End Point Of Clinical Benefit Research Articles

Advancing the drug development process in metastatic prostate cancer through machine learning.

192 Background: Despite advances in the development of systemic therapeutics, metastatic prostate cancer (mPC) remains a lethal disease. The drug approval process is slow, and delays in approving active agents translate into lives lost, and increased morbidity for men living with mPC. Clinical benefit end points proximate to survival that could support regulatory approval have been sought. Methods that accelerate the prediction of overall survival (OS) from baseline and short-term clinical data could dramatically accelerate the "readout" timeline for registrational studies. Methods: Curated, anonymized data from 5,679 mPC patients (pts) across six completed clinical trials were used: COU-AA-301, COU-AA302, ACIS, GALAHAD, LATITUDE, and TITAN. These trials comprise heterogeneous pts across castrate sensitive (TITAN, LATITUDE) and castrate resistant (COU-AA-301, COU-AA-302, ACIS, GALAHAD) populations. Transcriptomic profiles of primary tumors were available from a subset of these pts (N = 605) in COU-AA-302, ACIS, TITAN using the DECIPHER platform (Decipher Biosciences, Inc.). We harmonized pts study data and are developing machine learning models in an attempt to predict long term outcomes using baseline clinical features, short term PSA kinetics, and transcriptional profiling data. Associations between clinical and transcriptional signature profiles and overall survival were assessed with the Cox proportional hazards model. Results: Pts were assigned to training (N = 3167) and test (N = 2,512) cohorts. Cohorts were balanced by age, self-reported race, ECOG performance status, extent of disease, and disease site, and had statistically indistinguishable survival curves. At month 3 on study, 97% of pts had PSA data available; 88% had ≥ 2 PSA values. Matched genomic data was evaluated in 504 and 101 pts in training and test sets respectively. Training cohort pts with a 50% reduction in PSA by month 3 (m3-PSA50) had significantly longer OS (HR 0.51 [0.38-0.67]; p = 1.2 x 106, median 26 vs. 38 months). ANOVA analysis identified expression signatures in the Decipher GRID that significantly improved OS model performance when added to a model including only m3-PSA50. We stratified pts by a combined m3-PSA50 and signature score and identified signatures that improved model fit over m3-PSA50 alone and significantly stratified pts in the test cohort (P < 0.05). Conclusions: In this early analysis (prior to applying machine learning), m3-PSA50 was significantly associated with OS in a heterogeneous group of mPC pts. Although the transcriptomic analysis was conducted on primary tumors obtained many years earlier, we identified transcriptional signatures that significantly improved OS models (independent of m3-PSA50) in men who subsequently developed mPC many years later. These results suggest adding genomic signature data to models for predicting outcome using PSA kinetics may provide improved predictive power.

Early 6 months usage of single anTiplAtelet OR anTicoAgulant followed by single antiplatelet after transcatheter aortic valve replacement: protocol for a multicentre, open-label, randomised controlled clinical trial

IntroductionThe strategy for initiating antithrombotic therapy to prevent bioprosthetic valve thrombosis (BPVT) after transcatheter aortic valve replacement (TAVR) remains uncertain. There is still lacking evidence on the efficacy and safety...

Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis.

Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study. We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n= 2,740) and validation (n= 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis. LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026-1.054) and 1.042 (1.029-1.056), respectively (p <0.0001 for both). Adjusted C-statistics (95% CI) at baseline were 0.83 (0.79-0.87) and 0.92 (0.89-0.95), respectively. Between 5 and 30kPa, the log-HR increased as a monotonic function of LSM. The predictive value of LSM was stable in time. LSM improved the prognostic ability of biochemical response criteria, fibrosis scores, and prognostic scores. The 8kPa and 15kPa cut-offs optimally separated low-, medium-, and high-risk groups. Forty percent of patients were at medium to high risk according to LSM. LSM by VCTE is a major, independent, validated predictor of PBC outcome. Its value as a surrogate endpoint for clinical benefit in PBC should be considered. Primary biliary cholangitis (PBC) is a chronic autoimmune disease, wherein the body's immune system mistakenly attacks the bile ducts. PBC progresses gradually, so surrogate markers (markers that predict clinically relevant outcomes like the need for a transplant or death long before the event occurs) are often needed to expedite the drug development and approval process. Herein, we show that liver stiffness measurement is a strong predictor of clinical outcomes and could be a useful surrogate endpoint in PBC trials.

Optimal Choice of Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer: Clinical Insights.

The neoadjuvant setting provides immense opportunities for translational research and drug development. The acceptance of pathological complete response (pCR) as a surrogate endpoint for clinical benefit has led to the widespread use of neoadjuvant treatment. Optimal neoadjuvant therapies are determined based on their ability to achieve the highest rates of pCR. Predicted rates of pCR for triple negative breast cancer (TNBC) treated with sequential taxane/anthracycline regimens range from 35% to 48%. With the addition of a platinum agent pCR rates of 55% are predicted. Further increases have been observed with the addition of immune checkpoint inhibitors to this standard chemotherapy backbone. In the pivotal KEYNOTE-522 clinical trial pCR rates of 65% and 69% were reported for chemotherapy plus pembrolizumab in the overall and PD-L1-positive subgroup respectively. The role of the neoadjuvant chemotherapy is less clear in hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer. In general, HR–positive cancers have the least chance of achieving a pCR after neoadjuvant chemotherapy, especially if they are low-grade. If neoadjuvant chemotherapy is given for high-risk HR-positive, HER2-negative breast cancer, standard adjuvant anthracycline/taxane regimens are appropriate. Optimum endocrine therapy is the standard-of-care in the adjuvant setting regardless of pCR. There are several genomic signatures available to guide decisions regarding adjuvant chemotherapy use however these assays are not routinely used in the neoadjuvant setting. For high-risk patients meeting the criteria for the monarchE trial adjuvant abemaciclib in addition to endocrine therapy is associated with an improvement in disease free survival (DFS) at 3 years. Based on the OlympiA trial patients with germline BRCA mutations should be considered for adjuvant olaparib therapy. In this article we review neoadjuvant clinical trials that guide optimum treatment options for TNBC and HR-positive, HER2-negative breast cancer.

Abstract 1639: Human immune system mouse model of ER+ metastatic breast cancer

Abstract In a recent clinical trial in heavily pretreated estrogen receptor alpha-positive (ER+) metastatic breast cancer (MBC), ~23% of patients reached the primary endpoint of clinical benefit of &amp;gt;24 weeks on Fulvestrant plus the anti-androgen Enzalutamide. ESR1 mutant biopsies had more T regulatory cells (t test p&amp;lt;0.021) and macrophages (p&amp;lt;0.003) than ESR1 wild type (WT), which had more TP53 mutations and higher levels of cytotoxic T effector cells (p&amp;lt;0.01). In addition, PD-L1 increased in post- vs. pre-treatment biopsies (paired t test p&amp;lt;0.002). This increase in PD-L1 post-treatment warrants testing if the addition of a checkpoint inhibitor to the Fulvestrant-Enzalutamide combination will enhance therapy efficacy in ER+ MBC resistant to standard endocrine therapy. However, the lack of immune competent ER+ breast cancer pre-clinical models is a major barrier to these studies. Human immune system (HIS) mouse models were developed as a platform in which to test immune checkpoint inhibitors in other human cancers, and one HIS model was recently shown to support the growth and immune infiltration of ER+ patient-derived xenograft (PDX) primary tumors. We tested whether HIS mice are a robust model in which to define ER+ tumor-immune microenvironment interactions at metastatic sites. We implanted NCG mice (NOD-Prkdcem26Cd52Il2rgem26Cd22/NjuCrl) humanized by engraftment of human umbilical cord blood-derived CD34+ (huCD34+) stem cells with the estrogen-independent HCI-013EI (013EI) PDX, derived from an ER+, invasive lobular MBC which harbors the Y537S ESR1 mutation. Mice were monitored for tumor latency and growth rate, and primary tumors and organs were collected for immunohistochemistry, single-cell RNA sequencing (scRNAseq), and phasor-fluorescence lifetime imaging microscopy (FLIM). The ER mutated PDX 013EI had a longer tumor latency in HIS (median 77 days) vs. age-matched immune deficient control mice (27.5 days, log-rank p=0.043). Once formed, 013EI tumors in HIS mice grew slower than those in controls (mixed-effects analysis, p=0.035). HIS mice had visible lung, liver, and/or gastrointestinal tract metastases despite small primary tumors. Lung metastases from HIS mice retain ER expression and are infiltrated by human CD4+, CD8+, and CD68+ immune cells. Initial scRNAseq analysis also suggests infiltration by diverse immune cell populations in primary tumors from HIS mice. Initial phasor-FLIM for NADH autofluorescence suggests that 013EI tumors are highly glycolytic in HIS mice. In conclusion, our results show that huCD34+ HIS mice effectively support growth, metastasis, and immune infiltration of an ESR1 mutant MBC PDX. Ongoing studies will further define the tumor-immune microenvironment in this and ESR1 WT MBC PDX, focusing on immune cell infiltration, PD-L1 expression, steroid receptor status, metabolic signaling and changes in these parameters following novel combinations of endocrine, immunotherapy and metabolic agents. Citation Format: Ayodeji Olukoya, Shaymaa Bahnassy, Nicole S. Spoelstra, Lu Jin, Suman Ranjit, Anthony Elias, Jennifer K. Richer, Rebecca B. Riggins. Human immune system mouse model of ER+ metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1639.

Effects of Empagliflozin on Symptoms, Physical Limitations, and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial.

Background:Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized).Methods:Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model.Results:In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01–2.20], 1.37 [0.94–1.99], and 1.48 [1.00–2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32–8.59], P=0.03; 4.80 [95% CI, 0.00–9.61], P=0.05; 4.66 [95% CI, 0.32–9.01], P=0.04; 4.85 [95% CI, 0.77–8.92], P=0.02; and 4.40 points [95% CI, 0.33–8.48], P=0.03, respectively).Conclusions:Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT0415775.

Response Rate, Event-Free Survival (EFS) and Overall Survival (OS) in Higher-Risk Myelodysplastic Syndromes (HR-MDS): U.S. Food and Drug Administration (FDA) Patient-Level Analyses

Background: Hypomethylating agents (HMAs) have changed the treatment landscape for patients with higher-risk myelodysplastic syndromes (HR-MDS) in the past two decades. However, less than half of patients respond to HMA therapy and even the best responses are transient and non-curative. Therapeutic options for those who have failed HMAs are limited, and these patients have very poor prognosis. To speed the development of novel therapeutics, varying response rate definitions and event-free survival (EFS) have been suggested as clinical benefit endpoints for regulatory approvals. However, the relationship between complete remission (CR), partial remission (PR), hematologic improvement (HI), event-free survival (EFS) and overall survival (OS) in MDS has not been conclusively established. To evaluate the relationship between these endpoints, we conducted patient-level response analyses of MDS trials submitted to the FDA.Methods: We searched for trials submitted with New Drug Applications for treatment of MDS between 2000 and 2020. Trials which supported the efficacy of approved treatments for HR-MDS were included. Patients with chronic myelomonocytic leukemia (CMML), bone marrow blasts ≥ 20%, or missing bone marrow blast information were excluded. A patient-level responder analysis was performed to compare OS and EFS between responders and non-responders, regardless of treatment assignment in the pooled dataset. Separate analyses were formed for CR, PR, and HI. Response rates were defined per protocol; criteria included IWG 2000, IWG 2006, and custom criteria. EFS was defined as time from randomization, or first dose of study drug for single-arm trials, to treatment failure (defined as date of transformation to AML, given availability across trials) or death from any cause. For each trial, the hazard ratio of response vs. no-response on OS and EFS was estimated using a Cox model with response as a time-varying covariate and treatment, sex, age, and percentage blast count as baseline covariates. The resulting hazard ratios were combined assuming a common effect of response on clinical outcome to estimate a pooled hazard ratio. Unadjusted distributions of OS and EFS by response were obtained using the Kaplan-Meier method.Results: We identified 8 trials with a total of 772 patients with HR-MDS investigating 3 experimental agents (azacitidine, decitabine, and decitabine + cedazuridine) for the treatment of HR-MDS. Three trials were randomized trials to assess efficacy (N=116, 124, 215), two were randomized crossover trials to assess bioequivalence (N=116, 61), and 3 were single arm trials (N=29, 34, 77). Across all trials, the population characteristics were: median age 69 years (range: 23-92); 70% male, 67% White, 29% Asian, 2% Black; 17% High Risk per IPSS, 25% Intermediate-1, 33% Intermediate-2, 2% Low Risk, and 24% unknown. IPSS information was missing for 3 trials (187 patients).We assessed the effect of CR vs. PR vs. HI in a pooled analysis. Patients who achieved a CR had better OS (HR=0.40 [95% CI: 0.25-0.64]) and EFS (HR=0.39 [95% CI: 0.24-0.63]) compared with non-responders, defined as patients who failed to achieve CR, PR, or HI. Patients who achieved a PR had better OS (HR=0.51 [95% CI: 0.28-0.92]) and EFS (HR=0.66 [95% CI: 0.37-1.17]) compared to non-responders. Patients who achieved an HI response had better OS (HR=0.60 [95% CI: 0.46-0.76]) and EFS (HR=0.60 [95% CI: 0.47-0.76]) compared to non-responders. Patients who achieved a CR+PR had a trend for longer OS (HR=0.73 [95% CI: 0.49-1.11]) and EFS (HR=0.76 [95% CI: 0.51-1.14]) compared with those who achieved HI alone. Between-study variances of these effects were not able to be reliably estimated due to the low number of responses per trial and low number of trials included in the analysis. Figures 1 and 2 present unadjusted Kaplan-Meier estimates of OS and EFS by response group.Conclusions: Patient-level responder analyses suggest that CR, PR, and HI responders have better OS and EFS compared with non-responders. A limitation of these analyses is that response criteria are not standardized across trials. Future work includes standardizing response criteria across trials. However, our results suggest that CR, PR, and HI may be associated with long-term benefit in patients with HR-MDS. While HI responses had better OS compared to no response, CR and CR+PR remain the response endpoints associated with greatest long-term benefit. [Display omitted] DisclosuresVallejo: AstraZeneca: Other: Spouse is employed by AstraZeneca..

Abstract PS12-14: Phase II trial of fulvestrant plus enzalutamide in ER+/Her2- advanced breast cancer

Abstract Up to 91% of ER+ breast cancers express androgen receptor (AR), but its function is uncertain. Although AR expression is associated with more indolent tumors, high AR expression relative to ER is associated with endocrine resistance, and in the absence of estradiol or if ER function is blocked, preclinical studies suggest that AR can take over to signal cell survival and proliferation. Following extensive preclinical studies and a brief phase I to demonstrate a lack of significant PK interaction, this phase II trial of fulvestrant plus enzalutamide in ER+/Her2- metastatic breast cancer was conducted. Methods: Eligible patients were women with ECOG 0-2, ER+/Her2- measurable or evaluable metastatic breast cancer without CNS disease. Prior fulvestrant was allowed, if clinically indicated as per treating physician. Fulvestrant was administered in standard dosing at 500 mg IM days 1, 15, 29 and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily on a continual basis. Fresh tumor biopsies were required at study entry and at about 4 weeks on therapy. The primary efficacy endpoint of the trial was clinical benefit rate at 24 weeks (CBR24). Assuming the undesirable rate of 10% and desirable rate of 30%, a sample size of 24 provided 89% power to detect this 25% rate difference using an exact binomial test with a one-sided alpha of 0.085. Due to the exploratory nature of biomarker analysis, the type I error rate was not adjusted for exploring multiple biomarkers. Results: A total of 38 patients were consented, of whom 32 were eligible. Median age was 61 years (46-87); PS 1 (0-1); a median of 2 prior chemotherapy and 2 prior hormonal therapies for metastatic disease. Twelve patients had prior fulvestrant, and 90% had visceral disease. TEAEs &amp;gt;20% included fatigue, nausea/vomiting, constipation, headache, anorexia, although most were low grade. There were no G4 or G5 toxicities. Median PFS was 2.0 months (0.5-12). CBR24 was 25% (7/28 evaluable).Conclusions: In a heavily pretreated population of women with metastatic ER+/Her2- BC, the combination of fulvestrant plus enzalutamide had manageable side effects, and modest activity. About 25% reached the primary endpoint of clinical benefit of more than 6 months on therapy. Extensive molecular studies of paired fresh biopsies from pretreatment and at 4 weeks are underway. These analyses and correlations with clinical outcome will be described. Citation Format: Anthony D Elias, Nicole Spoelsta, Gregory A Vidal, Sharon Sams, Peter Kabos, Jennifer R Diamond, Elena Shagisultanova, Anosheh Afghahi, Jose Mayordomo, Tessa McSpadden, Gloria Crawford, Lisa Carter, Kathryn Zolman, Stephanie Armstead, Alyse Winchester, Virginia Borges, Julia Wulfkuhle, Emanuel Petricoin, Dexiang Gao, Jennifer Richer. Phase II trial of fulvestrant plus enzalutamide in ER+/Her2- advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-14.

Ticagrelor alone or conventional dual antiplatelet therapy in patients with stable or acute coronary syndromes.

The aim of this study was to investigate the effect of ticagrelor monotherapy after one-month dual antiplatelet therapy (DAPT) or conventional DAPT in patients with or without acute coronary syndrome (ACS) in the GLOBAL LEADERS Adjudication Sub-StudY (GLASSY). Risk estimates were expressed as rate ratios (RR) with 95% confidence intervals (CI). A total of 3,840 ACS and 3,745 stable ischaemic heart disease (SIHD) patients were included. At two years, rates of the co-primary efficacy endpoint, a composite of death, myocardial infarction, stroke or urgent target vessel revascularisation, were 7.94% in the experimental and 9.68% in the control group (RR 0.82, 95% CI: 0.66-1.01) among ACS patients and 6.31% in the experimental and 7.14% in the control group (RR 0.89, 95% CI: 0.69-1.13) among SIHD patients (pint=0.63). Trends for lower and higher risk of BARC 3 or 5 bleeding with the experimental strategy in ACS (2.27% vs 3.00%, RR 0.76, 95% CI: 0.51-1.12) and SIHD (2.70% vs 1.96%, RR 1.39, 95% CI: 0.91-2.12) patients, respectively, were observed with significant interaction testing (pint=0.039). A net clinical benefit endpoint, the composite of both co-primary study endpoints, favoured the experimental treatment among ACS patients only. Ticagrelor monotherapy after one-month DAPT provided consistent treatment effects on ischaemic endpoints in patients with or without ACS but only the former experienced a net clinical benefit. ClinicalTrials.gov identifier: NCT03231059.

Osimertinib in non-small cell lung cancer (NSCLC) with atypical EGFR activating mutations: A retrospective multicenter study.

9570 Background: Osimertinib (osi) is a 3rd generation EGFR tyrosine kinase inhibitor (TKI) approved for first line (1L) treatment of metastatic NSCLC harboring EGFR Exon 19 del and L858R (representing &gt; 80% of EGFR activating mutations) or in NSCLC with EGFRT790M (the most common resistance mutation to 1st or 2nd generation TKI). However, it has not been well-studied in EGFR-mutant NSCLC harboring less common EGFR activating mutations such as G719X, L861Q, S768I, and exon 20 insertion (ins), among others. Methods: We conducted a multi-institution, retrospective study approved on institutional IRB protocols in a series of patients (pts.) with metastatic NSCLC treated with osi who harbored at least one atypical EGFR mutation, excluding those with concurrent L858R, Exon 19 del, or T790M. Kaplan-Meier analyses were generated with SPSS, v25 (IBM Corp., USA). Response was assessed by RECIST 1.1 in evaluable pts. Time on osi was employed as a surrogate endpoint for clinical benefit in this retrospective analysis. Results: Fifty-one NSCLC pts with uncommon EGFR mutations were identified among six US institutions. Pt characteristics: 72.5% women, median age 65 yo (44-83 yo), 82.3% ECOG PS 0-1, 43.1% never smoker, 100% lung adenocarcinoma, 58.8% Caucasian, 25.5% Asian, 3.9% Black, 2.0% Hispanic, and 9.8% Other. The most frequent mutations were L861Q (35.3%, N = 18), G719X (27.5%, N = 14), and Exon 20 ins (15.7%, N = 8). Osi was used in the 1L setting in 39.2% (N = 20). Median time on osi was 7.1 months (mo.) in the overall cohort (95% CI, 5.4 to 8.8 mo.) and 8.9 mo. (95% CI, 7.0 to 10.8 mo.) in pts receiving 1L osi. Patients harboring G719X (N = 4) and L861Q (N = 10) mutations had a median time on 1L osimertinib of 5.8 mo. and 19.3 mo., respectively. One patient’s tumor had an EGFR exon 19 ins and was on 1L osi with a partial response for 16.8 months. Two patients with Exon 20 ins were on 1L osi for 9.3 mo. and 8 mo., respectively. Conclusions: In this largest known clinically annotated dataset of patients with atypical EGFR-mutations treated with osi, activity was noted, though 1L clinical benefit on osi appears lower in this multicenter US cohort than in E19del or L858R. These results are comparable to the recently published prospective phase II trial ( Cho et al, 2019) conducted in Korea. Patients with L861Q and Exon 19 insertion appeared to benefit the most from osi in this time on treatment retrospective analysis. More detailed analysis of this cohort is planned and further prospective studies are warranted to determine clinical benefit of osi amongst diverse atypical EGFR-mutations.

Comparison of Benefit of Transcatheter Aortic Valve Implantation in Patients With Low Gradient Versus High Gradient Aortic Stenosis and Left Ventricular Dysfunction

Patients with low gradient severe aortic stenosis (LG-AS) often exhibit significant limitations in functional status and quality of life. We aimed to evaluate the clinical effect of transcatheter aortic valve implantation (TAVI) on LG-AS patients compared to those with high transvalvular gradients and similar left ventricular dysfunction. Retrospective analysis of records for all patients with a left ventricular ejection fraction <50% who underwent TAVI at our institution was performed. Patients were grouped according to their transvalvular gradient. Data were collected from The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Clinical benefit endpoints included improvements in left ventricular ejection fraction and changes in the Kansas City Cardiomyopathy Questionnaire. Additional outcomes analyzed included 1-year all-cause mortality, stroke rates, rates of rehospitalization, need for a permanent pacemaker, and hospital length of stay. Two hundred three patients met our inclusion criteria. one hundred one LG-AS patients (mean transvalvular gradient <40 mm Hg) were compared to 102 patients with high transvalvular gradients (mean transvalvular gradient >40 mm Hg). LG-AS patients yielded similar improvements in left ventricular ejection fraction (43.5% ± 63.7 vs 37.7% ± 58.7; p = 0.525) and Kansas City Cardiomyopathy Questionnaire scores (423.51% ± 1257.02 vs 266.56% ± 822.81; p = 0.352). There were no differences between the groups with respect to 1-year mortality (16.8% vs 12.7%; p = 0.412), stroke rates, hospital length of stay, need for permanent pacemaker implantation or hospital readmissions. In conclusion, we found that TAVI is associated with comparable improvement in clinical and echocardiographic outcomes in LG-AS patients as compared to those with high gradient severe aortic stenosis.

Efficacy of Vemurafenib in Patients With Non-Small-Cell Lung Cancer With BRAF V600 Mutation: An Open-Label, Single-Arm Cohort of the Histology-Independent VE-BASKET Study.

PURPOSETo study whether BRAF V600 mutations in non–small-cell lung cancer (NSCLC) may indicate sensitivity to the BRAF inhibitor vemurafenib, we included a cohort of patients with NSCLC in the vemurafenib basket (VE-BASKET) study. On the basis of observed early clinical activity, we expanded the cohort of patients with NSCLC. We present results from this cohort.METHODSThis open-label, histology-independent, phase II study included six prespecified cohorts, including patients with NSCLC, and a seventh all-comers cohort. Patients received vemurafenib (960 mg two times per day) until disease progression or unacceptable toxicity. The primary end point of the final analysis was objective response rate (Response Evaluation Criteria in Solid Tumors, version 1.1). Secondary end points included progression-free survival, overall survival, and safety. Because the prespecified clinical benefit endpoint was met in the initial NSCLC cohort, the cohort was expanded.RESULTSSixty-two patients with BRAF V600–mutant NSCLC were enrolled and treated: 13% (n = 8) had received no prior systemic therapy, and 87% (n = 54) had received prior therapies. The objective response rate was 37.1% (95% CI, 25.2% to 50.3%) overall, 37.5% (95% CI, 8.5% to 75.5%) in previously untreated patients, and 37.0% (24.3% to 51.3%) in previously treated patients. Median progression-free survival was 6.5 months (95% CI, 5.2 to 9.0 months), and median overall survival was 15.4 months (95% CI, 9.6 to 22.8 months). The most common all-grade adverse event was nausea (40%). The safety profile of vemurafenib was similar to that observed in melanoma studies.CONCLUSIONVemurafenib showed promising activity in patients with NSCLC harboring BRAF V600 mutations. The safety profile of vemurafenib was similar to previous observations in patients with melanoma. Our results suggest a role for single-agent BRAF inhibition in patients with NSCLC and BRAF V600 mutations.

Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase 1 dose escalation/randomised phase 2a trial

PurposeRadium 223 dichloride (radium-223) is an alpha particle–emitting bone-directed therapy that prolongs overall survival in men with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Docetaxel is an antimicrotubule cytotoxic agent that improves survival in mCRPC. We investigated whether combining these potentially cross-sensitising agents to dually target tumour and bone would be safe and effective. Patients and methodsPhase 1 was a dose escalation study to define a recommended phase 2 dose (RP2D) of docetaxel and radium-223. In phase 2a, patients were randomised 2:1 to the recommended combination regimen or docetaxel at a dose of 75 mg/m2 every 3 weeks (q3w). Patients with bone-predominant mCRPC were eligible. End-points were safety, efficacy and treatment-related changes in serum and imaging biomarkers. ResultsTwenty patients were enrolled in phase 1; 53 patients were randomised in phase 2a: 36 to combination treatment and 17 to docetaxel alone. The RP2D for the combination was radium-223 55 kBq/kg every six weeks × 5 doses, plus docetaxel 60 mg/m2 q3w × 10 doses. Febrile neutropenia was dose limiting. A higher rate of febrile neutropenia was seen in the docetaxel monotherapy arm (15% vs 0%); the safety profile of the treatment groups was otherwise similar. The combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 vs 4.8 months, respectively), alkaline phosphatase (9 vs 7 months) and osteoblastic bone deposition markers. ConclusionsRadium-223 in combination with docetaxel at the RP2D was well tolerated. Exploratory efficacy data suggested enhanced antitumour activity for the combination relative to docetaxel alone. Comparative studies with end-points of clinical benefit are warranted. ClinicalTrials.gov number: NCT01106352.

Clinical and molecular characteristics of responders versus non-responders to immune checkpoint inhibitors (ICI) in NSCLC.

114 Background: Evidence from randomized clinical trials and retrospective studies has shown that tumors with specific driver mutations may be less likely to respond to ICI; the optimal timing of ICI is unknown in this population. In this analysis, we evaluated the characteristics of responders to ICI compared to non-responders, with emphasis on the role of driver mutations. Methods: We retrospectively collected clinical characteristics and outcomes for patients who received ICI for NSCLC at Stanford University between April 2015 and August 2016. Patients were classified as responders if time on ICI was 180 days or more, and as non-responders if less than 180 days. Outcomes included radiographic improvement while on ICI, survival from diagnosis, and survival from ICI initiation. Results: Data were available for 84 patients, with median follow-up of 31 months. 18 patients were deemed responders (21%); 66 were deemed non-responders (79%). Of the patients who underwent genomic testing, 13% (2/15) of responders had mutations in EGFR/ALK/ROS1, compared to 32% (17/49) of non-responders (p = 0.195). Within the responders, 89% (16/18) had an associated radiographic improvement, compared to 11% (7/66) of non-responders (p &lt; 0.0001). Patients with mutations in EGFR/ALK/ROS1 had a median overall survival of 46 months from diagnosis, compared to 26 months in those without these mutations (p = 0.08). Patients with mutations in EGFR/ALK/ROS1 had a median survival of 4.9 months from ICI initiation, compared to 7.0 months in those without (p = 0.45). Conclusions: Patients receiving ICI for 180 days or more had a significantly higher rate of radiographic improvement, suggesting that time on therapy appears to be a surrogate endpoint of clinical benefit. While there was not a statistically significant smaller number of responders with EGFR/ALK/ROS1, there appeared to be clinically meaningful lower response rate in these patients. This was likely limited by sample size; expansion of the sample size is planned. There was a trend to overall survival benefit in patients with driver mutations, likely driven by targeted therapy as there were no statistical differences in survival from time of ICI initiation.

PMU72 - ESTIMATED COSTS OF PIVOTAL TRIALS FOR NOVEL THERAPEUTIC AGENTS APPROVED BY THE FDA, 2015-2016

To assess the estimated costs and scientific characteristics of pivotal efficacy trials that supported the approval of new therapeutic agents by the US Food and Drug Administration (FDA) in 2015-2016. We used FDA reviews, ClinicalTrials.gov, and peer-reviewed studies to identify 51 characteristics of each efficacy trial. Costs were calculated with a global clinical trial cost assessment tool available to contract research organizations and pharmaceutical sponsors. Main outcomes and measured were estimated mean cost and 95% confidence intervals based on industry benchmark data from 60 countries. Measures of scientific rigor included design (uncontrolled, placebo, active drug), endpoint (surrogate, clinical scale, clinical benefit), enrollment, and treatment duration. In 2015-2016, 138 pivotal clinical trials provided the basis for FDA approval of 59 new therapeutic agents with a median estimated cost of $19.0 million (interquartile range [IQR], $12.2 million to $33.1 million). Estimated costs varied with scientific rigor, and ranged from less than $5 million for uncontrolled trials for 3 orphan drugs with fewer than 15 patients each, to $346.8 million (95% confidence interval [CI], $252.0 million - $441.5 million) for a non-inferiority trial with endpoints assessing clinical benefit. Twenty-six of 138 (18.8%) trials were uncontrolled, with a mean estimated cost of $13.5 million (95% CI, $10.1 million - $16.9 million). Trials with placebo or active comparators had an estimated mean cost of $35.1 million (95% CI, $25.4 million - $44.8 million). Costs also varied by trial endpoint, treatment duration, patient enrollment, and therapeutic class. The most expensive trials were ones where the new agent had to be proved non-inferior with clinical benefit endpoints to one already available, or required larger patient populations to achieve statistical power to document smaller treatment effects or infrequently occurring endpoints.

Estimated Costs of Pivotal Trials for Novel Therapeutic Agents Approved by the US Food and Drug Administration, 2015-2016

A critical question in health care is the extent of scientific evidence that should be required to establish that a new therapeutic agent has benefits that outweigh its risks. Estimating the costs of this evidence of efficacy provides an important perspective. To estimate costs and assess scientific characteristics of pivotal efficacy trials that supported the approval of new therapeutic agents by the US Food and Drug Administration (FDA) from 2015 to 2016. This study identified 59 novel therapeutic drugs using the annual summary reports from the FDA Center for Drug Evaluation and Research. ClinicalTrials.gov, FDA reviews, and peer-reviewed publications that were publicly available in 2017 were used to identify 52 characteristics of each efficacy trial. Costs were calculated with a global clinical trial cost assessment tool available to contract research organizations and pharmaceutical sponsors. Estimated mean cost and 95% CIs based on industry benchmark data from 60 countries. Measures of trials' scientific characteristics included trial design (no control group, placebo, and active drug), end point (surrogate outcome, clinical scale, and clinical outcome), patient enrollment, and treatment duration. A total of 138 pivotal clinical trials provided the basis for approval of 59 new therapeutic agents by the FDA from 2015 to 2016, with a median estimated cost of $19.0 million (interquartile range, $12.2 million-$33.1 million). Estimated costs ranged from less than $5 million for trials without a control group for 3 orphan drugs with fewer than 15 patients each to $346.8 million (95% CI, $252.0 million-$441.5 million) for a noninferiority trial with end points assessing clinical benefit. Twenty-six of 138 trials (18.8%) were uncontrolled, with a mean estimated cost of $13.5 million (95% CI, $10.1 million-$16.9 million). Trials designed with placebo or active drug comparators had an estimated mean cost of $35.1 million (95% CI, $25.4 million-$44.8 million). Costs also varied by trial end point, treatment duration, patient enrollment, and therapeutic area. The highest-cost trials were those in which the new agent had to be proved to be noninferior with clinical benefit end points compared with an agent already available or those that required larger patient populations to achieve statistical power to document smaller treatment effects or accrue infrequently occurring end points.

Chemotherapy is of Value in Second Line and Beyond, Relapsed High-grade, Serous Epithelial Ovarian Cancer

Epithelial ovarian cancer is chemotherapy responsive, and multiple lines of chemotherapy are often given. However, there are few data with regard to its effectiveness in later lines. Our aim was to assess its benefit in the high-grade, serous subtype relative to the line of therapy, using etoposide as the example. Women treated with oral etoposide at the British Columbia Cancer Agency upon recurrence/progression in the years 2000 to 2010 were reviewed. Kaplan-Meier and Cox regression methods were used to correlate line of therapy with overall survival, progression-free survival, and interval between etoposide initiation and next progression or death (EPFS). A total of 219 women, median age 61, received etoposide as second (17%), third (30%), fourth (26%), fifth (17%), and sixth to eighth (11%) lines of therapy. The median number of cycles was 2 to 4. Patients who received etoposide as fourth-line to eighth-line treatment had a significantly longer median overall survival and initial progression-free survival (from diagnosis to first relapse) when compared with those who received it as second-line to third-line treatment (47.8 vs. 25.8 mo, P<0.0001; and 16.1 vs. 12.1 mo, P<0.0001, respectively); that is, a selected population of survivors received it later in the course of their disease. On univariate analysis, there was no significant difference in median EPFS (range, 2 to 2.9 mo) on the basis of line of therapy. On multivariate analysis, the hazard ratios improved through the third, fourth, and fifth lines (hazard ratios: 0.82, 0.77, and 0.34, respectively), and was statistically significant in the fifth line. The a priori-defined endpoint of clinical benefit was the "percentage not progressing at 3 months," and this was achieved in 32% to 48%. In this retrospective study, a similar degree of benefit from etoposide, as defined by the percentage remaining progression free at 3 months, was seen in all lines of therapy.

Efficacy of vemurafenib in patients (pts) with non-small cell lung cancer (NSCLC) with BRAFV600 mutation.

9074 Background: BRAFV600 mutations occur in 1–2% of pts with NSCLC. We previously reported the efficacy of vemurafenib, a selective BRAFV600 inhibitor, in BRAF mutation-positive non-melanoma tumors (VE-BASKET study). We now present final data for the expanded NSCLC cohort. Methods: This open-label, histology-independent, phase 2 study included 6 prespecified cohorts (including NSCLC) plus one ‘all-others’ cohort. Pts received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (RECIST v1.1). Secondary endpoints included best overall response rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Because the pre-specified clinical benefit endpoint was met in the initial NSCLC cohort, the cohort was expanded. ClinicalTrials.gov identifier NCT01524978. Results: Database lock was 12 Jan 2017. Of 208 pts enrolled at 25 centers worldwide, 62 pts had NSCLC: median age 65 years; 56% male; 13% had no prior systemic therapy; 50% had ≥2 prior therapies. Responses were seen in previously treated and untreated pts (Table). The most common all-grade adverse event (AE) was nausea (40%); grade 3–5 AEs included keratoacanthoma (15%) and squamous cell carcinoma of the skin (15%). Six pts discontinued vemurafenib due to AEs; two had non-treatment-related fatal AEs. Conclusions: Vemurafenib showed evidence of encouraging efficacy in pts with NSCLC with BRAFV600 mutation, with prolonged PFS in previously untreated pts; median OS was not estimable due to ongoing responses. The safety profile of vemurafenib was similar to that seen in melanoma studies. Our results suggest a role for BRAF inhibition in NSCLC with BRAF mutations. Clinical trial information: NCT01524978. [Table: see text]

Effect of Lenalidomide (LEN) Exposure on Response and Outcomes in Patients (Pts) with Lower-Risk Non-Del(5q) Myelodysplastic Syndromes (MDS)

▪Introduction: In the phase 3 MDS-005 study, LEN treatment was associated with a significant increase in transfusion independence (TI) vs placebo (26.9% vs 2.5%; P < 0.001) (Santini et al. J Clin Oncol. 2016;pii:JCO.2015.66.0118) and greater clinical benefit vs placebo (31.9% vs 3.8%) (Garcia-Manero et al. Haematologica. 2016;101:abstract P252) in red blood cell (RBC) transfusion-dependent (TD) pts with lower-risk non-del(5q) MDS who were ineligible for or refractory to erythropoiesis-stimulating agents (ESAs). For pts with lower-risk del(5q) MDS, a starting dose of LEN 10 mg is recommended, followed by subsequent dose modifications in response to adverse events (AEs), in order to maximize duration of treatment and thereby improve pt outcomes. This study evaluated the relationship between LEN exposure, including dose reductions, and duration of treatment, and the clinical benefit to pts with lower-risk, non-del(5q) MDS in the multicenter, randomized, double-blind, phase 3 MDS-005 study.Methods: Eligible pts were age ≥ 18 years, had TD anemia due to International Prognostic Scoring System (IPSS)-defined Low- or Intermediate-1-risk MDS, lacked the del(5q) mutation, and were ineligible for or refractory to ESAs. Pts were randomized 2:1 to receive LEN 10 mg (n = 160) or placebo (n = 79) once daily (both in 28-day cycles). Pts randomized to LEN with creatinine clearance ≥ 40 to < 60 mL/min (n = 57) received LEN 5 mg. Cumulative dose, dose reductions, and discontinuations were recorded; association between these parameters and clinical benefit or RBC-TI was evaluated. Clinical benefit ≥ 8 weeks was defined as the composite endpoint of RBC-TI ≥ 8 weeks, or transfusion reduction of ≥ 4 units packed RBCs (pRBCs) ≥ 8 weeks, or hemoglobin (Hb) increase ≥ 1.5 g/dL ≥ 8 weeks (International Working Group 2006), or cytogenetic response (CyR). Rate of transfusion reduction was calculated using data collected during a 112-day assessment period to account for on-study differences in transfusion burden. LEN dose modifications due to AEs were defined in the study protocol. The analysis included all pts receiving LEN.Results: Of 160 LEN-treated pts included in the analysis, 77 (48.1%) underwent ≥ 1 LEN dose reduction. A total of 73 pts experienced ≥ 1 dose reduction due to AEs, amounting to 102 dose reductions overall. Of these AE-related dose reductions, 47 were due to neutropenia, 33 due to thrombocytopenia, and 2 due to other hematologic conditions. Median time to first dose reduction was 85 days (interquartile range [IQR] 50-114 days). A total of 145 LEN-treated pts discontinued therapy: 52 discontinued due to AEs; 32 discontinued before the end of cycle 3, of which 23 were due to AEs.Of the 77 pts who had ≥ 1 dose reduction, 6 (7.8%) pts had a dose reduction in the first cycle; 37 (48.1%) pts had dose reductions during cycles 1-3. During the first 3 cycles of LEN, pts with ≥ 1 dose reduction received a lower median dose than those with no dose reductions (385 mg [IQR 318-520 mg] vs 660 mg [IQR 415-840 mg]). However, when analyzed over the course of the entire study, pts undergoing ≥ 1 dose reduction received a higher median cumulative dose than those with no dose reductions (950 mg [IQR 595-1,435 mg] vs 715 mg [IQR 370-1,660 mg]). Duration of treatment was also longer for pts with ≥ 1 dose reduction vs those with no dose reductions (172 days [IQR 140-391 days] vs 92 days [IQR 46-168 days]).Pts with ≥ 1 dose reduction were more likely to achieve RBC-TI ≥ 8 weeks than pts with no dose reductions (39% vs 16%; odds ratio [OR] 3.44 [95% confidence interval {CI} 1.63-7.26]). Pts with ≥ 1 dose reduction were also more likely to achieve clinical benefit ≥ 8 weeks vs pts with no dose reductions (47% vs 18%; OR 3.98 [95% CI 1.94-8.15]).Conclusions: In this post hoc analysis of the MDS-005 study, pts undergoing ≥ 1 LEN dose reduction had a longer duration of treatment, and were more likely to achieve RBC-TI and the composite endpoint of clinical benefit (RBC-TI ≥ 8 weeks, transfusion reduction ≥ 4 units pRBCs ≥ 8 weeks, Hb increase ≥ 1.5 g/dL ≥ 8 weeks, or CyR) than pts with no dose reductions. DisclosuresSantini:Novartis: Consultancy, Honoraria; Onconova: Other: advisory board; Amgen: Other: advisory board; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astex: Other: advisory board. Almeida:BMS: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Shire: Speakers Bureau. Fenaux:Celgene, Novartis, Teva: Honoraria; Celgene, Janssen, Novartis, Astex, Teva: Research Funding. Gatterman:Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Heinrich-Heine-Universitat Dusseldorf: Employment. Ozawa:Sumitomo Dainippon Pharma Co. Ltd: Research Funding; JCR Pharmaceutical Inc: Consultancy; Celgene Japan: Consultancy; Takara Bio Inc: Research Funding. Goldberg:COTA Inc: Employment; Novartis: Consultancy; Pfizer: Honoraria; Bristol Myers Squibb, Novartis: Speakers Bureau; Neostem: Equity Ownership. Weaver:Celgene Corporation: Employment, Equity Ownership. Sugrue:Celgene Corporation: Employment, Equity Ownership.

Long-term maintenance of efficacy of dapagliflozin in patients with type 2 diabetes mellitus and cardiovascular disease.

To evaluate the long-term efficacy, safety and tolerability of dapagliflozin versus placebo added to usual care in patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Data were pooled from two phase III studies (NCT01031680 and NCT01042977) in high-risk patients (N = 1887) with T2DM and CVD treated with dapagliflozin (10 mg/day) or placebo. Patients completing the double-blind treatment studies (24 weeks) entered one or two sequential double-blind, long-term (LT) extensions of 28 (LT1; n = 1649) and 52 (LT2; n = 568) weeks. Baseline and CVD characteristics were similar in the two groups. Patients entering LT1 and LT2 on dapagliflozin maintained a greater mean reduction in glycated haemoglobin (HbA1c) versus placebo at 52 weeks [LT1, -0.58% (95% confidence interval -0.68, -0.49)] and 104 weeks [LT2, -0.35% (95% confidence interval -0.59, -0.12)]. Mean body weight and systolic blood pressure (SBP) reductions versus placebo were maintained in patients entering LT1 (52 weeks; -2.23 kg and -3.25 mmHg, respectively) and LT2 (104 weeks; -3.16 kg and -2.03 mmHg, respectively). Patients on dapagliflozin had a better three-item composite endpoint of clinical benefit (glycaemia, weight and SBP) compared with placebo at week 24 (LT1, 10.1% vs. 1.1%) and week 104 (LT2, 6.7% vs. 1.4%). Genital and urinary tract infections were more frequent with dapagliflozin than with placebo. Events of hypoglycaemia, renal impairment/failure and volume depletion were similar between groups. The long-term efficacy of dapagliflozin to maintain reductions in HbA1c, SBP and body weight over 2 years, together with its tolerability profile, make dapagliflozin an appropriate option in high-risk patients with T2DM and CVD.