Long-Term Efficacy and Safety Results of CT-P10 and Reference Rituximab in Patients with Newly Diagnosed Advanced Stage Follicular Lymphoma: Phase III Updated Study Results with Median Follow-up of 40 Months

Introduction: CT-P10 is an approved biosimilar to the innovator rituximab by both US FDA and EMA based on a review of comprehensive data package inclusive of foundational and extensive analytical characterization, nonclinical and clinical data. In patients with newly diagnosed advanced stage follicular lymphoma (AFL), equivalence of pharmacokinetics and noninferiority of efficacy was demonstrated in the primary analysis (Kim WS et al. Lancet Hematol. 2017), and progression-free survival (PFS) and overall survival (OS) at a median follow-up of 22.6 months showed the therapeutic similarity between the CT-P10 and Rituxan (RTX) (Kim WS et al. Blood 2018;132:1616). Here, we report the updated data at a median follow-up of 40 months regarding time-to-event endpoints and safety in this CT-P10 3.3 study.

Methods: This phase III, randomized, and double-blind study in patients with previously untreated AFL (NCT02162771) was completed within the planned study period. Patients received R-CVP induction therapy (every 3 weeks for 8 cycles) in the Core Study Period and rituximab monotherapy (every 2 months for 12 cycles) in the Maintenance Study Period. Computerized Tomography scans were performed at baseline, month 3 and 6 during the Core Study Period, and then every 6 months for 2 years during the Maintenance Study Period. After 2 years, patients were followed every 6 months for tumor evaluation up to 3 years from the last patient's first infusion date. Kaplan-Meier (KM) method was used to estimate the time-to-event endpoints.

Results: In total, 140 patients with AFL were enrolled (CT-P10-CVP; N=70, R-CVP; N=70) with a median age of 58 years and 55.0% of female. The majority of patients completed the induction therapy (62 patients [88.6%] in each group, respectively). Among them, 122 patients (62 [88.6%] patients in CT-P10 and 60 [85.7%] patients in RTX) entered the Maintenance Period and 84 patients (46 [65.7%] patients in CT-P10 and 38 [54.3%] patients in RTX) completed the maintenance therapy.

To date, investigator assessed PFS, time-to-progression (TTP) and OS, medians had not been reached in either group due to insufficient number of events. The median follow-up durations of each group were 40 months (25^th-75^th percentile, 37 to 44) in CT-P10 and 39 months (25^th-75^th percentile, 36 to 43) in RTX.

A total of 42 patients (21 [30.0%] patients in each group, respectively) experienced disease progression and 12 patients reported death during the study. Of these 12 patients, 5 patients (3 [4.3%] patients in CT-P10 and 2 [2.9%] patients in RTX) died due to lymphoma and the other 7 patients (5 [7.1%] patients in CT-P10 and 2 [2.9%] patients in RTX) died due to adverse events or other reasons.

There were no significant differences between the 2 groups in PFS (Cox proportional Hazard Ratio [HR]: 1.33; 95% Confidence Interval [CI]: 0.67-2.63; 4-year PFS: CT-P10 60.9% [95% CI: 46.5%-72.5%], RTX 54.7% [95% CI: 36.1%-70.0%]; Figure 1).

The TTP revealed the trends similar to PFS. The KM curves showed no significant differences between the 2 groups in TTP (Cox proportional HR: 1.17; 95% CI: 0.58-2.37; 4-year TTP: CT-P10 64.2% [95% CI: 49.4%-75.7%], RTX 55.8% [95% CI: 36.8%-71.1%]; Figure 2).

Even with a limited number of events, OS was comparable between the 2 groups (Log rank p-value: 0.287; 4-year OS: CT-P10 88.0% [95% CI: 77.5%-93.8%], RTX 93.3% [95% CI: 83.2%-97.4%]).

Overall safety profiles of CT-P10 were consistent with those of RTX (Table 1). No new safety signals were identified during the study and a similar number of patients in each group experienced at least 1 treatment-emergent adverse event, infusion-related reaction, or infection considered to be related to the study drug. One patient from each group reported hepatitis B virus activation related to the study drug. The proportion of patients with positive anti-drug antibody was also similar in both groups (4.3% [3/70] vs 5.7% [4/70] in CT-P10 and RTX) and 2 patients (2.9%) in each group showed the positive neutralizing antibody results.

Conclusion: Long-term efficacy results in patients with AFL showed comparable PFS, TTP and OS between the 2 groups, indicating therapeutic similarity of CT-P10 to originator RTX. In addition, CT-P10 was consistently well tolerated and showed comparable safety profiles, including immunogenicity, over the entire study period without any unexpected toxicities compared to RTX.

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