Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma.

PURPOSE: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents. METHODS: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284). RESULTS: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response. CONCLUSIONS: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.

Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial.

BACKGROUND: Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma. METHODS: CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing. FINDINGS: Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7-23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15-27·93) of 92 evaluable patients. INTERPRETATION: These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab). FUNDING: MacroGenics.

Impact of percutaneous coronary intervention on biomarker levels in patients in the subacute phase following myocardial infarction: the Occluded Artery Trial (OAT) biomarker ancillary study.

BACKGROUND: The purpose of the Occluded Artery Trial (OAT) Biomarker substudy was to evaluate the impact of infarct related artery (IRA) revascularization on serial levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and dynamics of other biomarkers related to left ventricular remodeling, fibrosis and angiogenesis. METHODS: Patients were eligible for OAT-Biomarker based on the main OAT criteria. Of 70 patients (age 60.8 ± 8.8, 25% women) enrolled in the substudy, 37 were randomized to percutaneous coronary intervention (PCI) and 33 to optimal medical therapy alone. Baseline serum samples were obtained prior to OAT randomization with follow up samples taken at one year. The primary outcome was percent change of NT-proBNP from baseline to 1 year. The secondary outcomes were respective changes of matrix metalloproteinases (MMP) 2 and 9, tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), Vascular Endothelial Growth Factor (VEGF), and Galectin-3. RESULTS: Paired (baseline and one-year) serum samples were obtained in 62 subjects. Baseline median NT-proBNP level was 944.8 (455.3, 1533) ng/L and decreased by 69% during follow-up (p < 0.0001). Baseline MMP-2 and TIMP-2 levels increased significantly from baseline to follow-up (p = 0.034, and p = 0.027 respectively), while MMP-9 level decreased from baseline (p = 0.038). Levels of VEGF and Galectin-3 remained stable at one year (p = NS for both). No impact of IRA revascularization on any biomarker dynamics were noted. CONCLUSIONS: There were significant changes in measured biomarkers related to LV remodeling, stress, and fibrosis following MI between 0 and 12 month. Establishing infarct vessel patency utilizing stenting 24 hours-28 days post MI did not however influence the biomarkers' release.

Risk factors for detectable HIV-1 RNA at delivery among women receiving highly active antiretroviral therapy in the women and infants transmission study.

BACKGROUND: Detectable HIV-1 RNA at delivery is the strongest predictor of mother-to-child transmission. The risk factors for detectable HIV, including type of regimen, are unknown. We evaluated factors, including highly active antiretroviral (HAART) regimen, associated with detectable HIV-1 RNA at delivery in the Women and Infants Transmission Study (WITS). METHODS: Data from 630 HIV-1-infected women who enrolled from 1998 to 2005 and received HAART during pregnancy were analyzed. Multivariable analyses examined associations between regimens, demographic factors, and detectable HIV-1 RNA (>400 copies/milliliter) at delivery. RESULTS: Overall, 32% of the women in the cohort had detectable HIV-1 RNA at delivery. Among the subset of 364 HAART-experienced women, a lower CD4 cell count at enrollment [adjusted odds ratio (AOR) = 1.20 per 100 cells/microL, confidence interval (CI) 1.04 to 1.37] and higher HIV-1 RNA at enrollment (AOR = 1.52 per log10 copies/milliliter, CI 1.32 to 1.75) were significantly associated with detectable HIV-1 RNA levels at delivery. For the 266 HAART-naive women, both lower CD4 cell count at enrollment (AOR = 1.24 per 100 cells/microL, CI 1.05 to 1.48) and higher HIV-1 RNA at enrollment (AOR = 1.35 per log10 copies/milliliter, CI 1.12 to 1.63) were associated with detectable HIV-1 RNA at delivery. In addition, age at delivery (AOR = 0.92 per 10 years older, CI 0.86 to 0.99) and maternal illicit drug use (AOR = 3.15, CI 1.34 to 7.41) were significantly associated with detectable HIV-1 RNA at delivery among HAART-naive women. Type of HAART regimen was not significant in either group. CONCLUSIONS: Lack of viral suppression at delivery was common in the WITS cohort, but differences by antiretroviral regimen were not identified. Despite a transmission rate below 1% in the last 5 years of the WITS cohort, improved measures to maximize HIV-1 RNA suppression at term among high-risk women are warranted.

Gender influences Health-Related Quality of Life in IPF.

BACKGROUND: HRQL in IPF patients is impaired. Data from other respiratory diseases led us to hypothesize that significant gender differences in HRQL in IPF also exist. METHODS: Data were drawn from the NIH-sponsored Lung Tissue Research Consortium (LTRC). Demographic and pulmonary physiology data along with MMRC, SF-12, and SGRQ scores from women vs. men were compared with two-sample t-tests. Multivariate linear regression was used to examine the association between SF-12 component scores and gender while adjusting for other relevant variables. RESULTS: The study sample consisted of 147 men and 74 women. Among several baseline variables, only DL(CO)% predicted differed between women and men, (43.7 vs. 38.0, p=0.03). In general, men exhibited lower (better) MMRC scores (1.7 vs. 2.4, p=0.02), particularly those with milder disease as measured by DL(CO)% predicted. In an adjusted analysis, SF-12 PCS scores in men were lower (worse) than women (p=0.01), an effect that was more pronounced in men with greater dyspnea scores. In a similar analysis, SF-12 MCS scores in women were lower than men (worse) (48.3 vs. 54.4, p=0.0004), an effect that was more pronounced in women with greater dyspnea scores. CONCLUSIONS: Significant gender differences in HRQL exist in IPF. As compared to women, men reported less severe dyspnea, had worse SF-12 PCS scores, but better SF-12 MCS scores. Dyspnea appears to have a greater impact on the physical HRQL of men and the emotional HRQL of women. An improved understanding of the mechanism behind these differences is needed to better target interventions.

Urine concentrating ability in infants with sickle cell disease: baseline data from the phase III trial of hydroxyurea (BABY HUG).

BACKGROUND: A urine concentrating defect is quite common in sickle cell anemia, has its onset in early childhood, and may be reversible with transfusion. The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) is a double-blind, placebo-controlled trial to assess efficacy of hydroxyurea in preventing organ damage in young children with sickle cell anemia. PROCEDURES: Enrolled infants were subjected to parent-supervised fluid deprivation, and urine and serum osmolality were determined. RESULTS: Of 185 infants age 7.5-17.9 months (mean 13.0 +/- 2.7) and fluid-deprived 7.4 +/- 2.4 hr (range 4-13), 178 had concurrent determinations of urine and serum osmolality. Mean serum osmolality was 286 +/- 6 mOsm/kg H(2)O (range 275-312) and independent of age, height, weight, or duration of fluid deprivation. Urine osmolality (mean 407 +/- 151, range 58-794 mOsm/kg H(2)O) was greater than serum (P < 0.0001) and correlated with duration of fluid deprivation (P = 0.001). Of 142 (77.2%) who concentrated urine, 54 (29.4%) had urine osmolality >500 mOsm/kg H(2)O. Urine osmolality correlated with (99m)Tc-DTPA clearance (P = 0.02) and serum urea nitrogen (P < 0.0001), but not with serum osmolality, gender, age, height, weight, or serum creatinine. Infants able to produce urine with osmolality >500 mOsm/kg H(2)O had higher mean fetal hemoglobin concentrations than did those who could not (P = 0.014). CONCLUSIONS: Even with often limited fluid deprivation, 77.2% of young infants with sickle cell anemia were able to concentrate urine. Preservation of concentrating ability was associated with higher fetal hemoglobin concentration. Assessment will be repeated after 2 years of hydroxyurea or placebo treatment (ClinicalTrials.gov number, NCT00006400).

Clinical significance of radiologic characterizations in COPD.

COPD is a heterogeneous disorder with clinical assessment becoming increasingly multidimensional. We hypothesized HRCT phenotype would strongly influence clinical outcomes including health status, exacerbation frequency, and BODE. COPD subjects were characterized via the SF-12, SGRQ, MMRC, physiologic testing, and standardized volumetric chest HRCT. Visual semi-quantitative estimation of bronchial wall thickness (VBT) and automated quantification of emphysema percent and bronchial wall thickness were generated. Multivariate modeling compared emphysema severity and airway abnormality with clinical outcome measures. Poisson models were used to analyze exacerbation frequency. SGRQ and SF-12 physical component scores were influenced by FEV(1)% predicted, emphysema percent, and VBT. VBT scores > 2 (scale 0-48) were associated with increased exacerbation frequency (p = 0.009) in the preceding year adjusting for age, gender, emphysema percent, smoking history and FEV(1)% predicted, although this effect was attenuated by age. Emphysema percent correlated with total BODE score in unadjusted (r = 0.73; p < 0.0001) and adjusted (p < 0.0001) analyses and with BODE individual components. HRCT provides unique COPD phenotyping information. Radiographic quantification of emphysema and bronchial thickness are independently associated with SGRQ and physical component score of the SF-12. Bronchial thickness but not emphysema is associated with exacerbation frequency, whereas emphysema is a stronger predictor of BODE and its systemic components MMRC, 6MWT, and BMI. Future research should clarify whether CT parameters complement BODE score in influencing survival.