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J.A. Rosenberg



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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-113 - Nonclinical Development of PF-06439535, a Potential Biosimilar to Bevacizumab (ID 1217)

      09:30 - 17:00  |  Author(s): J.A. Rosenberg

      • Abstract
      • Slides

      Background:
      Bevacizumab is a recombinant, humanized, IgG1 monoclonal antibody that binds to and inhibits the activity of vascular endothelial growth factor (VEGF), and is approved to treat a variety of advanced solid tumors. PF‑06439535 is under development as a potential biosimilar to bevacizumab.

      Methods:
      Amino acid sequences of PF‑06439535 and EU‑ and US‑sourced bevacizumab (bevacizumab‑EU and bevacizumab‑US, respectively) were compared by peptide mapping; post-translational modifications and biochemical properties were analyzed by N-linked oligosaccharide profiling and imaged capillary electrophoresis. Functional analysis of PF‑06439535, bevacizumab‑EU, and bevacizumab‑US included an enzyme-linked immunosorbent assay to detect binding to the 4 major VEGF isoforms (VEGF~121~, VEGF~165~, VEGF~189~, VEGF~206~), and a cell growth inhibition assay in human umbilical vein endothelial cells (HUVEC). Toxicokinetics and potential toxicity of PF‑06439535 and bevacizumab‑EU were evaluated following intravenous (IV) administration (10 mg/kg twice weekly for 1 month, 9 doses total) in sexually- and skeletally-immature male cynomolgus monkeys; control animals received vehicle.

      Results:
      PF‑06439535, bevacizumab‑EU, and bevacizumab‑US had identical primary amino acid sequences and similar levels of N-linked oligosaccharides. Predominant charge isoforms were similar; charge heterogeneity was due to variations between PF‑06439535 and reference products in relative proportions of species with C-terminal lysines. Target binding to each VEGF isoform showed similar dose responses between PF‑06439535, bevacizumab‑EU, and bevacizumab‑US; comparable biological activity was observed by inhibition of VEGF-induced HUVEC proliferation. In cynomolgus monkeys, PF‑06439535 and bevacizumab‑EU (n=4 each) were well tolerated, with no PF‑06439535- or bevacizumab‑EU–related clinical, laboratory, or histopathology findings, except physeal dysplasia of the distal femur with similar incidence and severity for both molecules. Induction of anti‑drug antibodies was not observed in the PF‑06439535- or bevacizumab‑EU–dosed groups. Systemic exposure (mean area under the serum drug concentration–time curve from 0 to 72 hr ± standard deviation) was similar for PF‑06439535 and bevacizumab‑EU on Day 1 (12100 ± 876 vs 14700 ± 2260 μg·hr/mL) and Day 25 (45500 ± 5420 vs 45100 ± 3670 μg·hr/mL).

      Conclusion:
      Results from the analytical similarity assessments and nonclinical studies have supported the clinical development of PF‑06439535 as a potential biosimilar to bevacizumab. These data supported a randomized, double-blind phase I study (NCT02031991) in healthy human male volunteers in the United States, which assessed pharmacokinetics, safety, and immunogenicity of a single 5 mg/kg IV dose of PF‑06439535, bevacizumab‑EU, or bevacizumab‑US. A global, randomized phase III trial (NCT02364999) comparing PF‑06439535 and bevacizumab‑EU, plus paclitaxel/carboplatin, for first-line treatment of advanced non-squamous non‑small cell lung cancer is enrolling patients.

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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P3.01-083 - Phase III Trial of PF-06439535 or Bevacizumab-EU plus Paclitaxel/Carboplatin in NSCLC (ID 178)

      09:30 - 17:00  |  Author(s): J.A. Rosenberg

      • Abstract
      • Slides

      Background:
      The recombinant, humanized, monoclonal antibody bevacizumab targets vascular endothelial growth factor (VEGF) and is approved globally, including in the United States (US) and European Union (EU), for the treatment of select solid tumors, including as a first-line therapy, in combination with platinum-based chemotherapy, for advanced non-squamous non-small cell lung cancer (NSCLC). PF‑06439535 is being developed as a potential biosimilar to bevacizumab and has the same primary amino acid sequence as EU- and US-sourced bevacizumab (bevacizumab‑EU and bevacizumab‑US, respectively), with sufficiently equivalent physiochemical properties and comparable inhibition of VEGF/VEGF-receptor binding in vitro. In a nonclinical model using sexually- and skeletally-immature male cynomolgus monkeys, PF‑06439535 showed similar toxicokinetic parameters to bevacizumab‑EU and no induction of anti-drug antibodies. In a phase I trial in healthy male volunteers, PF‑06439535 showed pharmacokinetic similarity to bevacizumab‑EU and bevacizumab‑US and had a comparable safety profile. These strong foundational data supported implementation of a phase III study. This phase III, multinational, double-blind, randomized, parallel-group clinical trial (NCT02364999) is evaluating the efficacy, safety, pharmacokinetics, and immunogenicity of PF‑06439535 versus bevacizumab‑EU, in combination with paclitaxel and carboplatin, in previously untreated patients with advanced non-squamous NSCLC.

      Methods:
      A total of 798 patients (399 per treatment arm) will be enrolled. Eligible patients are aged ≥18 years (or ≥ age of consent in the region), and have newly diagnosed stage IIIB/IV NSCLC or recurrent NSCLC with no prior chemotherapy for metastatic disease; predominantly non-squamous disease; ≥1 measureable lesion per RECIST 1.1; Eastern Cooperative Oncology Group performance status 0/1; and adequate hematologic, renal, and hepatic organ function. Patients with known sensitizing mutations in epidermal growth factor receptor (EGFR) or translocation positive mutations in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) are excluded. Patients will be stratified by region, gender, and smoking status, and randomized 1:1 to receive PF‑06439535 or bevacizumab‑EU (15 mg/kg intravenously [IV]) plus paclitaxel (200 mg/m[2] IV) and carboplatin (area under the curve 6 mg·min/mL IV) on Day 1 of 21-day cycles. Following 4–6 cycles of chemotherapy, patients will continue to receive PF‑06439535 or bevacizumab‑EU as blinded monotherapy every 3 weeks until disease progression or unacceptable toxicity. Tumors will be radiographically assessed every 6 weeks according to RECIST v1.1 until Week 25, after which tumor assessments will be performed every 9 weeks. The primary objective of the study is to compare objective response rate (ORR) achieved by Week 19 between treatment arms; objective responses will be subsequently confirmed by 6 weeks thereafter. Secondary objectives include evaluation of safety, additional measures of tumor control (eg, duration of response and 1-year progression-free survival and overall survival rates), population pharmacokinetics, and immunogenicity. The main hypothesis to be tested is that the 90% confidence interval of the relative risk of ORR of PF‑06439535 versus that of bevacizumab‑EU by Week 19 is within a pre-specified margin of 76%–132%. The study is open for enrollment.

      Results:
      Not applicable

      Conclusion:
      Not applicable

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