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ABP 798 (RIABNI™) is a biosimilar to rituximab reference product (RP), a monoclonal antibody that targets CD20. Approval of ABP 798 was based on the totality of evidence generated using a stepwise approach which began by showing that it is structurally and functionally similar to rituximab RP. This analytical assessment was followed by a demonstration of pharmacokinetic/pharmacodynamic similarity in patients with rheumatoid arthritis. Comparative clinical efficacy and safety of ABP 798 with rituximab RP was demonstrated as a final step in patients with non-Hodgkin lymphoma and in those with rheumatoid arthritis. Overall, the totality of evidence supported the conclusion that ABP 798 is highly similar to rituximab RP and provided scientific justification for extrapolation to other approved indications of rituximab RP.

Purpose ABP 980 (KANJINTI™) is a biosimilar to reference product HERCEPTIN® (trastuzumab RP). The goal of this study was to characterize the safety, tolerability, and immunogenicity of ABP 980 plus pertuzumab (PERJETA®) when co-administered in a single infusion bag in healthy subjects. Methods This randomized, double-blind, single-dose, 2-arm, parallel-group study (LAVENDER Study) evaluated an intravenous (IV) infusion of ABP 980 (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag relative to an IV infusion of trastuzumab RP (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag given over 60 min. The subjects were followed for 92 days post dosing. Results A total of 42 subjects were enrolled in the study and treated with investigational product. Due to an operational issue during dosing, the first 6 subjects enrolled in the study were replaced. A total of 36 randomized subjects, n = 18 for ABP 980 plus pertuzumab and n = 18 for trastuzumab RP plus pertuzumab, were treated. Resulting serum concentrations of ABP 980 and trastuzumab RP were similar. There were no serious adverse events, no deaths, and no cardiac disorders during the study. No subject developed anti-drug antibodies throughout the study. Conclusions This study demonstrated the safety and tolerability of ABP 980 and pertuzumab admixture in a single infusion bag. The safety profiles and pharmacokinetic parameters of ABP 980 and pertuzumab were consistent with what is known for trastuzumab RP and pertuzumab. Clinical trial listing EudraCT 2018-002903-33.

ABP 980 (KANJINTI™, Amgen, Thousand Oaks, CA, USA; Amgen Europe B.V., The Netherlands) is a biosimilar to trastuzumab (Herceptin®), a monoclonal antibody that selectively binds human epidermal growth factor receptor-2 (HER2). Here we provide a brief overview of the totality of evidence (including analytical [structural and functional] characterization, nonclinical evaluation, and human pharmacokinetic [PK], pharmacodynamic, and clinical assessment comparing ABP 980 with trastuzumab reference product [RP]) that supported the approval of ABP 980, along with practical considerations on the reconstitution and use of the lyophilized product to ensure safe and effective administration. ABP 980 has been shown to be highly similar to the RP, with similar mechanism of action, binding, and potency. Key PK parameters, geometric means ratio (GMR [90% CI]) of Cmax and AUCinf, are comparable and within the equivalence margin of 0.80 to 1.25 (ABP 980: 1.04 [0.99–1.08] versus trastuzumab US: 1.06 [1.00–1.12]; ABP 980: 0.99 [0.95–1.03] versus trastuzumab EU: 1.00 [0.95–1.06]). No clinically meaningful differences were found between ABP 980 and RP in a comparative clinical trial in patients with HER2-positive early breast cancer. Pathological complete response—ABP 980: 48% versus RP: 41% (risk difference [RD], 90% CI: 7.3%, 1.2–13.4; relative risk [RR], 90% CI: 1.188, 1.033–1.366). Sensitivity analyses per central pathology review—ABP 980: 48%; RP: 42% (RD: 5.8%, −0.5 to 12.0; RR: 1.142, 0.993–1.312), with RD and RR falling within predefined equivalence margins. Similar to trastuzumab RP, KANJINTI™ is supplied as a sterile, lyophilized cake to be reconstituted with bacteriostatic water for injection (BWFI) for multiple-dose injection or sterile WFI for single use. Stability data support storage of reconstituted solution at 2–8°C (36–46°F), up to 28 days. Reconstituted solution can be diluted in infusion bags containing 0.9% saline and stored for up to 24 h prior to intravenous administration. Electronic supplementary material The online version of this article (10.1007/s40487-020-00129-x) contains supplementary material, which is available to authorized users.

Introduction ABP 798 is being developed as a biosimilar to rituximab reference product (RP), a CD20-directed cytolytic antibody that is approved in the US and EU for the treatment of non-Hodgkin lymphoma (NHL). Methods This randomized, double-blind, comparative clinical study (JASMINE) evaluated the efficacy and safety of ABP 798 compared with rituximab RP. Adult, anti-CD20 treatment naïve patients diagnosed with grade 1, 2, or 3a follicular B-cell NHL expressing CD20 were randomized 1:1 to receive a 375 mg/m2 infusion of either ABP 798 or rituximab RP once weekly for 4 weeks and at weeks 12 and 20. Tumor assessments were performed at baseline and weeks 12 and 28. Primary endpoint was the risk difference (RD) of overall response rate (ORR) of complete response, unconfirmed complete response, or partial response by week 28 based on data from central, independent, and blinded assessments of disease. Results Of the 256 randomized patients, 254 were treated with ABP 798 (n = 128; 100%) or rituximab RP (n = 126; 98.4%); 96 (78.0%) patients in the ABP 798 group and 87 (70.2%) in the rituximab RP group had a best ORR by week 28. The point estimate of RD in ORR between ABP 798 and rituximab RP from the adjusted generalized linear model for stratification factors was 7.7%. Clinical equivalence was based on sequential testing of the one-sided 95% lower confidence limits and one-sided 95% upper confidence limits of RD in ORR (− 1.4% and 16.8%, respectively) which was within the prespecified non-inferiority margin (− 15%) and non-superiority margin (35.5%), respectively. Results of sensitivity analyses were consistent with the primary efficacy analysis. ABP 798 was also comparable to rituximab RP across additional secondary endpoints, further supporting the conclusion of similarity, and including: RD of ORR at week 12; trough serum concentrations; percent of patients with complete depletion of CD19+ cell count at day 8; safety; and immunogenicity. Conclusions These results support a conclusion of similar clinical efficacy between ABP 798 and rituximab RP in patients with follicular lymphoma. NCT Number NCT02747043; first posted April 21, 2016. EudraCT Number 2013-005,542-11; submitted 14 October, 2014.

Although the human epidermal growth factor receptor 2 (HER2) blocker trastuzumab is generally well tolerated, cardiotoxicity can be an important therapeutic limitation.Objective.In this prespecified analysis, we compared the cardiac safety of the trastuzumab biosimilar ABP 980 (KANJINTI™) and the trastuzumab reference product (RP; Herceptin®) in the phase III LILAC study (ClinicalTrials.gov identifier NCT01901146).Methods.In the neoadjuvant phase of LILAC, after run-in chemotherapy, 725 patients were randomized 1:1 to ABP980 (n = 364) or trastuzumab RP (n = 361) plus paclitaxel (every 3weeks [Q3W] or every week [QW]) for four cycles. After surgery, patients continued treatment Q3W for up to 1year; ABP980-treated patients continued ABP980 (ABP980/ABP980;n = 364), and trastuzumab RP-treated patients either continued on the RP (trastuzumab RP/trastuzumab RP;n = 190) or switched to ABP980 (trastuzumab RP/ABP980;n = 171). Cardiac safety was monitored by computerized 12-lead electrocardiogram, and left ventricular ejection fraction (LVEF) was assessed by two-dimensional (2D) echocardiogram. LVEF decline was defined as LVEF value decrease from study baseline by ≥ 10 percentage points and to&thinsp

Background: Elevated circulating growth differentiation factor 15 (GDF15) and increased GDF15 expression in tumor tissues has been observed in patients with advanced pancreatic cancer (APC). These changes were correlated with poor survival. Effects of GDF15 on tumor progression, metastasis and immune escape may play a role. NGM120, a novel antibody to GFRAL that blocks the effects of GDF15, has resulted both in antitumor and anti-cachexia effects in experimental models. Here we report updated findings of the ongoing Phase 1b study with NGM120 in patients with APC. Methods: Metastatic pancreatic cancer patients with elevated serum GDF15 were treated with NGM120 (30 or 100 mg, s.c., q4wks) in a 1st line setting in combination with Gem/nab-paclitaxel. Primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetics, preliminary evidence of antitumor activity (RECIST) and anti-cachexia effects. Results: Eight patients received NGM120 in combination with Gem/nab-paclitaxel. Median age was 67 years, all patients had advanced disease. NGM120 was well tolerated with no dose-limiting toxicities. Most of the AEs or SAEs observed were Gem/nab-paclitaxel related and none of them attributed to NGM 120 treatment. As of data cut off on March 25, 2022, preliminary results include 3 patients with PR (extending >32 wks), 3 patients SD; 2 patients discontinued early (before first post-dose scan) due to toxicity attributed to Gem/nab-paclitaxel. Among the 6 evaluable patients, the disease control rate (DCR) is 100%, mPFS has not been reached, 12-month survival rate (12-month OS) is 83.3%. Over the course of the study, 5/6 of the patients gained or maintained their body weight (BW) and 5/6 of the patients gained or maintained their lean body mass (LBM) based on maximum change from baseline. Conclusions: NGM120 given in combination with Gem/nab-paclitaxel to patients with APC resulted in a 50% ORR (3 PR in 6 evaluable patients), 100% DCR, 83.3% 12-month OS and a “not reached” mPFS. Compared to historical Gem/nab-paclitaxel data, these findings are encouraging and support the potential role of NGM120 in the treatment of patients with APC. The positive effects on BW and LBM is also encouraging compared to the historical cachexia rate of 30% observed within 12 weeks of starting first-line chemotherapy in APC. A sign of NGM120 engages the GDF15-GFRAL pathway in managing body weight regulation. A Ph2a study is ongoing to further evaluate NGM120 in combination with Gem/nab-paclitaxel in the 1st line setting for the treatment of APC. Citation Format: Andrew Hendifar, Efrat Dotan, Benjamin Weinberg, Edward Kim, Peter Hosein, Jian Luo, Jiping Zha, Alex DePaoli, Vladimir Hanes, Cecilia Tranmuchowski, Kefei Zhou, Carol Tseng, Hsiao Lieu. Initial results of a cohort of advanced pancreatic cancer patients in a phase 1b Study of NGM120, a first-in-class anti-GDNF Family Receptor Alpha Like (GFRAL) antibody [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR006.

Pathological complete response (pCR) after neoadjuvant therapy is an accepted surrogate endpoint for breast cancer registration trials and is a strong prognostic biomarker especially in high-risk tumor biology. The LILAC study, a comparative trial for the trastuzumab biosimilar ABP 980, was the first international multicenter neoadjuvant breast cancer trial using local and central pathology review for pCR. Here we report concordance between local and central review for the most commonly used pCR definitions. This study included 725 patients with early HER2-positive breast cancer, comparing neoadjuvant ABP 980 and trastuzumab reference product (RP) in combination with anthracycline and taxane-containing chemotherapy. Equivalence of both arms was defined at a significance level of 0.05 by comparing the 2-sided 90% confidence interval (CI) for the risk difference (RD) of pCR between ABP 980 and RP within a predefined margin (-13%, 13%) using definition 2 as described below. pCR was evaluated in local laboratories and in a central laboratory blinded to the local result. The purpose of the independent, central review was to reduce the inter-pathologist variability and provide a more consistent assessment. Central review was performed by 2 independent pathologists; in cases of discordance the specimen was reviewed and decided by a third pathologist (adjudicator). The pCR definition in the primary analysis was no invasive breast cancer in breast and axillary nodes, regardless of ductal carcinoma in situ (DCIS). No invasive tumor in the breast was pCR definition 1, no invasive breast cancer in breast and axillary nodes regardless of DCIS was pCR definition 2, and no invasive breast cancer in breast and axillary nodes and absence of DCIS was pCR definition 3. The RDs and CIs were evaluated for local and central pCR review for all 3 pCR definitions. The results of the neoadjuvant LILAC study have been reported previously, demonstrating no clinically meaningful differences between ABP 980 and RP in HER2-positive early breast cancer. Of the 696 subjects who underwent surgery and had specimens evaluable for pCR review by the local pathologists, 669 specimens were available for central review. Rates of pCR in the local review were 51.1% (ABP 980) and 45% (RP) for definition 1, 48% (ABP 980) and 40.5% (RP) for definition 2, and 37.7% (ABP 980) and 29.6% (RP) for definition 3. The corresponding pCR rates in the central review were 51.3% and 47.3% for definition 1, 47.8% and 41.8% for definition 2, and 29.9% and 26.1% for definition 3. The CI for RD was within the predefined margins for pCR definition 1 in local and central review, whereas it exceeded the prespecified margin in local review for pCR definitions 2 and 3. In the central review the CI was within the margin for the pCR definitions 2 and 3, with the difference between local and central pathology review 1.6% for pCR definition 2 and 4.4% for pCR definition 3, respectively. RDs (90% CI) for all 3 pCR definitions are shown in the Table. The LILAC study demonstrated that a central pathology review for pCR is feasible in a large, international, multicenter neoadjuvant breast cancer trial. Our results show that concordance between local and central pathology can decrease with increasing complexity of the pCR definition. Based on the results, it may be justified to include a central pathology review in neoadjuvant multicenter breast cancer trials with strict pCR definitions. Citation Format: Hanz-Christian Kolberg, Marco Colleoni, Georgia Savva Demetriou, Patricia Santi, Hans Tesch, Yasuhiro Fujiwara, Vladimir Hanes. The importance of central pathology pCR review in an international multicenter neoadjuvant study in HER2 positive early breast cancer - Results of the ABP 980 LILAC trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-03-04.

ABP 215 (MVASI™) is the first approved biosimilar to Avastin® (bevacizumab). It is approved in the USA and the European Union (EU) for all bevacizumab indications in these jurisdictions except for ovarian cancer in the USA due to orphan drug exclusivity. ABP 215 was shown to be structurally, functionally and clinically (pharmacokinetic, efficacy and safety) similar to the bevacizumab reference product; the pharmacokinetic study was conducted in healthy adult men (n = 202); safety and efficacy were evaluated in patients with advanced nonsquamous non-small-cell lung cancer (n = 642). Together, these results comprise the totality of evidence that provides scientific justification for extrapolation to all approved indications of the reference product and supports the clinical value of ABP 215 as an additional treatment option.

As originator biologic medicines lose patent protection, some biopharmaceutical companies are focusing on developing similar versions of these costly and complex therapies with a goal of providing more affordable treatment options. Many of these molecules, known as biosimilars, are now approved worldwide and several more are expected to be introduced in the near future. As more biosimilars become available, it is important for clinicians to become familiar with this new category of products and understand how biosimilars are developed, how their development differs from that of originator biologics and how they differ from generics. This review aims to provide the practicing clinician with the knowledge needed to understand biosimilars, along with some guidance on their use in treating oncologic diseases.

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.

ABP 215 (MVASI™, Amgen, Thousand Oaks, CA; MVASI™, Amgen Europe B.V., Netherlands) is a biosimilar to bevacizumab (Avastin®, Genentech, South San Francisco, CA) reference product (RP), a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A). Here we provide a brief overview of the totality of evidence that supported the approval of ABP 215, along with practical considerations to ensure safe and effective administration. ABP 215 has been shown to be highly similar to the RP, with similar mechanism of action, analytical (structural and functional) characteristics, binding, and potency. The similarity of PK parameters of ABP 215 and bevacizumab RP has been confirmed in healthy volunteers. In a comparative clinical trial, patients with stage IV or recurrent non-squamous non-small cell lung cancer receiving carboplatin and paclitaxel were randomized to ABP 215 or bevacizumab RP. No clinically meaningful differences were found between ABP 215 and RP. The objective response rate (ORR) was 39% for ABP 215 and 41.7% for bevacizumab RP. The risk ratio for the ORR was 0.93 [90% confidence interval (CI), 0.80–1.09], which fell within the prespecified margin for equivalence of 0.67–1.5, indicating similar clinical efficacy. Similar to bevacizumab RP, ABP 215 is supplied as a clear to slightly opalescent, colorless to pale yellow, sterile solution in a glass vial. It should be diluted in 0.9% sodium chloride in polyvinylchloride or polyolefin bags before administering as an intravenous infusion. The ABP 215 solution should be stored at 2–8 °C (36–46°F) prior to use. Physicochemical stability studies showed that there were no meaningful changes in purity or potency and no loss of protein after storage at 2–8 °C for 35 days followed by storage at 30 °C for 48 h. Electronic Supplementary Material The online version of this article (10.1007/s40487-020-00133-1) contains supplementary material, which is available to authorized users.

Purpose Analytic, pharmacokinetic (PK), and clinical similarity between the biosimilar ABP 215 and bevacizumab has previously been demonstrated in global studies. Here we present a phase 1 study in healthy adult Japanese men. Methods This study was a randomized, single-blind, single-dose, parallel-group study comparing PK parameters of ABP 215 versus EU-authorized bevacizumab in healthy Japanese men. Primary endpoints were maximum observed serum concentration (Cmax) and area under the serum concentration—time curve from time 0 to infinity (AUCinf). Secondary endpoints included AUC from time 0 to time of last quantifiable concentration (AUClast), safety, tolerability, and immunogenicity. Results Baseline characteristics were similar among study subjects (n = 24/group). After a 3-mg/kg intravenous infusion, the geometric means (GMs) of Cmax, AUCinf, and AUClast were 71.2 µg/mL, 25,259 µg h/mL, and 22,499.3 µg h/mL, respectively, for ABP 215 and 70.16 µg/mL, 25,801 µg h/mL, and 22,604.6 µg h/mL, respectively, for bevacizumab. The GM ratios (90% confidence interval; CI) for Cmax, AUCinf, and AUClast were 1.015 (0.946–1.088), 0.979 (0.914–1.049), and 0.995 (0.941–1.053) for ABP 215 versus bevacizumab. All CIs fell within the prespecified bioequivalence margin (0.80–1.25). Adverse events (AEs) occurred in 2/24 subjects receiving ABP 215 and 1/24 receiving bevacizumab. There were no deaths or AEs leading to study discontinuation; no subject was positive for binding anti-drug antibodies (ADAs). Conclusions ABP 215 and bevacizumab showed PK similarity in Japanese men. Safety profiles were comparable between the two groups. The pharmacokinetics in Japanese subjects were consistent with those in a previous global PK equivalence study.

ABP 980 was developed as a biosimilar to trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), that is indicated for the treatment of HER2-positive metastatic breast cancer, early breast cancer (EBC), and metastatic gastric cancer. ABP 980 is approved in the United States, European Union, and Japan for all the indications of trastuzumab, based on the totality of evidence (TOE) gathered by the systematic step-wise accumulation of comparative analytical, preclinical, and clinical (pharmacokinetics [PK], efficacy, safety and immunogenicity) data for ABP980 and trastuzumab reference product (RP). As a key first step of the ABP 980 biosimilar program, comprehensive analytical characterization of critical quality attributes established that ABP 980 is structurally and functionally similar to trastuzumab RP. Complementing these data, results of non-clinical pharmacology, toxicology, and toxicokinetic studies supported similarity between ABP 980 and trastuzumab RP. A randomized study in healthy subjects demonstrated clinical PK equivalence of ABP 980 relative to trastuzumab RP in these subjects. In the final clinical evaluation step, arandomized comparative study (LILAC) confirmed the lack of clinically meaningful differences between ABP 980 and trastuzumab RP in efficacy, safety, and immunogenicity in women with HER2-positive EBC in the neoadjuvant-adjuvant setting. Neoadjuvant EBC represented a sensitive homogenous population for biosimilar demonstrations, and the primary endpoint of pathologic complete response served as a sensitive surrogate endpoint. An important aspect of the LILAC study design is that it is the only study that evaluated the effect of switching from the trastuzumab RP to a trastuzumab biosimilar during the adjuvant phase. No new or unexpected safety signals emerged in the clinical evaluations, with the safety profile of ABP 980 consistent with that previously described for trastuzumab. Overall, the TOE data generated for ABP 980 support the conclusion that it is highly similar to trastuzumab RP, thus providing the scientific justification for extrapolation to all the approved indications of trastuzumab.

Summary Background ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer. Methods We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 every 3 weeks in 30 min intravenous infusions (or 80 mg/m 2 paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3–7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast tissue and axillary lymph nodes assessed at a local laboratory in all patients who were randomly assigned and received any amount of neoadjuvant investigational product and underwent surgery. We assessed safety in all patients who were randomly assigned and received any amount of investigational product. This trial is registered with ClinicalTrials.gov, number NCT01901146 and Eudra, number CT 2012-004319-29. Findings Of 827 patients enrolled, 725 were randomly assigned to receive ABP 980 (n=364) or trastuzumab (n=361). The primary endpoint was assessable in 696 patients (358 who received ABP 980 and 338 who received trastuzumab). Pathological complete response was recorded in 172 (48%, 95% CI 43–53) of 358 patients in the ABP 980 group and 137 (41%, 35–46) of 338 in the trastuzumab group (risk difference 7·3%, 90% CI 1·2–13·4; RR 1·188, 90% CI 1·033–1·366), with the upper bounds of the CIs exceeding the predefined equivalence margins of 13% and 1·318, respectively. Pathological complete response in the central laboratory assessment was seen in 162 (48%) of 339 patients assigned to ABP 980 at baseline and 138 (42%) of 330 assigned to trastuzumab at baseline (risk difference 5·8%, 90% CI −0·5 to 12·0, and RR 1·142, 90% CI 0·993 to 1·312). Grade 3 or worse adverse events during the neoadjuvant phase occurred in 54 (15%) of 364 patients in the ABP 980 group and 51 (14%) of 361 patients in the trastuzumab group, of which the most frequent grade 3 or worse event of interest was neutropenia, occurring in 21 (6%) patients in both groups. In the adjuvant phase, grade 3 or worse adverse events occurred in 30 (9%) of 349 patients continuing ABP 980, 11 (6%) of 171 continuing trastuzumab, and 13 (8%) of 171 who switched from trastuzumab to ABP 980, the most frequent grade 3 or worse events of interest were infections and infestations (four [1%], two [1%], and two [1%]), neutropenia (three [1%], two [1%], and one [1%]), and infusion reactions (two [1%], two [1%], and three [2%]). Two patients died from adverse events judged to be unrelated to the investigational products: one died from pneumonia while receiving neoadjuvant ABP 980 and one died from septic shock while receiving adjuvant ABP 980 after trastuzumab. Interpretation Although the lower bounds of the 90% CIs for RR and risk difference showed non-inferiority, the upper bounds exceeded the predefined equivalence margins when based on local laboratory review of tumour samples, meaning that non-superiority was non-conclusive. In our sensitivity analyses based on central laboratory evaluation of tumour samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study. Funding Amgen.

Background: Analytical, functional, and pharmacokinetic similarity between ABP 980 and trastuzumab (TRAS) has been demonstrated. Here we report results from the single switch treatment arm in the adjuvant phase of the corresponding clinical study. Methods: The objective of this randomized, multicenter, double-blind study was to compare ABP 980 with TRAS in women with HER2-positive early breast cancer. After run-in anthracycline-based chemotherapy, patients were randomized 1:1 to intravenous ABP 980 or TRAS plus paclitaxel Q3W for 4 cycles. Surgery (breast and sentinel node or axillary lymph node dissection) was completed 3-7 weeks after the last dose of study drug. Following surgery, patients who initially received TRAS were allocated to either continue TRAS or undergo a single switch to receive ABP 980 Q3W for up to 1 year from the first dose of investigational product (IP) in the neoadjuvant phase. Allocation occurred at randomization and was maintained blinded. The objective of the single switch was to evaluate safety and immunogenicity of subjects transitioning from TRAS to ABP 980. Results: Here we report data collected at the time of the primary analysis, when all patients had completed the first post-surgery clinical visit or withdrawn from the study. The majority of patients had completed the study at the time of this analysis. Of the 827 enrolled patients, 725 were randomized (ABP 980: n=364; TRAS: n=361). Of the 361 patients randomized to TRAS in the neoadjuvant phase, 173 and 174 patients in the TRAS/TRAS and TRAS/980 arm completed surgery, respectively, and 171 patients in each group entered the adjuvant phase following surgery. A total of 89 (52.0%) and 98 (57.3%) patients had an adverse event (AE) in the TRAS/TRAS and TRAS/980 group, respectively; 10 (5.8%) patients in each group had a grade ≥3 AE. AEs of interest are listed in Table 1. Table 1: Adverse Events of Interest TRAS/980 (n = 171)TRAS/TRAS (n = 171) Total, n (%)Grade ≥3, n (%)Total, n (%)Grade ≥3, n (%)Any AE of interest45 (26.3)5 (2.9)39 (22.8)5 (2.9)Infections and Infestations21 (12.3)2 (1.2)14 (8.2)2 (1.2)Neutropenia13 (7.6)1 (0.6)16 (9.4)2 (1.2)Infusion reactions15 (8.8)3 (1.7)10 (5.8)1 (0.6)Hypersensitivity7 (4.1)03 (1.8)0Pulmonary toxicity1 (0.6)1 (0.6)2 (1.2)1 (0.6)Cardiac failure1 (0.6)01 (0.6)0 One patient in the TRAS/980 arm developed binding, non-neutralizing anti-drug antibodies (ADAs) during the adjuvant phase, compared with 4 patients (2 each in the ABP 980 and TRAS arms) in the neoadjuvant phase. The percentage of patients with disease progression or recurrence or death was 5.3% and 2.9% in the TRAS/TRAS and TRAS/980 arm, respectively (hazard ratio for TRAS/980 vs TRAS/TRAS, 0.48; 90% CI: [0.181, 1.292]). Conclusions: Switching from TRAS to ABP 980 following surgery was safe in patients with breast cancer. Switching did not increase the frequency or severity of AEs and no unexpected safety signals were noted, and it did not increase the incidence of developing ADAs. Event-free survival was also similar between treatment groups. Citation Format: von Minckwitz G, Turdean M, Zhang N, Santi P, Hanes V. Biosimilar ABP 980 in patients with early breast cancer: Results of single switch from trastuzumab to ABP 980 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-13.

Background: Analytical, functional, and pharmacokinetic similarity between the proposed biosimilar ABP 980 and trastuzumab (TRAS) has been shown. Similar efficacy and safety have also been demonstrated in the neoadjuvant phase of the phase 3 comparative clinical study. Here we focus on the safety and immunogenicity results from the adjuvant phase of this study. Methods: The objective of this study was to compare ABP 980 with TRAS in women with HER2 positive early breast cancer. After run-in anthracycline-based chemotherapy, patients were randomized 1:1 to intravenous ABP 980 or TRAS plus paclitaxel Q3W for 4 cycles. Surgery was completed 3-7 weeks after the last dose of neoadjuvant study drug. After surgery, patients who initially received TRAS were allocated to either continue TRAS (TRAS/TRAS arm) or undergo a single switch to receive ABP 980 (TRAS/980 arm) and patient who initially received ABP 980 continued to receive ABP 980 (980/980 arm) Q3W for up to 1 year. This report is based on safety data collected at the time of primary analysis, when all patients had completed the first post-surgery clinical visit or had withdrawn. The majority of patients had completed the study at the time of this analysis. Results: 725 patients were randomized; 364 and 361 patients were randomized to ABP 980 and TRAS, respectively, in the neoadjuvant phase. Following surgery, 349 patients in the 980/980 arm, 171 patients in the TRAS/TRAS arm, and 171 patients in the TRAS/980 arm entered the adjuvant phase. Adverse events (AEs) during the adjuvant phase are shown in Table 1; data from the neoadjuvant safety phase have been previously reported. Table 1 980/980 (N = 349)TRAS/TRAS (N = 171)TRAS/980 (N = 171)AE category, n (%) Any AE201 (57.6)89 (52.0)98 (57.3)Any grade ≥3 AE27 (7.7)10 (5.8)10 (5.8)Any fatal AE001 (0.6)Any serious AE14 (4.0)4 (2.3)4 (2.3)AEs of Interest, n (%) Infections and infestations46 (13.2)14 (8.2)21 (12.3)Neutropenia37 (10.6)16 (9.4)13 (7.6)Infusion reactions27 (7.7)10 (5.8)15 (8.8)Hypersensitivity11 (3.2)3 (1.8)7 (4.1)Pulmonary toxicity3 (0.9)2 (1.2)1 (0.6)Cardiac failure01 (0.6)1 (0.6)LVEF decline by ≥10% and to below 50%, n/N* (%)9/313 (2.9)3/154 (1.9)3/153 (2.0)LVEF = left ventricular ejection fraction; N* = Number of patients with data available One patient in the TRAS/980 arm developed binding antibodies during the adjuvant phase; this patient tested negative for neutralizing antibodies. In the neoadjuvant phase, 2 patients in the ABP 980 arm and 2 in the TRAS arm developed binding antibodies but tested negative for neutralizing antibodies. The percent of patients with disease progression or recurrence or death was 5.2% in the 980/980 arm, 5.3% in the TRAS/TRAS arm, and 2.9% in the TRAS/980 arm. The estimated hazard ratio from a stratified Cox proportional hazards regression model for 980/980 versus TRAS/TRAS was 1.01 (90% CI: [0.530, 1.930]) and for TRAS/980 versus TRAS/TRAS was 0.48 (90% CI: [0.181, 1.292]). Conclusions: Safety of ABP 980 is similar to TRAS in patients with HER2+ early breast cancer in both the neoadjuvant and adjuvant phases and consistent with the historical safety profile of TRAS. The immunogenicity profile of ABP 980 is low and consistent with TRAS. Citation Format: Kolberg H-C, Demetriou GS, Zhang N, Tomasevic Z, Hanes V. Safety results from a randomized, double-blind, phase 3 study of ABP 980 compared with trastuzumab in patients with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-10.

This study compared the pharmacokinetic (PK) profiles of the proposed biosimilar ABP 215 with bevacizumab in healthy males. In this randomized, single-blind, single-dose, three-arm, parallel-group study, healthy subjects were randomized to receive ABP 215 (n = 68), bevacizumab (US) (n = 67), or bevacizumab (EU) (n = 67) 3 mg/kg intravenously. Primary endpoints were area under the serum concentration–time curve from time 0 extrapolated to infinity (AUCinf) and the maximum observed concentration (C max). Secondary endpoints included safety and immunogenicity. AUCinf and C max were similar across the three groups. Geometric means ratio (GMR) for C max and AUCinf, respectively, was 0.98 and 0.99 for ABP 215 versus bevacizumab (US); 1.03 and 0.96 for ABP 215 versus bevacizumab (EU); and 1.05 and 0.97 for bevacizumab (US) versus bevacizumab (EU). The 90% confidence intervals for the GMRs of AUCinf and C max were within the prespecified standard PK bioequivalence criteria of 0.80 to 1.25. The incidence of adverse events (AEs) was 47.1, 32.8, and 61.2% in the ABP 215, bevacizumab (US) and bevacizumab (EU) groups, respectively. When analyzed by investigational site, the incidence and severity of AEs were comparable in the ABP 215 and bevacizumab groups. There were no AEs leading to study discontinuation. No binding or neutralizing anti-drug anti-bodies was detected. This study demonstrated the PK similarity of ABP 215 to both bevacizumab (US) and bevacizumab (EU), and of bevacizumab (US) to bevacizumab (EU). Safety and tolerability were comparable between treatments and no subject developed binding or neutralizing anti-drug anti-bodies.

This study compared the pharmacokinetic (PK) profiles of the proposed biosimilar ABP 980 and trastuzumab in healthy males. In this single-blind study, 157 healthy males were randomized 1:1:1 to a single 6 mg/kg intravenous infusion of ABP 980, FDA-licensed trastuzumab [trastuzumab (US)], or EU-authorized trastuzumab [trastuzumab (EU)]. Primary endpoints were area under the serum concentration–time curve from time 0 to infinity (AUCinf) and maximum observed serum concentration (C max). To establish equivalence, the geometric mean ratio (GMR) and 90% confidence interval (CI) for C max and AUCinf had to be within the equivalence criteria of 0.80–1.25. The GMRs and 90% CIs for C max and AUCinf, respectively, were: 1.04 (0.99–1.08) and 1.06 (1.00–1.12) for ABP 980 versus trastuzumab (US); 0.99 (0.95–1.03) and 1.00 (0.95–1.06) for ABP 980 versus trastuzumab (EU); and 0.96 (0.92–1.00) and 0.95 (0.90–1.01) for trastuzumab (US) versus trastuzumab (EU). All comparisons were within the equivalence criteria of 0.80–1.25. Treatment-emergent adverse events (TEAEs) were reported in 84.0, 75.0, and 78.2 of subjects in the ABP 980, trastuzumab (US), and trastuzumab (EU) groups, respectively. There were no deaths or TEAEs leading to study discontinuation and no binding or neutralizing anti-drug anti-bodies were detected. This study demonstrated the PK similarity of ABP 980 to both trastuzumab (US) and trastuzumab (EU), and of trastuzumab (US) to trastuzumab (EU). No differences in safety and tolerability between treatments were noted; no subject tested positive for binding anti-bodies.

Background: ABP 798 is a proposed biosimilar to rituximab reference product (RP). Regulatory approval of biosimilars is based on a totality of evidence (TOE) approach which includes similarity in analytical characteristics (structural and functional), in mechanism of action (MoA) -clinical pharmacology, pharmacokinetics (PK), pharmacodynamics (PD), and in comparative clinical studies. Evidence from analytical, functional, clinical PK/PD, and efficacy and safety evaluations indicate that ABP 798 is similar to rituximab RP. Similarity of efficacy and safety in patients with non-Hodgkin lymphoma (NHL) was demonstrated in a randomized, double-blind, comparative clinical study in which the primary analysis was based on data from central, independent, and blinded assessments of disease and the sensitivity analysis was based on data using investigator assessments of disease. Here we present in vitro chemo synergy, preclinical in-vivo tumor efficacy data and show how the results of the sensitivity analysis using investigator assessments of the response rate from the NHL clinical study further add to the TOE supporting similarity of ABP 798 with the RP. Methods: In vitro synergy with chemotherapeutic agents was investigated by assessing the effect of docetaxel, gemcitabine, or doxorubicin with ABP 798 and rituximab RP in SU-DHL-6 cell lines and measured using the ATP-based cell viability endpoint (ATPLite). In vivo efficacy was assessed by evaluating the anti-tumor activity of ABP 798 and rituximab RP in NHL xenograft models in NOD/SCID mice using CD20-expressing RL and Raji cell lines. A sensitivity analysis was conducted to assess the robustness of the results of the primary efficacy endpoint of the proportion of patients with the best overall response of complete response, partial response, or unconfirmed complete response (ORR) in the NHL comparative clinical study using the investigator's assessment of disease on the full analysis set. Waterfall plots of the maximum percent reduction in the sum of the products of the greatest diameters (SPD) for index nodal lesions based on both the central, independent, blinded assessment of disease and the investigator's assessment of disease were used. Results: In vitro study results demonstrated synergistic activity of the combination of docetaxel and ABP 798 or the RP (synergy score = 6.35±0.69 [with ABP 798]; 6.79±0.12 [with RP]). In contrast, combinations with gemcitabine (synergy score = 2.68±0.20 [with ABP 798] and 2.54±0.29 [with RP]) or doxorubicin (synergy score = 1.95±0.56 [with ABP 79]) and 3.23±0.53 [with RP]) were additive. In RL cell lines, ABP 798 inhibited tumor growth similarly to rituximab RP, with no statistical difference between dose groups at 3 and 30 mg/kg (p = 0.951 and p = 0.996, respectively). In Raji cells, ABP 798 and rituximab RP significantly and similarly inhibited tumor growth when compared to an IgG1 isotype control (p < 0.001 for 3 and 30 µg/kg doses). ABP 798, at both dose levels, inhibited tumor growth similarly to rituximab RP by 27-41%, with no statistical difference. In the NHL comparative clinical study, risk difference (RD) of ORR with 1-sided 95% lower and upper confidence limits from the adjusted linear model was 7.7% (-3.2%, 18.6%) using central, blinded, independent assessments of the modified full analysis set based on randomized treatment assignment. The sensitivity analysis using investigator assessments of disease of the full analysis set of all randomized subjects based on the randomized treatment assignment received was RD = 0.5% (-7.8%, 8.8%). Waterfall plots of the maximum percent reduction in the SPD for index nodal lesions further demonstrate similarity of efficacy with central or local assessments of disease. Conclusions: In vitro and in vivo preclinical studies demonstrated chemo synergy and in vivo tumor efficacy. The sensitivity analysis of ORR using local assessments in the NHL comparative clinical study was consistent with results from the primary efficacy analysis; the maximum percent reduction in index nodal lesions was similar for central and local assessments of disease. These results further support that ABP 798 is similar to the RP across a range of efficacy evaluations as well as primary and secondary mechanisms of action and add additional supporting data to the TOE. Disclosures Niederwieser: Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Daiichi: Research Funding; Amgen: Speakers Bureau. Hamm:Amgen: Consultancy. Cobb:Amgen: Consultancy. Thway:Amgen: Current Employment, Current equity holder in publicly-traded company. Forsyth:Amgen: Consultancy; Janssen Pharmaceuticals Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tucci:Amgen: Consultancy. Delwail:Amgen: Consultancy. Hajek:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; Oncopeptides: Consultancy. Hanes:Amgen: Current Employment, Current equity holder in publicly-traded company.

In the original version of [this article][1] ([1][2]), Fig. 1 was incomplete and the “Methods” sections of both the abstract and the article stated that patients received drugs thrice weekly instead of every three weeks. These errors have been corrected in the latest online HTML and PDF versions

8044 Background: ABP 798* is being developed as a biosimilar to rituximab, a CD20-directed cytolytic antibody. A randomized, double-blind, active-controlled study compared the efficacy, safety, and immunogenicity of ABP 798 with rituximab reference product (RP) in subjects with CD20-positive NHL; results of the final analysis are presented here. Methods: Adult subjects with grade 1, 2, or 3a follicular B-cell NHL and low tumor burden were randomized to receive intravenous ABP 798 or RP (375 mg/m2) once weekly for 4 weeks, then at weeks 12 and 20. The primary endpoint was risk difference (RD) of overall response rate (ORR) by week 28. Secondary endpoints included RD of ORR at week 12, pharmacokinetics, pharmacodynamics, safety, and immunogenicity. Results: 254/256 randomized subjects were treated with at least one infusion of ABP 798 (n = 128) or RP (n = 126); ORR by week 28, based on independent central blinded assessment of the modified full analysis set, was comparable between the ABP 798 and RP groups (78% vs. 70%, respectively). The 2-sided 90% confidence interval of RD of ORR (-1.4%; 16.8%) was within the pre-specified margin (-15%; 35.5%) thereby establishing clinical equivalence between ABP 798 and RP. This result was supported by analyses of the secondary efficacy endpoint of RD of ORR at week 12. In the two groups, the geometric least squares means for serum concentrations over time (e.g., week 12, pre-dose: ABP 798, 21.89 vs. RP, 20.57; week 12 post-dose: ABP 798, 201.30 vs. RP, 203.52) and the extent of B-cell depletion from day 1 to day 8 (ABP 798, 98.3% vs. RP, 98.3%) were similar. Frequency, type, and severity of adverse events (AEs) were comparable between ABP 798 and RP groups; grade ≥3 AEs were reported in 10.9% and 10.3% of subjects and serious AEs in 3.9% and 4.0%, respectively. Most common AEs were headache, fatigue, and nausea; the most common AE of interest was infusion reactions. No new or unexpected safety signals were observed. Binding and neutralizing anti-drug antibodies were comparable between groups. Conclusions: Results of this study demonstrated clinical similarity between ABP 798 and rituximab RP in subjects with CD20-positive NHL. *At the time of this submission, ABP 798 had not been approved by the FDA or any relevant regulatory agency and the indications are yet undetermined. Please consult ABP 798’s later approved label in the relevant country for information regarding the approved uses for ABP 798.

Purpose: This phase III study compared clinical efficacy and safety of the biosimilar ABP 215 with bevacizumab reference product (RP) in patients with advanced nonsquamous non–small cell lung cancer (NSCLC). Patients and Methods: Patients were randomized 1:1 to ABP 215 or bevacizumab 15 mg/kg every three weeks for 6 cycles. All patients received carboplatin and paclitaxel every three weeks for ≥4 and ≤6 cycles. The primary efficacy endpoint was risk ratio of objective response rate (ORR); clinical equivalence was confirmed if the 2-sided 90% confidence interval (CI) of the risk ratio was within the margin of 0.67 to 1.5. Secondary endpoints included risk difference of ORR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS); pharmacokinetics, adverse events (AEs), and incidence of antidrug antibodies (ADAs) were monitored. Results: A total of 820 patients were screened; 642 were randomized to ABP 215 (n = 328) and bevacizumab (n = 314). Overall, 128 (39.0%) and 131 (41.7%) patients in the ABP 215 and bevacizumab groups, respectively, had objective responses [ORR risk ratio: 0.93 (90% CI, 0.80–1.09)]. In the ABP 215 and bevacizumab group, 308 (95.1%) and 289 (93.5%) patients, respectively, had at least 1 AE; 13 (4.0%) and 11 (3.6%) experienced a fatal AE. Anti-VEGF toxicity was low and comparable between treatment groups. At week 19, median trough serum drug concentration was 132 μg/mL (ABP 215 group) and 129 μg/mL (bevacizumab group). No patient tested positive for neutralizing antibodies. Conclusions: ABP 215 is similar to bevacizumab RP with respect to clinical efficacy, safety, immunogenicity, and pharmacokinetics. The totality of evidence supports clinical equivalence of ABP 215 and bevacizumab.

e20708 Background: ABP 215 (MVASI™ [bevacizumab]) is the first biosimilar to Avastin (bevacizumab) approved in the US and EU. This phase 3, double-blind study compared efficacy of ABP 215 with bevacizumab reference product (RP) in patients with advanced non-squamous NSCLC. Here we report the totality of evidence supporting similarity between ABP 215 and RP, including preclinical VEGF-A isoform binding relevant to the mechanism of action across indications, and clinical results of central and investigator evaluation of tumor response. Methods: VEGF-A kinetic parameters were compared for common isoforms 121, 165 and 189. Patients were randomized 1:1 to ABP 215 or RP 15 mg/kg Q3Wx6 cycles. All patients received carboplatin and paclitaxel Q3W for up to 6 cycles. Disease assessments (CT/MRI) were performed at screening, weeks 7, 13, 19, and Q9W thereafter by the investigator and, independently, by central, blinded radiologists. Efficacy was based on objective tumor assessments according to RECIST 1.1. Copies of all radiographs were submitted for central analysis. The primary efficacy endpoint was risk ratio of objective response rate (ORR); clinical equivalence was confirmed if the 2-sided 90% CI of the risk ratio was within the margin of 0.67-1.5. Additional efficacy analyses included duration of response (DOR) and progression-free survival (PFS). Results: Binding to all 3 isoforms was similar for ABP 215 and RP. In the MAPLE study, 642 patients (ABP 215, 328; RP, 314) were randomized. Based on central analysis, ORR was achieved in 128 (39.0%) patients in the ABP 215 and 131 (41.7%) in the RP groups, (ORR risk ratio: 0.93 [90% CI: 0.80, 1.09]). Based on investigator analysis, ORR was achieved in 157 (47.9%) patients in the ABP 215 and 151 (48.1%) in the RP groups (ORR risk ratio: 1.01 [90% CI: 0.88, 1.16]). Hazard ratio (HR, ABP 215 vs RP) for DOR was 1.08 (95% CI, 0.76, 1.54) and 0.76 (95% CI, 0.48, 1.23) per investigator and central assessment. PFS HR was 1.10 (90% CI, 0.92, 1.33) and 1.03 (90% CI, 0.83, 1.29) per investigator and central assessment. Conclusions: These results further confirm the similarity of ABP 215 and RP and support extrapolation to all available bevacizumab indications. Clinical trial information: NCT01966003.

557 Background: Although trastuzumab is generally well-tolerated, cardiotoxicity is the main limitation in its use, leading to a severe heart failure in 2-4% of patients in adjuvant trials. In the phase 3 LILAC trial, trastuzumab biosimilar ABP 980 demonstrated similar efficacy, safety, and immunogenicity to trastuzumab reference product (RP) in women with HER2-positive early breast cancer. Here we report analyses comparing cardiac safety of ABP 980 and RP. Methods: In the neoadjuvant phase, all 725 patients received 4 cycles of chemotherapy with epirubicin + cyclophosphamide Q3W and were then randomized 1:1 to ABP 980 (n = 364) or RP (n = 361) with a loading dose of 8 mg/kg, then 6 mg/kg IV Q3W for 3 cycles plus paclitaxel Q3W (4 cycles) or QW (12 cycles). After surgery, patients received investigational product (IP) Q3W for up to 1 year; ABP 980-treated patients continued ABP 980, and RP-treated patients either continued RP (n = 190) or switched to ABP 980 (RP/ABP 980; n = 171). AEs were assessed every 3 weeks and cardiac safety every 3 months. Cardiac safety was monitored by computerized 12-lead ECG; LVEF was assessed by 2D ECHO. LVEF decline was defined as LVEF value decrease from study baseline by ≥10 percentage points and to < 50%. Results: Treatment groups were well balanced with regard to IP disposition. Over the entire study, 22 (3.1%) patients had LVEF decline by ≥10 percentage points compared to baseline and to < 50%; no meaningful between-group differences were observed (ABP 980:10/359 [2.8%], RP: 6/184 [3.3%], RP/ABP 980: 6/171 [3.5%]). The incidence of cardiac AEs was low and comparable in treatment groups. One grade 3 cardiac failure event was reported in the RP/ABP 980 arm; another in the RP arm was coincident with LVEF decline. No patient discontinued IP during adjuvant phase because of cardiac failure. Conclusions: These pre-specified analyses confirm the tolerability of ABP 980 and demonstrate clinical similarity of ABP 980 and RP with respect to cardiac safety. The incidence of LVEF decline was consistent with the known cardiac safety profile of the RP. No new cardiac safety signals were observed whether patients were on ABP 980 or switched from RP to ABP 980. Clinical trial information: NCT01901146.

583Background: The phase 3 LILAC Study compared ABP 980 with trastuzumab (TRAS) on pathologic complete response (pCR) in women with HER2+ early breast cancer. The primary efficacy results, based on...

Purpose This study compared the pharmacokinetic (PK) profiles of the proposed biosimilar ABP 215 with bevacizumab in healthy males. Methods In this randomized, single-blind, single-dose, three-arm, parallel-group study, healthy subjects were randomized to receive ABP 215 (n = 68), bevacizumab (US) (n = 67), or bevacizumab (EU) (n = 67) 3 mg/kg intravenously. Primary endpoints were area under the serum concentration–time curve from time 0 extrapolated to infinity (AUCinf) and the maximum observed concentration (C max). Secondary endpoints included safety and immunogenicity. Results AUCinf and C max were similar across the three groups. Geometric means ratio (GMR) for C max and AUCinf, respectively, was 0.98 and 0.99 for ABP 215 versus bevacizumab (US); 1.03 and 0.96 for ABP 215 versus bevacizumab (EU); and 1.05 and 0.97 for bevacizumab (US) versus bevacizumab (EU). The 90% confidence intervals for the GMRs of AUCinf and C max were within the prespecified standard PK bioequivalence criteria of 0.80 to 1.25. The incidence of adverse events (AEs) was 47.1, 32.8, and 61.2% in the ABP 215, bevacizumab (US) and bevacizumab (EU) groups, respectively. When analyzed by investigational site, the incidence and severity of AEs were comparable in the ABP 215 and bevacizumab groups. There were no AEs leading to study discontinuation. No binding or neutralizing anti-drug anti-bodies was detected. Conclusions This study demonstrated the PK similarity of ABP 215 to both bevacizumab (US) and bevacizumab (EU), and of bevacizumab (US) to bevacizumab (EU). Safety and tolerability were comparable between treatments and no subject developed binding or neutralizing anti-drug anti-bodies.

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.

9095Background: ABP 215 is a biosimilar candidate highly similar to BEV, a VEGF inhibitor, in analytical and functional comparisons. Pharmacokinetic similarity between ABP 215 and BEV has been demo...