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Aim: This study assessed the safety, efficacy, pharmacokinetics and immunogenicity of the bevacizumab biosimilar candidate BI 695502 plus mFOLFOX6 in patients with metastatic colorectal cancer (mCRC). Materials & methods: Patients with untreated mCRC received BI 695502 and chemotherapy (oxaliplatin, leucovorin and 5-fluorouracil). Primary end point: proportion of patients with prespecified adverse events (AEs). Results: Of 123 patients enrolled and treated, 58.5% experienced prespecified AEs. Median progression-free survival was 10.5 months, median overall survival was 19.4 months, and objective response rate was 61.0%. There were no antidrug antibody or neutralizing antidrug antibody-positive samples post-baseline. Trough BI 695502 plasma concentrations increased until cycle 9 and stabilized thereafter. Conclusion: BI 695502 has an acceptable safety and efficacy profile in the treatment of mCRC. Trial Registration Number: NCT02776683 ( ClinicalTrials.gov ), 2015-003718-25 (EudraCT, European Clinical Trials Database https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-003718-25 ) Study name: Study 1302.3

INTRODUCTION Biological therapies such as bevacizumab have improved survival in patients with non-small-cell lung cancer (NSCLC). This study was conducted to confirm equivalent efficacy of the biosimilar candidate BI 695502 to bevacizumab reference product (RP). METHODS In this phase III, multicenter, randomized, double-blind trial, adult patients with recurrent or metastatic NSCLC received up to 18 weeks of induction treatment with BI 695502 or bevacizumab RP 15 mg/kg plus paclitaxel and carboplatin. Subsequent maintenance therapy comprised BI 695502 or bevacizumab RP monotherapy until disease progression or unacceptable toxicity. The primary endpoint was best overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 assessed by central imaging review, until 18 weeks after the start of treatment. RESULTS In total, 671 patients were randomized 1:1 to BI 695502 or bevacizumab RP, of whom 335 and 328, respectively, received treatment. Of these, 228 (68.1%) and 256 (78.0%), respectively, proceeded to maintenance monotherapy. A manufacturing issue led to a small number of patients treated with BI 695502 switching to bevacizumab RP late in the study. The primary endpoint, best ORR, was 54.0% in the BI 695502 group and 63.1% in the bevacizumab RP group. The 90% confidence interval for the between-group ratio of best ORR (0.770–0.951) was within the pre-specified range for equivalence (0.736–1.359). Adverse events were class-related and similar between the two treatment arms. CONCLUSIONS This study demonstrated equivalent ORR after 18 weeks of treatment with BI 695502 or bevacizumab RP, with similar adverse event profiles.

This Phase I trial (INVICTAN®-1) evaluated three-way bioequivalence and safety of BI 695502 a bevacizumab biosimilar candidate, and reference product bevacizumab from two sources (US-approved Avastin®, Genentech; EU-approved Avastin, Roche).Healthy male subjects (N = 91) were randomized 1:1:1 to receive a single intravenous infusion of 1 mg/kg of BI 695502 or US- or EU-approved Avastin. An interim analysis was planned when ~50% of subjects were evaluable for the primary end point to determine if the prespecified criteria for bioequivalence were achieved; if demonstrated, the study could be stopped early. The primary end point was area under the concentration-time curve (AUC) of the analyte in plasma from time zero extrapolated to infinity (AUCThe interim analysis demonstrated three-way bioequivalence for all comparisons. The confidence intervals around the geometric mean ratios of the primary and secondary PK parameters were within the predefined acceptance ranges. Study drugs were well tolerated with no clinically relevant differences in safety.BI 695502 and US- and EU-approved Avastin showed three-way bioequivalence with similar safety profile.NCT01608087.

The nonselective human corticotropin-releasing factor receptor 1 (hCRF-R1) and the ligand-selective Xenopus CRF-R1 (xCRF-R1) were compared. To understand the interactions of sauvagine and ovine CRF, both high-affinity ligands for hCRF-R1 but surprisingly weak ligands for xCRF-R1, chimeric receptors of hCRF-R1 and xCRF-R1 followed by double or multiple point mutations were constructed. Binding studies and cAMP assays demonstrated that the N-terminal domain exhibited the complete ligand selectivity of xCRF-R1. The important region was mapped between amino acids 70 and 89; replacement of amino acids Arg 76 , Asn 81 , Gly 83 , Leu 88 , and Ala 89 in hCRF-R1 with the corresponding amino acids of xCRF-R1 (Gln 76 , Gly 81 , Val 83 , His 88 , and Leu 89 ) resulted in a receptor that had ∼30-fold higher affinity for human/rat CRF than for sauvagine. Mutagenesis of these amino acids in xCRF-R1 to the human sequence completely abolished the ligand selectivity of xCRF-R1. Mutagenesis of amino acids 88 and 89 in hCRF-R1 or xCRF-R1 had only a minor (∼2.5-fold) effect on the ligand selectivity of the mutant receptor. Substitution of Arg 76 , Asn 81 , and Gly 83 in hCRF-R1 with the corresponding sequence of xCRF-R1 (Gln 76 , Gly 81 , and Val 83 ) resulted in a receptor with ∼11-fold higher affinity for human/rat CRF compared with ovine CRF or sauvagine. When only two of these three amino acids were mutated, no effect on the ligand selectivity was observed. On the basis of these data, it is suggested that amino acids 70–89 of CRF-R1 are important for the ligand binding site.