Rituximab Biosimilar Nears EU Approval for Oncologic and Other Indications

Chris Boshoff, MD, PhD, senior vice president and head of Immuno-Oncology, Early Development, Translational Oncology, Pfizer Global Product Development

Chris Boshoff, MD, PhD

The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for a Marketing Authorization Application for the rituximab (Rituxan) biosimilar PF-05280586 (rituximab-pvvr; Ruxience) for the treatment of patients with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and pemphigus vulgaris.¹

The regulatory submission is supported by a comprehensive data package demonstrating biosimilarity with PF-05280586 to reference rituximab, including results from the REFLECTIONS B3281006 study that evaluated the efficacy, safety and immunogenicity, pharmacokinetics, and pharmacodynamics of PF-05280586. Results showed that there were no clinically meaningful differences in safety or efficacy between the biosimilar and standard rituximab in patients with CD20-positive, low tumor burden follicular lymphoma.²

The European Commission is expected to make a decision on the approval in the first half of 2020, stated Pfizer, the developer of the biosimilar, in a press release.

"Biosimilars like Ruxience can play an important role in cancer care, helping to expand patient access to potentially life-changing therapies,” Chris Boshoff, MD, PhD, chief development officer, Oncology, Pfizer Global Product Development, stated in the press release. “We are committed to bringing biosimilars like Ruxience to the market as a treatment option with similar safety and efficacy to the originator product at a potentially lower cost. If approved, Ruxience would become Pfizer’s fifth oncology biosimilar to receive regulatory approval in Europe.”

In July 2019, the FDA approved PF-05280586 for the treatment of adult patients with CD20-positive B-cell NHL as a single agent or in combination with chemotherapy, or for patients with CD20-positive CLL in combination with chemotherapy. It was also the first biosimilar approved to treat patients with GPA and MPA.

In the REFLECTIONS B3281006 study, patients with previously untreated CD20-positive, low tumor burden follicular lymphoma were randomized 1:1 to receive intravenous PF-05280586 or rituximab-sourced from the European Union (rituximab-EU) at 375 mg/m² once weekly for 4 weeks on days 1, 8, 15 and 22. Patients were stratified at randomization using the Follicular Lymphoma International Prognostic Index 2 (FLIPI2) classification and had an ECOG performance status of 0 or 1.

The primary endpoint was overall response rate (ORR) at week 26, which was defined as the percentage of patients achieving complete response (CR) or partial response (PR), based on central review. Secondary endpoints included progression-free survival (PFS), CR rate at week 26, time to treatment failure, duration of response, overall survival, safety, immunogenicity, pharmacokinetics and pharmacodynamics. The primary endpoint was evaluated once all patients completed week 26 assessments.

A total 394 patients were randomized to receive PF-05280586 (n = 196) or rituximab-EU (n = 198). Moreover, 54.8% of patients were female, the median age was 60.0 years, and 28.4% had low, 66.0% medium, and 5.6% had high risk, according to FLIPI2. Additionally, 26.9% of subjects had Ann Arbor Stage II, 44.2%, Stage III, and 28.9%, Stage IV disease.

Results showed that the ORR at week 26 was 75.5% with the biosimilar compared with 70.7% for rituximab-EU for a difference of 4.66%; moreover, the corresponding 95% CI (-4.16—13.47) was within the prespecified equivalence margin of ±16%. The CR rates were 29.3% vs 31.0% with the biosimilar and rituximab-EU arms, respectively.

Updated findings showed that the estimated 1-year PFS rates were 78.2% (95% CI: 70.2-84.2) and 83.0% (95% CI: 75.0-88.6) in the PF-05280586 and rituximab-EU groups, respectively.³

Regarding safety, the incidence of treatment-emergent adverse events (TEAEs) were similar at 78.6% with PF-05280586 versus 72.1% with rituximab-EU. The most frequently reported TEAEs included infusion-related reactions (25.5% vs 29.9% with PF-05280586 and rituximab-EU, respectively), pruritus (6.6% vs 11.2%) and headache (8.2% vs. 9.6%). Serious AEs were similar at 7.7% and 6.6% with PF-05280586 and rituximab-EU, respectively.

The most common adverse events associated with PF-05280586 include infusion-related reactions, fever, lymphopenia, neutropenia, chills, infection, weakness, nausea, diarrhea, headache, muscle spasms, anemia, and peripheral edema. Similar to standard rituximab, the FDA label for the biosimilar includes a Boxed Warning for increased risks of the following: fatal infusion-related reactions; severe skin and mouth reactions; hepatitis B virus reactivation; and progressive multifocal leukoencephalopathy.

In the United States, PF-05280586 was introduced to the US market in January 2020 and was launched at a WAC of $71.68 per 10 mg, which translates to a 24% discount to the WAC of the reference product.

References

1. Pfizer receives positive CHMP opinion for oncology biosimilar, Ruxience (rituximab) [news release]. Pfizer. Published January 31, 2020. https://bit.ly/2OpE4ON. Accessed February 3, 2020.
2. Sharman J, Liberati A, Silva R, et al. A randomized, double-blind efficacy and safety study of PF-05280586 (a potential rituximab biosimilar) compared with rituximab reference product (MabThera) in subjects with previously untreated CD20-positive, low tumor burden follicular lymphoma (LTB-FL). Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 394.
3. Sharman JP, Liberati AM, Ishizawa K, et al. A randomized, double-blind, efficacy and safety study of PF-05280586 (a rituximab biosimilar) compared with rituximab reference product (MabThera^®) in subjects with previously untreated CD20-positive, low-tumor-burden follicular lymphoma (LTB-FL) [published online ahead of print December 9, 2019]. BioDrugs. doi: 10.1007/s40259-019-00398-7.