Search

Objective Data on the magnitude of benefit of modern therapies for pulmonary arterial hypertension (PAH) in connective tissue disease (CTD)–associated PAH are limited. In this study, we performed meta‐analyses of randomized, controlled trials (RCTs) and registries to quantify the benefit of these modern therapies in patients with CTD‐PAH. Methods The PubMed and Embase databases were searched for articles reporting data from RCTs or registries published between January 1, 2000 and November 25, 2019. Eligibility criteria included multicenter studies with ≥30 CTD‐PAH patients. For an RCT to be included, the trial had to evaluate an approved PAH therapy, and long‐term risks of clinical morbidity and mortality or 6‐minute walk distance had to be reported. For a registry to be included, survival rates had to be reported. Random‐effects models were used to pool the data. Results Eleven RCTs (total of 4,329 patients; 1,267 with CTD‐PAH) and 19 registries (total of 9,739 patients; 4,008 with CTD‐PAH) were included. Investigational therapy resulted in a 36% reduction in the risk of clinical morbidity/mortality events both in the overall PAH population (hazard ratio [HR] 0.64, 95% confidence interval [95% CI] 0.54, 0.75; P < 0.001) and in CTD‐PAH patients (HR 0.64, 95% CI 0.51, 0.81; P < 0.001) as compared to control subjects. The survival rate was lower in CTD‐PAH patients compared to all PAH patients (survival rate 62%, 95% CI 57, 67% versus 72%, 95% CI 69, 75% at 3 years). The survival rate in CTD‐PAH patients treated primarily after 2010 was higher than that in CTD‐PAH patients treated before 2010 (survival rate 73%, 95% CI 62, 81% versus 65%, 95% CI 59, 71% at 3 years). Conclusion Modern therapy provides a similar reduction in morbidity/mortality risk in patients with CTD‐PAH when compared to the PAH population overall. Risk of death is higher in CTD‐PAH patients than in those with PAH overall, but survival has improved in the last 10 years, which may be related to increased screening and/or new treatment approaches. Early detection of PAH in patients with CTD and up‐front intensive treatment are warranted.

In this article, we study how the export behaviors of new and incumbent exporters differentially respond to exchange rate shocks. We establish a dynamic model, in which new exporters strategically charge a lower price than incumbent exporters to grow their customer base and increase future sales. The model predicts that new exporters adjust their prices more aggressively relative to their incumbent counterparts in response to exchange rate fluctuations. Using a transaction-level data set containing all Chinese exporters during the 2000–2009 period, we find supporting evidence for the model's predictions: new exporters adjust their price 1.5 times more than incumbent exporters. This, in turn, results in export quantities being less responsive to exchange rate shocks among new exporters. The result holds for a series of robustness checks. The findings imply that there are different degrees of exchange rate pass-through among new and incumbent exporters.

Smoking prevalence and its association with pulmonary arterial hypertension (PAH) outcomes have not been described in patients in the United States.Using the US-based Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), the prevalence, demographics, and outcomes in ever- versus never-smokers with PAH were determined.Ever-smoking status was more prevalent in males (61.7%) than in females (42.9%) enrolled in REVEAL. Ever-smokers were older than never-smokers at the time of PAH diagnosis and REVEAL enrollment. The time to first hospitalization, transplant-free survival, and survival did not differ between ever- and never-smokers overall; however, in newly diagnosed males, ever-smoking was associated with earlier death (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.1-3.0; p = 0.0199), the composite of transplant or death (HR 2.2, 95% CI 1.4-3.6; p = 0.0008), and first hospitalization (HR 1.8, 95% CI 1.2-2.7; p = 0.0063), though smoking exposure (pack-years) did not differ between newly and previously diagnosed males.REVEAL PAH data demonstrate that smoking prevalence in male PAH patients is disproportionate. The prevalence of cigarette smoking was significantly higher in males than females enrolled in REVEAL. Ever-smoking status was associated with increased age at PAH diagnosis and, in newly diagnosed male PAH patients, earlier time to hospitalization and shorter survival after PAH diagnosis.

Background SPHERE is a US, multicentre, prospective registry collecting real-world data from pts with pulmonary arterial hypertension (PAH) treated with selexipag, a selective oral IP prostacyclin receptor agonist. Methods SPHERE (planned N=800) included newly initiated (NI, receiving selexipag ≤60 days) and previously initiated (PI) pts. We describe disease characteristics, selexipag dose and clinical course of the first 500 pts and risk assessment based on REVEAL 2.0 risk calculator and COMPERA risk assessment strategy. Results Disease characteristics at initiation were: 75.0% female, median age 61.0 years, idiopathic etiology (49.2%) or associated with connective tissue disease (26.4%). Pts were mostly WHO functional class (FC) II (31.0%) or III (49.6%) (unknown for 9.2%). Median time from PAH diagnosis to selexipag initiation was 3.4 years. Of the first 500 pts enrolled, 138 (28%) were NI and 362 (72%) were PI; characteristics were consistent between NI and PI. Risk classification at initiation differed depending on method used: with REVEAL 2.0, low/intermediate/high risk were 41.8%/29.6%/28.6% (38.4%/26.1%/35.5% for NI and 43.1%/30.9%/26.0% for PI, respectively) and with COMPERA were 22.0%/67.2%/9.6% (13.8%/73.2%/10.9% for NI and 25.1%/64.9%/9.1% for PI), respectively. Note, missing variables in real-world registry data may affect risk assessment. In both cohorts, median individualised maintenance dose was 1200 μg twice daily (NI 1000 μg, PI 1200 μg); median time to individualised maintenance dose was 8.1 weeks. Median treatment duration was 21.7 months (17.7 months NI, 25.8 months PI). Overall, 32.4% of pts discontinued selexipag (46.4% NI, 27.1% PI), most commonly (22.8%) for adverse events (AEs) (34.8% NI, 18.2% PI). Of note, disease progression is classified as an AE. No selexipag-related deaths were reported. At 18 months, WHO FC improved/remained stable in the majority of pts (205/235, 87%; improved, 24%; stable, 63%), but worsened in 12.8% of pts. At 18 months, the majority of pts had improved/stable risk by REVEAL 2.0 (265/334, 79% [improved, 22%; stable, 57%]) and by COMPERA (255/316, 81% [improved, 23%; stable, 58%]). This was consistent for NI and PI. For both risk assessment tools higher risk was associated with increased risk of death. With REVEAL 2.0, risk of death was 2.9 and 9.3 times higher for intermediate and high risk, respectively vs low risk. Similarly with COMPERA, risk of death was 3.2 and 11.4 times higher in intermediate and high risk, respectively vs low risk. Conclusions Of the first 500 pts in SPHERE, the vast majority were prevalent PAH cases in FC II or III. Around one-quarter of pts had improved FC and/or risk; the majority of pts remained stable risk. Higher risk was associated with increased mortality risk. Over 50% of pts completed 18 months of selexipag. Discontinuations were most commonly for AEs and/or PAH progression. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Actelion Pharmaceuticals US, Inc.

Background CTD-PAH has historically represented a PAH subtype with poor prognosis. New therapies, as well as combination therapy approaches targeting multiple pathways have been approved for PAH based on RCTs. CTD-PAH patients comprise a subgroup of the RCT populations and efficacy analyses are based on subgroup analyses which can be less reliable than the overall analysis. We conducted a meta-analysis of RCTs of approved PAH therapies to evaluate outcomes of patients with CTD-PAH. Purpose To use meta-analysis to determine response to treatment in patients with CTD-PAH. Methods The PubMed and EMBASE databases were searched for English-only articles published between January 1, 2000 and November 25, 2019. Inclusion criteria were multicenter RCTs that enrolled adults with WHO group 1 pulmonary hypertension (PAH); enrollment in 2000 or later; long-term clinical morbidity and/or mortality event or 6-minute walk distance (6MWD) as an efficacy endpoint reported for ≥30 patients with CTD-PAH; and evaluation of a US Food and Drug Administration-approved PAH therapy. The primary outcomes were treatment effect as measured by the study time to first morbidity or morality event and change in 6MWD from baseline to between 3–6 months, per the data provided in each article. Results from individual studies were combined using a random-effects model for overall study population (PAH patients) and the subgroup of CTD-PAH patients. Results Ten RCTs (N=4329 PAH patients; n=1263 (29%) with CTD-PAH) met inclusion criteria and were included in the meta-analysis. At baseline, PAH patients had a mean age of 50 years, approximately 78% were female, and approximately 58% had functional class III or IV disease. These characteristics were balanced between treatment and control groups. Baseline 6MWD was 356 m for the overall population and 337 m for patients with CTD-PAH. Five RCTs (N=3172; n=941 with CTD-PAH [30%]) reported hazard ratios (HRs) for time to a morbidity or mortality event by drug treatment and PAH etiology: overall population HR=0.63 (95% confidence interval [CI], 0.56–0.72; P Conclusions The improvement in 6MWD in patients with CTD-PAH is smaller than in those with other types of PAH, perhaps reflecting comorbidities and CTD-induced mobility constraints, independent of their cardiopulmonary capacity. Data from long term clinical morbidity/mortality endpoint studies in this large group of patients with CTD-PAH demonstrate that these patients derive significant benefit from currently available PAH therapies which, in many patients, comprised the addition of a drug targeting a second or third pathway involved in the pathophysiology of PAH. Treatment effect on morbidity/mortality Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Actelion Pharmaceuticals US, Inc.

Aim: Data on impact of smoking on pulmonary hypertension is conflicting. REVEAL (Registry to Evaluate Early and Long-term PAH Disease Management) a US-based, multicentre observational registry characterising clinical features and outcomes of PAH patients (pts) was queried to assess the relationship between smoking status (NEVER- vs EVER-smoker) and onset and outcome in PAH. Methods: REVEAL (NCT00370214) pts ≥18 years (yrs), group 1 PAH, with pulmonary capillary wedge pressure ≤15 mmHg at diagnosis were included. 5-yr mortality (all cause), the composite of transplant or mortality and time to first hospitalisation were evaluated for NEVER- vs EVER-smokers, and by newly vs previously diagnosed pts unadjusted (un-) and adjusted (adj) for age, time from diagnosis to enrolment, sex and log transformed pulmonary vascular resistance (PVR). Results: NEVER (N=1619) vs EVER-smokers (N=1427) differed for: median age at diagnosis, 48.3 vs 52.5 years; obstructive lung disease, 7.8% vs 21.7%; male, 15.2% vs 27.8% (all p Conclusions: In REVEAL, PAH pts who were EVER- vs NEVER-smoker were older at diagnosis. In newly diagnosed PAH pts smoking was associated with worse clinical outcomes irrespective of PVR.

BACKGROUND Selexipag is a selective oral prostacyclin receptor agonist indicated for pulmonary arterial hypertension (PAH) treatment. SelexiPag: tHe usErs dRug rEgistry (SPHERE) (NCT03278002) is collecting data from selexipag-treated patients in real-world clinical practice to elucidate and describe the clinical characteristics, outcomes, and dosing/titration regimens of patients treated with selexipag in routine clinical practice. METHODS SPHERE is a United States (US)-based, ongoing, multicenter, prospective observational study (target N = 800). This study enrolls patients who are either newly initiated on selexipag (≤60 days before enrollment) or were previously receiving selexipag with documentation of dose titration at study enrollment. Data collection for the study occurs at routine clinic visits. In this paper, we report on the first 500 patients enrolled. RESULTS Median follow-up was 17.8 months; 77.6% of patients completed the planned 18 months follow-up, and 22.4% discontinued early from the study. At diagnosis, 94.8% of patients had PAH (World Health Organization [WHO] Group 1), most commonly idiopathic (49.2%) and connective tissue disease associated (26.4%). Most patients (72.4%) initiated selexipag more than 60 days before enrollment. At initiation, 31.0% of patients had WHO functional class (FC) II disease, and 49.6% had WHO FC II or III disease. In addition, 55.0% of patients were receiving double therapy (most commonly an endothelin receptor antagonist plus phosphodiesterase type 5 inhibitor [42.3%]), whereas 30.6% were receiving monotherapy . Despite most patients already receiving PAH-specific therapy, at selexipag initiation, 67.2% (336 of 500) were at intermediate risk, and 9.6% (48 of 500) were at high risk of 1-year mortality. Risk scores remained stable in ∼55% of patients and improved in ∼20% at the end of the study. In total, 72.2% of patients had at least 1 adverse event (AE), and 37.6% reported a serious AE. The median selexipag maintenance dose was 1,200 µg twice daily (interquartile range: 800–1,600 µg twice daily). CONCLUSIONS Real-world, US-based patients with PAH initiating selexipag typically have WHO FC II/III disease and are at intermediate risk, despite receiving PAH-specific treatment. Selexipag was prescribed as part of a combination regimen in most patients. The study identified no unexpected adverse effects.

We use a panel of over 600,000 Chinese firms (1998–2009) to investigate the effects of credit constraints on firm productivity. We find that both internal finance through a firms own cash flow and external credit supply significantly promote firm productivity and productivity growth rates. Specially, there is a substitution effect between internal finance and external credit supply: the marginal effect of internal finance on firm productivity is weaker when firms have sufficient external credit. Also, internal finance is more important for firms in those financially vulnerable industries. Finally, we observe that marginal effect of both external credit supply and internal finance on firm's productivity is weaker for SOEs than non-SOEs.

Supplemental low-flow oxygen is recommended by treatment guidelines as supportive therapy for patients with pulmonary arterial hypertension (PAH), based largely on expert opinion. Reduced diffusing capacity of lung carbon monoxide (DLCO) is associated with increased mortality in PAH. Reduced DLCO is also associated with relative hypoxemia, making the effects of supplemental oxygen use of particular interest in this sub-population.Patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a 5-year observational study of Group 1 PAH, were categorized by presence or absence of supplemental oxygen use and by degree of DLCO reduction. Kaplan-Meier survival estimates were calculated by group.Of 3,046 patients, 57% used supplemental oxygen and 43% did not. Supplemental oxygen users had worse prognostic factors and more PAH-specific medication use. Of the 424 patients with severe DLCO reduction (40% of predicted), 76% used oxygen and 24% did not. Patients with severe DLCO reduction who used supplemental oxygen had a significantly lower risk of all-cause mortality than those who did not (hazard ratio 0.56; 95% confidence interval 0.39 to 0.83; p = 0.0033). This was true for newly diagnosed and previously diagnosed patients. There was no relationship between oxygen use and outcomes in patients with no, mild, or moderate DLCO reduction.In this observational study, the risk of death was significantly lower for patients with severe DLCO reduction who received supplemental oxygen compared with those who did not. A randomized trial is warranted to further investigate the relationship between supplemental oxygen use and outcomes in PAH.

Background Plasma brain natriuretic peptide (BNP) level is a prognostic biomarker in pulmonary arterial hypertension (PAH). Its impact on long-term overall survival (OS) was investigated in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL), a 5-year observational, multicenter, US registry of patients with PAH. Methods Patients were ≥ 18 years of age, met right heart catheterization criteria at rest, had World Health Organization group I PAH, and had BNP measurement at enrollment. Optimal BNP threshold was obtained via receiver operating characteristic curve analysis. OS was compared in patients with low (≤ 340 pg/mL) vs high (> 340 pg/mL) BNP at baseline; changes between baseline and last assessment were also examined. Patients were categorized based on baseline (low or high) and follow-up (low or high) BNP values; hazard ratios (HRs) for OS were estimated and compared using Cox regression. Results Overall, 1,426 patients were analyzed. Mortality risk was significantly higher in patients with baseline high vs low BNP (HR, 3.6; 95% CI, 3.0-4.2). BNP change analysis at ≤ 1 year postenrollment demonstrated that the low-low group had the lowest and the high-high group had the highest 5-year mortality risk (HR, 0.23; 95% CI, 0.19-0.27). Changes in BNP score also correlated with change of risk of death. Conclusions Baseline BNP threshold of 340 pg/mL strongly predicted survival up to 5 years in patients with PAH. A BNP reduction at 1 year since enrollment was associated with decreased mortality risk, whereas an increase in BNP at 1 year was associated with an increased mortality risk, supporting BNP as a surrogate marker of PAH survival.

This paper presents theory and evidence on firms’ import responses to current and future exchange rates along both intensive and extensive margins. The paper first builds a dynamic heterogeneous-firm model to study how firms adjust their import decision by taking into account both current and future exchange rates. In the model, individual firms pay a fixed sunk cost and face a probability of failure when searching for foreign intermediate suppliers. The impact of future exchange rate on import is different from that of current exchange rate: spot exchange rate appreciation would increase both the intensive margin (import value of individual firm) and the extensive margin (the number of importing firms), while future exchange rate appreciation increases the extensive margin rather than the intensive margin of imports. The model predictions are strongly supported by an empirical analysis using disaggregated data on China’s imports from the United States and forward rates between US Dollar (USD) and Chinese Yuan (CNY) on the non-deliverable exchange market.

Purpose To assess the efficacy and safety of macitentan in pts with PH post-LVAD. Methods SOPRANO (NCT02554903) was a double-blind, randomized, study of macitentan 10 mg once-daily vs placebo. Pts were ≥18 years with LVAD implanted within 90 days prior to randomization, had mean pulmonary arterial pressure (mPAP) ≥25 mmHg, pulmonary artery wedge pressure (PAWP) ≤18 mmHg and pulmonary vascular resistance (PVR) >3 Wood units (WU). The primary endpoint was change in PVR at week 12 of therapy from baseline. Results Fifty-seven pts were randomized: macitentan (n=28) or placebo (n=29). Baseline pt demographics and characteristics were well balanced. Baseline PVR (mean [SD]) was 4.3 [0.9] WU (macitentan) and 4.3 [1.3] WU (placebo). At week 12, mean PVR decreased to 58.5% (macitentan) and to 75.5% (placebo) of baseline. Mean placebo-corrected reduction in PVR of macitentan was 26.1% (95% CI: 58.0, 94.3; p=0.0158). Predefined secondary endpoints, notably including changes in PAWP, were not significantly different with macitentan vs placebo (Table). Another relevant hemodynamic parameter, transpulmonary gradient, significantly decreased with macitentan vs placebo (p=0.0499). The incidence of treatment adverse events (TAEs) was 21.4% (macitentan) and 24.1% (placebo); no TAEs occurred in >1 patient in the macitentan arm. AEs of interest included edema, anemia and hypotension: reported in 7 (25.0%), 3 (10.7%), and 4 (14.3%) pts on macitentan (mostly mild-moderate) and in 5 (17.2%), 2 (6.9%) and 1 (3.6%) pts on placebo, respectively. Two pts on macitentan and 1 pt on placebo discontinued for treatment-related AEs. Conclusion In the first prospective, multicenter, randomized controlled trial of pulmonary vasodilators in the early post-LVAD population, macitentan significantly reduced PVR and was well tolerated. The impact of macitentan on post-LVAD exercise capacity and RV failure warrants further study.

Purpose: Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Methods: The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician’s choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted. Results: In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P, SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction SPHERE is an ongoing US-based, multicentre, prospective, registry collecting data on use of the oral selective IP prostacyclin receptor agonist selexipag in real-world settings. Here, we report selexipag dosing and titration in the first 500 patients. Methods SPHERE, initiated in November 2016, will enrol 800 patients newly initiated on or already treated with selexipag at enrolment who have a documented titration regimen. Patients are followed for up to 18 months. Patients were considered “newly initiated” on selexipag if they were enrolled in SPHERE ≤60 days after starting selexipag and were considered “previously initiated” if they enrolled >60 days after starting selexipag. The highest dose is the maximum dose reached during up-titration within 6 months since initiation. Selexipag “maintenance dose” is defined as the first dose received for ≥14 days without interruption or change; “titration speed” is defined as the highest dose reached within the first 6 months after initiation divided by the time (in weeks) to reach it. Results The data cut-off for this analysis was December 20, 2018. Most patients had Group 1 pulmonary hypertension (PH) (95.4%), which was primarily idiopathic (49.6%) or connective tissue disease associated (26.0%). At selexipag initiation 49.8% of patients had functional class III symptoms. At the time of selexipag initiation, 19.2% of patients were on PH therapy containing a prostacyclin pathway agent (PPA) (8.5% with a parenteral PPA). The median maintenance dose of selexipag was 1200 μg BID (IQR: 800–1600 μg BID) and the median time to reach it was 8.1 wks (IQR: 5.3–11.0 wks). Low (≤400 μg BID), medium (600–1000 μg BID), and high (≥1200 μg BID) maintenance doses were attained by 15.1%, 30.8%, and 49.5% of patients, respectively (and in 23.2%, 31.2%, and 36.2%, respectively, in GRIPHON). The median titration speed was 175 μg BID/wk (IQR: 110.5–195.3 μg BID/wk), slower than the protocol-outlined 200 μg BID/wk in GRIPHON. In SPHERE, most patients titrated at speeds Conclusion The median maintenance selexipag dose in SPHERE was 1200 μg BID. While the median titration speed was 175 μg BID/wk, there was marked variation and the vast majority of patients titrated slower than 200 μg BID/wk. No new safety signals were observed. Acknowledgement/Funding Actelion Pharmaceuticals US, Inc.

BACKGROUND Prior research has suggested that the prevalence and outcomes of pulmonary arterial hypertension (PAH) may vary by race or ethnicity. However, these studies have been limited by small sample size or methodological techniques relying on epidemiologic data. The purpose of this study is to evaluate the relationship between race/ethnicity and survival in a large U.S.-based prospective multicenter registry. METHODS Patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a 5-year observational study of Group 1 PAH, were categorized by race/ethnicity. Baseline hemodynamic characteristics, clinical characteristics, and medication use was described. The relationship between race/ethnicity and outcome was evaluated by Kaplan–Meier and Cox proportional hazards modeling techniques. Left-truncation analysis, which adjusted for time from diagnosis to study enrollment, was used to minimize the effect of survivor bias. RESULTS This analysis included 3,046 patients; 2,202 identified as white, 393 as black, 263 as Hispanic, 100 as Asian or Pacific Islander, and 88 as other. Unadjusted Kaplan–Meier survival analysis indicated that white patients had the lowest survival rates. After adjusting for variables of prognostic impact, race/ethnicity was no longer significantly associated with survival. Other results showed that black patients were more likely to have connective tissue disease–associated PAH, Hispanic patients were more likely to have portopulmonary hypertension, and Asian patients were more likely to have congenital heart disease–associated PAH. CONCLUSIONS Analysis of the REVEAL registry did not find race/ethnicity to be a significant predictor of mortality. This is the largest analysis to date evaluating the role of race/ethnicity on outcomes in PAH.

This paper shows that the pricing behavior of exporting firms exhibits a “forward-looking” nature with sticky prices. As a result, the expectations of future exchange rates affect current prices at both the product level and firm level. We find evidence by employing both highly disaggregated Harmonized System (HS) 10-digit product-level import data of the USA and firm–product level customs data on China's exports to the USA. These findings provide evidence for a previously unexplored micro-level forward-looking nature of trade price adjustment as response to future exchange rates, and suggest a potentially important factor in helping explain incomplete exchange rate pass-through.

Background: The need remains for novel agents that prolong survival and/or improve QOL in women with aBC. EP is a long-acting topoisomerase 1 inhibitor engineered to produce sustained exposure to irinotecan and its active metabolite SN38. Given previous efficacy seen in an earlier phase II trial in MBC, EP 145 mg/m2 every 3 weeks was compared to TPC (one of 7 single-agent regimens) in the randomized phase 3 BEACON study (NCT01492101). As reported at ASCO 2015 (abstract 1001), EP prolonged median overall survival by 2.1 months, although this did not reach statistical significance (12.4 vs 10.3 months; HR 0.87, p=0.08). Grade ≥ 3 adverse events were significantly less common with EP (48% vs 63% with TPC, p Methods: Patients completed validated health-related QoL (HRQoL) questionnaires, EORTC QLQ-C30 (version 3.0) and breast cancer-specific QLQ-BR23, pretreatment and every 8 weeks until progression, death or withdrawal of consent. Questionnaires were scored according to the EORTC manual. For each scale, raw scores were standardized via a linear transformation to a range from 0 to 100. Absolute scores and changes from baseline were analyzed longitudinally and categorically using a 5-point difference calculated by treatment group. Comparisons between treatment groups were conducted to evaluate the differences in global health status, functional scores and symptoms over time. Results: The majority of patients who were randomized (total: 733/852 [86%], EP: 378/429 [88%], TPC: 355/423 [84%]) completed at least one post-baseline HRQoL questionnaire. In the EORTC QLQ-C30, grade ≥ 3 AEs significantly impacted HRQoL measured by global health status and 5 additional functional domains. Of the six domains, compared to TPC in a longitudinal analysis, EP was statistically superior in the mean treatment effect through Week 32 in global health status p=0.02 and physical functioning scale p=0.01. EP was also numerically superior in all other scales. In EORTC QLQ-C30 and BR-23, a total of 13 symptoms were measured and categorically analyzed. There were no treatment differences in 7 of 13 symptom scales. EP was associated with worsening of 3 symptom scales: appetite loss, nausea/vomiting, and diarrhea. TPC was associated with worsening of 2 symptom scales: dyspnea and systemic side effects. Conclusions: In the phase 3 BEACON trial comparing EP to TPC, the more favorable toxicity profile of EP resulted in an improvement in global health status and physical function (results of the symptom scales confirmed the different toxicities of the two arms). EP remains a promising investigational therapy for aBC. Citation Format: Cortes J, Awada A, Perez EA, Rugo HS, Twelves C, Im S-A, Zhao C, Hoch U, Ney J, Hannah AL, O'Shaughnessy J. Impact of treatment on quality of life (QOL) in the BEACON study, a randomized phase III trial of etirinotecan pegol (EP) versus treatment of physician's choice (TPC) in patients (pts) with advanced breast cancer (aBC) whose disease has progressed following anthracycline (A), taxane (T) and capecitabine (C). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-08.

Background:Although patients with CTD-PAH comprise approximately one third of the overall PAH population, the literature on survival outcomes in CTD-PAH patients overall and by CTD subtype is limited by small sample sizes. We conducted a meta-analysis of more than 4,000 patients with CTD-PAH enrolled in observational registries.Objectives:To determine survival rates in patients with CTD-PAH overall and by CTD subtypes.Methods:The PubMed and EMBASE databases were searched for English-only articles published between January 1, 2000 and November 25, 2019. Inclusion criteria were multicenter registries of adults with WHO group 1 pulmonary hypertension (PAH); conducted in 2000 or later; and survival data for ≥30 patients with CTD-PAH. Meta-analysis of survival was performed using a random-effects model. Survival was estimated for CTD-PAH overall; for CTD-PAH stratified by registries primarily conducted before and after 2010 to assess the impact of new therapies, as well as combination therapy approaches targeting multiple pathways; and for CTD subtypes (systemic sclerosis [SSc] and systemic lupus erythematosus [SLE]).Results:Nineteen registries met inclusion criteria and reported data on 4,008 patients with CTD-PAH. Of these patients, 1,485 had SSc, 456 had SLE, and CTD subtype was not specified in 2,067. CTD-PAH patients had a mean age of 55 years and 87% were female. Most patients (70%) had functional class III or IV disease and the mean 6-minute walk distance at enrollment was 327 m. Among registries that enrolled patients of all PAH etiologies (N=7,829), survival rates in the CTD-PAH subpopulation (n=2113), were 83%, 73%, and 62% at 1-, 2-, and 3- years, respectively. These survival rates were lower than those reported for the overall PAH population: 88%, 79%, and 72% at 1-, 2-, and 3- years, respectively. Numerically higher survival rates at 1-, 2-, and 3- years were observed in CTD-PAH patients treated in 2010 and later: 85% vs 90%, 74% vs 82%, and 65% vs 73%. Among all CTD-PAH patients, survival rates were lower for patients with SSc compared to those with SLE: 88% vs 92%, 75% vs 90%, 67% vs 87% at 1-, 2-, and 3- years, respectively (Figure).Conclusion:Patients with CTD-PAH have a substantial risk of death, however, CTD-PAH patients treated within the last ten years have numerically higher survival rates than those treated earlier. This may be related to increased screening for PAH, especially in SSc (leading to earlier diagnosis) and/or the availability of new treatment approaches. Consistent with clinical observations, patients with SSc have worse survival rates than those with SLE. Given the high risk of mortality in these patients, early detection and upfront aggressive treatment are warranted.References:Acknowledgments:This analysis was funded by Actelion Pharmaceuticals.Disclosure of Interests:Dinesh Khanna Shareholder of: Eicos, Grant/research support from: NIH NIAID, NIH NIAMS, Consultant of: Acceleron, Actelion, Bayer, BMS, Boehringer-Ingelheim, Corbus, Galapagos, Genentech/Roche, GSK, Mitsubishi Tanabi, Sanofi-Aventis/Genzyme, UCB Pharma, Carol Zhao Shareholder of: Actelion Pharmaceuticals US, Inc., Employee of: Actelion Pharmaceuticals US, Inc., Lorinda Chung Grant/research support from: United Therapeutics, Boehringer Ingelheim, Consultant of: Bristol-Myers Squibb, Boehringer Ingelheim, Mitsubishi Tanabe, Eicos Sciences, Gerry Coghlan Grant/research support from: Johnson & Johnson, Consultant of: Bayer, Johnson & Johnson, GlaxoSmithKline, Speakers bureau: Bayer, Johnson & Johnson, GlaxoSmithKline, Rajan Saggar Grant/research support from: Actelion, Gilead Science, United Therapeutics, Consultant of: Actelion, Gilead Science, United Therapeutics, Speakers bureau: Actelion, Gilead Science, United Therapeutics, Stephen Mathai Consultant of: Actelion, Liquidia, Arena, United Therapeutics, Mehul Shah Shareholder of: Actelion Pharmaceuticals US, Inc, Employee of: Actelion Pharmaceuticals US, Inc, John Hartney Shareholder of: Actelion Pharmaceuticals US, Inc, Employee of: Actelion Pharmaceuticals US, Inc, Vallerie McLaughlin Grant/research support from: Reata Pharmaceutics, SoniVie, United Therapeutics, Bayer, Acceleron, Actelion Pharmaceuticals US, Inc., Consultant of: Actelion Pharmaceuticals US, Inc., Acceleron, Arena Pharmaceuticals, Bayer, Caremark, CiVi Biopharma, United Therapeutics

BackgroundCurrent risk stratification tools in pulmonary arterial hypertension (PAH) are limited in their discriminatory abilities, partly due to the assumption that prognostic clinical variables have an independent and linear relationship to clinical outcomes. We sought to demonstrate the utility of Bayesian network-based machine learning in enhancing the predictive ability of an existing state-of-the-art risk stratification tool, REVEAL 2.0.MethodsWe derived a tree-augmented naïve Bayes model (titled PHORA) to predict 1-year survival in PAH patients included in the REVEAL registry, using the same variables and cut-points found in REVEAL 2.0. PHORA models were validated internally (within the REVEAL registry) and externally (in the COMPERA and PHSANZ registries). Patients were classified as low-, intermediate- and high-risk (10% 12-month mortality, respectively) based on the 2015 European Society of Cardiology/European Respiratory Society guidelines.ResultsPHORA had an area under the curve (AUC) of 0.80 for predicting 1-year survival, which was an improvement over REVEAL 2.0 (AUC 0.76). When validated in the COMPERA and PHSANZ registries, PHORA demonstrated an AUC of 0.74 and 0.80, respectively. 1-year survival rates predicted by PHORA were greater for patients with lower risk scores and poorer for those with higher risk scores (pConclusionOur Bayesian network-derived risk prediction model, PHORA, demonstrated an improvement in discrimination over existing models. This is reflective of the ability of Bayesian network-based models to account for the interrelationships between clinical variables on outcome, and tolerance to missing data elements when calculating predictions.

Introduction: Selexipag is an oral selective prostacyclin receptor (IP) agonist shown to delay disease progression and reduce the risk of hospitalization in patients with PAH. SPHERE is a currently enrolling US-based, multicenter, prospective, observational registry designed to obtain data on real-world use of selexipag. We describe background PAH-targeted therapies used in SPHERE. Methods: Eligible individuals are patients newly initiated on selexipag or patients already treated with selexipag at enrollment who have a documented selexipag titration regimen. Background therapy and clinical characteristics at selexipag initiation and at SPHERE enrollment are collected. Results: This analysis (data cut-off October 2, 2017) reports data from the first 250 patients. The median time from selexipag initiation to enrollment was 7.1 months (IQR: 1.9–11.5). Per ESC/ERS 2015, at selexipag initiation, 65% of patients were classified as intermediate risk, 7% high risk, and 16% low risk. Of 234 patients with available data at selexipag initiation, 72 (31%) were on monotherapy (including 7, or 3%, on a prostanoid), 127 (54%) were on dual therapy (including 19, or 8%, with a prostanoid), and 30 (13%) were on a triple regimen containing a prostanoid (Figure). Conclusion: In this real-world registry, the majority of patients were on dual (54%) or triple (13%) therapy at selexipag initiation.

Purpose We propose an alternative approach to the extensively validated REVEAL risk score calculator using Bayesian network (BN) modeling. We derived a BN model with the same variables and discretization cut points as the REVEAL risk score calculator and data from the REVEAL registry. This study compared the performance and relative impact of the variables in the two PAH risk assessment tools. Methods 2,456 adult patients from the REVEAL registry were used to develop a Bayesian network model to predict 1-year survival using the Tree Augmented Naive Bayes (TAN) algorithm. We used 10-fold cross validation to measure the BN performance, reported as the area under the Receiver Operating Characteristic curve (AUC). We compared hazard ratios of the variables in the REVEAL calculator to cross entropy between risk factors and the outcome variable in the BN model. Cross-entropy measures the expected change in entropy of the probability distribution of the outcome variable as the risk becomes known and is generally a measure of expected information gain from knowing a risk. Cross-entropy is a dynamic measure and changes as other variables are observed. Results The BN model demonstrated an AUC of 0.77 for predicting one-year survival. This was an improvement to the existing AUC of 0.71 for the original REVEAL calculator. There is a high correlation (r = 0.786) for the hazard ratio and the cross entropy, when all risk factors are absent (Figure 1a). In the same context of variables, the cross-entropy and the hazard ratio capture the similar influences to the outcome. However, when the risk factors are partially known for a given patient (Figure 1b), the cross-entropy changes based on the context of which risk factor are observed. Conclusion BN demonstrated a modest improvement in performance over the REVEAL 1.0 model. Moreover, it improved the understandability of the relationship between risk factors, the dynamic influences of each risk factor, and relaxes the assumption of independence between risk factors.

Background Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician's choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL. Patients and methods HRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol (n = 378; 145 mg/m2 every 3 weeks (q3wk)) or single-agent TPC (n = 355). Patients completed assessments at screening, every 8 weeks (q8wk) during treatment, and end-of-treatment. Changes from baseline were analysed, and the proportions of patients achieving differences (≥5 points) in HRQoL scores were compared. Results Differences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales (P, SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND Renal dysfunction is associated with abnormal cardiopulmonary hemodynamics, in-hospital death and poor survival in patients with pulmonary arterial hypertension (PAH), and thus it may be a prognostic biomarker. In our analysis we assess the relationship between change in estimated glomerular filtration rate (eGFR) and outcomes in PAH patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL). METHODS Overall 2,368 patients were classified into chronic kidney disease (CKD) stages based on baseline eGFR: normal or Stages 1 or 2 (n = 1,699); Stage 3a (n = 399); Stage 3b (n = 196); and Stages 4 or 5 (n = 74). We evaluated the relationship between baseline CKD stage and survival, as well as the composite end-point of survival and freedom from all-cause hospitalization. The relationships between change in eGFR at ≥1 year and these clinical end-points were also evaluated. RESULTS Patients with a ≥10% decline in eGFR from baseline over ≥1 year had a significantly increased risk of death (hazard ratio 1.66; p < 0.0001) and the composite of all-cause hospitalization and death (hazard ratio 1.33; p = 0.002). This decline predicted survival independently of changes in 6-minute walk distance and functional class. However, a ≥10% increase in eGFR was not significantly associated with either end-point. CONCLUSION In REVEAL, a ≥10% decline in eGFR over ≥1 year independently predicted poorer survival. Thus, eGFR may be a simple and economical biomarker in PAH.

Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels.The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician's choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted.In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P 0.01) versus TPC; median OS was 10.0 and 4.8 months, respectively. Improvement in OS was observed in both poorer and better GPA prognostic groups. Survival rates at 12 months were 44.4% for EP versus 19.4% for TPC. Consistent with the overall BEACON population, fewer patients on EP experienced grade ≥3 toxicity (50 vs. 70%).The significant improvement in survival in BCBM patients provides encouraging data for EP in this difficult-to-treat subgroup of patients. A phase three trial of EP in BCBM patients is underway (ClinicalTrials.gov NCT02915744).

Purpose: New treatments with novel mechanisms of action and non-overlapping toxicities are needed for patients with metastatic breast cancer. Etirinotecan pegol (EP) is a long-acting topoisomerase-I inhibitor with a unique toxicity profile. The randomized phase 3 BEACON study that compared EP to treatment of physician’s choice (TPC) demonstrated its clinical activity. We now present detailed safety data from the BEACON trial. Methods: Patients with locally recurrent or metastatic breast cancer who had received at least two prior cytotoxic regimens for advanced disease were randomized to EP or TPC. Prior treatment with an anthracycline, a taxane and capecitabine was required. The frequencies of treatment-emergent AEs (TEAEs) and serious TEAEs were evaluated for the safety population, comprising all patients who received at least one dose of assigned treatment. Results: A total of 831 patients were evaluated (n = 425, EP; n = 406, TPC). Compared with TPC, EP was associated with a slightly higher median relative dose intensity (98.3 vs. 92.8 %, respectively) and significantly fewer grade ≥3 toxicities (48.0 vs. 63.1 %, P, SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose Prior research suggests that PAH prevalence and subtype may vary by race/ethnicity. Although some data suggest that disease severity and clinical outcomes also differ by race/ethnicity, these data are limited and based on single-center analyses. The relationship between race/ethnicity and survival was evaluated in a US prospective multicenter registry of WHO group 1 PAH, the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL). Methods Included patients were ≥18 years of age with pulmonary capillary wedge pressure ≤15 mmHg. Cox proportional hazard models were used to assess the association between race/ethnicity and survival, unadjusted or adjusted for prognostic factors of age, diagnostic status (i.e. newly or previously diagnosed), PAH etiology, and sex. The relationship between race/ethnicity and survival was also analyzed using a left-truncation which adjusts for time from diagnosis to study enrollment with covariates of age and PAH etiology. Results This analysis included 3,046 patients: 2,202 identified as white, 393 as black, 263 as Hispanic, 100 as Asian or Pacific Islander, and 88 as other. A Kaplan-Meier estimate of survival by race/ethnicity indicated that white patients had the lowest survival rate. Results of an unadjusted Cox model were consistent with this, in that Asian or Pacific Islander (HR=0.46, 95% CI 0.28-0.76, p=0.002) or Hispanic (HR=0.74, 95% CI 0.56-0.97, p=0.029) patients had a lower risk of death than white patients; black patients had a similar risk as white patients. An evaluation of potentially prognostic factors by race/ethnicity revealed that white patients were older than patients of other races/ethnicities. When the Cox model was adjusted for age and other variables of potential prognostic impact that varied by race/ethnicity in this population, race/ethnicity was no longer significantly associated with survival (Asian or Pacific Islander vs. white HR=0.69, 95% CI 0.46-1.05, p=0.09; Hispanic vs. white HR=1.05, 95% CI 0.82-1.33, p=0.71; black vs white; HR=1.04, 95% CI 0.86-1.23; p=0.72). Survival analysis using left-truncation also showed no effect of race/ethnicity on survival. Conclusion Contrary to earlier analyses and other diseases in which race/ethnicity substantially impacts outcome, these data suggest that race/ethnicity is not a predictor of survival in patients with PAH.

Purpose Etirinotecan pegol (NKTR-102) is a unique, long-acting topoisomerase-I inhibitor with prolonged systemic exposure to SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan. This randomized phase II trial investigated two dosing schedules of etirinotecan pegol in patients with platinum-resistant/refractory ovarian carcinoma. Patients and Methods A total of 71 eligible patients were randomly assigned to receive etirinotecan pegol 145 mg/m2 every 14 or 21 days until progression or unacceptable adverse events (AEs). The primary end point was objective response rate (ORR) by RECIST (version 1.0). Secondary end points included response by Gynecologic Cancer Intergroup criteria, duration of ORR, progression-free survival (PFS), and overall survival (OS). Results The overall confirmed ORR was 20% (95% CI, 10% to 30%): 20% for once every 14 days, and 19% for once every 21 days. Median response duration was 4.1 months for once every 14 days and 4.0 months for once every 21 days. Median PFS for every 14 and every 21 days was 4.1 and 5.3 months, respectively, and median OS was 10.0 and 11.7 months, respectively. Etirinotecan pegol was well tolerated, with the most common grade 3 to 4 AEs being dehydration (24%) and diarrhea (23%). Diarrhea, dehydration, nausea, and neutropenia were less frequent with the schedule of once every 21 days than with that of once every 14 days. Conclusion Both schedules of etirinotecan pegol showed activity in patients with heavily pretreated ovarian cancer, with encouraging ORR and PFS rates. The schedule of once every 21 days was better tolerated and had slightly longer PFS and OS rates. The treatment schedule of etirinotecan pegol 145 mg/m2 once every 21 days was selected for the expanded phase II study and is preferred for future phase III studies. These findings provide support to directly compare etirinotecan pegol versus one of the approved drugs (eg, pegylated liposomal doxorubicin or topotecan) in platinum-resistant ovarian cancer.

New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer.In this open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), conducted at 135 sites in 11 countries, patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine (and two to five previous regimens for advanced disease) were randomly assigned (1:1) centrally via an interactive response system to etirinotecan pegol (145 mg/m(2) as a 90-min intravenous infusion every 3 weeks) or single-drug treatment of physician's choice. Patients with stable brain metastases and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Randomisation was stratified with a permuted block scheme by region, previous eribulin, and receptor status. After randomisation, patients and investigators were aware of treatment assignments. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01492101.Between Dec 19, 2011, and Aug 20, 2013, 852 patients were randomly assigned; 429 to etirinotecan pegol and 423 to treatment of physician's choice. There was no significant difference in overall survival between groups (median 12·4 months [95% CI 11·0-13·6] for the etirinotecan pegol group vs 10·3 months [9·0-11·3] for the treatment of physician's choice group; hazard ratio 0·87 [95% CI 0·75-1·02]; p=0·084). The safety population includes the 831 patients who received at least one dose of assigned treatment (425 assigned to etirinotecan pegol and 406 to treatment of physician's choice). Serious adverse events were recorded for 128 (30%) patients treated with etirinotecan pegol and 129 (32%) treated with treatment of physician's choice. Fewer patients in the etirinotecan pegol group had grade 3 or worse toxicity than those in the treatment of physician's choice group (204 [48%] vs 256 [63%]; p0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [10%] in the experimental group vs five [1%] in the control group), neutropenia (41 [10%] vs 125 [31%]), and peripheral neuropathy (two [1%] vs 15 [4%]). Three patients in the etirinotecan pegol group died of treatment-related adverse events (pneumonia, myelodysplastic syndrome, and acute renal failure) and two in the treatment of physician's choice group (neutropenic sepsis and septic shock).This trial did not demonstrate an improvement in overall survival for etirinotecan pegol compared to treatment of physician's choice in patients with heavily pre-treated advanced breast cancer. The toxicity profile noted in the etirinotecan pegol group differed from that in the control group. In view of the frequency of cross-resistance and overlapping toxicities noted with many available drugs and the need for effective drugs in highly refractory disease, etirinotecan pegol may warrant further research in some subgroups of patients.Nektar Therapeutics.

This paper explores how the distribution of credit supply within an industry affects that industry's export intensity (the export-to-sales ratio) and export propensity (the ratio of the number of exporters to the total number of firms). Using a heterogeneous firm trade model, we derive two opposing hypotheses: for industries with relatively low (high) foreign market penetration costs, a more dispersed credit distribution decreases (increases) the industry's export intensity and the number of exporters. The empirical results using Chinese firm-level data and bank loan data support both hypotheses and confirm the significant heterogeneous impacts of credit distribution on exports across industries.

This paper shows that the pricing behavior of exporting firms exhibits a “forward-looking” nature under sticky prices. It offers a channel by which the expectations of future exchange rates affect current prices. To seek the micro-level evidence, we adopt detailed product-level import data of the United States and firm-product-level export data of China combined with forward premiums to study the exchange rate pass-through. We find that not only current (and past) exchange rate fluctuations but also anticipated future exchange rate changes effectively pass through into current prices, suggesting a potentially important factor in help explaining incomplete exchange rate pass-through.

This paper shows that the pricing behavior of exporters exhibits a \forward-looking" nature due to the existence of sticky prices. It oers

This paper presents theory and empirical evidence on that a forward-looking potential importer facing sunk costs will respond to expectation of future exchange rate fluctuations. This finding indicates the importance of sunk costs in firms' decisions to import goods. Building upon a heterogeneous-firm framework, the model makes a variety of predictions about the effect of anticipated fluctuations in the domestic currency exchange rate. First, changes in the expectation of future exchange rates lead to the entry/exit of marginally productive firms, reshaping the extensive margin of imports, and inducing significant changes in aggregate import values. Second, the firm level marginal benefit/loss of importing diminishes as expected appreciation/depreciation persists, due to the impact of continued entry/exit on markups. This changing marginal benefit/loss consequently weakens the adjustment of the extensive margin in the long run. Third, firms present heterogeneous responses to forward exchange rate fluctuations in the presence of sunk costs; these responses are related to their access to credit and other firm-level characteristics. Using disaggregated transaction level data of Chinese imports from the United States combined with data on the US dollar-RMB future rates on the non-deliverable forward market, this paper confirms that the extensive margin of import significantly responds to forward exchange rate premiums. This paper also finds evidence on firms' heterogeneous responses to anticipated exchange rate changes that support the model predictions by merging import data with firm-level balance sheet data.

Summary Background New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. Methods In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m 2 every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00802945. Findings 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4–40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6–46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6–46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none). Interpretation On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m 2 every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer. Funding Nektar Therapeutics.

1001 Background: EP is the first long-acting topoisomerase 1 inhibitor providing sustained levels of SN38. In Phase II, EP demonstrated a 29% ORR following a median of 2 prior regimens for aBC. BEA...