The FDA has approved the first rituximab (Rituxan) biosimilar, CT-P10 (Truxima; rituximab-abbs), for the treatment of adult patients with CD20-positive, B-cell non-Hodgkin lymphoma (NHL) as a single agent or in combination with chemotherapy.
This is the first biosimilar approved by the FDA for the treatment of patients with NHL.
CT-P10, which is developed by Celltrion and Teva Pharmaceutical Industries, has approved indications that are equivalent to reference rituximab, which includes: relapsed/refractory, low-grade or follicular lymphoma, CD20-positive B-cell NHL as a single agent; previously untreated follicular lymphoma, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy; and non-progressing or stable low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine and prednisone (CVP) chemotherapy.
"The Truxima approval is our third biosimilar approval in the past month," said Scott Gottlieb, MD, FDA Commissioner, in a press release. "The growing pipeline of biosimilars is encouraging. We’re seeing more biosimilar drugs gain market share as this industry matures. We’ll continue to make sure biosimilar medications are evaluated efficiently through a process that makes certain that these new medicines meet the FDA’s rigorous standards for approval."
The approval is based on data that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrated the similarity of CT-P10 to reference rituximab.
In October 2018, the FDA's Oncologic Drugs Advisory Committee voted 16-0 recommending approval of the biosimilar. The panel specifically considered data from 2 randomized, double-blinded trials submitted with the biologics license application for the biosimilar, both of which showed no clinically meaningful differences between CT-P10 and reference rituximab.2
In the first trial, 140 patients with advanced follicular lymphoma were randomized 1:1 to 375 mg/m2
intravenously (IV) of CT-P10 or rituximab combined with CVP chemotherapy every 3 weeks for a maximum of 8 cycles. If, after cycle 8, patients achieved a complete response (CR), an unconfirmed CR (CRu), or a partial response (PR), they were eligible for maintenance therapy with their assigned drug every 8 weeks for up to 12 cycles. Baseline patient demographics and disease characteristics were mostly similar between the 2 arms.
Results showed that the overall response rates (ORRs) were comparable between the 2 cohorts, at 95.7% with CT-P10 versus 90.0% with rituximab. The ORR difference was 5.7% (90% CI, -1.7% to 14.7%), meeting the primary objective for noninferiority of ORR, as the lower bound of the 90% CI (-1.7%), was greater than the -7% noninferiority margin stipulated in the study design.
The CR, CRu, and PR rates were also comparable with CT-P10 versus rituximab, at 30.0% versus 21.4%; 8.6% versus 11.4%; and 57.1% each, respectively. The median duration of response was not estimable for the CT-P10 arm compared with 28.6 months for the rituximab arm. Additionally, the stable disease (SD) rate was 1.4% with CT-P10 compared with 2.9% with rituximab, and the progressive disease rates were also 1.4% versus 2.9%, respectively.
The median progression-free survival (PFS) was 31.2 months with the biosimilar versus 31.1 months with rituximab. The median overall survival (OS) was not evaluable in either arm; however, Kaplan-Meier curves did not show a significant difference in OS.
Ninety percent of the CT-P10 arm had at least 1 treatment-emergent adverse event (TEAE), compared with 85.7% in the rituximab arm. The rates of at least 1 serious AE were 30% versus 18.6%, respectively. TEAE-related discontinuation rates were 10% in the biosimilar arm versus 7.1% in the rituximab arm. In the CT-P10 group, there were 3 patient deaths related to TEAEs versus 1 death in the rituximab arm.
In the second trial, 258 patients with low tumor burden follicular lymphoma were randomized 1:1 to 375 mg/m2
IV of CT-P10 (n = 130) or reference rituximab (n = 128) once weekly for 4 weeks (induction period). Patients achieving a CR, CRu, PR, or SD were eligible for a maintenance phase, continuing to receive their assigned drug every 8 weeks for up to 12 cycles. Again, baseline patient demographics and disease characteristics were mostly similar between the 2 arms.
The ORRs per central review were comparable between the 2 arms, at 83.1% with CT-P10 versus 81.3% with rituximab, respectively. Per the FDA analysis, the ORR difference was 1.8%, with a 90% confidence interval (CI) of -6.16% to 10.02%. The 90% CIs were within the equivalence margin of ±17% established by the study protocol.
The CR, CRu, and PR rates were also similar with CT-P10 versus rituximab at 27.7% versus 33.6%; 4.6% versus 1.6%; and 50.8% versus 46.1%, respectively. The SD rate was 13.1% with CT-P10 compared with 14.1% with rituximab. The progressive disease rates were 0% versus 3.1% respectively.
Among patients in the CT-P10 arm, 72.3% had at least 1 TEAE, compared with 70.3% in the rituximab arm. The rates of at least 1 serious AE were 5.4% versus 2.3%, respectively. Moreover, 4 patients in the CT-P10 arm discontinued therapy due to TEAEs versus 0 patients in the rituximab arm. In the biosimilar group, there were 2 patient deaths related to TEAEs, compared with 0 in the rituximab arm.
The FDA listed the most common AEs with the biosimilar as infusion reactions, fever, lymphopenia, chills, infection, and asthenia. Patients should be monitored for tumor lysis syndrome, cardiac adverse reactions, renal toxicity, and bowel obstruction and perforation. Additionally, patients should not receive vaccinations while undergoing treatment, and the biosimilar should not be administered to those who are pregnant or breastfeeding, the FDA stated in the press release.
Similar to reference rituximab, the CT-P10 label contains a boxed warning regarding increased risks of fatal infusion reactions, severe skin and mouth reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy, a rare, serious brain infection that can result in severe disability or death.
"As part of the FDA's Biosimilars Action Plan, we’re advancing new policies to make the development of biosimilars more efficient and to enable more opportunities for biosimilar manufacturers to make these products commercially successful and competitive. Our goal is to promote competition that can expand patient access to important medicines," Gottlieb stated in the release.
- FDA approves first biosimilar for treatment of adult patients with non-Hodgkin’s lymphoma. FDA. Published November 28, 2018. https://bit.ly/2KD2hOu. Accessed November 28, 2018.
- FDA Briefing Information for the October 10, 2018 Meeting of the Oncologic Drugs Advisory Committee (PDF - 6MB). FDA. Accessed October 10, 2018. https://bit.ly/2OesLuH.