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Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST (NCT02848651), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB–IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB

Time-to-event data such as time to death are broadly used in medical research and drug development to understand the efficacy of a therapeutic. For time-to-event data, right censoring (data only observed up to a certain point of time) is common and easy to recognize. Methods that use right censored data, such as the Kaplan-Meier estimator and the Cox proportional hazard model, are well established. Time-to-event data can also be left truncated, which arises when patients are excluded from the sample because their events occur before a specific milestone, potentially resulting in an immortal time bias. For example, in a study evaluating the association between biomarker status and overall survival, patients who did not live long enough to receive a genomic test were not observed in the study. Left truncation causes selection bias and often leads to an overestimate of survival time. In this tutorial, we used a nationwide electronic health record-derived de-identified database to demonstrate how to analyze left truncated and right censored data without bias using example code from SAS and R.

BackgroundNon-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.MethodsThree cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.ResultsHigh PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classic EGFR, EGFR exon 20 and HER2-mutant tumors, and 34%–55% in tumors with ALK, BRAF V600E, ROS1, RET, or MET alterations. Compared with KRAS-mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (pEGFR, HER2, ALK, ROS1, RET, or MET alterations had short progression-free survival (PFS; 1.8–3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, pConclusionsHigh TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK, ROS1, RET, and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.

Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST ( NCT02848651 ), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB-IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers.

Objectives To assess the safety and efficacy of atezolizumab and docetaxel in patients with and without a history of asymptomatic, treated brain metastases in the phase III OAK trial. Materials and methods Patients received 1200 mg atezolizumab or 75 mg/m2 docetaxel every 3 weeks until unacceptable toxicity, disease progression, or loss of clinical atezolizumab benefit. Patients with asymptomatic, treated supratentorial metastases were eligible. Patients had brain scans before enrollment; follow-up brain scans and treatment were required when clinically indicated. Results Approximately 14% of patients in each arm had a history of asymptomatic, treated brain metastases (61/425 in the atezolizumab arm and 62/425 in the docetaxel arm). Fewer treatment-related adverse events (AEs), serious AEs, and treatment-related neurologic AEs were reported with atezolizumab than with docetaxel, regardless of history of asymptomatic, treated brain metastases. In patients with a history of asymptomatic, treated brain metastases, median overall survival (OS) was longer with atezolizumab than with docetaxel (16.0 vs 11.9 months; hazard ratio = 0.74; 95% CI: 0.49–1.13). Median OS was also longer with atezolizumab in patients without a history of asymptomatic, treated brain metastases (13.2 vs 9.3 months; hazard ratio = 0.74; 95% CI: 0.63–0.88). Landmark analyses showed that patients with a history of asymptomatic, treated brain metastases had a lower probability of developing new symptomatic brain lesions with atezolizumab vs docetaxel at 6–24 months. Patients without a history had a lower probability with atezolizumab at 18–24+ months. Conclusion Atezolizumab had an acceptable neurologic safety profile, showed a trend toward an OS benefit, and led to a prolonged time to radiographic identification of new symptomatic brain lesions compared with docetaxel in patients who had a history of asymptomatic, treated brain metastases. Clinicaltrials.gov registration number: NCT02008227.

6524 Background: Disparities in health outcomes can be affected by biological factors associated with GA and social determinants of health. These factors can be teased apart using GA data from comprehensive genomic profiling (CGP) in pts with cancer. CGDBs that link EHR data with CGP enable the selection of pts with similar GA. Holding GA constant provides an opportunity to directly study the effects of reported race in health disparities. This study evaluated a published racial disparity (BRCA testing rates in African American [AA] vs White pts with BC) in a population with fixed, similar GA. Methods: The nationwide (US-based) deidentified Flatiron Health and Foundation Medicine (FMI) BC CGDB (Q3 2020) was used. For each pt, GA fractions from 5 geographic ancestry groups (African [AFR]; Admixed American; East Asian; European [EUR]; South Asian) were derived by FMI using an admixture analysis workflow using genes captured in the CGP assay. To focus on BRCA testing in AA vs White pts and find a sufficient population with similar GA but AA or White race, pts with admixture of both EUR and AFR ancestry were selected. The chosen fractions were: Cohort 1=35%-65% AFR and EUR each; Cohort 2=25%-60% AFR and EUR each; Cohort 3=30%-60% AFR. Cohorts overlap but were chosen to increase sample size. In each cohort, documented BRCA testing prevalence, time from diagnosis to BRCA test date, age at BRCA test and overall survival (OS) were compared between races. Other race (OR) and missing race (MR) were also reported. Results: Most pts (4130/6903) in the BC CGDB had ≥75% EUR ancestry; 129 pts had AFR ancestry fractions ≥25% with EUR ancestry >0%. AA pts had the lowest BRCA testing rates (39%, 43%, 44% for Cohorts 1-3, respectively), which were 18%, 10% and 17% lower compared with White pts, respectively (Table). In Cohorts 1-3, AA pts experienced a longer median time between diagnosis and testing (399, 668, 900 days) compared with White pts (93, 667, 106 days). The median age at BRCA test was 16, 9 and 8 years younger in AA pts (49, 47 and 50 years) compared with White pts. Although pts with MR data had the lowest OS compared with the other races within each cohort, the sample size of each arm for all cohorts was too small to make conclusions. Conclusions: This study demonstrated that when holding GA constant, racial disparities persist in BRCA testing patterns and outcome in pts with BC from a CGDB. With increasing availability of linked clinical and genomic data, further exploration of disparities in genetically similar cohorts can provide deeper insight for cancer outcomes and health disparities research.[Table: see text]

e18514 Background: DLBCL, an aggressive disease, is the most common subtype of non-Hodgkin lymphoma. Few studies have addressed socioeconomic and racial/ethnic disparities in treatment patterns and health outcomes for pts with DLBCL. We present a retrospective cohort study, leveraging real-world data from a nationwide database, to investigate these disparities. Methods: Pts with DLBCL treated with first-line (1L) therapy within 90 days of diagnosis were selected from the nationwide Flatiron Health EHR-derived de-identified database from January 2011 to May 2020. During the study, the de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). Pts’ baseline characteristics, treatment patterns, overall survival (OS), time to next therapy or death to any cause (TTNTD) were compared between race groups (non-Hispanic White [W], non-Hispanic African American [AA], Hispanic or Latino [H], non-Hispanic Asian [A]) and socioeconomic groups (Medicaid without Commercial [Medicaid] vs Commercial without Medicaid [Commercial]). Baseline characteristics were compared using Fisher’s exact, chi-squared or t-tests. Time to event endpoints were compared using Cox models adjusting baseline characteristics. Results: In total, 4,648 pts with DLBCL (82% W, 7% AA, 8% H, 3% A) were included. Compared with other race groups, W pts were older (mean age: 67 vs 60, 62, 62 [W vs AA, H, A]), had a higher proportion of pts with Eastern Cooperative Oncology Group score ≥2 (8% vs 5%, 4%, 4%), and fewer pts with Medicaid insurance (1.7% vs 5%, 6%, 3%). Across race groups, 1L treatments received were similar; 82% had R-CHOP. There were no significant differences in OS (P = 0.278; HR [AA, H, A vs W]: 0.87, 0.85, 0.84) and TTNTD (P = 0.158; HR: 0.89, 0.88, 1.19). There were statistically significant differences in time from diagnosis to treatment (P < 0.0001; HR: 0.83, 0.79, 1.12), although the magnitude of the median differences were relatively small (22, 24, 25, 19 days [W, AA, H, A]). In pts aged < 65, commercially insured pts had less advanced disease (Group Stage IV: 28% vs 59%), better OS (HR [95% CI]: 0.50 [0.31–0.81], P = 0.005) and later TTNTD (HR: 0.70 [0.48–1.03], P = 0.067) compared with Medicaid insured pts. In pts aged ≥65, commercially insured pts had similar disease stage, OS (HR: 1.09 [0.65–1.84], P = 0.756) and TTNTD (HR: 0.94 [0.61–1.44], P = 0.763) compared with Medicaid insured pts. Insurance was not a significant factor for time from diagnosis to treatment for pts aged < 65 (HR: 1.05 [0.80–1.37], P = 0.727) and ≥65 (HR: 1.05 [0.78–1.42], P = 0.742). Conclusions: In this analysis of over 4,500 pts with DLBCL treated in the real-world, access to commercial insurance was associated with health outcomes in pts under 65 years of age, possibly due to earlier diagnosis; race was not a significant factor.

Wind turbines can provide energy in developing countries. However, there are limitations to the skilled labor and manufacturing equipment required to manufacture these systems in these regions. Accordingly, the manufacturing process needs to be adapted to the potential of the developing world. In this work, a simplified wind turbine blade design is investigated. The turbine efficiency is analyzed by the blade element momentum (BEM) theory. Two different scenarios are considered to simplify the design of the wind turbine blade. The shape of the blade is simulated by a rectangular root connected to several trapezoidal segments. This results in a simple chord length distribution. The design of the twist angle is also considered. The area under the power curve is used to compare the performance of the simplified blades with that of the original design. Results show that the twist angle can be completely omitted as a tradeoff between efficiency and manufacturability. Depending on the number of simplified design segments, the area under the power curve is reduced between 13% and 25 % with respect to the original blade. The model also demonstrates how the loss in efficiency increases as the simplicity of blade design increases. Still, the design simplification enables a manufacturing process which may facilitate the use of wind energy in the developing world.

Background B-F1RST (ITT, n = 152) was the first prospective trial to evaluate bTMB as a predictive biomarker in 1L NSCLC. In the biomarker evaluable population (BEP, ctDNA with max somatic allele frequency [MSAF] ≥ 1%), bTMB high (≥ 16) predicted a better overall response rate (ORR) to atezo vs bTMB low (< 16; 28.6 vs 4.4%). In exploratory analyses, numerically higher ORR was also seen in the biomarker non-evaluable population (ORR, 34.5%), although these pts were not evaluable for bTMB due to reduced assay sensitivity at very low ctDNA levels (MSAF < 1%). Here we further evaluate the ≥ 1% MSAF and < 1% MSAF subgroups. Methods Baseline characteristics were compared across MSAF < 1% (n = 29) and MSAF ≥ 1% (n = 119) subgroups. Factors with a notable difference between groups (P < 0.15) were included in an inverse probability weighting (IPW) method to adjust for baseline imbalances. Clinical outcomes from unadjusted and adjusted models were compared. Results Baseline factors with imbalances between MSAF groups (P < 0.15) were age, smoking status, PD-L1 status, no. of target lesions and SLD (Table). In the unadjusted analysis, ORR for MSAF < 1% vs ≥ 1% was 34.5 vs 10.1% (odds ratio [OR], 4.69; P = 0.002). After IPW adjustment, ORR was 19.9 vs 11.1% (OR, 1.99; P = 0.43). Unadjusted mPFS for MSAF < 1% vs ≥ 1% was 6.8 vs 4.0 mo (HR, 0.63; P = 0.065), and adjusted mPFS was 2.8 vs 4.0 mo (HR, 0.88; P = 0.72). Conclusions Consistent with previous findings regarding low levels of ctDNA, pts with MSAF < 1% had better baseline prognostic factors than those with MSAF ≥ 1%, likely accounting for their better outcomes. After adjusting for baseline imbalances, ORR and mPFS did not differ significantly between subgroups. These results do not alter interpretation of high bTMB results in the BEP (MSAF ≥ 1%). Clinical validation of the bTMB assay continues in B-F1RST and BFAST. Table.Unadjusted and Adjusted Baseline Characteristics Included in the IPW ModelUnadjustedAdjustedMSAF ≥ 1%MSAF < 1%PMSAF ≥ 1%MSAF < 1%Pn11929119.027.5Age < 65 y, %29.448.30.0933.030.20.80Never smoker, %5.013.80.146.66.90.52PD-L1+, %a37.851.70.1340.949.20.65Number of target lesions, mean (SD)2.38 (1.23)1.79 (0.86)0.022.27 (1.20)2.26 (1.13)0.98SLD, mmmedian (range)70.0 (12.7, 257.0)42.4 (13.0, 200.0)0.00162.0 (12.7, 257.0)48.2 (13.0, 200.0)0.77HR, hazard ratio; SD, standard deviation; SLD, sum of longest diameters.a PD-L1+ defined as ≥ 1% PD-L1 on tumor cells by any commercially available assay. Citation Format: Mark A. Socinski, Sarah M. Paul, Cindy Yun, Sylvia Hu, Vincent Shen, Vamsidar Velcheti, Tony S. Mok, David R. Gandara, Young Kwang Chae, Erica Schleifman, David A. Fabrizio, David S. Shames, See Phan, Edward S. Kim. Exploratory subgroup analysis of atezolizumab (atezo) clinical characteristics in patients (pts) with low circulating tumor DNA (ctDNA) in B-F1RST—a Phase II trial evaluating blood-based tumor mutational burden (bTMB) in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT194.

Background. Capecitabine administered for 7 days biweekly with oxaliplatin (XELOX) biweekly has been reported to have activity and safety profiles similar to those of standard capecitabine given for 14 days triweekly. Multiple studies have shown that the addition of bevacizumab to 5-fluorouracil–based chemotherapy is active and well tolerated. Methods. Patients with metastatic colorectal cancer (mCRC) were randomized to XELOX plus bevacizumab using a standard triweekly cycle (Q3W) or a dose-dense biweekly cycle (Q2W) schedule. The primary endpoint was the progression-free survival (PFS) interval. This trial is registered on ClinicalTrials.gov (identifier, NCT00159432). Results. In total, 435 U.S. patients were randomized. The median PFS intervals were 9.6 months in the Q3W group and 9.1 months in the Q2W group. The median overall survival times were 28.4 months and 22.1 months and the median times to treatment failure were 5.5 months and 3.4 months, respectively. Overall, gastrointestinal disorders were the most common (93%) adverse event (AE). Grade 3 or 4 AEs occurred in 75% and 81% of patients in the Q3W and Q2W groups, respectively. Treatment discontinuation as a result of diarrhea (5% versus 10%) and hand–foot syndrome (2% versus 9%) was less common in the Q3W group than in the Q2W group, respectively. Conclusions. Based on these results, the first-line treatment of U.S. patients with mCRC using a biweekly combination of XELOX and bevacizumab at the doses studied cannot be recommended. XELOX Q3W remains the preferred schedule for the management of mCRC.

We sought to determine if an association exists between age and capecitabine efficacy among patients with metastatic breast cancer (MBC). Pooled analysis of five phase II or III registration trials of capecitabine 2,500-2,510 mg/m(2)/day for 2 weeks and 1 week off, or combination therapy was performed. Four trials enrolled patients previously exposed to other chemotherapy, generally a taxane. Of 570 patients, 193 (34%) were 18-49 years old, 246 (43%) were 50-64, and 131 (23%) were ≥ 65. Median average daily dose was 2,067 mg/m² in the 18- to 49-year-old group and 2,105 mg/m² in the 50-64 and ≥ 65 year groups. Overall survival (OS) in all groups was similar by log-rank test for the individual trials (P = 0.71-0.95) and Cox regression of the pooled trials. Univariate analysis demonstrated no difference in clinical benefit or objective response between groups. Treatment failure analysis showed 283 (50%) patients experienced progressive disease, while 114 (20%) withdrew for safety. Serious adverse events (AEs) occurred in 71 (36.8%), 85 (34.6%), and 59 (45.0%) patients in the 18-49, 50-64, and ≥ 65 years groups, respectively. There was no statistically significant association between age and OS, clinical benefit, or objective response in patients with MBC treated with capecitabine. Frequency of AEs and serious AEs was not related to age at treatment, although women ≥ 65 years were more likely to withdraw from treatment because of an AE than younger women.

Background bTMB assays determine TMB using a noninvasive blood test. B-F1RST (ITT, n = 152) is the first prospective trial to evaluate bTMB as a biomarker to predict benefit of 1L atezo monotherapy in advanced NSCLC. bTMB high (score of ≥ 16; ≥ 14.5 mut/Mb) predicted better ORR with atezo vs bTMB low ( Methods Eligibility criteria included untreated stage IIIB-IVB NSCLC and ECOG PS 0/1. Pts received atezo 1200 mg IV q3w until PD, intolerance or loss of benefit. Co-primary endpoints were investigator assessed ORR for efficacy (ITT) and PFS for biomarker analysis (BEP) at a prespecified bTMB cutoff of 16 for high (≥ 16) vs low ( Results With ≥ 18 mo follow up (data cutoff, 14 May 2019) in ITT pts, ORR was 17% (95% CI: 12, 24), mPFS was 4.1 mo (95% CI: 2.8, 4.9) and mOS was 14.8 mo (95% CI: 12.7, 21.3). In bTMB ≥ 16 vs Conclusions B-F1RST shows the clinical utility of bTMB as a predictive biomarker for pts receiving 1L atezo monotherapy. The final analysis confirmed that pts with bTMB ≥ 16 had numerical benefit for PFS and OS. Decrease in serum CRP over 6 wk predicted PFS and OS benefit. No new safety signals were seen. Table . LBA83 PFS results Median (95% CI), mo ITT (N = 152) 4.1 (2.8, 4.9) BEP (n = 119) bTMB High (≥ bTMB cutoff) bTMB Low ( HR 90% CI bTMB cutoff Median, mo (n) Median, mo (n) 12 2.6 (44) 4.1 (75) 1.16 0.83, 1.64 16 5.0 (28) 3.5 (91) 0.80 0.54, 1.18 20 6.9 (19) 2.9 (100) 0.59 0.37, 0.93 OS results Median (95% CI), mo ITT (N = 152) 14.8 (12.7, 21.3) BEP (n = 119) bTMB High (≥ bTMB cutoff) bTMB Low ( HR 90% CI bTMB cutoff Median, mo (n) Median, mo (n) 12 15.7 (44) 13.8 (75) 0.95 0.62, 1.46 16 23.9 (28) 13.4 (91) 0.66 0.40, 1.10 20 23.9 (19) 13.1(100) 0.44 0.23, 0.85 Clinical trial identification NCT02848651. Editorial acknowledgement Medical writing assistance was provided by Chris Lum, PhD, of Health Interactions, and funded by F. Hoffmann-La Roche, Ltd. Legal entity responsible for the study F. Hoffmann-La Roche, Ltd. Funding F. Hoffmann-La Roche, Ltd. Disclosure M. Socinski: Research grant / Funding (institution), Non-remunerated activity/ies: F. Hoffmann-La Roche. V. Velcheti: Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech, Inc.; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Foundation Medicine. T. Mekhail: Speaker Bureau / Expert testimony: Roche/Genentech. Y.K. Chae: Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Biodesix; Honoraria (self): F. Hoffmann La Roche; Honoraria (self): AstraZeneca; Honoraria (self): Merck; Research grant / Funding (institution): BMS. T.A. Leal: Advisory / Consultancy: Genentech, Inc.; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy: Bayer; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Mirati Therapeutics. J.E. Dowell: Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Trizell. V. Shen: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche/Genentech. S. Hu: Full / Part-time employment: Genentech, Inc.. S.M. Paul: Full / Part-time employment: Genentech, Inc.. D.S. Shames: Full / Part-time employment: Genentech, Inc.. E. Schleifman: Full / Part-time employment: Genentech, Inc.. D.A. Fabrizio: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine, Inc. M. Nowicki: Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffmann-La Roche. C. Yun: Full / Part-time employment: Genentech, Inc.. S. Phan: Full / Part-time employment: Genentech, Inc.. E.S. Kim: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda. All other authors have declared no conflicts of interest.

12001Background: TMB in both tissue and blood has shown promise in selecting for patients (pts) who clinically benefit from PD-L1/PD-1 inhibitors. In the randomized, 2L NSCLC Phase III OAK and Phas...

Antagonizing the glucagon signaling pathway represents an attractive therapeutic approach for reducing excess hepatic glucose production in patients with type 2 diabetes. Despite extensive efforts, there is currently no human therapeutic that directly inhibits the glucagon/glucagon receptor pathway. We undertook a novel approach by generating high-affinity human monoclonal antibodies (mAbs) to the human glucagon receptor (GCGR) that display potent antagonistic activity in vitro and in vivo. A single injection of a lead antibody, mAb B, at 3 mg/kg, normalized blood glucose levels in ob/ob mice for 8 days. In addition, a single injection of mAb B dose-dependently lowered fasting blood glucose levels without inducing hypoglycemia and improved glucose tolerance in normal C57BL/6 mice. In normal cynomolgus monkeys, a single injection improved glucose tolerance while increasing glucagon and active glucagon-like peptide-1 levels. Thus, the anti-GCGR mAb could represent an effective new therapeutic for the treatment of type 2 diabetes.

IP-10 secretion is induced by pro-inflammatory cytokines and mediates the migration of CXCR3+ cells. Its elevation in clinical samples has been associated with multiple inflammatory diseases and its antagonism has been reported to be effective in several animal models of inflammatory disease. We generated a mouse anti-mouse IP-10 monoclonal antibody (mAb; Clone 20A9) that specifically bound murine IP-10 with high affinity and inhibited in vitro IP-10 induced BaF3/mCXCR3 cell migration with an IC(50) of approximately 4 nM. The 20A9 mAb was completely absorbed in vivo and had dose proportional pharmacokinetic exposure with a serum half life of 2.4-6 days. The 20A9 mAb inhibited IP-10 mediated T-cell recruitment to the airways, indicating that it is effective in vivo. However, administration of the 20A9 mAb had no significant effect on disease in mouse models of delayed type hypersensitivity, collagen induced arthritis, cardiac allograft transplantation tolerance, EAE or CD4+ CD45RBHi T-cell transfer-induced IBD. These data suggest that the 20A9 mAb can antagonize IP-10 mediated chemotaxis in vitro and in vivo and that this is insufficient to cause a therapeutic benefit in multiple mouse models of inflammatory disease.

Black Americans (blacks) have a high prevalence of chronic hepatitis C virus (HCV) infection and respond poorly to therapy with interferon alfa-based regimens, but they have been underrepresented in clinical trials. The aim of this study was to assess the rate of sustained virological response (SVR) to peginterferon alfa-2a (40 kd) in combination with ribavirin in black patients chronically infected with HCV genotype 1. In a prospective, multicenter, open-label trial, 78 black and 28 white American interferon-naive patients were enrolled to receive once weekly subcutaneous injections of 180 μg peginterferon alfa-2a plus oral ribavirin (1000 mg/d for patients weighing less than 75 kg and 1200 mg/d for patients weighing 75 kg or more) for 48 weeks. Pre- and post-treatment liver biopsies were evaluated for necroinflammation and fibrosis. SVR, defined as undetectable (

Delivery of protein therapeutics often requires frequent injections because of low activity or rapid clearance, thereby placing a burden on patients and caregivers. Using glycoengineering, we have increased and prolonged the activity of proteins, thus allowing reduced frequency of administration. Glycosylation analogs with new N-linked glycosylation consensus sequences introduced into the protein were screened for the presence of additional N-linked carbohydrates and retention of in vitro activity. Suitable consensus sequences were combined in one molecule, resulting in glycosylation analogs of rHuEPO, leptin, and Mpl ligand. All three molecules had substantially increased in vivo activity and prolonged duration of action. Because these proteins were of three different classes (rHuEPO is an N-linked glycoprotein, Mpl ligand an O-linked glycoprotein, and leptin contains no carbohydrate), glycoengineering may be generally applicable as a strategy for increasing the in vivo activity and duration of action of proteins. This strategy has been validated clinically for glycoengineered rHuEPO (darbopoetin alfa).

TPS9103 Background: The anti–PD-L1 monoclonal antibody atezolizumab inhibits the interaction of PD-L1 with its receptors PD-1 and B7.1, thereby restoring T-cell immunity. In the Phase III OAK study, patients with previously treated advanced NSCLC had improved mOS in the atezolizumab arm (13.8 mo) vs the docetaxel arm (9.6 mo) (HR 0.73 [95%CI: 0.62, 0.87]; P= 0.0003), irrespective of PD-L1 expression or histology. A Phase III clinical trial of atezolizumab monotherapy for first-line, PD-L1–selected patients with NSCLC is underway; however, first-line atezolizumab monotherapy for NSCLC treatment in a biomarker-unselected population has not yet been investigated. Current assays to measure PD-L1 expression by IHC require tumor biopsies, which can be difficult to obtain in some patients. Novel blood-based biomarkers will be evaluated retrospectively in B-F1RST (Blood-First-Line Ready Screening Trial) in patients receiving atezolizumab monotherapy in first-line NSCLC. Methods: A Phase II, open-label, single-arm study, B-F1RST (NCT02848651), will evaluate the efficacy and safety of atezolizumab in PD-L1–unselected patients with first-line locally advanced or metastatic NSCLC. Eligibility criteria include stage IIIB-IVB NSCLC, ECOG PS 0-1, measurable disease per RECIST v1.1 and adequate hematologic and end-organ function. Exclusion criteria include the presence of EGFRmutations or ALKfusions, active CNS metastases and prior immunotherapy for NSCLC. Patients will receive atezolizumab 1200 mg IV q3w until disease progression or loss of clinical benefit. Prospective collection of blood samples is mandatory; collection of tissue biopsies is optional. The co-primary endpoints of the study are investigator-assessed ORR per RECIST v1.1 for the efficacy objective and PFS per RECIST v1.1 for evaluating blood-based predictive biomarkers for atezolizumab efficacy, including mutation status. Approximately 150 patients will be enrolled at 25 or more centers in the United States. Clinical trial information: NCT02848651.

Background: Limited studies of hypothalamic-pituitary-adrenal axis regulation in posttraumatic stress disorder have been performed in premenopausal women. We therefore undertook a study of hypothalamic-pituitary-adrenal axis regulation in this population. Methods: Outpatient posttraumatic stress disorder subjects were compared with healthy, age- and weight-matched nontraumatized subjects. Subjects were free from psychotropic medications, alcohol and other illicit substances for at least 4 weeks before study. Menstrual cycle phase was determined by monitoring the LH surge and plasma progesterone levels. Corticotropin releasing factor and adrenocorticotropin stimulation tests, as well as 24-hour urinary-free cortisol measurements were performed. Results: Corticotropin releasing factor test: Baseline adrenocorticotropic hormone and cortisol levels did not differ between the 12 PTSD and 11 comparison subjects, but the posttraumatic stress disorder group had greater adrenocorticotropic hormone and cortisol responses to corticotropin releasing factor, as well as a later cortisol peak. Adrenocorticotropic hormone test: Baseline cortisol levels did not differ between the 10 posttraumatic stress disorder subjects and seven controls, but the posttraumatic stress disorder group showed greater cortisol responses to adrenocorticotropic hormone. Peak cortisol responses to corticotropin releasing factor and adrenocorticotropic hormone were correlated with each other and with 24-hour urinary-free cortisol excretion. Conclusions: Pituitary and adrenal hyperreactivity to exogenous corticotropin releasing factor and adrenocorticotropic hormone is demonstrated in premenopausal women with chronic posttraumatic stress disorder. Cortisol hyperreactivity thus may play a role in the pathophysiology of posttraumatic stress disorder in women.

IL-18-binding protein (IL-18BP) is a natural IL-18 inhibitor. Human IL-18BP isoform a was produced as fusion construct with human IgG1 Fc and assessed for binding and neutralizing IL-18. IL-18BP-Fc binds human, mouse, and rat IL-18 with high affinity (KD 0.3–5 nM) in a BIAcore-based assay. In vitro, IL-18BP-Fc blocks IL-18 (100 ng/ml)-induced IFN-γ production by KG1 cells (EC50 = 0.3 μg/ml). In mice challenged with an LD90 of LPS (15 mg/kg), IL-18BP-Fc (5 mg/kg) administered 10 min before LPS blocks IFN-γ production and protects against lethality. IL-18BP-Fc administered 10 min before LPS blocks IFN-γ production induced by LPS (5 mg/kg) with ED50 of 0.005 mg/kg. Furthermore, IL-18BP-Fc (5 mg/kg) abrogates LPS (5 mg/kg)-induced IFN-γ production even when administered 6 days before LPS but shows no effect when administered 9 or 12 days before LPS. Given 10 min before LPS challenge to mice primed 12 days in advance with heat-killed Propionibacterium acnes, IL-18BP-Fc prevents LPS-induced liver damage and IFN-γ and Fas ligand expression. Given at the moment of priming with P. acnes, IL-18BP-Fc decreases P. acnes-induced granuloma formation, macrophage-inflammatory protein-1α and macrophage-inflammatory protein-2 production and prevents sensitization to LPS. IL-18BP-Fc also prevents Con A-induced liver damage and IFN-γ and Fas ligand expression as well as liver damage induced by Pseudomonas aeruginosa exotoxin A or by anti-Fas agonistic Ab. In conclusion, IL-18BP can be engineered and produced in recombinant form to generate an IL-18 inhibitor, IL-18BP-Fc, endowed with remarkable in vitro and in vivo properties of binding and neutralizing IL-18.

Amyloid peptides of 39-43 amino acids (Abeta) are the major constituents of amyloid plaques present in the brains of Alzheimer's (AD) patients. Proteolytic processing of the amyloid precursor protein (APP) by the yet unidentified beta- and gamma-secretases leads to the generation of the amyloidogenic Abeta peptides. Recent data suggest that all of the known mutations leading to early onset familial AD alter the processing of APP such that increased amounts of the 42-amino acid form of Abeta are generated by a gamma-secretase activity. Identification of the beta- and/or gamma-secretases is a major goal of current AD research, as they are prime targets for therapeutic intervention in AD. It has been suggested that the sterol regulatory element-binding protein site 2 protease (S2P) may be identical to the long sought gamma-secretase. We have directly tested this hypothesis using over-expression of the S2P cDNA in cells expressing APP and by characterizing APP processing in mutant Chinese hamster ovary cells that are deficient in S2P activity and expression. The data demonstrate that S2P does not play an essential role in the generation or secretion of Abeta peptides from cells, thus it is unlikely to be a gamma-secretase.

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor family that acts specifically on epithelial cells in a paracrine mode. We employed a mammalian expression system to synthesize recombinant human KGF and isolated two preparations, KGF-a and KGF-b, from medium conditioned by Chinese hamster ovary cells. On an SDS-PAGE gel, KGF-a migrates as two bands near 25-29 kDa and contains both N- and O-linked sugar moieties attached near the N-terminus. Detailed structural characterization confirms that KGF-a contains a single amino acid sequence predicted from cDNA sequence and the molecule has two intramolecular disulfide bridges, Cys1-Cys15 and Cys102-Cys106. An additional Cys at position 40 is free and resides in a solvent-inaccessible environment. Mass spectrometric analyses of KGF-a peptides verify the occurrence of several post-translational modifications in the molecule, including partial oxidation at Met28, partial sulfation at Tyr27, and glycosylation at Asn14 and Thr22. The Asn-linked carbohydrate structures are heterogeneous, which include biantennary, triantennary, and tetraantennary structures with none or up to four sialic acids attached to various structures, while the Thr-linked carbohydrates contain typical mucin-type structures. KGF-b is an N-terminally truncated form of KGF-a posttranslationally processed at Arg23 and is not glycosylated. Both KGF-a and KGF-b forms are capable of stimulating DNA synthesis in quiescent Balb/MK mouse epidermal keratinocytes.

A panel of mAbs were generated against the purified soluble form of erbB2/Her2 receptor, corresponding to the extracellular region of the receptor, and examined for their ability to mimic the receptor ligand. Some of the mAbs strongly induced tyrosine phosphorylation of 180-185 kDa proteins, including not only Her2 but also Her3 and Her4 receptors, when they were expressed on the surface of breast cancer cells. These mAbs do not cross-react with Her3 or Her4 as demonstrated by competition study. Receptor phosphorylation was also observed with the cell lines transfected with Her2 or a chimeric receptor consisting of the extracellular domain of Her2 and the transmembrane and cytoplasmic domains of epidermal growth factor receptor. Selected mAbs were tested for their ability to change cell morphology, and one specific mAb, mAb74, induced cell morphology changes and apoptosis.