median patient age was 69 and 33 percent were aged 75 years or older. Forty-five percent of patients had not received prior therapy. Thirty-eight percent were considered high risk per the International Prognostic Scoring System for Waldenström Macroglobulinemia, and 79 percent of patients had extramedullary disease at baseline. Among 136 patients with available baseline mutational data, 85 percent had MYD88^L265P mutations and 36 percent had CXCR4^WHIM mutations.

The median number of prior therapies in patients with relapsed disease was two (range, 1-6), and 85 percent had prior Rituxan. Patients who had prior Rituxan had to have achieved at least a minimal response to their last Rituxan-based treatment.

Patients received IV Rituxan at 375 mg/m² once weekly for four straight weeks, followed by another four-week Rituxan course after a three-month interval. Imbruvica (420 mg) or placebo were taken once daily continuously. PFS was the primary endpoint, with secondary endpoints including overall response rate (ORR), hematological improvement measured by hemoglobin, time-to-next treatment, overall survival (OS), and safety.

The PFS benefit with the combination was observed across key subgroups, including previously untreated patients, relapsed patients, MYD88^L265P/CXCR4-mutation wild-type, MYD88^L265P/CXCR4^WHIM and MYD88^WT/CXCR4-mutation WT.

The 24-month PFS rate in treatment-naive patients was 84 percent in the experimental arm versus 59 percent in the control arm. In relapsed patients, the 30-month PFS rates were 80 percent vs 22 percent, respectively.

In the overall population, the ORR was 92 percent with the Imbruvica combination versus 47 percent with Rituxan alone. The major response rate (at least a partial response) was 72 percent versus 32 percent, respectively.

Three-fourths of patients in the combination arm remained on treatment at the data cutoff. Sustained increases in hemoglobin level occurred in 73 percent of the Imbruvica/Rituxan group versus 41 percent of the Rituxan-alone arm. The median time to next treatment was not reached for the Imbruvica arm versus 18 months for the control arm.

The OS rate at 30 months was 94 percent versus 92 percent, in the combination versus control arms, respectively. Dimopoulos noted that 30 patients in the control arm crossed over to receive single-agent Imbruvica.

In the experimental arm, patients received Imbruvica for a median of 25.8 months (range, 1.0-37.2). The primary reason for Imbruvica discontinuation was progressive disease (seven patients), followed by adverse events (AEs; four patients).

Grade 3 or higher treatment-emergent side effects occurred in 60 percent of the combination arm versus 61 percent of the control arm. Grade 3 or higher side effects that were more common with the Imbruvica combo than Rituxan alone included atrial fibrillation (12 percent vs 1 percent) and hypertension (13 percent vs 4 percent). Dimopoulos noted that 55 percent of the incidents of atrial fibrillation in the Imbruvica arm occurred in patients aged 75 years or older.

Grade 3 or higher treatment-emergent side effects occurring more frequently in the Rituxan-alone arm included IgM flare (3 percent vs 0 percent) and infusion-related reactions (16 percent vs 1 percent). Of note, IgM flare of any grade occurred in 47 percent of the control arm versus 8 percent of the combination arm.

The rates of serious side effects were 43 percent versus 33 percent in the Imbruvica versus control arms, respectively. In the Rituxan-alone arm, three deaths related to side effects occurred during active treatment (intracranial hemorrhage, nervous system disorder, and not specified). No deaths occurred during active treatment with the combination.

The FDA approved single-agent Imbruvica for patients with Waldenström macroglobulinemia in January 2015, based on results from a phase 2 study.