Bevacizumab biosimilars

Humanised IgG1 monoclonal antibody of about 149 kDa, produced in Chinese hamster ovary cells, with murine complementarity-determining regions on a human framework.

Binds circulating vascular endothelial growth factor A and prevents it from engaging VEGFR-1 and VEGFR-2 on endothelial cells, so tumour angiogenesis and vascular permeability are reduced. Its action is neutralisation of a soluble ligand rather than binding to tumour cells, so Fc effector function is not part of its mechanism.

Intravenous infusion; half-life about 20 days (range 11 to 50 days), with clearance higher in men and in patients with larger tumour burden. Steady state is reached in about 100 days.

5 to 15 mg/kg every two or three weeks depending on the indication, as concentrate for infusion in 100 mg/4 mL and 400 mg/16 mL vials (25 mg/mL). Given with chemotherapy or, in hepatocellular carcinoma, with atezolizumab.

• Metastatic colorectal cancer
• Non-squamous non-small cell lung cancer
• Metastatic renal cell carcinoma
• Epithelial ovarian, fallopian tube and primary peritoneal cancer
• Persistent, recurrent or metastatic cervical cancer
• Glioblastoma (United States)
• Unresectable hepatocellular carcinoma, with atezolizumab

Immunogenicity is very low in reference-product studies. Comparative programmes therefore lean on analytical similarity and a pharmacokinetic study in healthy volunteers, with the comparative efficacy study run in first-line non-squamous non-small cell lung cancer using overall response rate at 18 or 19 weeks.

Avastin was licensed by FDA on 26 February 2004 (BLA 125085) and authorised in the EU on 12 January 2005 (EMEA/H/C/000582). Indications were added through 2020, ending with hepatocellular carcinoma in combination with atezolizumab. The first biosimilar, Mvasi, was approved by FDA in September 2017 and in the EU in January 2018; US launch waited until July 2019 under the terms of a settlement.

Sources: Purple Book (S016), EMA medicines data (S017), CDSCO import list (S013); launch timing from company reports.

Bevacizumab combines a broad, multi-indication label with a mechanism that does not depend on effector function, so extrapolation across indications has been accepted by every major regulator on the strength of a single lung-cancer study. That, and the volumes used in colorectal and lung cancer, made it an early target: India's Reliance Life Sciences was permitted in January 2016, before any FDA or EMA approval, and seven Indian manufacturers now hold permissions.