Search

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.

Objectives ABP 959 is a proposed biosimilar to eculizumab, a monoclonal antibody targeting the human C5 complement protein. The objective of this randomized, double-blind, three-arm, study was to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity of ABP 959 relative to the eculizumab reference product (RP) in healthy adult male subjects. Methods Eligible subjects aged 18-45 years were randomized to receive a 300-mg IV infusion of ABP 959, or FDA-licensed eculizumab (eculizumab US), or EU-authorized eculizumab (eculizumab EU). Primary PK endpoint was area under the total serum concentration-time curve from 0 to infinity (AUC0-∞ ); primary PD endpoint was area between the effect curve (ABEC) of CH50-time data. Results The geometric mean of PK and PD parameters were similar between ABP 959 versus eculizumab US and eculizumab EU; PK and PD similarity was established based on 90% confidence intervals of the geometric mean ratio being within prespecified equivalence margin of 0.8 and 1.25. The incidence of treatment-emergent adverse events was similar across groups. The incidence of binding anti-drug antibodies was similar across treatments; no subjects developed neutralizing antibodies. Conclusions This study demonstrated PK and PD similarity of ABP 959 to eculizumab RP; safety and immunogenicity profiles were also similar.

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.

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.

Objectives ABP 959 is a proposed biosimilar to eculizumab, a monoclonal antibody targeting the human C5 complement protein. The objective of this randomized, double‐blind, three‐arm, study was to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity of ABP 959 relative to the eculizumab reference product (RP) in healthy adult male subjects. Methods Eligible subjects aged 18‐45 years were randomized to receive a 300‐mg IV infusion of ABP 959, or FDA‐licensed eculizumab (eculizumab US), or EU‐authorized eculizumab (eculizumab EU). Primary PK endpoint was area under the total serum concentration‐time curve from 0 to infinity (AUC0−∞); primary PD endpoint was area between the effect curve (ABEC) of CH50‐time data. Results The geometric mean of PK and PD parameters were similar between ABP 959 versus eculizumab US and eculizumab EU; PK and PD similarity was established based on 90% confidence intervals of the geometric mean ratio being within prespecified equivalence margin of 0.8 and 1.25. The incidence of treatment‐emergent adverse events was similar across groups. The incidence of binding anti‐drug antibodies was similar across treatments; no subjects developed neutralizing antibodies. Conclusions This study demonstrated PK and PD similarity of ABP 959 to eculizumab RP; safety and immunogenicity profiles were also similar.

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.

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

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.

Background: ABP 959 is being developed as a biosimilar to eculizumab, a recombinant humanized IgG2/4 chimeric monoclonal antibody that binds to the human C5 complement protein (C5), thereby inhibiting the complement cascade. Eculizumab is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH), generalized myasthenia gravis (gMG), atypical hemolytic uremic syndrome (aHUS), and neuromyelitis optica spectrum disorder (NMOSD). ABP 959 has demonstrated pharmacokinetic (PK) and pharmacodynamic (PD) similarity to eculizumab reference product (RP) in healthy male subjects (Chow et al., EHA 2019). Treatment with eculizumab can result in the development of anti-drug antibodies (ADAs), which may lead to loss of clinical efficacy; therefore, evaluating the incidence of ADAs and assessing their relationship to PK parameters is important. Objectives: To assess the relationship between PK parameters and ADAs for ABP 959 and eculizumab RP. Methods: This was a randomized, double-blind, single-dose, 3-arm, parallel-group study in healthy adult male subjects, between 18 to 45 years of age, with a body mass index of 18 to 30.0 kg/m2, who were randomized to receive a 300 mg IV infusion of ABP 959, FDA-licensed eculizumab (eculizumab US), or EU-authorized eculizumab (eculizumab EU). Serum samples for PK evaluations were collected over 57 days. A primary objective of the study was to demonstrate PK equivalence of ABP 959 versus eculizumab RP, as assessed by area under the total serum concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf). Secondary PK endpoints included AUC from time 0 to the time of the last observed quantifiable concentration (AUClast) and maximum observed concentration (Cmax). The pre-specified equivalence criterion for the primary PK parameters was a 90% confidence interval (CI) for the geometric means ratio (GMR) within 0.80 to 1.25, for ABP 959 versus eculizumab US and ABP 959 versus eculizumab EU comparisons. Immunogenicity assessment was a secondary endpoint of the study. Sensitivity analysis of the PK primary endpoint was performed for the binding ADA-negative and neutralizing ADA-negative subjects, with the point estimates and 90% CIs for test-to-reference GMR calculated for PK parameters (AUCinf, AUClast, and Cmax) for total eculizumab and total ABP 959. Samples for ADA assessments were collected predose on Day 1, Day 11, Day 29, and at the end of study (EOS) Visit (Day 57) or upon early study discontinuation. Results: A total of 219 subjects were enrolled (ABP 959, n=71; eculizumab US, n=74; eculizumab EU, n=74); overall, 19 (8.8%) subjects had positive binding ADAs over the course of the study. At any time during the study, the incidence of binding ADAs across treatments was: ABP 959, n=7 (9.9%); eculizumab US, n=5 (6.9%); and eculizumab EU, n=7 (9.5%). At EOS, 4 (1.9%) subjects had positive binding ADAs (ABP 959, n=1 [1.4%]; eculizumab US, n=2 [2.9%]; and eculizumab EU, n=1 [1.4%]). In these subjects, their PK or exposure was within the same range as ADA-negative subjects. In binding ADA-negative subjects, the 90% CIs for the adjusted least square GMRs for all comparisons were within the bioequivalence range of 0.80 to 1.25. No subjects developed neutralizing antibodies throughout the study. Conclusions: The incidence of ADAs was similar between ABP 959 and eculizumab RP and did not impact the overall PK similarity assessment. Disclosures Hanes: Amgen Inc.: Employment. Pan:Amgen Inc.: Employment. Mytych:Amgen Inc.: Employment. Chien:Amgen Inc.: Employment. Chow:Amgen Inc.: Employment.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease that manifests with complement-mediated chronic intravascular hemolysis resulting in hemolytic anemia, tendency to thrombosis, and peripheral blood cytopenias. Eculizumab is a recombinant humanized IgG2/4 chimeric monoclonal antibody that is approved for the treatment of PNH, generalized myasthenia gravis (gMG), atypical hemolytic uremic syndrome (aHUS), and neuromyelitis optica spectrum disorder (NMOSD). Eculizumab specifically binds to the human C5 complement protein (C5), thereby inhibiting the complement cascade. To obtain a better understanding of PNH biology and provide insight toward improving the clinical management of patients with this disease, a retrospective chart review was performed from pre-existing medical records of patients with PNH treated with eculizumab. This analysis is expected to inform eculizumab biosimilar development; data collected on clinical characteristics of this patient population are presented here. Methods: This is a multicenter retrospective chart review study of pre-existing medical records of patients ≥18 years old with PNH who were treated with eculizumab between 01 January 2008 and 31 January 2016. Anonymized data from eligible patients were recorded by sites onto an electronic case report form (eCRF) and collected into an electronic data capture (EDC) system. The primary objective of the study was to assess the lactate dehydrogenase (LDH) concentration over time in eculizumab-treated patients with PNH, including during clinical events and after discontinuation of therapy. Secondary objectives included assessment of coexisting disease, vital signs, laboratory results, and clinical findings. Subjects' LDH time profiles and mean change from baseline of LDH in the maintenance phase were assessed. Maintenance phase was defined as the time period from the first of every 2 weeks (Q2W) eculizumab dose to the data cutoff date, or from the first Q2W eculizumab dose date to the last Q2W dose date for patients who discontinued prior to data cutoff. Baseline of the maintenance phase was defined as the last non-missing assessment taken prior to or on the same day of the first Q2W eculizumab dose. The inter- and intra-subject coefficient of variation (CV) of the 12-week area under effective curve (AUEC) of LDH was based on patients who had at least 2 LDH measurements during the maintenance treatment phase within 12 weeks of each other. Results: The medical records of 47 patients with PNH who were treated with eculizumab during the study period were reviewed; of these, 27 (57.4%) were female. At the time of the diagnosis, the mean age of all patients was 35.0 years and LDH values were reported for 5 of the 47 patients, 3 of which were ≥1.5 times the upper limit of normal. LDH values for most subjects during the study were within the expected ranges for the PNH population with stabilized hemoglobin levels on eculizumab. The mean change from baseline of LDH in the maintenance phase showed a decrease or no change for most time points. For the 26 patients who had ≥2 LDH measurements that were ≤ 12 weeks of each other, inter- and intra-subject CVs for the 12-week AUEC of LDH were 74.70% (95% confidence interval [CI] of 58.23%, 88.15%) and 34.05% (95% CI of 30.65%, 38.34%), respectively. The most commonly reported disease-related symptoms were hemoglobinuria (25 patients [53.2%]), abdominal pain (14 patients [29.8%]), thrombosis (11 patients [23.4%]), and infection (8 patients [17.0%]). Disease-related symptoms listed as 'Other' were reported in 14 (29.8%) patients and included dyspnea, fatigue, exertional dyspnea, aplastic anemia, kidney failure, and dysphagia. All reported concurrent medical conditions and symptoms have been previously well-documented in PNH patients. Ninety-two transfusions were administered to 15 (31.91%) patients within 6 weeks of the first eculizumab dose. Vital signs data did not demonstrate any clinically significant findings. Conclusions: The LDH levels for the majority of PNH patients with stabilized hemoglobin levels on eculizumab were well controlled and within the expected range; the inter- and intra-subject variability of 12-week AUEC of LDH were 74.70% and 34.05%, respectively. There were no unexpected or remarkable findings with respect to disease-related symptoms, vital signs, clinical findings, or laboratory data. Disclosures Hanes: Amgen Inc.: Employment. Pan:Amgen Inc.: Employment. Chow:Amgen Inc.: Employment.

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.

Introduction The Female Sexual Function Index (FSFI) has consistently been shown to have discriminant validity, test–retest reliability, and internal consistency as a measure of female sexual function. However, the content validity (relevance, clarity, comprehensiveness) of the instrument in women with hypoactive sexual desire disorder (HSDD) must also be established. Aim The aim of this study were to assess the content validity of the FSFI, specifically the FSFI desire domain, in pre‐ and postmenopausal women with HSDD. Methods Two single‐visit content validation studies were conducted in the United States. Eligible premenopausal (both studies) and postmenopausal (second study only) women with HSDD completed the FSFI followed by one‐on‐one, face‐to‐face cognitive debriefing interviews including open‐ended questions to capture information on their perceptions of the instrument. Information on women's experiences of decreased sexual desire was also captured. Main Outcome Measures The main outcome measures of this study were the women's ratings of the clarity, ease of understanding, comprehensiveness, and relevance of the 19 items of the FSFI. Results Interviews with 15 premenopausal women (first study), and 30 pre‐ and 31 postmenopausal women (second study), were analyzed. Across the whole sample, most women (80–100%) found every item of the FSFI clear and easy to understand. The majority (53–70%) felt that the FSFI captured all their feelings about decreased sexual desire and other sexual problems, and most (84–90%) indicated that additional questions were unnecessary. Most women in both studies (93–100%) reported that the two items comprising the FSFI desire domain were clear, easy to understand, and were relevant to them. The majority of women thought that a recall period of ≥7 days is most relevant for recall of their sexual desire. Conclusions These studies establish the content validity of the FSFI in pre‐ and postmenopausal women with HSDD, supporting the use of this instrument as a measure of sexual function in women with this condition. Revicki DA, Margolis MK, Bush EN, DeRogatis LR, and Hanes V. Content validity of the female sexual function index (fsfi) in pre‐ and postmenopausal women with hypoactive sexual desire disorder (HSDD). J Sex Med 2011;8:2237–2245.

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...

The effects of combination hormone therapy of drospirenone (DRSP), a novel progestin with antialdosterone properties, and 17beta-estradiol (E2) on hydrochlorothiazide (HCTZ) pharmacokinetics/pharmacodynamics versus placebo were investigated in a double-blind, placebo-controlled, crossover study. Thirty-six postmenopausal women with stage 1 hypertension maintained on 25 mg of HCTZ once daily were randomized to receive either 3 mg of DRSP/1 mg of E2 or placebo once daily for 4 weeks. Plasma HCTZ, serum DRSP, E2, potassium, aldosterone, and plasma renin activity were determined at baseline and after 4 weeks. Results showed that the combination of DRSP/E2 plus 25 mg of HCTZ is safe and well tolerated in hypertensive postmenopausal women. The pharmacokinetics of HCTZ were not affected by coadministration of DRSP/E2. The geometric mean ratios and 90% confidence intervals ([HCTZ + DRSP/E2]/[HCTZ + placebo]) for HCTZ (a) area under the serum/plasma concentration-time curve from 0 to 24 hours and (b) maximum plasma concentration were 101 (90.7, 112) and 103 (92.8, 115), respectively. In the HCTZ + DRSP/E2 group, serum potassium, aldosterone, and plasma renin activity all increased in a manner marginally consistent with a beneficial antialdosterone effect, counteracting the HCTZ-induced potassium loss and lowering both systolic and diastolic blood pressure. No dose adjustment is required when DRSP/E2 is added to antihypertensive therapy with HCTZ in hypertensive postmenopausal women.

Objective: Drospirenone (DRSP), a spironolactone analog with aldosterone antagonist activity, is a novel progestogen developed for use as hormone therapy in postmenopausal women in combination with 17A-estradiol (E2). DRSP/E2 lowers blood pressure when used alone in hypertensive postmenopausal women or when administered concomitantly with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. DRSP/E2 has not been studied in combination with the widely prescribed hydrochlorothiazide (HCTZ). We investigated the effects of 3 mg DRSP/1 mg E2 versus placebo on blood pressure and potassium balance when added to existing therapy with 25 mg HCTZ in postmenopausal women with established stage I hypertension. Design: This was a single-center, double-blind, randomized, placebo-controlled, two-treatment, two 4-week treatment period crossover study in 36 postmenopausal women with stage I hypertension maintained on 25 mg HCTZ. The endpoint was a change from baseline in systolic and diastolic blood pressures by 24-hour ambulatory blood pressure monitoring. Safety monitoring included serum potassium (mEq/L) and adverse events. Results: Mean systolic and diastolic blood pressures by 24-hour ambulatory blood pressure monitoring were reduced significantly, by j7.2 and j4.5 mm Hg, respectively, with DRSP/E2 as compared with placebo. The decrease in potassium with HCTZ was 0.2 mEq/L less with DRSP/E2 than placebo, suggesting a potassiumsparing effect. The most frequently observed adverse events with DRSP/E2 were vaginal bleeding and breast tenderness, which were attributable to the hormone therapy. Conclusions: DRSP/E2 substantially lowers systolic and diastolic blood pressure when added to existing antihypertensive therapy with HCTZ in hypertensive postmenopausal women. In addition, DRSP/E2 has a potassium-sparing effect that counteracts HCTZ-induced potassium loss.

The prevalence of hypertension increases in women after the menopause. Associated with the rise in postmenopausal blood pressure (BP) are increased salt sensitivity and imbalance between the renin-angiotensin-aldosterone system and nitric oxide pathways that lead to sodium and water retention. Drospirenone is the first synthetic progestogen with antialdosterone activity similar to natural progesterone. Drospirenone counteracts the salt- and water-retaining effects of estrogen and causes natriuresis, which leads to a reduction in BP. In preclinical studies as well as early efficacy studies (for menopausal symptoms), drospirenone exhibited antihypertensive and natriuretic effects. Subsequent clinical trials in postmenopausal women proved that drospirenone with 17beta-estradiol has a significant BP-lowering effect in untreated hypertension and has additive effects when coadministered with ACE inhibitors, angiotensin II type 1 receptor antagonists and thiazide diuretics. The lowest effective dose of drospirenone for reduction in BP is 2mg, a dose that is also protective of the uterus in women treated with estrogen therapy. Additionally, clinical trials have shown that drospirenone up to 3 mg/day has an acceptable safety profile with no clinically significant elevations in plasma potassium in patients with concomitant NSAID use, diabetes mellitus or mild to moderate renal insufficiency. In addition to effectively relieving menopausal symptoms and lowering BP, drospirenone reduces bodyweight and lipoprotein concentrations. Thus, drospirenone is a unique progestogen that confers the additional benefit of BP reduction, an effect that could lead to potential benefit with respect to some cardiovascular risk concerns in women taking hormone therapy.

Accurate measurement of low serum estradiol (E(2)30 pg/ml or110 pmol/liter) is needed to study relationships between endogenous E(2) and risks of diseases in older women.The objective of this study was to determine whether an extraction-based (indirect) assay or a non-extraction-based (direct) assay correlates better with mass spectrometry and body mass index (BMI).In a pilot study of 40 postmenopausal women, endogenous E(2) measurements from three indirect and four direct assay methods and gas chromatography-tandem mass spectrometry (GC-MS/MS) were compared. A confirmatory study compared an indirect and a direct assay, selected among those in the pilot study, to GC-MS/MS; this study was conducted in 374 postmenopausal women not taking hormone therapy from the Ultra Low-dose TRansdermal estrogen Assessment (ULTRA) trial.Pearson correlation coefficients among E(2) measurements by assay methods and BMI, and their confidence intervals, by bias-corrected bootstrap method, were used.In the pilot study, E(2) by three indirect assays correlated better (P0.03) with GC-MS/MS and with BMI than measurements by four direct assays. In the confirmatory study, the indirect assay correlated better (P0.01) with GC-MS/MS and BMI than the direct assay. Measurements by the indirect and direct assays were overestimated, but deviations in direct assay measurements were less precise. Mean E(2) by the indirect and direct assays were higher (by 14 and 68%, respectively) and less reproducible than by GC-MS/MS.Until mass spectrometry is practical for wide use, extraction-based indirect assays may be preferable for measuring low postmenopausal serum E(2).

Objective To investigate the effect of ultralow-dose transdermal estradiol on postmenopausal symptoms and side effects in a cohort of largely asymptomatic postmenopausal women aged 60 to 80 years. Design This secondary analysis used data from the UltraLow-dose Transdermal estRogen Assessment trial, a randomized, placebo-controlled, double-blind trial in postmenopausal women to determine the skeletal effects and safety of ultralow-dose transdermal estradiol. Four hundred seventeen postmenopausal women, aged 60 to 80 years, were randomly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d (n = 208) or placebo (n = 209). Participants were queried at each clinic visit about postmenopausal symptoms and side effects purported to be associated with estrogen therapy using a standardized questionnaire. Results At baseline, 16% of women reported hot flashes, 32% reported vaginal dryness, and 35% reported trouble sleeping. Women who received ultralow-dose estradiol were no more likely to report improvement of hot flashes, vaginal dryness, or sleep difficulties than those who received placebo. Treatment with ultralow-dose estradiol did not cause breast tenderness, uterine bleeding, or other symptoms often attributed to estrogen, but vaginal discharge was more common in women who received estradiol compared with those who received placebo. Conclusion In this population of older, largely asymptomatic women, ultralow-dose transdermal estradiol did not improve postmenopausal symptoms and did not cause side effects other than vaginal discharge. Further study is needed to determine whether this dose of transdermal estradiol is effective in treating symptoms of postmenopause in younger, more symptomatic women.

Background— Drospirenone (DRSP) is a novel progestin with antimineralocorticoid activity that has been developed for hormone therapy in combination with 17β-estradiol (E2) in postmenopausal women. In prior studies with DRSP in postmenopausal women that were focused on relief of menopausal symptoms, DRSP/E2 yielded significant reductions in blood pressure (BP). Methods and Results— The effects of 3 mg DRSP/1 mg E2 on clinic and 24-hour ambulatory BP as well as potassium homeostasis were evaluated in postmenopausal women with stage 1 hypertension (systolic, 140 to 159 and/or diastolic, 90 to 99 mm Hg) in a 12-week, multicenter, double-blind, randomized, placebo-controlled study. Clinic BPs were measured at baseline and at 2, 4, 6, 8, and 12 weeks of therapy, whereas potassium was measured at 2, 6, and 12 weeks of therapy. Ambulatory BP was performed in a substudy at baseline and at the end of the trial. In the intention-to-treat population of 213 women, the clinic BP was reduced significantly on DRSP/E2 (clinic BP, −14.1/−7.9 for DRSP/E2 versus −7.1/−4.3 mm Hg for placebo, P P =0.002/0.07). There were no significant changes from baseline in potassium levels or in the incidence of hyperkalemia (≥5.5 meq/L) on DRSP/E2 compared with placebo. Conclusions— Combination therapy with DRSP/E2 significantly lowered both clinic and 24-hour systolic BP in postmenopausal women with stage 1 systolic hypertension. This characteristic may lead to benefit for cardiovascular risk reduction in this population.

Background Drospirenone (DRSP) is a novel progestin with aldosterone receptor antagonist activity developed for hormone therapy as DRSP /17-β estradiol (DRSP/E2). Because of a significant aldosterone antagonist activity, we studied the effects of DRSP/E2 on serum potassium (K) and blood pressure (BP) in hypertensive postmenopausal women with and without diabetes mellitus. Methods This was a multicenter trial in postmenopausal women 44 to 70 years of age, either with type 2 diabetes mellitus ( n = 82) or without type 2 diabetes mellitus ( n = 148) and using an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist. Patients were randomized to 28 days of DRSP/E2 or placebo. Study endpoints were the number and percentage subjects who developed hyperkalemia (K ≥ 5.5 mEq/L) and changes from baseline in clinic systolic and diastolic BP. To increase the likelihood of unmasking hyperkalemia, the nondiabetic group was also administered ibuprofen for 5 days. Results There were no statistical differences in the overall number and percentage of subjects with hyperkalemia for DRSP/E2 versus placebo. No subject had symptoms or electrocardiographic changes related to hyperkalemia. Blood pressure was reduced by −8.6/−5.8 mm Hg in patients receiving DRSP/E2 versus −3.7/−2.9 mm Hg in those receiving placebo ( P Conclusions In hypertensive postmenopausal women, treatment with DRSP/E2 was not associated with a greater incidence of hyperkalemia than with placebo in patients with and without type 2 diabetes mellitus and concomitant use of ACE inhibitors, angiotensin receptor antagonists, or ibuprofen. Furthermore, DRSP/E2 was found to have a significant antihypertensive effect in this high-risk population.

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.

This study aimed to assess the efficacy and safety of flibanserin, a serotonin receptor 1A agonist/serotonin receptor 2A antagonist, in postmenopausal women with hypoactive sexual desire disorder (HSDD).Naturally postmenopausal women with HSDD received flibanserin 100 mg once daily at bedtime (n = 468) or placebo (n = 481) for 24 weeks. Co-primary endpoints were changes from baseline to week 24 in the number of satisfying sexual events (SSEs) across 28 days and in the Female Sexual Function Index (FSFI) desire domain score. Secondary endpoints included change from baseline in Female Sexual Distress Scale-Revised (FSDS-R) Item 13 score (which assesses distress due to low sexual desire), FSDS-R total score, and FSFI total score. The Patient Benefit Evaluation was asked on treatment discontinuation.There were significant improvements with flibanserin versus placebo in the mean (SE) changes in the number of SSEs (1.0 [0.1] vs 0.6 [0.1]), FSFI desire domain score (0.7 [0.1] vs 0.4 [0.1]), FSDS-R Item 13 score (-0.8 [0.1] vs -0.6 [0.1]), FSDS-R total score (-8.3 [0.6] vs -6.3 [0.6]), and FSFI total score (4.2 [0.4] vs 2.7 [0.4]; all P0.01). More women on flibanserin (37.6%) than women on placebo (28.0%) reported experiencing meaningful benefits from the study medication on treatment discontinuation. The most frequent adverse events associated with flibanserin were dizziness, somnolence, nausea, and headache.In naturally postmenopausal women with HSDD, flibanserin, compared with placebo, has been associated with improvement in sexual desire, improvement in the number of SSEs, and reduced distress associated with low sexual desire, and is well tolerated.

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...

Drospirenone (DRSP), is a unique progestin with antimineralocorticoid activity that has been combined with 17-beta estradiol (E2) for the treatment of symptoms of the menopause in women with hypertension. We assessed the effects of DRSP/E2, E2 alone, and placebo on early morning systolic blood pressure (BP) as well as the rate of rise in systolic BP in 748 postmenopausal women with stage 1 and 2 hypertension at baseline and after 8 weeks of double-blind therapy. Patient characteristics (mean age, 56.5 years, 73% to 77% Caucasian; 13% to 17% African-American) and the clinic (152/95 mm Hg) and 24-hour BP (139/83 mm Hg) measurements were similar at baseline. The early morning systolic BP was reduced significantly on DRSP at 3 mg, 2 mg, and 1 mg with E2 compared with placebo, while E2 alone was similar to placebo. The reductions in early morning systolic BP were larger with increasing dose. Changes in the rate of rise in systolic BP between the lowest values during sleep and following a plateau period post-awakening was significant for the 3 mg DRSP group. In conclusion, DRSP/E2 induced significant reductions in early morning systolic BP in post-menopausal women. This attribute could play a potential role in reducing some of the untoward cardiac and cerebrovascular events that have been observed in studies of other progestins/estrogens in postmenopausal women.