Ibrutinib Plus Rituximab Combo Granted FDA Priority Review for Waldenstrom Macroglobulinemia

A supplemental new drug application (sNDA) for ibrutinib (Imbruvica) in combination with rituximab (Rituxan) has been granted a priority review by the FDA. According to Pharmacyclics (AbbVie) and Janssen Biotech, the codevelopers of ibrutinib, this combination could be a treatment option across all lines of therapy for patients with Waldenström macroglobulinemia.

The sNDA comes based on findings from the phase III iNNOVATE (PCYC-1127) trial where the combination of ibrutinib plus rituximab lowered the risk of disease progression or death by 80% comapred to rituximab alone in this patient population. These results were also presented at the 2018 ASCO Annual Meeting and published in theNew England Journal of Medicine.^1,2

At a median follow-up of 26.5 months, the median progression-free survival (PFS) was not reached with the ibrutinib combination and was 20.3 months with rituximab alone (HR, 0.20; 95% CI, 0.11-0.38,P<.0001). The 30-months PFS rates were 82% versus 28%, 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 Waldenstr&ouml;m's macroglobulinemia patient subgroups that were studied," Thorsten Graef, MD, PhD, 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 III iNNOVATE trial included 150 relapsed/refractory or treatment-na&iuml;ve patients with confirmed symptomatic Waldenstr&ouml;m macroglobulinemia. Patients were enrolled at 45 sites in 9 countries between July 2014 and January 2016.

The median patient age was 69 and 33% were aged &ge;75 years. Forty-five percent of patients had not received prior therapy. Thirty-eight percent were considered high risk per the International Prognostic Scoring System for Waldenstr&ouml;m Macroglobulinemia, and 79% of patients had extramedullary disease at baseline. Among 136 patients with available baseline mutational data, 85% had&nbsp;MYD88^L265Pmutations and 36% had&nbsp;CXCR4^WHIMmutations.

Patients received IV rituximab at 375 mg/m²once weekly for 4 straight weeks, followed by another 4-week rituximab course after a 3-month interval. Ibrutinib (420 mg) or placebo were taken once daily continuously.&nbsp;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 (HR, 0.34; 95% CI, 0.12-0.95), relapsed patients (HR, 0.17; 95% CI, 0.08-0.36),MYD88^L265P/CXCR4-mutation wild-type (WT; HR, 0.17; 95% CI, 0.06-0.49),MYD88^L265P/CXCR4^WHIM(HR, 0.24; 95% CI, 0.09-0.66), and&nbsp;MYD88^WT/CXCR4-mutation WT (HR, 0.21; 95% CI, 0.04-1.08).

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

In the overall population, the ORR was 92% with the ibrutinib combination versus 47% with rituximab alone (P<.0001). The major response rate (at least a partial response) was 72% versus 32%, respectively (P<.0001).&nbsp;

Three-fourths of patients in the combination arm remained on treatment at the data cutoff. Sustained increases in hemoglobin level occurred in 73% of the ibrutinib/rituximab group versus 41% of the rituximab-alone arm (P<.0001). The median time to next treatment was not reached for the ibrutinib arm versus 18 months for the control arm (HR, 0.096;&nbsp;P< .0001).&nbsp;

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

In the experimental arm, patients received ibrutinib for a median of 25.8 months (range, 1.0-37.2). The primary reason for ibrutinib discontinuation was progressive disease (n = 7), followed by adverse events (AEs; n = 4).

Grade &ge;3 treatment-emergent adverse events (AEs) occurred in 60% of the combination arm versus 61% of the control arm. Grade &ge;3 AEs that were more common with the ibrutinib combo than rituximab alone included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%). Dimopoulos noted that 55% of the incidents of atrial fibrillation in the ibrutinib arm occurred in patients aged &ge;75 years.

Grade &ge;3 treatment-emergent AEs occurring more frequently in the rituximab-alone arm included IgM flare (3% vs 0%) and infusion-related reactions (16% vs 1%). Of note, IgM flare of any grade occurred in 47% of the control arm versus 8% of the combination arm.

The rates of serious AEs were 43% versus 33% in the ibrutinib versus control arms, respectively. In the rituximab-alone arm, 3 deaths related to AEs 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 ibrutinib for patients with Waldenstr&ouml;m macroglobulinemia in January 2015, based on results from a phase II study.

References:

1. Dimopoulos MA, Tedeschi A, Trotman J, et al. Randomized phase 3 trial of ibrutinib/rituximab vs placebo/rituximab in Waldenstr&ouml;m's macroglobulinemia.J Clin Oncol. 2018;36 (suppl; abstr 8003).
2. Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 trial of ibrutinib plus rituximab in Waldenstr&ouml;m&rsquo;s macroglobulinemia [published online June 1, 2018).N Engl J Med. doi: 10.1056/NEJMoa1802917.

The median number of prior therapies in patients with relapsed disease was 2 (range, 1-6), and 85% had prior rituximab. Patients who had prior rituximab had to have achieved at least a minimal response to their last rituximab-based treatment.