bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy and a CDK4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC).
Authors: Wander Seth Andrew , Juric Dejan , Supko Jeffrey G. , Micalizzi Douglas Scott , Spring Laura , Vidula Neelima , Beeler Maureen , Habin Karleen R. , Viscosi Elene , Fitzgerald Donna Michelle , Scarpetti Lauren , Tripp Elizabeth , Hepp Rachel , Moy Beverly , Isakoff Steven J. , Ellisen Leif W. , Bardia Aditya 
Published: May 2020

1066 Background: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), with an anti-estrogen, are the standard of care for HR+/HER2- MBC. Insights from patient biopsies and preclinical analysis suggest that AKT1 activation can provoke CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may provide clinical benefit. Methods: TAKTIC is an open-label phase Ib trial exploring the combination of the AKT1 inhibitor, ipatasertib (ipat), with an aromatase inhibitor (Arm A), fulvestrant (Arm B), or the triplet combination (Arm C) of fulvestrant + ipat + palbociclib (palbo). The primary objective is to evaluate the safety and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an interim analysis from the triplet combination (Arm C). Results: As of 1/31/2020, 25 pts have enrolled, including 12 on Arm C, all of whom received prior CDK4/6i (median no of prior lines = 5.5, range 2-7). Along with fulvestrant, 3 pts received ipat at 200mg + 125mg palbo, 7 pts received 300mg + 125mg palbo, and 2 pts received 400mg + 100mg palbo. To date, 8/12 pts remain on treatment including 2 with partial response, 3 with stable disease, 3 with restaging studies pending and 4 with progressive disease. The triplet combination was well tolerated. Grade 3 toxicities included reduced WBC (8/12), reduced neutrophil count (11/12), reduced lymphocyte count (2/12) and single instances of transaminitis, rash, and reduced platelet count. The only grade 4 toxicity was reduced neutrophil count (4/12). There were no DLTs observed and no discontinuations due to toxicity. Mean steady state pharmacokinetic parameters for ipat were similar to historical data from single agent trials suggesting that combined treatment with palbo + fulvestrant did not affect the pharmacokinetics of ipat. Updated analysis will be presented at the meeting. Conclusions: The triplet combination of endocrine therapy with CDK 4/6i and AKTi appears to be well tolerated in heavily pre-treated pts, with a subset demonstrating signs of clinical benefit. The trial demonstrates how insights into the molecular mechanisms of CDK4/6i resistance could be leveraged into actionable therapeutic regimens for HR+/HER2- MBC. Clinical trial information: NCT03959891 .
A phase Ib trial of the cyclin-dependent kinase inhibitor dinaciclib (dina) in combination with pembrolizumab (P) in patients with advanced triple-negative breast cancer (TNBC) and response correlation with MYC-overexpression.
Authors: Chien Amy Jo , Gliwa Amelia S , Rahmaputri Siti , Dittrich Heidi F , Majure Melanie Catherine , Rugo Hope S. , Melisko Michelle E. , Munster Pamela N. , Park John W. , Moasser Mark M. , Matloubian Mehrdad , Lea Tasha , Rohrberg Julia , Krings Gregor , Goga Andrei 
Published: May 2020

1076 Background: Increased expression of the MYC transcriptional oncogene is found in about 70% of TNBC and is associated with poor prognosis. In MYC-overexpressing TN xenografts, CDK1 inhibition with dina results in synthetic lethality, and attenuates distant metastasis. In syngeneic models, the combination of dina with anti-PD1 therapy is synergistic and increases immune cell tumor infiltration and activation. Methods: Patients (pts) with advanced TNBC received dina IV day 1 and 8 in combination with fixed dose P 200 mg once every 21 days. Dina was dose escalated using a toxicity probability interval design targeting a dose limiting toxicity (DLT) rate of 25%. Evaluable disease and pre-treatment metastatic biopsies were required. After 17 pts were enrolled, eligibility was amended to require ≤2 lines of prior chemotherapy, and LDH ≤1.5x normal. MYC IHC was performed on baseline tumor biopsies and correlated with clinical response using Welch’s unequal variances t-test. Results: 32 pts were enrolled (median age 53, median 2 prior lines of therapy, 13 pts (41%) had disease which was previously ER+). 18 pts were enrolled in the dose escalation phase with no observed DLTs; 33 mg/m2 was determined to be the recommended phase 2 dose (RP2D). 14 additional patients were enrolled in dose expansion at 33 mg/m2, completing trial accrual. Grade ≥3 adverse events (AEs) in all pts included neutropenia (ntp) (37.5%), febrile ntp (12.5%), fatigue (12.5%), transaminitis (3.2%), and neuromuscular weakness (3.2%). Most common all grade AEs included fatigue (63%), diarrhea (63%), nausea (63%), and ntp (53%). Possible immune-related AEs included sinusitis (4 pts), hemolytic anemia (1 pt), pneumonitis (1 pt), rash (2 pts), neuromuscular weakness (1 pt), and transaminitis (1 pt). Of the 29 patients evaluable for response, 1 pt (3.4%) had a CR, 4 pts (13.8%) had a PR, and 6 pts (20.6%) had SD. MYC IHC staining on baseline metastatic tumor biopsies in 19 pts correlated significantly with clinical response. Additional biomarker testing will be reported. Conclusions: The RP2D of dina given in combination with standard dose P is 33 mg/m2 on D1, 8 of a 21-day cycle. Toxicities were generally manageable and non-overlapping. In exploratory analysis, greater MYC IHC staining correlated significantly with response to study therapy. Clinical trial information: NCT01676753 .
Real-world clinical effectiveness and safety of olaparib monotherapy in HER2-negative gBRCA-mutated metastatic breast cancer: Phase IIIb LUCY interim analysis.
Authors: Gelmon Karen A. , Fasching Peter A. , Couch Fergus , Balmana Gelpi Judith , Delaloge Suzette , Labidi-Galy Intidhar , Bennett James , McCutcheon Susan , Ano Sabine , O'Shaughnessy Joyce 
Published: May 2020

1087 Background: OlympiAD (NCT02000622) demonstrated the benefit of olaparib over standard of care in patients (pts) with HER2-negative (HER2-) metastatic breast cancer (MBC) and germline BRCA mutations (gBRCAm). LUCY (NCT03286842) aimed to provide additional data on the real-world effectiveness and safety of olaparib monotherapy in this setting. Methods: This Phase IIIb, open-label, single-arm study of olaparib 300 mg twice-daily, enrolled pts with HER2- gBRCAm MBC who had received a taxane and/or anthracycline in the (neo)adjuvant/metastatic setting, and ≤2 lines of chemotherapy for MBC. Hormone receptor-positive (HR+) pts had progressed on prior endocrine therapy (ET), and further ET was considered unsuitable. Primary endpoint: investigator-defined progression-free survival (PFS). Secondary endpoints: overall survival, time to first subsequent therapy or death (TFST), and investigator-assessed clinical response rate (CRR). The interim analysis was planned after 160 PFS events. Results: From Oct 2018-Sept 2019, 252 pts were enrolled (160 sites, 15 countries; mean age 46.2 [range 22-75] years; 73.4% ECOG PS 0). Median total treatment duration: 7.9 months (mo; range 0.2-20.0). Median PFS: 8.1 mo (95% confidence interval [CI] 6.9, 8.7; 166 events [65.9%]). Clinical trial information: NCT03286842 . Median TFST: 9.7 mo (95% CI 8.7, 11.1). CRR: 48.6% (95% CI 42.2, 55.0). Adverse events (AEs) in >20% of pts (all grades): nausea, anemia, asthenia, vomiting, and fatigue. 24.6% of pts reported a grade ≥3 AE, including anemia (n=33 [13.1%]). 4.4% of pts had an AE leading to treatment discontinuation. Conclusions: Interim results in this real-world population of pts with HER2- gBRCAm MBC were consistent with the OlympiAD study, and support olaparib as a chemotherapy-free alternative treatment for pts with gBRCAm advanced BC. [Table: see text]
Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion+ solid tumors.
Authors: Subbiah Vivek , Hu Mimi I-Nan , Gainor Justin F. , Mansfield Aaron Scott , Alonso Guzman , Taylor Matthew H. , Zhu Viola Weijia , Garrido Lopez Pilar , Amatu Alessio , Doebele Robert C , Cassier Philippe Alexandre , Keam Bhumsuk , Schuler Martin H. , Zhang Hui , Clifford Corinne , Palmer Michael , Green Jennifer , Turner Christopher D. , Curigliano Giuseppe 
Published: May 2020

109 Background: RET gene fusions are targetable oncogenic drivers in multiple tumor types, including up to 20% of papillary thyroid cancers (PTC). Pralsetinib is an investigational, highly potent, selective inhibitor of oncogenic RET alterations. In the registration-enabling Phase 1/2 ARROW study (NCT03037385), pralsetinib demonstrated an overall response rate (ORR; response-evaluable patients [REP], central review) of 73% (19/26) in treatment-naïve patients and 61% (49/80; 2 pending confirmation) in platinum-exposed patients with RET fusion+ non-small cell lung cancer (NSCLC) and was well tolerated (data cut-off November 18, 2019). We provide an update on the clinical activity of pralsetinib in other RET fusion+ solid tumor types. Methods: ARROW consists of a phase 1 dose escalation (30–600 mg once [QD] or twice daily) followed by a phase 2 expansion (400 mg QD) in patients with advanced RET-altered solid tumors. Primary objectives were ORR and safety. Results: As of November 18, 2019, 29 patients with metastatic solid tumor types other than NSCLC (16 PTC, 1 undifferentiated thyroid, 3 pancreatic, 3 colon, 6 other) bearing a RET fusion have received pralsetinib. Efficacy data are presented for REP enrolled by July 11, 2019. In patients with thyroid cancer that is RET fusion+, ORR (investigator assessment) was 75% (9/12; all confirmed). Median (range) duration of response (DOR) was 14.5 (3.7+, 16.8) months (mo), with 67% of responding patients continuing treatment. Two patients with stable disease were continuing treatment at 11.5+ and 19.3+ mo. In other RET fusion+ cancers, ORR was 60% (3/5; all confirmed) with partial responses in 2/2 patients with pancreatic cancer (DOR 5.5, 7.4+ mo) and 1 patient with intrahepatic bile duct carcinoma (DOR 7.5 mo). Two patients with colon cancer had stable disease for 7.3 and 9.3 mo. Responses were observed across multiple fusion genotypes. In the entire safety population (all patients treated with 400 mg QD pralsetinib, regardless of diagnosis; n = 354), most treatment-related adverse events (TRAEs) were grade 1-2, and included increased aspartate aminotransferase (31%), anemia (22%), increased alanine aminotransferase (21%), constipation (21%) and hypertension (20%). Only 4% of patients in the safety population discontinued due to TRAEs. Conclusions: Pralsetinib demonstrated broad and durable antitumor activity across multiple advanced solid tumor types, regardless of RET fusion genotype, and was well tolerated. The study is ongoing and still enrolling patients in this cohort. Clinical trial information: NCT03037385.
Systemic therapy for patients with breast cancer and one to three brain metastases (BM).
Authors: Soomro Zaid A , Alhalabi Omar , Sun Ryan , Albittar Aya , Hsu Limin , Valero Vicente , Ibrahim Nuhad K. 
Published: May 2020

1090 Background: Despite advances in systemic therapies and improved overall survival of metastatic breast cancer (MBC) patients, the development of brain metastases (BMs) remains a challenging complication that affects quality of life and increases morbidity and mortality. Current clinical practice guidelines recommend local treatment of BMs without changing systemic therapy (CST) in patients with stable systemic disease. Methods: We retrospectively investigated the impact of CST (when applicable as per treating physician’s discretion) after diagnosis of the initial 1-3 BMs on the patient’s progression-free survival time (PFS), defined as time to death, to a second BMs or to extracranial metastases. All MBC patients with 1 to 3 BMs only (without extracranial disease) treated at our institution between 2002 and 2017 were identified. For each patient, full information on follow-up and administered therapies were mandatory for inclusion. Hazard ratios (HR) were calculated using the Cox proportional hazard model. We also computed the restricted mean survival time (RMST) up to 5 years of follow-up. Results: Among the 2645 patient with BM treated at our institution, 80 were included for analysis. In regards to primary BMs management in patients, 46 of 80 (57%) were treated by radiation therapy, 6 of 80 (7.5%) underwent surgical resection, and 28 of 80 (35%) were managed by a combination of surgery and radiation therapy. All patients had staging imaging documenting lack of extracranial metastases at the time of local therapy of BMs. Following the primary management of BM, we observed that providers changed systemic therapy in 32 of 80 (40%), defined as the CST group. CST included both initiation of therapy in 16 of 80 (20%) and switching of adjuvant therapy in 16 of 80 (20%). Median PFS among CST was 7.7 months vs. 7.2 months among no CST (HR = 0.855, 95% confidence interval (CI) 0.53-1.38, p = 0.52). 5-year RMST for the CST group was 16.6 months vs. 12.8 months in no CST group. The difference of 3.8 months (95% CI 4.3-11.8) was not statistically significant. Conclusions: Patients with 1-3 BMs without extracranial disease had a median PFS close to 7.5 months after local therapy. Consistent with current standard of care of maintaining the same systemic therapy approach upon developing isolated BMs, our findings did not demonstrate a significant difference in PFS between patients who experienced a change in systemic therapy compared to those who did not.
Trends of skeletal related events in patients with breast cancer metastasized to bone.
Authors: Lingamaneni Prasanth , Vohra Ishaan , Moturi Krishna Rekha , Farooq Muhammad Zain , Ba Aqeel Sheeba Habeeb , Gupta Shweta 
Published: May 2020

1098 Background: Up to three-quarters of women with advanced breast cancer develop bone metastases, predisposing to Skeletal Related Events (SRE), which are associated with a significant health care burden, poor prognosis, loss of functional independence and a decrease in quality of life. We performed a retrospective analysis on predictors of SRE in this population. We also evaluated temporal trends of outcomes and resource utilization in those with SRE. Methods: Adult breast cancer patients with metastases to bone, admitted from January 2012 to September 2015 were identified from the Nationwide Inpatient Sample database. Based on previous studies, SRE was defined by using ICD-9 codes for pathologic fracture, spinal cord compression, necessity for radiation to bone or surgery to bone. Multivariable analysis of predictors of SRE in patients with breast cancer metastatic to bone, as well as mortality in the SRE group were performed. Temporal trends of resource utilization across the years were evaluated. Results: A total of 143,455 patients with breast cancer with metastases to bone were identified, of which 17.2% had SRE. Patients with SRE had a mean age of 66 years and were predominantly white (70.2%). After adjusting for confounders, African Americans and Hispanics were less likely than Whites to develop SRE. On multivariable analysis, only comorbidity burden (in the form of high Charlson comorbidity index) predicted inpatient mortality. Rates of SRE in breast cancer patients with bone metastases did not change over the years (17.2% to 17.1%). Inpatient mortality of patients with SRE remained stable (3.76% to 3.79%). There was a statistically significant increase in surgical intervention (43.4% to 47.7%, p<0.01) and decrease in radiation to bone (25.7% to 19.7%, p<0.001) over time. Length of hospital stay and total hospital charges, after adjusting for inflation, remained largely unchanged. Conclusions: Incidence of SRE, inpatient outcomes and health care costs remained stagnant in those with metastatic breast cancer between 2012 and 2015, despite the advent of novel bone-targeted agents. There has been an increased trend towards surgical intervention and less utilization of local radiation over time. [Table: see text]
Trainee and workforce diversity in hematology and oncology: Ten years later what has changed?
Authors: Velazquez Manana Ana I. , Leibrandt Ryan , Duma Narjust 
Published: May 2020

11000 Background: The diversification of the healthcare workforce has been identified as a strategy to address health disparities and increase patient-physician trust. A prior review of diversity among oncology fellows up to 2010, showed an increase in female representation over 17 years, but no change in underrepresented minorities (URM). We aim to assess the changes in hematology and oncology (HO) fellowship diversity over the last decade and how this compares to our workforce. Methods: Publicly available registries were used to assess differences among female and URM HO fellows, HO fellowship applicants, internal medicine (IM) academic faculty, IM residents, medical school graduates (MSG), and the US population in 2019. These were compared to the 2016 HO practicing physicians. Changes in URM and female HO fellow representation from 2009 to 2019 were assessed. Data was analyzed using binomial tests and simple linear regression models. Results: Female representation among HO fellows (43.8%) was increased when compared with HO practicing physicians (+11.8%, p < 0.0001) and IM faculty (+3.2%, p = 0.0079); no difference from IM residents or HO applicants. Female HO fellows were underrepresented when compared with MSG (-4.0%, p = 0.0014) and US population (P < 0.0001). Hispanic HO fellows (6.1%) had increased representation when compared to IM faculty (+2.7%, p < 0.0001), but were underrepresented when compared to IM residents (-2.2%, p = 0.0012) and US population (p < 0.0001). The proportion of Hispanic HO fellows was no different when compared to HO practicing physicians, HO applicants, and MSG. African American (AA) fellows (3.8%) were underrepresented when compared to IM residents (-2.0%, p = 0.0005), HO applicants (-1.7%, p = 0.0465), MSG (-2.4%, p = 0.0001), and US population (p < 0.0001). AA fellows were increased when compared to HO practicing physicians (+1.5%, p = 0.0002), but no different than IM faculty. Asian HO fellows were increased when compared to IM residents, MSG, and US population. Over the last 10 years there has been no significant change in the proportion of AA or female HO fellow representation, with a decreasing trend in Hispanics (-0.14% per year, p = 0.04).Conclusions: The current state of diversity in HO workforce still requires attention. Despite ongoing efforts, females, AA, and Hispanics continue to be underrepresented. The decreasing trend in Hispanic representation and clear differences in diversity between HO fellowships and IM residencies calls for action among fellowship programs and national societies to increase URM engagement and recruitment.
Feasibility of developing a Twitter journal club for hematology/oncology education.
Authors: Henry Elizabeth , Das Devika Govind , Murphy Martina Cathryn 
Published: May 2020

11004 Background: Medical trainees are increasingly utilizing social media platforms for professional development, networking and education. Twitter chats (TC) are a growing tool to engage health professionals in virtual multi-institutional, cross-discipline discussions. A meta-analysis of Twitter as a tool in residency education demonstrated high rates of satisfaction and concept retention. Despite rapid uptake, few studies address needs for social media use and implementation in graduate medical education. Methods: We created a Twitter account (@HOjournalclub) and registered a certified hashtag (#HOJournalClub) with healthcare symplur. For each monthly TC, a specific tumor type and relevant publication was selected. This information was disseminated and amplified to reach trainees on Twitter. A content expert was invited to each TC to provide additional commentary. During TCs, participants answer questions based on domains of critical journal appraisal. Qualitative and quantitative analysis was performed. Basic demographics and tracked hashtag use to measure impressions, participants, and tweets per TC were gathered. Responses were collated and general themes were assessed. Participants were surveyed on ease of participation, article accessibility, and prior use of social media for education. Results: Since inception, @HOJournalClub has grown to >650 followers. Most are US-based (83%) medical trainees or healthcare professionals. Additional followers are in South America, Africa, UK, Europe, Middle East, India, East Asia and Australia. Gender is evenly distributed (51% male, 49% female.) Five #HOJournalClub chats have been held to date. Each attracted a mean of 30 participants, generating a mean of 217 tweets. Chats garnered a mean of 270,000 impressions (221,000-319,000) in the 48h after TC. Most participants accessed the chat in real time, with a small subset responding at alternate times. This asynchronous use has enhanced international participation. In post-TC surveys, majority of respondents report being new (48%) or sporadic (48%) users of TCs. Survey participants reported TC participation increased interaction with others in the field, improved literature appraisal skills and led to changes in clinical practice. Conclusions: Implementation of a Twitter-based journal club is feasible and attracts participation from trainees, promoting engagement and networking. It represents a novel educational tool for engagement in multi-institutional, multi-national and cross-discipline discussion of relevant hematology/oncology literature.