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ODAC Recommends FDA Approval of Rituximab Biosimilar

Published Online:4:11 PM, Wed October 10, 2018
In a 16-0 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) has recommended the approval of the rituximab biosimilar CT-P10 for 3 of the anti-CD20 monoclonal antibody’s non-Hodgkin lymphoma indications.

Should the FDA decide to agree with this recommendation and approve CT-P10, the biosimilar would be approved to treat adult patients with CD20-positive follicular lymphoma combined with chemotherapy in the frontline setting, followed by single-agent maintenance in responders; as a monotherapy for relapsed/refractory, low-grade CD20+ follicular lymphoma; and as a single agent in patients with low-grade, CD20-positive follicular lymphoma who do not progress following frontline chemotherapy.

ODAC was tasked with determining whether data submitted in a biologics license application (BLA) for CT-P10 demonstrated the biosimilarity between CT-P10 and rituximab in terms of efficacy, safety, pharmacology, analytical similarity, and immunogenicity. The BLA was submitted by Celltrion and Teva Pharmaceutical Industries, the co-developers of CT-P10.

"The totality of the evidence supports licensure, anti-CD20 therapies have really transformed B-cell lymphoma therapy and the sponsors convincingly demonstrated that CTP-10 is highly similar to US Rituxan, with the expect of minor components with no biologic activity. The clinical PK, efficacy and safety data are consistent with equivalence," said ODAC panel member Thomas S. Uldrick, MD, deputy head, Global Oncology, associate member, Vaccine and Infectious Disease Division, associate member, Clinical Research Division, Fred Hutchinson Cancer Research Center.

In making its decision, the panel specifically considered findings from 2 randomized, double-blinded trials submitted with the BLA showing no clinically meaningful differences between CT-P10 and rituximab-US (Rituxan).

In the first study, 140 patients with advanced follicular lymphoma were randomized 1:1 to 375 mg/m2 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, 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. 

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%). This met 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. 

The stable disease rate was 1.4% with CT-P10 compared with 2.9% with rituximab. 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, but 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 discontinuations occurred in 10% of the biosimilar arm, compared with 7.1% of the rituximab arm. In the CT-P10  group, there were 3 patient deaths related to TEAEs versus 1 death in the rituximab arm.

"I thought the preclinical analytics were fairly consistent. I think the clinical data supports efficacy in terms of response rate. There were some concerns about safety, and I think that is what you get when you have a lower number of patients treated in this type of development program. There are some imbalances in baseline characteristics that to me, seem to explain some of the differences observed," said Brian I. Rini, MD, chairperson of the ODAC meeting, and professor of Medicine, Lerner College of Medicine Leader, GU Program Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute.

In the second study, 258 patients with low tumor burden follicular lymphoma were randomized 1:1 to 375 mg/m2 IV of CT-P10 (n = 130) or rituximab-US (n = 128) once weekly for 4 weeks (induction period). Patients achieving a CR, CRu, PR, or stable disease were eligible for a maintenance phase, continuing to receive their assigned drug every 8 weeks for up to 12 cycles. 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 FDA analysis, the ORR difference was 1.8%, with a 90% confidence interval 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 stable disease 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. Four 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.

"Obviously, [there is] the totality of the data. I did not see any major signals of safety, and I think and hope that in future, this can be applied to other applications where rituximab is used," said ODAC panelist Massimo Cristofanilli, MD, associate director of Translational Research and Precision Medicine at Robert H. Lurie Comprehensive Cancer Center.

Beyond follicular lymphoma, rituximab has approved indications for diffuse large B-cell lymphoma and chronic lymphocytic leukemia.
FDA Briefing Information for the October 10, 2018 Meeting of the Oncologic Drugs Advisory Committee (PDF - 6MB). FDA. Accessed October 10, 2018.

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