FDA Grants Ibrutinib/Rituximab Priority Review for Waldenstrom Macroglobulinemia

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

The sNDA is based on findings from the phase III 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 ibrutinib/rituximab combination lowered the risk of disease progression or death by 80% versus rituximab 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 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 Waldenström'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-naïve patients with confirmed symptomatic Waldenström 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 ≥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 Waldenström Macroglobulinemia, and 79% of patients had extramedullary disease at baseline. Among 136 patients with available baseline mutational data, 85% had MYD88^L265P mutations and 36% had CXCR4^WHIM mutations.

Patients received IV rituximab at 375 mg/m² once 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. 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 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).

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; P < .0001).

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 ≥3 treatment-emergent adverse events (AEs) occurred in 60% of the combination arm versus 61% of the control arm. Grade ≥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 ≥75 years.

Grade ≥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 Waldenström 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 Waldenström'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 Waldenström’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.