Justification For Extrapolation Research Articles

Abstract P6-17-21: Matching the critical function of the biosimilar ABP 980 and trastuzumab: Totality of evidence and scientific justification for extrapolation across trastuzumab indications

Abstract Background Approval of biosimilars is based on the totality of evidence (TOE) supporting clinical equivalence between the proposed biosimilar and the reference product (RP). TOE comprises comprehensive studies designed to evaluate structural, functional, pharmacokinetic (PK), and clinical similarity. TOE provides scientific justification for possible extrapolation across indications that share a common mechanism of action. ABP 980 has been shown to be biosimilar to trastuzumab using robust analytical and functional assessments. Results from phase 1 and phase 3 studies have shown PK and clinical similarity to trastuzumab. Here, we extend the similarity assessment using multiple orthogonal assays for the primary mechanism of action. Methods Multiple lots of ABP 980, trastuzumab (US) and trastuzumab (EU) were compared in the biological activity assessment. In addition to the primary assessment, we conducted additional characterization assays assessing human epidermal growth factor receptor 2 (HER2) cell binding, inhibition of HER2 signaling, inhibition of HER2 ligand-independent proliferation in gastric cancer cells, and a synergy study conducted with docetaxel chemotherapy in gastric cancer cells. HER2 cell-based binding assays were performed using SKBR-3 target cells and a competitive inhibition format. Inhibition of AKT phosphorylation was assessed by comparing the effect of test samples on basal pAkt in the BT-474 breast cancer line. Inhibition of HER2 ligand-independent proliferation was assessed using the gastric cell line NCI-N87 and specificity of inhibition was evaluated using MCF-7 cells that do not have amplified HER2 expression. The synergy study was conducted using NCI-N87 gastric cancer cells and docetaxel using the Combinatorix™ method. Results Relative cell binding to HER2 was similar (ABP 980, 93%-112%; trastuzumab [EU], 98%-109%; trastuzumab [US], 96%-102%). Synergy scores (mean ± SD) with docetaxel (in NCI-N87 cells) for ABP 980, trastuzumab (US) and trastuzumab (EU), respectively, were 16.1 ± 1.4, 16.4 ± 1.8, and 15.8 ± 1.3. Functionally, ABP 980 and trastuzumab similarly inhibited HER2 ligand-independent proliferation in NCI-N87 gastric cancer cells, exhibited specificity against MCF7 non-amplified HER2 expressing breast cancer cells, and showed similar inhibition of pAkt phosphorylation in BT-474 breast cancer cells. Conclusions In this study, we show similar activity between ABP 980 and trastuzumab RP, either alone or in combination with docetaxel, in both breast cancer and gastric cancer cell lines. Our results add to the TOE supporting the biosimilarity of ABP 980 and trastuzumab, and the justification for extrapolation across its approved indications. Citation Format: Kolberg H-C, Colleoni MA, Tomasevic Z, Ponomarova O, McBride HJ, Tesch H, Hanes V. Matching the critical function of the biosimilar ABP 980 and trastuzumab: Totality of evidence and scientific justification for extrapolation across trastuzumab indications [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-21.

365 (PB-160) - Clinical comparison of the biosimilar ABP 980 and trastuzumab in early breast cancer: Results of the phase 3 LILAC study and justification for extrapolation across approved trastuzumab indications

365 (PB-160) - Clinical comparison of the biosimilar ABP 980 and trastuzumab in early breast cancer: Results of the phase 3 LILAC study and justification for extrapolation across approved trastuzumab indications

Clinical comparison of ABP 215 and bevacizumab in patients with NSCLC: Pharmacokinetic results and justification for extrapolation across bevacizumab indications.

9050 Background: Approval of biosimilars is based on totality of evidence (TOE) that includes demonstration of analytical, functional, and pharmacokinetic (PK) similarity, and comparable clinical efficacy, safety, and immunogenicity. The TOE supports scientific justification for extrapolation across other indications that a share common mechanism of action (MOA). The proposed biosimilar ABP 215 is similar to bevacizumab (BEV) with respect to inhibition of vascular endothelial growth factor (VEGF)-induced signaling; PK in healthy adults; and clinical efficacy, safety, and immunogenicity in patients with non-small cell lung cancer (NSCLC). The PK results from the NSCLC study are reported here. Methods: In this double-blind study, adults with non-squamous NSCLC receiving first-line chemotherapy with carboplatin and paclitaxel were randomized 1:1 to ABP 215 or BEV (15 mg/kg IV Q3W for 6 cycles). Trough (pre-dose) PK samples were collected at baseline, at weeks 4, 7, and 13, and at end of study. Clinical evaluations included efficacy, safety, and immunogenicity. Results: 642 patients (ABP 215, n = 328; BEV, n = 314) were randomized. Demographic and baseline characteristics were well balanced. The primary endpoint of risk ratio for objective response rate was 0.93 (2-sided 90% CI, 0.80-1.09), which was contained within the pre-specified equivalence margin. The incidence of adverse events was comparable between ABP 215 and BEV. During the study, 4 (1.4%) and 7 (2.5%) patients in the ABP 215 and BEV group, respectively, developed binding antibodies; no patient tested positive for neutralizing antibodies. Steady-state trough serum concentrations for both ABP 215 and BEV were reached by week 13 (median 124.9 vs 124.4 µg/mL, respectively) and were consistent between ABP 215 and BEV throughout the study. Conclusions: ABP 215 is similar to BEV in multiple analytical, functional, and clinical assessments. PK results in patients presented here provide further evidence for similarity between ABP 215 and BEV and contribute to the TOE supporting extrapolation of clinical similarity across BEV indications based on its common MOA. Clinical trial information: NCT01966003.