Employee Of AstraZeneca Research Articles

Reducing α-Synuclein in Human CSF; An Evaluation of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEDI1341, an α-Synuclein-specific antibody, in Healthy Volunteers and Parkinson’s Disease Patients (P1-11.007)

<h3>Objective:</h3> To evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of MEDI1341 (TAK-341) in single (SAD; NCT03272165) and multiple ascending dose (MAD; NCT04449484) studies undertaken in healthy volunteers (HVs) and Parkinson’s disease patients, respectively. <h3>Background:</h3> MEDI1341 is a human IgG1λ monoclonal antibody, engineered for selective, high-affinity binding of α-synuclein (ASN) and for reduced effector function. MEDI1341 recognises both monomeric and aggregated forms of human ASN. In rats and cynomolgus monkeys, MEDI1341 decreases free ASN in brain interstitial fluid and cerebrospinal fluid (CSF). In a mouse model, MEDI1341 attenuates ASN axonal propagation and accumulation in the brain. <h3>Design/Methods:</h3> HVs aged 18–80 years were eligible for the SAD study. Subjects eligible for the MAD study were aged 40–85 years with a diagnosis of mild-moderate Parkinson’s disease according to the UK Parkinson’s Disease Society Brain Bank criteria and stage 1–3 on the Hoehn and Yahr scale. In the SAD study, N=49 subjects received placebo or MEDI1341 administered intravenously (IV) across six dose levels. In the MAD study, two dose levels were evaluated in Parkinson’s patients (N=25), administered IV every 4 weeks for 3 infusions. <h3>Results:</h3> Administration of MEDI1341 or placebo to HVs or Parkinson’s patients was not associated with any medically important changes in safety parameters across all doses tested. Dose-dependent changes in serum concentrations for MEDI1341 were observed across cohorts. CSF concentrations demonstrated central nervous system penetration of MEDI1341. PD data showed dose-dependent suppression of free ASN in CSF, consistent with the results seen in preclinical species. <h3>Conclusions:</h3> MEDI1341 was generally well tolerated following IV administration to HVs or Parkinson’s patients after single or repeat doses, respectively. The PK and PD data provide evidence of dose-dependent and selective ASN target engagement by MEDI1341 in the central compartment. Full study design and data from the Phase 1 studies will be presented. <b>Disclosure:</b> Dr. Shering has received personal compensation for serving as an employee of AstraZeneca. An immediate family member of Dr. Shering has received personal compensation for serving as an employee of eResearch Technology Inc. Dr. Shering has stock in AstraZeneca. Dr. Shering has received intellectual property interests from a discovery or technology relating to health care. Michael Pomfret has nothing to disclose. Dr. Kubiak has received personal compensation for serving as an employee of AstraZeneca. Dr. Kubiak has stock in AstraZeneca. Mrs. Pouliquen has received personal compensation for serving as an employee of AstraZeneca. Mrs. Pouliquen has received personal compensation for serving as an employee of GSK. Mrs. Pouliquen has stock in GSK. Mrs. Pouliquen has stock in AstraZeneca. Wei Yin has received personal compensation for serving as an employee of Takeda. Wei Yin has stock in Takeda. Arthur Simen has received personal compensation for serving as an employee of Takeda. Dr. Ratti has received personal compensation for serving as an employee of Takeda. Dr. Ratti has received personal compensation for serving as an employee of Biogen. Dr. Ratti has stock in Takeda. Dr. Ratti has stock in Biogen. Dr. Perkinton has stock in AstraZeneca. Dr. Tan has received personal compensation for serving as an employee of AstaZeneca. An immediate family member of Dr. Tan has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for SOBI. Dr. Tan has stock in AstraZeneca. Dr. Chessell has received personal compensation in the range of $100,000-$499,999 for serving as a Employee with AstraZeneca. Dr. Ostenfeld has received personal compensation for serving as an employee of AstraZeneca. Dr. Ostenfeld has stock in AstraZeneca. Dr. Ostenfeld has received intellectual property interests from a discovery or technology relating to health care.

Evaluation of methodologies for indirect comparison of eplontersen and vutrisiran for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy (P12-4.005)

<h3>Objective:</h3> To investigate comparative efficacy and safety of eplontersen and vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). <h3>Background:</h3> ATTRv-PN is a rare, autosomal dominant disease caused by mutations in the gene encoding transthyretin (TTR) protein, resulting in accumulation of ATTR amyloid in multiple tissues including the peripheral nervous system. TTR silencers developed and in development to treat ATTRv-PN include vutrisiran (recently approved by the FDA and EMA), and eplontersen, which met its co-primary endpoints and demonstrated an overall favourable safety profile in a planned Week 35 interim analysis of the phase III NEURO-TTRansform trial (NCT04136184). The eplontersen and vutrisiran trials both used an external placebo arm from earlier trials. No head-to-head studies have been conducted for eplontersen and vutrisiran to date. Therefore, the feasibility and implications of indirect treatment comparisons (ITCs) should be evaluated. ATTRv-PN exhibits substantial clinical heterogeneity, which challenges traditional ITC methods. Additional challenges relate to the trial designs, including the use of external placebo comparators. Different ITC approaches will be evaluated to assess the impact of these factors on the ability to compare efficacy and safety of eplontersen and vutrisiran. <h3>Design/Methods:</h3> In addition to a naïve comparison, population-adjusted methods that attempt to account for heterogeneity and differences in trial designs were evaluated, including matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC). Whilst MAIC may fail to match characteristics demonstrating substantial heterogeneity, this is not an issue for STC. However, unlike MAIC, STC can falter when dealing with non-linear outcomes. Efficacy will be assessed based on the Modified Neuropathy Impairment +7 and Norfolk Quality of Life-Diabetic Neuropathy scores, and safety will also be assessed. <h3>Results:</h3> Results will become available ahead of AAN2023. <h3>Conclusions:</h3> This ITC feasibility assessment supports interpretation of comparative efficacy and safety analyses, which is important for decision-making by clinicians, payers and researchers. <b>Disclosure:</b> Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alnylam. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis. Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Karam has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neuroderm. Julian D. Gillmore has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alnylam Pharmaceuticals. Julian D. Gillmore has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Intellia. Julian D. Gillmore has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AstraZenica. Julian D. Gillmore has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BridgeBio. Julian D. Gillmore has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Mrs. Chen has received personal compensation for serving as an employee of AstraZeneca. Mrs. Chen has stock in AstraZeneca. Miss Jenkins has nothing to disclose. Dr. Hale has received research support from Cancer Research UK. Dr. Taylor has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NIH France. Dr. Chen has received personal compensation for serving as an employee of AstraZeneca. Dr. Chen has stock in AstraZeneca. Nicholas Viney has received personal compensation for serving as an employee of Ionis Pharmaceuticals Inc.. Nicholas Viney has stock in Ionis Pharmaceuticals. Nicholas Viney has received intellectual property interests from a discovery or technology relating to health care. Dr. Schneider has received personal compensation for serving as an employee of ionis pharmaceuticals.

Pregnancy Outcomes in Multiple Sclerosis patients with or without exposure to Disease Modifying Therapies during pregnancy (N2.003)

Pregnancy Outcomes in Multiple Sclerosis patients with or without exposure to Disease Modifying Therapies during pregnancy (N2.003)

Treatment Utilization in Dermatomyositis: An Analysis of Electronic Medical Records in the United States (P9-5.032)

Treatment Utilization in Dermatomyositis: An Analysis of Electronic Medical Records in the United States (P9-5.032)

Safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of subcutaneous and intravenous ALXN1720 in healthy volunteers: a phase 1, randomized, double-blind, placebocontrolled, single and multiple ascending dose study (P1-5.016)

<h3>Objective:</h3> To report the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of subcutaneous (SC) ALXN1720 in healthy volunteers (HVs) (NCT04920370). <h3>Background:</h3> ALXN1720, a novel 28 kD bispecific variable domain on a heavy chain (VHH) antibody, binds complement component 5 (C5), inhibiting its cleavage into C5a and C5b. ALXN1720 also binds to albumin, which extends its half-life. The low molecular weight of ALXN1720 enables SC injection, designed for self-administration. <h3>Design/Methods:</h3> HVs aged 18–45 years were recruited into 12 cohorts at a single site in the UK. In each cohort, participants were randomized (3:1) to receive ALXN1720 or placebo. HVs received either SC ALXN1720 as a single dose (30–1700 mg), multiple doses (100 or 300 mg) once weekly for three weeks, or a single dose of IV ALXN1720 (300 mg). One cohort received SC 900 mg loading dose then 600 mg maintenance doses once weekly for seven weeks. Primary objective was the evaluation of ALXN1720’s safety and tolerability in healthy adults. <h3>Results:</h3> The study enrolled 97 HVs. ALXN1720 was well tolerated with no serious adverse events (SAEs) reported. All AEs were mild in severity. Dose proportionality was concluded across the range of single doses. ALXN1720 serum exposure increased dose dependently over 3 weekly doses of 100 mg and 300 mg. Single doses ≥100 mg and extended multiple dosing achieved complete terminal complement inhibition (serum free C5 &lt; 0.5 ug/mL). Low-titer, treatment-emergent (TE)-anti-drug antibodies were observed in 12% (9/73) of participants who received ALXN1720 SC. There was no indication that TE-anti-drug antibodies had any impact on drug concentration (PK) or safety profiles. Mean absolute bioavailability of SC ALXN1720 was 96%. <h3>Conclusions:</h3> Healthy adults tolerated ALXN1720 well. ALXN1720 exposure was dose-proportional and was associated with corresponding decreases in serum free C5 concentrations. Immunogenicity was low. <b>Disclosure:</b> Dr. Ortiz has received personal compensation for serving as an employee of Alexion/AstraZeneca Rare Disease. Dr. Ortiz has stock in Alexion. Dr. McEneny has received personal compensation for serving as an employee of Alexion Pharmaceuticals Inc.. Dr. McEneny has stock in Alexion Pharmaceuticals. Dr. Amancha has nothing to disclose. Mrs. Rice has received personal compensation for serving as an employee of AstraZeneca. Mrs. Rice has stock in AstraZeneca. Dr. Scholz has received personal compensation for serving as an employee of Alexion AstraZeneca Rare Disease. Dr. Scholz has stock in Alexion AstraZeneca Rare Disease. Dr. Scholz has stock in Biogen. Dr. Rakhade has received personal compensation for serving as an employee of Alexion Pharmaceuticals . Dr. Rakhade has stock in Alexion Pharmaceuticals. Dr. Rakhade has stock in Astra Zeneca. Dr. Rakhade has received intellectual property interests from a discovery or technology relating to health care. Dr. Yee has nothing to disclose.

Health disparity in use of novel agents for first-line therapy in Black and White patients with chronic lymphocytic leukemia in the Department of Veterans Affairs.

BACKGROUND: Novel agents (NAs) (ibrutinib, idelalisib, and venetoclax) were first introduced in 2013 as therapeutic options to treat chronic lymphocytic leukemia (CLL). OBJECTIVES: To determine if the uptake of NAs for first-line treatment was similar in Black and White patients with CLL treated in the Department of Veterans Affairs (VA). METHODS: We conducted a retrospective cohort study including adults with CLL managed in the VA from October 1, 2013, to September 30, 2017. Descriptive statistics were used to summarize demographic data, and appropriate bivariable statistical tests were used to compare NA use, baseline characteristics, health outcomes, and complications. A multivariable logistic regression model was used to identify factors associated with uptake of NAs. The study included 565 patients; 86% were White and 14% were Black. Black patients were younger than White patients (median age [66 vs 69 years; P < 0.01]) but had similar median baseline Charlson comorbidity scores (4 vs 5). RESULTS: Overall, Black patients were less likely to receive NAs than White patients (14% vs 26%; P = 0.02). The gap narrowed over the study period: 4% vs 17% (2014), 13% vs 25% (2015), 17% vs 33% (2016), and 31% vs 33% (2017). Black race (P = 0.02) and fiscal year (P < 0.01) were the only variables significantly associated with NA use in the multivariable model. Health outcomes and most complications were similar for Black and White patients despite the difference in prescribing patterns. CONCLUSIONS: This is the first study to identify a potential health disparity with respect to use of NAs among Black and White patients with CLL treated in the VA. Fortunately, health outcomes and most complications were similar for Black and White patients despite the difference in prescribing patterns. DISCLOSURES: Funding for the study was provided by AstraZeneca as a research grant to the Foundation for Advancing Veterans' Health Research (FAVHR), a non-profit entity within the Audie L. Murphy Veterans Hospital, San Antonio, TX. Drs Nooruddin and Frei have received research grants (paid to FAVHR) from AstraZeneca in the last 3 years. Ms Ryan is an employee of AstraZeneca. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, the National Institutes of Health, or the authors' affiliated institutions.

Cardiorenal disease in the United States: Future health care burden and potential impact of novel therapies.

BACKGROUND: Currently, concerted efforts to identify, prevent, and treat type 2 diabetes mellitus (T2DM), heart failure (HF), and chronic kidney disease (CKD) comorbidities are lacking at the institutional level, with emphasis placed on individual specialties. An integrated approach to tackle T2DM, HF, and CKD within the context of cardiorenal disease has the potential to improve outcomes and reduce costs at the system level. OBJECTIVE: To synthesize published evidence describing the burden of those diagnosed with T2DM, HF, and CKD in the United States as individual discrete chronic conditions, in order to evaluate the potential economic impact of novel therapies in this population. METHODS: We developed a compartmental Markov model with an annual time cycle to model an evolving prevalent US patient population with T2DM, HF, or CKD over the period 2021-2030 (either in isolation or combined). The model was used to explore the potential impact of novel therapies such as sodium-glucose cotransporter 2 inhibitors on future disease burden, by extrapolating the results of relevant clinical trials to representative patient populations. RESULTS: The model estimates that total prevalence across all disease states will have increased by 28% in 2030. Cumulatively, the direct health care cost of cardiorenal disease between 2021 and 2030 is estimated at $4.8 trillion. However, treatment with dapagliflozin has the potential to reduce disease prevalence by 8.0% and estimated cumulative service delivery costs by 3.6% by 2030. CONCLUSIONS: Considering a holistic approach when managing patients with cardiorenal disease offers an opportunity to reduce the disease burden over the next 10 years in the US population. DISCLOSURES: This work was funded by AstraZeneca, which provided support for data analysis. McEwan, Morgan, and Boyce are employees of Health Economics and Outcomes Research Ltd., Cardiff, UK, which received fees from AstraZeneca in relation to this study. Song and Huang are employees of AstraZeneca. Bergenheim is an employee of AstraZeneca and holds AstraZeneca stocks/stock options. Green has no conflicts of interest to declare.

Effectiveness of Sodium Zirconium Cyclosilicate in Hemodialysis Patients With Severe Hyperkalemia

Effectiveness of Sodium Zirconium Cyclosilicate in Hemodialysis Patients With Severe Hyperkalemia

Real-World Costs of Adverse Events in First-Line Treatment of Metastatic Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer in the United States. Immunotherapies and cytotoxic chemotherapies used to treat advanced NSCLC carry a substantial risk of adverse events (AEs), but real-world data on the incidence and costs associated with the unique AE profiles of these treatments are sparse. To examine the AE incidence and costs among patients initiating non-driver mutation-targeted first-line therapy for metastatic NSCLC (mNSCLC) in clinical practice. This was a retrospective administrative claims study conducted among commercial and Medicare Advantage health plan members who initiated first-line, nontargeted systemic anti-NSCLC therapy between January 1, 2008, and February 28, 2018. Patients were assigned to mutually exclusive treatment cohorts (cytotoxic chemotherapy [CHEM], immuno-oncology agents [IO], or immuno-oncology + cytotoxic chemotherapy [IO-CHEM]) and were observed from the index date (start of first-line therapy) through the earliest of health plan disenrollment, death, or March 31, 2018. AE incidence rates and associated health care costs were measured from the index date through the earliest of the start of a new therapy, 180 days after the end of first-line therapy, or the end of the study period. The factors influencing whether patients incurred high AE-related health care costs were assessed using multivariable models adjusted for patient demographic and clinical characteristics. The final study population (mean [SD] age 68.6 [9.5] years, 53.9% male) included 8,818 in the CHEM cohort, 482 in the IO cohort, and 412 in the IO-CHEM cohort. Overall, 74.4% had at least 1 AE during follow-up. The AE incidence rate was lowest for the IO cohort, with incidence rate ratios (95% CI) of 1.4 (1.3-1.6) for the CHEM cohort and 1.4 (1.2-1.6) for the IO-CHEM cohort. Mean AE-related costs were lowest for the IO cohort ($16,319) and highest for the CHEM cohort ($23,009; P < 0.001). In the multivariable analysis, the odds of incurring any AE costs were similar for the IO and IO-CHEM cohorts compared with the CHEM cohort (OR = 0.82; P = 0.135 and OR = 0.98; P = 0.888, respectively). Among patients who incurred AE costs, those in the IO cohort were less likely than those in the CHEM cohort to have high costs (OR = 0.60; P = 0.030); the difference between the IO-CHEM and CHEM cohorts was not statistically significant. Among real-world patients initiating nontargeted first-line therapy for mNSCLC, those receiving immunotherapy experienced fewer AEs and had lower total AE-related costs than those treated with cytotoxic chemotherapy. Immunotherapy-treated patients were no more likely than chemotherapy-treated patients to incur AE-related costs and were less likely to have high AE costs if they incurred any at all. These findings indicate that immunotherapy-related AEs are not a differentiating factor in cost of care for this patient population in clinical practice. This study was sponsored by AstraZeneca. Ryan is an employee of AstraZeneca. Engel-Nitz, Johnson, and Bunner are employees of Optum, which was contracted by AstraZeneca to conduct this study, and shareholders in UnitedHealth Group. Engel-Nitz has also worked on cancer-related studies for which Optum received funding from Bayer AG, Clovis Oncology, Eli Lilly, EMD Serono, Exact Sciences, Janssen, and Novartis. Johnson worked on cancer-related studies for which Optum received funding from Eli Lilly, Medtronic, Sanofi, and UnitedHealthcare. Bunner has worked on cancer-related studies for which Optum received funding from Celgene and Incyte.

Late-Breaking Science Abstracts From the American Heart Association's Scientific Sessions 2018 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2018.

Late-Breaking Science Abstracts From the American Heart Association's Scientific Sessions 2018 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2018.

LBA8 - Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study

Background: In the Phase III FLAURA study (NCT02296125), osimertinib showed superior efficacy compared with standard of care (SoC) EGFR-TKIs in patients (pts) with previously untreated EGFRm advanced NSCLC. Here, we report preliminary data on mechanisms of acquired resistance to osimertinib in pts who progressed during the FLAURA study. Methods: Pts with previously untreated EGFRm (tissue, ex19del/L858R) advanced NSCLC (N = 556) were randomised 1:1 to osimertinib 80 mg once daily (QD; n = 279) or SoC EGFR-TKI (n = 277, gefitinib 250 mg QD or erlotinib 150 mg QD). Paired plasma samples were collected at baseline and following RECIST progression and/or treatment discontinuation up to March 2018. Plasma samples were analysed using next generation sequencing (NGS, Guardant Health; Guardant360 73 gene panel or Omni 500 gene panel). Results: In the osimertinib and SoC EGFR-TKI arms, respectively, 113/279 (41%) and 159/277 (57%) pts had experienced a progression event and/or discontinued treatment and had paired plasma samples analysed by NGS. Only pts with detectable plasma EGFRm (ex19del/L858R) at baseline were evaluable for this analysis: 91/113 (81%; osimertinib) and 129/159 (81%; SoC). In the osimertinib arm, there was no evidence of acquired EGFR T790M and the most common acquired resistance mechanism detected was MET amplification (amp; 14/91; 15%), followed by EGFR C797S mutation (6/91; 7%); other mechanisms included HER2 amp, PIK3CA and RAS mutations (2–7%). In the SoC arm, the most common resistance mechanisms were T790M mutation (60/129; 47%), MET amp (5/129; 4%) and HER2 amp (3/129; 2%). Conclusions: In this paired sample preliminary analysis of a subpopulation of pts (with detectable baseline plasma EGFRm) who had experienced disease progression and/or discontinued treatment, heterogeneous resistance mechanisms were detected with first-line osimertinib, with MET amplification and EGFR C797S mutation being the most commonly observed. In line with previous analyses, T790M was acquired in approximately 50% of SoC-treated pts, and none of the osimertinib-treated pts; no unexpected resistance mechanisms were observed in osimertinib-treated pts. Exploration into novel acquired mutations is ongoing. Editorial acknowledgement: Ellen Maxwell, PhD, from iMed Comms, funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines (ismpp.org/gpp3). Clinical trial identification: NCT02296125. Legal entity responsible for the study: AstraZeneca. Funding: AstraZeneca. Disclosure: B.C. Cho: Honoraria/advisory boards: AstraZeneca, Roche, Boehringer Ingelheim, Novartis, MSD, Yuhan; Research grants: AstraZeneca, Novartis, Yuhan; Speakers' bureaus: AstraZeneca, Novartis, MSD, Yuhan. C. Zhou: Honoraria: Roche, Eli Lilly, BI, Merck, Hengrui, Qiru. Y. Ohe: Grants/personal fees: AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai, MSD, Novartis, Kyorin, Dainippon-Sumitomo, Daiichi-Sankyo, Boehringer Ingelheim, Bayer, Lilly, Pfizer, Ignyta, Kissei. F. Imamura: Honoraria and research grants: AstraZeneca. R. Shah: Advisory boards: AstraZeneca. Y. Rukazenkov: Employee, shareholder: AstraZeneca. A. Todd: Employee of AstraZeneca. A. Markovets, J. Chmielecki: Employee, shareholder: AstraZeneca. C. Barrett: Employee, stock holder: AstraZeneca. J.E. Gray: Advisor: AstraZeneca; Research grant: AstraZeneca and Genentech for work not directly related to this project. S.S. Ramalingam: Advisory board membership: Abbvie, Amgen, AstraZeneca, BMS, Celgene, Genentech, Lilly, Merck, Roche, Nektar, Loxo, Takeda. All other authors have declared no conflicts of interest.

392P - Generation of a novel preclinical PK/PD model provides insights into PARP inhibitor clinical monotherapy activity

Background: In Phase II trials, an olaparib capsule dose that inhibits PARP (100 mg bd) was clinically inferior to the MTD (400 mg bd). Using an in vivo model, we investigated this discrepancy and the effect of dose and schedule on tumour progression. Methods: PK, PD and antitumour activity were assessed using olaparib (100, 50, 25, 10, 2.5 mg/kg qd) in a breast cancer patient-derived xenograft (PDX) with mutated BRCA2 and TP53. We studied the relationship between PARP1 inhibition and DNA single-strand breaks (SSBs) by creating a mathematical model. We also compared PK/PD model parameters with free minimum olaparib steady-state plasma concentration (Cmin,ss) in seven Phase I–III clinical studies. Results: Only 100 and 50 mg/kg olaparib doses caused tumour regression, yet all but the lowest led to acute PAR inhibition. The differentiating factor was time over PAR IC95; simulations using the mathematical model at steady state predicted a threshold where >95% reduction in PAR caused >20-fold increase in DNA SSBs. Overlaying clinical data, we saw that 400 mg bd capsule and 300 mg bd tablet doses provide continuous PAR inhibition (Cmin,ss>IC95 upper confidence level); 100 mg bd capsule does not. Dosing schedule assessment showed PDX regression with continuous 100 mg/kg olaparib (0/10 tumours progressed by day 100). By contrast, continuous dosing at 50 mg/kg or intermittent dosing (1 wk on/1 wk off) at 100 mg/kg resulted in 2/10 and 10/10 progressions, respectively. Treatment withdrawal upon regression led to regrowth in all cases; re-challenge at continuous 100 mg/kg was effective (9/10 regressions), 50 mg/kg was not (0/10). In a maintenance setting, switching to lower or intermittent dosing resulted in tumour response more similar to that of continuous 100 mg/kg (1/10, 2/10 and 0/10 progressions, respectively). Conclusions: Discrepancy between biologically and clinically effective olaparib doses is explained by a need for continuous >95% PAR inhibition. Both the 400 mg bd capsule and 300 mg bd tablet dose, used in the ongoing clinical programme, provide this. Dosing schedule data suggest continuous PAR inhibition is also needed for long-term responses. These data highlight important principles for treatment of patients with PARP inhibitor monotherapy. Legal entity responsible for the study: AstraZeneca Funding: AstraZeneca Disclosure: M. O'Connor, E. Cadogan, A. Hughes, M. Learoyd, H. Xu, J. Li, J. Yates: Employee of AstraZeneca and owns stock with AstraZeneca. E. Leo: Employee of AstraZeneca.

1353P - CNS response to osimertinib in Asian-Pacific patients (pts) with T790M-positive advanced NSCLC: data from an open-label Phase II trial (AURA17)

Background: Osimertinib has shown CNS efficacy in a pooled analysis of two Phase II trials (AURA extension: NCT01802632, AURA2: NCT02094261) in pts with T790M-positive advanced NSCLC. We report osimertinib efficacy in CNS metastases (mets) from a Phase II, open-label, single-arm trial (AURA17: NCT02442349) in Asia-Pacific pts with T790M-positive advanced NSCLC who had progressed on prior EGFR-TKI therapy, with or without additional anti-cancer regimens. Methods: Pts with stable, asymptomatic, CNS mets were eligible for enrolment and received osimertinib 80 mg once daily. This prespecified subgroup analysis was conducted in pts with CNS mets present on baseline brain scan as assessed by blinded independent central neuroradiology review (BICR). Endpoints included CNS objective response rate (ORR), duration of response (DoR) and progression-free survival (PFS) by RECIST 1.1. The CNS full analysis set (cFAS) comprised pts with ≥1 measurable and/or non-measurable CNS lesion present on baseline brain scan by BICR; the CNS evaluable for response set (cEFR) comprised pts with ≥1 measurable CNS lesion. Results: At the data cut-off of 4 November 2016, 59/171 pts (35%) were included in the cFAS. In the cFAS and cEFR (n = 23), 3 and 0 pts had brain radiotherapy ≤6 months prior to study entry, respectively. CNS ORR was 42% (25/59; 95% CI 30, 56) for the cFAS and 70% (16/23; 95% CI 47, 87) for the cEFR. Median CNS DoR was not reached (95% CI 9.2, not calculable [NC]) for the cFAS and 11.1 months (95% CI 8.2, NC) for the cEFR. CNS DCR was 85% (95% CI 73, 93) for the cFAS and 91% (95% CI 72, 99) for the cEFR. Median CNS PFS was not reached in both cFAS (95% CI 12.4, NC) and cEFR groups (95% CI 9.4, NC), with a median follow-up for CNS PFS of 7.1 and 8.2 months, respectively. At 12 months, 70% (95% CI 53, 82) of pts in the cFAS and 61% (95% CI 31, 81) of pts in the cEFR were estimated to remain on study, alive and CNS progression-free. Conclusions: These data are consistent with previous reports of CNS response to osimertinib in pts with T790M-positive advanced NSCLC in global studies, and demonstrate clinically meaningful efficacy in Asian-Pacific pts with CNS mets. Clinical trial identification: NCT02442349 Legal entity responsible for the study: AstraZeneca Funding: AstraZeneca Disclosure: C. Zhou: Lecture honorarium: Eli Lily, AZ, Roche, Pfizer, Sanofi, BI, Henrui Advisory board: Roche, BI, AZ. Y. Lu: Consulting or Advisory Role: AstraZeneca, Hoffmann-La Roche, Eli Lilly, Pfizer, Elekta, Varian Medical Systems. J. Wang, Y. Chen: Employee of AstraZeneca. Y-L. Wu: Speaker fees from AstraZeneca, Roche, Eli Lilly, Sanofi, Pfizer. All other authors have declared no conflicts of interest.

Letter--Prudent Formulary Management or Underutilization of the Novel P2Y12 Receptor Inhibitors in Patients with Acute Coronary Syndrome Who Received Percutaneous Coronary Intervention?

The author is a former employee of AstraZeneca and owns stock in AstraZeneca. The author reports no conflicts of interest related to the subject of this letter.

580_PR: Clinical and demographic features that influence EGFR mutation detection in plasma from patients (pts) with aNSCLC: The ASSESS experience

s, ELCC 2016 Journal of Thoracic Oncology Vol. 11, Suppl. 4S (2016) S151 Deferred publication: Translational research 58O_PR Clinical and demographic features that influence EGFR mutation detection in plasma from patients (pts) with aNSCLC: The ASSESS experience N. Normanno1, H. Brown2, V. Haddad3, M. Ratcliffe2, R. McCormack2, S. Tjulandin4, K. Hagiwara5, B. Han6, M. Reck7. 1 Dept. Biologia Cellulare e Bioterapie, Istituto Nazionale Tumori – I.R.C.C.S – Fondazione Pascale, Naples, Italy , 2 Personalised Healthcare and Biomarkers, AstraZeneca, Macclesfield, UK, 3 Biostatistics & Information Sciences, AstraZeneca, Royston, UK, 4 Department of Clinical Pharmacology and Chemotherapy, Russian Cancer Research Centre, Moscow, Russian Federation, 5 Comprehensive Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan, 6 Department of Respiratory Medicine, Shanghai Chest Hospital, Jiao Tong University, Shanghai, China, 7 Department of Thoracic Oncology, LungenClinic Grosshansdorf GmbH, Airway Research Center North (ARCN), Grosshansdorf, Germany Background: Mutation detection from circulating free tumourderived DNA (ctDNA) in plasma offers a minimally invasive alternative when biopsy is not possible. Despite continuous improvement in detection methods, the sensitivity of EGFR mutation-positive detection remains lower in plasma compared with tumour tissue. The large non-interventional study ASSESS (NCT01785888) offers the ability to investigate if clinical characteristics of disease and/or pt demographics influence the ability to detect mutations in plasma. Methods: The accuracy of EGFR mutation-positive detection in plasma compared with tumour (sensitivity, specificity, concordance) was reported and analysed by the Coughlin method for Table (abstract 58O_PR). Characteristic Tumour and plasma evaluable N (%) EGFR mutation-positive by tumour Sensitivity (95% CI) Specificity (95% CI) p-value for interaction with tumour tissue Overall 1162 189 46.03 (38.8, 53.4) 97.43 (96.2, 98.3) − Age 65 680 (58.52) 126 37.3 (28.9, 46.4) 96.39 (94.5, 97.8) 0.66 months 579 (50.04) 96 46.88 (36.6, 57.3) 97.52 (95.7, 98.7) 0.7023 Concordance >79%. NC, non-calculable. the following covariates: gender, age, ethnicity, smoking status, disease stage, World Health Organization (WHO) performance status (PS), time since diagnosis, metastases and number of organs with metastases, in 1162 pts from Europe and Japan. Results: Of those pts with EGFR mutation-positive tumours, EGFR mutation-positive detection in plasma was higher in pts aged <65 (63.5% [95% confidence interval 50–75]) vs pts aged 65 (37.3% [29–46]) (interaction p-value = 0.0002) (Table). Increased sensitivity of EGFR mutation-positive detection in plasma was also associated with increasing number of organs with metastases (1: 35.9% [27–46]; 2: 60.5% [43–76]; 3: 69.4% [52–84]) and with higher metastatic grade (M1b: 63.4% [52–74] vs M1a: 22.8% [13–36]; interaction p-values not significant). Gender, ethnicity, smoking status and PS status did not influence plasma mutation detection. Conclusions: These data suggest that pt age significantly influences the ability to detect EGFR mutation-positive from plasma; detection is also more likely when pts have a higher metastatic tumour burden. Further studies are required to confirm these findings/identify underlying biological mechanisms. Clinical trial identification: NCT01785888 Legal entity responsible for the study: AstraZeneca Funding: AstraZeneca Disclosure: N. Normanno: Received grants/research support from, and been a Consultant for, AstraZeneca, Qiagen and Roche Diagnostics. H. Brown, V. Haddad, M. Ratcliffe, R. McCormack: Employee of AstraZeneca and holds shares in AstraZeneca. S. Tjulandin: Member of the speakers’ bureau for AstraZeneca, Pfizer and Sanofi-Aventis. K. Hagiwara: Member of the speakers’ bureau for AstraZeneca, Chugai Pharmaceuticals and Pfizer and holds a patent with LSI Medience. B. Han: Member of the speakers’ bureau for AstraZeneca and Roche and a Consultant for AstraZeneca and Pfizer. M. Reck: Member of speakers’ bureau for AstraZeneca, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Hoffmann-La Roche, Lilly and Pfizer; Consultant for AstraZeneca, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Hoffmann-La Roche, Lilly, MSD and Pfizer. Copyright © 2016 by the European Lung Cancer Conference organisers, ESMO and IASLC. Published by Elsevier Inc. All rights reserved.

A Comparison of the Pharmacological and Mechanistic Properties of Therapeutic Long-Chain Omega-3 Fatty Acid Formulations

Dr. Harper is an employee of AstraZeneca.

139TiP - Phase 2, Open-Label, International, Non-Comparative Study of MEDI4736 in Patients with Locally Advanced or Metastatic, Pd-L1 +, Stage 3B–4 Nsclc Who Have Received ≥2 Prior Systemic Treatment Regimens (ATLANTIC)

Background: The inhibitory programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway plays a major role in controlling T-cell activation. Many cancers appear to exploit this pathway to evade antitumour responses. Encouraging clinical activity against several tumour types has been seen for anti-PD-L1 mAbs. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80, and is associated with a low frequency of anti-drug antibodies. Evidence of clinical activity for MEDI4736 in NSCLC has been seen in a Phase 1 study, with initial data indicating that PD-L1 expression is associated with a higher objective response rate (ORR). An accelerated clinical development programme for MEDI4736 in NSCLC is underway. Here we describe the ATLANTIC (NCT02087423) study that is assessing the efficacy and safety of MEDI4736 in patients (pts) with locally advanced or metastatic NSCLC. Trial design: In this Phase 2, open-label, international, non-comparative study, the efficacy and safety of MEDI4736 (10 mg/kg IV every 2 weeks for up to 12 months) is being assessed in pts with PD-L1+ locally advanced or metastatic NSCLC (Stage 3B–4). Pts were initially included regardless of PD-L1 status, but once a diagnostic became available, this was amended to PD-L1+ tumours only. Eligible pts must have a WHO Performance Status of 0 or 1, and received ≥2 prior systemic treatment regimens, including 1 platinum-based chemotherapy. Around 188 PD-L1+ pts (Cohort 1: ∼50% epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] positive; Cohort 2: ∼50% EGFR and ALK-negative), will be treated at ∼100 sites across North America, Asia, and Europe. In Cohort 1, prior therapy must include the appropriate tyrosine kinase inhibitor. The primary outcome measure is ORR according to RECIST v1.1 based on independent central review. Secondary outcome measures will further assess efficacy (including disease control rate, duration of response, progression-free survival, overall survival, and deep sustained response), safety (CTCAE v4.03), tolerability, PK, and immunogenicity. Recruitment is ongoing. Clinical trial identification: NCT02087423 (March 4, 2014); EudraCT 2013-005427-16 (June 24, 2014) Disclosure: M.C. Garassino: Member of AstraZeneca Advisory Board. J.F. Vansteenkiste: Research funding at University Hospitals KU Leuven: AstraZeneca, Amgen. Advisory functions: GlaxoSmithKline, Merck-Serono, Novartis, BMS, Merck. Speaker bureau: Eli-Lilly, Boehringer-Ingelheim. M. Ballas: Employee of AstraZeneca and owns stock/stock options in AstraZeneca Owns stock in Bristol Myers Squibb. D. Jayawardene and P.K. Stockman: Employee of AstraZeneca and own stock/stock options in AstraZeneca. J.D. Powderly: Speaker Bureaus: BMS, Dendreon, Genentech. Research Funding: BMS, Genentech/Roche, AstraZeneca/MedImmune, Merck/EMD Serono, Amplimmune, CellDex, ABBVie, Lilly/Imclone, InCyte and MacroGenics Stock Ownership: BioCytics (Founder) N. Rizvi: Advisory Board/consulting: Merck, Genentech, Roche, Medimmune, Astrazeneca, Novartis, Astellas, BMS Research grant: BMS. All other authors have declared no conflicts of interest.

A Phase 3, Randomised, Double-Blind, Placebo-Controlled, International Study of MEDI4736 in Patients with Locally Advanced, Unresectable NSCLC (Stage III) Who have not Progressed following Platinum-Based, Concurrent Chemoradiation Therapy (Pacific)

ABSTRACT Background Thirty percent of patients with non-small cell lung cancer (NSCLC) present with Stage III disease. Concurrent chemoradiation therapy with curative intent is the treatment of choice for these patients. Despite treatment, progression-free survival (PFS) is usually short (approximately 9 months) and most patients ultimately die of metastatic disease. Chemotherapy and radiotherapy have been shown to up-regulate the expression of programmed cell-death ligand 1 (PD-L1), an important inhibitory checkpoint used by tumour cells to evade antitumour immune responses. MEDI4736 is a human IgG1 antibody that blocks PD-L1 binding to programmed cell-death 1 and CD80 and is engineered to prevent antibody dependent cell-mediated cytotoxicity. In a Phase 1 study, MEDI4736 has shown an encouraging safety profile and clinical activity in multiple tumour types, including NSCLC. Here we describe the PACIFIC study, which evaluates the efficacy and safety of MEDI4736 as sequential therapy in patients with locally advanced, unresectable NSCLC (Stage III) who have not progressed following definitive, platinum-based, concurrent chemoradiation therapy. Trial design In this phase 3, double-blind, international study (NCT02125461) patients will be randomised (2:1) to MEDI4736 (10 mg/kg intravenously every 2 weeks) or matching placebo for up to 12 months. Patients must have received at least 2 cycles of platinum-based chemotherapy concurrent with radiation therapy prior to randomisation. The primary objective is to assess the efficacy of MEDI4736 versus placebo in terms of overall survival and PFS (RECIST 1.1). Secondary outcome measures will assess efficacy (including proportion of patients alive at 24 months and objective response rate), safety and tolerability, pharmacokinetics, immunogenicity of MEDI4736 and its effect on symptoms and health-related quality of life. An independent data monitoring committee is in place to monitor safety. Recruitment is ongoing at sites across Australia, Asia, Europe, North and South America and South Africa. Disclosure S. Antonia: Consultant for MedImmune/AstraZeneca; A.D. Krebs, D. Jayawardene and P.K. Stockman: Employee of AstraZeneca and owns stock/stock options in AstraZeneca; M. Ballas: Employee of AstraZeneca and owns stock/stock options in AstraZeneca. Owns stock in Bristol Myers Squibb. All other authors have declared no conflicts of interest.

A Phase 2, Non-Comparative, Open-Label, International Study of MEDI4736 in Patients with Locally Advanced or Metastatic PD-L1-Positive NSCLC (Stage IIIB-IV) Who have Received ≥ 2 Prior Systemic Treatment Regimens (Atlantic)

ABSTRACT Background The inhibitory programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway plays a major role in controlling T cell activation and is utilised by tumour cells to evade antitumour responses. Anti-PD-L1 monoclonal antibodies (mAbs) have shown encouraging preclinical and clinical activity against a number of tumour types. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 and is associated with a low frequency of anti-drug antibodies. Clinical activity for MEDI4736 in non-small cell lung cancer (NSCLC) has been observed in a Phase 1 study, with preliminary evidence indicating that PD-L1 expression is associated with a higher objective response. Here we describe an ongoing study to assess the efficacy and safety of MEDI4736 in patients with locally advanced or metastatic NSCLC. Trial design ATLANTIC (NCT02087423) is a phase 2, non-comparative, multicentre, international, open-label study, evaluating the efficacy and safety of MEDI4736 (10 mg/kg administered intravenously every 2 weeks for up to 12 months) in patients with PD-L1-positive locally advanced or metastatic NSCLC (Stage IIIb – IV). Eligible patients will have a WHO Performance Status of 0 or 1, and must have received at least 2 prior systemic treatment regimens, including a platinum-based chemotherapy regimen. Approximately 188 patients (∼50% known epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] positive [Cohort 1] and ∼50% EGFR and ALK-negative [Cohort 2]), will be treated at ∼100 sites across North America, Asia, and Europe. Prior therapy for Cohort 1 patients must include the appropriate tyrosine kinase inhibitor. The primary outcome measure is objective response rate according to RECIST 1.1. Secondary outcome measures will further assess efficacy (including disease control rate, duration of response, deep sustained response, progression-free survival and overall survival), safety, tolerability, pharmacokinetics, and immunogenicity of MEDI4736. Recruitment is ongoing. This abstract was accepted and previously presented at ESMO 2014, Annals of Oncology, Volume 25, Supplement 4, 1335TiP. Disclosure N. Rizvi: I receive consulting income from MedImmune, Roche, Merck and BMS; M. Ballas: Employee of AstraZeneca and owns stock/stock options in AstraZeneca. Owns stock in Bristol Myers Squibb; D. Jayawardene and P.K. Stockman: Employee of AstraZeneca and owns stock/stock options in AstraZeneca; J.D. Powderly: Employment, Human Application Lab. Consultancy, BMS, Genentech, Amplimmune, Merck. Honoraria, BMS. Research funding, BMS, Genentech, Amplimmune, Merck, Astrazeneca, Imclone/Lilly. Speaker Bureau and Advisory Board BMS.

A Phase 2, Non-Comparative, Open-Label, Multicenter, International Study of Medi4736 in Patients with Locally Advanced or Metastatic Pd-L1-Positive Nsclc (Stage Iiib-Iv) Who Have Received ≥ 2 Prior Systemic Treatment Regimens, Including a Platinum-Based Chemotherapy (Atlantic)

ABSTRACT Background: Programmed cell death-ligand 1 (PD-L1) is a cell surface protein that delivers inhibitory signals to T cells through interaction with the programmed cell death-1 (PD-1) receptor and the CD80 receptor. Numerous cancers appear to exploit this PD-L1/PD-1 pathway and evade the immune system via upregulation and cell surface expression of PD-L1. Anti-PD-L1 monoclonal antibodies (mAbs) have shown encouraging preclinical and clinical activity against a number of tumor types. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 and is associated with a low frequency of anti-drug antibodies. Evidence of clinical activity for MEDI4736 in NSCLC has been observed in a Phase 1 study. The current Phase 2 study assesses the efficacy and safety of MEDI4736 treatment in patients with locally advanced or metastatic NSCLC. Trial design: ATLANTIC (NCT02087423) is a Phase 2, non-comparative, multicenter, international, open-label study, evaluating the efficacy and safety of MEDI4736 (administered IV every 2 weeks for up to 12 months) in patients with PD-L1-positive locally advanced or metastatic NSCLC (stage IIIb - IV). Eligible patients (age ≥18 years) will have a WHO Performance Status of 0 or 1 and must have received at least 2 prior systemic treatment regimens, including a platinum-based chemotherapy regimen. Approximately 188 PD-L1-positive patients (∼50% known EGFR or ALK positive [Cohort 1] and ∼50% EGFR and ALK-negative [Cohort 2]), will be treated at ∼100 sites across North America, Asia, and Europe. Prior therapy for Cohort 1 patients must include appropriate tyrosine kinase inhibitor. The primary outcome measure is objective response rate according to RECIST 1.1. Secondary outcome measures will further assess efficacy (including disease control rate, duration of response, deep sustained response, progression-free survival and overall survival), safety, tolerability, pharmacokinetics, and immunogenicity of MEDI4736. Recruitment is ongoing. Disclosure: N. Rizvi: I receive consulting income from Medimmune, Roche, Merck and BMS; J. Gray: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; M. Ballas: Employee of AstraZeneca and owns stock/stock options in AstraZeneca; D. Jayawardene: Employee of AstraZeneca and owns stock/stock options in AstraZeneca; P. Stockman: Employee of AstraZeneca and owns stock/stock options in AstraZeneca; J.D. Powderly: Speaker Bureaus BMS: Ipilimumab & ImmunoOncology. Dendreon: Sipileucel T. Genentech: Bevacizumab. Research Funding: BMS, Genentech/Roche, AstraZeneca/MedImmune, Merck/EMD Serono, Amplimmune, CellDex, ABBVie, Lilly/Imclone. Stock Ownership: BioCytics