Candidate Bevacizumab Biosimilar CT-P16 versus European Union Reference Bevacizumab in Patients with Metastatic or Recurrent Non-Small Cell Lung Cancer: A Randomized Controlled Trial

Abstract

Background: CT-P16 is a candidate bevacizumab biosimilar.

Objective: This double-blind, multicenter, parallel-group, phase III study aimed to establish equivalent efficacy between CT-P16 and European Union-approved reference bevacizumab (EU-bevacizumab) in patients with metastatic or recurrent non-squamous non-small cell lung cancer (nsNSCLC).

Patients and methods: Patients with stage IV or recurrent nsNSCLC were randomized (1:1) to receive CT-P16 or EU-bevacizumab (15 mg/kg every 3 weeks; ≤ 6 cycles) with paclitaxel (200 mg/m2) and carboplatin (area under the curve 6.0; both for 4-6 cycles), as induction therapy. Patients with controlled disease after induction therapy continued with CT-P16 or EU-bevacizumab maintenance therapy. The primary endpoint was objective response rate (ORR) during the induction period. Time-to-event analyses, pharmacokinetics, safety, and immunogenicity were also evaluated. Results obtained after 1 year of follow-up are presented.

Results: Overall, 689 patients were randomized (CT-P16, N = 342; EU-bevacizumab, N = 347). ORR was 42.40% (95% confidence interval [CI] 37.16-47.64) and 42.07% (95% CI 36.88-47.27) for CT-P16 and EU-bevacizumab, respectively. The risk difference (0.40 [95% CI - 7.02 to 7.83]) and risk ratio (1.0136 [90% CI 0.8767-1.1719]) for ORR fell within predefined equivalence margins (- 12.5 to + 12.5%, and 0.7368 to 1.3572, respectively), demonstrating equivalence between CT-P16 and EU-bevacizumab. Median response duration, time to progression, progression-free survival, and overall survival were comparable between treatment groups. Safety profiles were similar: 96.2% (CT-P16) and 93.0% (EU-bevacizumab) of patients experienced treatment-emergent adverse events. Pharmacokinetics and immunogenicity were comparable between groups.

Conclusions: Equivalent efficacy and similar pharmacokinetics, safety, and immunogenicity support bioequivalence of CT-P16 and EU-bevacizumab in patients with nsNSCLC.

Trial registration number: NCT03676192.

Conflict of interest statement

Fedor Moiseenko has received support for travel to meetings from AstraZeneca, Biocad, MSD, Novartis, Pfizer, and Roche; payment for lectures, including service on speakers’ bureaus, from AstraZeneca, Biocad, Eli Lilly, MSD, Novartis, Pfizer, and Roche; and has provided expert testimony for AstraZeneca, BMS, Eli Lilly, and Roche. SungHyun Kim, KeumYoung Ahn, and TaeHong Park are employees of and hold stocks in Celltrion, Inc. Sijin Park and Hana Ju are employees of Celltrion, Inc. Yuichiro Ohe has received grants from AstraZeneca, BMS, Chugai, Daiichi-Sankyo, Dainippon-Sumitomo, Janssen, Kissei, Kyorin, Lilly, LOXO, Novartis, ONO, Pfizer, Taiho, and Takeda; consulting fees or honoraria from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Chugai, Eli Lilly, Kyowa Hakko Kirin, MSD, Nippon Kayaku, ONO, Pfizer, and Taiho; fees for participation in review activities such as data monitoring boards from Amgen, AnHeart Therapeutics Inc., AstraZeneca, BMS, Boehringer Ingelheim, Celltrion, Chugai, Kyorin, Nippon Kayaku, and ONO; payment for the writing or reviewing of manuscripts from Eisai; and payment for lectures including service on speakers’ bureaus from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Chugai, Eli Lilly, Kyowa Hakko Kirin, MSD, Nippon Kayaku, ONO, Pfizer, and Taiho. Claire Verschraegen, Zoran Andric, Tamta Makharadze, Sergii Shevnya, Alona Oleksiienko, and Eduardo Yañez Ruiz have no conflicts of interest to declare.

© 2022. The Author(s).

Figures

Fig. 1

Patient disposition. aTwo patients who were randomized to the EU-bevacizumab group had EGFR mutations associated with lack of responsiveness to EGFR TKI therapy (EGFR exon 20 insertions). The patients were permitted to be enrolled by the investigator and sponsor since TKI therapy was not an option for their treatment. bOne patient in the CT-P16 group accidentally missed a CT-P16 dose in Cycle 4 but was considered as having completed the induction period and entered the maintenance period. cTwo patients in each treatment group discontinued as treatment could not be resumed within 6 weeks of the last dose; one patient in the CT-P16 group discontinued due to a change in the patient’s financial status. AE adverse event, EGFR epidermal growth factor receptor, EU-bevacizumab European Union-approved reference bevacizumab, FU follow-up, PD progressive disease, TKI tyrosine kinase inhibitor

Fig. 2

Kaplan–Meier plots depicting a progression-free survival as assessed by central review, and b overall survival (intent-to-treat population). CI confidence interval, EU-bevacizumab European Union-approved reference bevacizumab, HR hazard ratio