bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time intervals between U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) new cancer therapy approvals.
Authors: Lythgoe Mark , Krell Jonathan , Warner Jeremy Lyle , Desai Aakash , Khaki Ali Raza 
Published: June 2021

1575 Background: Novel therapies are transforming cancer care. Regulatory review and approval are essential to deliver safe and efficacious innovations to patients. Studies prior to 2010 describe quicker approval decisions for new oncology drug registrations with the FDA compared to the EMA (median delay 238 days). Both regulatory agencies have subsequently improved procedures to expedite approval times. We compared regulatory market authorisation dates at the FDA and EMA for new oncology therapies from 2010-2020. Methods: New oncology therapeutic approvals between 2010-2020 were identified from the FDA and EMA regulatory databases. We analysed only initial approvals (not supplementary licenses) for active anti-cancer therapies (excluding biosimilars and supportive drugs). The delay in regulatory approval between the FDA and EMA was calculated in calendar days. We further analysed therapies by therapeutic class, evaluating for significant differences. Results: We identified 108 new therapy registrations during the study period. 104 (96.3%) therapies were approved by the FDA and 90 (83.3%) had EMA market authorisation. 4 (3.7%) drugs were not FDA registered, including 3 unsuccessful applications and 1 which sought licensing in a different indication. 18 (16.5%) drugs were not EMA registered, including 9 (8.8%) which did not pursue EMA licensing, 3 (2.9%) withdrawn licensing applications, 3 (2.9%) sought licensing in different tumour group/indication, 1 (0.9%) rejected application and 2 (1.9%) with applications under review at submission date. Of the 86 drugs approved by both agencies, 80 were approved first by the FDA and 6 by the EMA. The median delay in approval between the FDA and EMA was 227 days (IQR:124-354 days). Table shows approvals by therapeutic class. The shortest median time difference for approval was for monoclonal antibodies (171 days) with the longest for kinase inhibitors (281 days). Conclusions: This study shows more new oncology therapies are approved by the FDA than the EMA. Patients in the US typically have access to approved therapies earlier than in Europe. From 2010 to 2020 the median delay between FDA and EMA approval was 227 days, falling by 11 days compared to 2003-10, [non-statistically significant]. Such lengthy delays could exceed the life expectancy of many patients with advanced cancer. Innovations for accelerated approval at both the FDA (e.g. Project Orbis) and EMA (e.g., PRIME) have potential to lead to faster approval.[Table: see text]
Improvement in incident resolution time with implementation of an electronic patient management solution at a community oncology practice.
Authors: Wilfong Lalan S. , Patel Amila , Ortega Lance , Boren Rhonda , Pearson Ben , Jensen Terry Lynn , Books Holly , Hudson Kathryn Elizabeth , Patt Debra A. 
Published: June 2021

1578 Background: Value-based care models such as the Oncology Care Model incentivize practices to reduce hospitalizations and emergency department (ED) visits. Texas Oncology found that most ED visits occurred during regular business hours. Prolonged patient call back times were consistently rated poorly on satisfaction surveys and often led to ED visits for symptoms that could be managed in our offices. We partnered with Navigating Cancer (NC) to implement an electronic patient management technology solution. Methods: For each of our 200 locations, call volume was estimated based on clinic volume. We then reallocated or hired dedicated triage nurses and operators. Incoming calls were entered into the NC dashboard by operators as incidents which were routed based on symptom priority following system generated prompts. Incident volumes and resolution times were tracked. We instituted PDSA cycles at all locations with a goal of less than 90-minute resolution of symptom-related incidents Utilizing the electronic dashboard allowed us to continue this initiative during the COVID-19 public health emergency as our staff could work remotely. Nurses were able to document if a potential ED visit was avoided. These data points allowed our practice to establish comprehensive and strategic actions plans for quality improvement. Results: We finalized implementation of the system in February of 2020. Total incidents for 2020 were over 1 million, averaging over 5000 per location. Resolution time for all incidents started at 3.2 hours pre-implementation and improved to 2.2 hours in December of 2020. Resolution times for symptom-related incidents started at 2.3 hours pre-implementation and ended at 1.5 hours in December of 2020 with over 60% resolved under one hour. 8% of symptom-related incidents resulted in definite or probable ED avoidances by nursing assessment. Shortness of breath, vomiting, chills, and weakness were the top symptom types addressed for ED avoidances. Conclusions: An electronic patient management solution with PDSA cycles of quality improvement can markedly reduce call back times, especially for symptom related calls. We believe managing symptoms in a timely fashion will lower ED visits and hospitalizations as well as improve patient satisfaction. We will report on these outcomes once available.[Table: see text]
Profiling of immune checkpoint biomarkers by multiplex immunofluorescence in breast cancer brain metastases.
Authors: Griguolo Gaia , Tosi Anna , Guarneri Valentina , Dieci Maria Vittoria , Fineberg Susan , Ventura Annavera , Bauchet Luc , Jacob Jack , Rigau Valerie , Jacot William , Rosato Antonio , Darlix Amelie , Conte Pierfranco 
Published: June 2021

2021 Background: Despite potential clinical implications, the complexity of immune microenvironment in breast cancer (BC) brain metastases (BM) is still poorly understood. Multiplex immunofluorescence (mIF) allows simultaneous visualization of several IF labeled proteins while maintaining spatial information. This novel technique can be used to comprehensively describe BCBM immune microenvironment, potentially providing useful information to guide novel therapeutic approaches. Methods: Clinical data and archival BM samples from 60 BC patients undergoing neurosurgery (2003-2018) at three institutions were collected. BCBMs were characterized using a custom mIF panel, including immune checkpoint and co-inhibitory molecules (CD3, PD1, PD-L1, TIM3, LAG3, CD163) and localization (keratin for tumor recognition) markers. Mean marker density was determined by digital image analysis (positive cells/mm2) and classified in tumor and stroma areas. Associations between immune marker densities, BC subtype and overall survival from BM diagnosis (OS) were studied. Results: Sixty BCBM samples were analyzed; 32% HR+/HER2-, 38% HER2+, 30% HR-/HER2-. At a median follow-up of 43 months, the only clinical variable associated with OS was BC subtype (shortest for HR-/HER2- and longest for HER2+, p=0.02). In the total sample area and tumor area, no significant difference in marker density was observed according to BC subtype. In the stroma area, a significant difference in TIM3+ cell density was observed according to BC subtype (highest density in HR+/HER2- and lowest density in HER2+ tumors, Kruskal-Wallis p=0.017). Higher CD163 density (a marker of M2 macrophage polarization), both in the tumor and in the stroma area, was significantly associated with worse OS, even after correction by BC subtype. In the subgroup of patients with HR+/HER2- BCBM, high TIM3+ cell density in the stroma area was significantly associated with longer OS (median OS 54.1 versus 23 months respectively for TIM3+ density above and below median value; p=0.01). Conclusions: In BCBM, stromal TIM3+ immune infiltrate differs according to BC subtype. M2 macrophage polarization is consistently associated with worse OS across all BC subtypes and might represent a potential therapeutic target for these patients.[Table: see text]
A phase II trial combining nivolumab and stereotactic brain radiosurgery for treatment of brain metastases in patients with NSCLC.
Authors: Wong Philip , Florescu Marie , Plourde Marc-Emile , Panet-Raymond Valerie , Pavic Michel , Owen Scott Peter , Masson-Cote Laurence , Menard Cynthia , Routy Bertrand , Tehfe Mustapha , Blais Normand , Roberge David , Masucci Laura 
Published: June 2021

2023 Background: Previous studies suggested activity of anti-PD-1 in brain metastases from non-small cell lung cancer (NSCLC) and renal cell cancer (RCC). This investigator initiated phase 2 trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with brain metastases from NSCLC and RCC. Methods: This is a multicentre open-label trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated brain metastases, no whole brain radiotherapy and no prior immunotherapy were eligible. Study treatment commenced with a dose of nivolumab (240mg or 480mg IV), which was continued for up to 2 years at bi-weekly or monthly intervals until progression. SRS (15-21Gy) to all visible un-irradiated brain lesions was administered within 14 days after the first dose of nivolumab (cycle 1). Patients were followed by brain MRI, CT scan of the chest, abdomen and pelvis, neurocognitive and quality of life questionnaires (FACT-Br) every 3 months. The primary endpoint was intracranial progression free survival (icPFS), with death and disease progression within the brain as events. Results from NSCLC patients are presented here. Results: Of the 26 study patients, 22 NSCLC patients were enrolled between Aug 2017 and January 2020. Patients had a median of 2 (1-9) brain metastases. The median diagnosis-specific graded prognostic score was 2 (1-3). Median treatment and follow-up durations were 4.3 months (0-24.8 months) and 11 months (0-24.8 months), respectively. Forty-two percent of the patients had received prior cytotoxic chemotherapy, and 1 patient had received prior brain SRS. PD-L1 status was known for 21 of the 22 NSCLC (12 with ≥50% PD-L1 expression (DAKO 22C3). Median icPFS was 5.0 months (3 intracranial progression and 8 deaths without progression in the brain). Accounting for death as a competing risk, the 1-year cumulative incidence of intracranial relapse was 17.4%. Median extracranial PFS and overall survival were 2.9 months and 14 months, respectively. Four grade 3 adverse events in 2 patients were related to nivolumab or SRS. The rate of survival free of neurocognitive decline (Hopkins Verbal Learning Test total recall) was estimated to be 89% by 4 months. Mean FACT-Br total scores were 89.4 at baseline and improved (p = 0.01) to 139.3 within 2-4 months. Conclusions: Neurocognitive and quality of life assessments suggest that upfront SRS during nivolumab is well tolerated. High intracranial control was observed, but deaths from extracranial disease progression resulted in short icPFS. Studies evaluating the strategic addition of SRS combined with more efficacious systemic treatments are needed. Clinical trial information: 02978404.
Palliative care service utilization and advance care planning issues for adult glioblastoma patients: A systematic review.
Authors: Wu Adela , Colon Gabriela Ruiz , Aslakson Rebecca , Pollom Erqi L. , Patel Chirag B 
Published: June 2021

2036 Background: Glioblastoma (GBM) is a devastating disease with a median survival under 2 years and a 10-year survival rate of 0.71%. As patients with GBM suffer simultaneously from both a terminal cancer and a neurodegenerative disease, proactive provision of advance care planning (ACP) and palliative care (PC) seem appropriate. We conducted a systematic review exploring the published literature on the prevalence of ACP, healthcare services utilization at the end of life (EOL, including PC services), and location of death among adults with GBM, and the experiences of their caregivers. Methods: We systematically searched PubMed, Embase, Scopus, and Cochrane Library from database inception until 12/20/2020, using search terms including ‘glioblastoma’, ‘end of life’, ‘advance care planning’, and ‘advance directive’. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed. Inclusion criteria were quantitative and qualitative studies written in English of adults with GBM and their caregivers, with at least 20 subjects. Included studies were assessed for quality using the Newcastle-Ottawa Scale. Results: We screened 344 article abstracts and 39 full text articles to yield a final cohort of 16 articles that fit inclusion criteria. These studies reported the experiences of 10,706 GBM patients and 123 caregivers. All were nonrandomized studies conducted in six countries with all but two published in 2014 or later. Across studies, ACP documentation varied from 4-55%, PC referral was pursued in 39-40% of cases, and hospice referrals were made for 66-76% of adult GBM patients. Hospitalizations frequently occurred at the EOL, 20-56% of patients spent over 25% of their overall survival time hospitalized, and 39-64 % of deaths occurred in the home setting. Caregivers commonly reported restrictions on their ability to work (60%), financial barriers to care (29%), and feeling unprepared (29%). Conclusions: Despite having both a terminal disease and neurocognitive decline, a majority of adults with GBM do not pursue ACP or have access to PC. There is a dearth of focused and high-quality studies on ACP, PC, and hospice use among adults with GBM. Prospective studies that address these and additional aspects related to end-of-life care in this population, such as healthcare costs and inpatient supportive care needs, are needed.
A phase II study of anlotinib combined with STUPP regimen in the treatment of patients with newly diagnosed glioblastoma (GBM).
Authors: Li Peijing , Chen Yuan yuan Yuan , Lai Shuzhen , Jiang Fagui , Liu Xiaohui , Tao Changjuan , Wang Lei , Liu Guihong , Huang Jing , Tang Yiqiang , Liu Zhigang , Shen Guoping , Li Chaoming , Xie Tieming , Lu Fangxiao 
Published: June 2021

2039 Background: STUPP regimen is now the standard treatment for newly diagnosed GBM, while the effectiveness is limited. This study assessed the efficacy and safety of anlotinib, a multitarget tyrosine kinase inhibitor, combined with the STUPP regimen in treating these patients. Methods: This is a phase II, multicenter, open-label, single-arm trial (NCT04119674). Thirty-three patients (17 males and 16 females) were enrolled from 8 hospitals in China between January 2019 and February 2021. Inclusion criterion included 1) newly diagnosed histologically confirmed glioblastoma (WHO grade IV), 2) 2-6 weeks (wks) after surgery with healed incision, 3) 18-70 years old, 4) KPS≥60, 5) at least one measurable lesion according to RANO criteria, 6) radiotherapy (RT), chemotherapy, immunotherapy or biotherapy naïve. All patients received 54-60 Gy radiation (1.8-2.0 Gy per fraction, five days per week) concurrently with temozolomide (TMZ, 75mg/m2, orally, QD) and anlotinib (8mg, orally, QD, d1-14/3wks). Adjuvant therapy started four weeks after RT completion, including six cycles of TMZ (150-200mg/m², orally, d1-5/4wks) and eight cycles of anlotinib (8mg, orally, QD, d1-14/3wks). Patients who completed adjuvant therapy were administrated anlotinib continuously until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Safety assessment was done in patients who received at least one dose of study agent. Results: The median age is 52 (range 32-69) years. Analyses included data collected through February 6, 2021. The median treatment duration was 6.5 months. The median PFS was not reached, and the median overall survival (OS) was 17.4 months [95%CI 11.6-23.2]. The 1-year PFS and OS rate was 84.0% and 100.0%, respectively. Tumor response occurred in 21 patients, 63.6% (21/33) objective response (CR/PR), and 24.2% (8/33) patients had stable disease (SD).The clinical benefit rate (CBR), defined as the proportion of patients who achieved durable disease control (CR/PR/SD) more than six months, was 57.6% (19/33). Hypertension (6.1%) was the most common ≥grade 3 adverse event. No treatment related death occurred in this study through the last follow-up. Overall, toxicities are mild and manageable. Conclusions: Anlotinib combined with the STUPP regimen is efficacious and well-tolerated in newly diagnosed GBM patients. Clinical trial information: NCT04119674.
A phase II, open-label, single-arm trial of pembrolizumab for refractory atypical and anaplastic meningioma and hemangiopericytoma.
Authors: Yust-Katz Shlomit , Amiel Alexandera , Siegal Tali , Limon Dror 
Published: June 2021

2064 Background: Grade II and III meningiomas are invasive tumors which tend to recur following initial treatment and are associated with shorter survival (relative to grade I). Hemangiopericytoma (HPC) is a dural based tumor that originates in the pericytes in the walls of capillaries. Treatment options for these tumors include surgical resection and radiation. There are no defined standard treatments after failure of these modalities, and efficient systemic treatments are lacking. This trial concept was formed following previous reports of high PD-L1 levels in anaplastic meningioma. We currently report our initial experience with pembrolizumab for refractory atypical/anaplastic meningioma (RAM) and HPC patients. Methods: This is a single arm, single institute, phase 2 trial. Inclusion criteria included patients with RAM or HPC whose all previous lines of treatment were exhausted. All patients were treated with pembrolizumab (200mg every 3 weeks) until disease progression. Primary endpoint was 6- and 12-months progression free survival (PFS). The study was planned for 25 patients and we report here preliminary results. Results: Through February 2021, 12 patients were enrolled to this study (two with HPC, 10 with RAM). After a median follow up of 18.5 months, the 6 and 12 months PFS were 25% and 16.7% respectively, with a median PFS of 2.75 months. Two patients had a partial response while all others progressed, making the overall response rate 16.7%. One of the responders had HPC and has been stable for 30 months, while the second had atypical meningioma and was stable for 13 months. Median survival has not been yet reached; 1 year survival rate was 82.5%. Grade 3 toxicities included hyperglycemia, elevated liver enzymes and fatigue (that did not cause treatment discontinuation), with no grade 4 or 5 toxicities. PD-L1, mutation burden, MSI and other genomic analyses are still pending. Conclusions: Pembrolizumab induced a low response rate for RAM and HPC. However, a subset of patients might benefit from this treatment with a prolonged response period. To define this subpopulation further molecular studies are needed. Clinical trial information: NCT03016091.
ARTISTRY-1: Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors.
Authors: Boni Valentina , Winer Ira Seth , Gilbert Lucy , Vaishampayan Ulka N. , Rosen Seth David , Muzaffar Jameel , Spreafico Anna , McDermott David F. , Chu Quincy S. , Dumas Olivier , Chauhan Aman , Chaudhry Arvind , Tomczak, MD Piotr , Bruno Debora S. , Du Yangchun , Bidollari Ilda , Rege Jessicca Martin , Ernstoff Marc S. , Strauss James F. , Velcheti Vamsidhar 
Published: June 2021

2513 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds the intermediate-affinity interleukin-2 (IL-2) receptor complex to preferentially activate CD8+ T cells and natural killer cells with minimal expansion of regulatory T cells, designed to leverage antitumor effects of the IL-2 pathwaywhile mitigating potential toxicity that would limit use. Methods: ARTISTRY-1 (NCT02799095) is a phase 1/2 study. Parts A (dose escalation 0.1-10 µg/kg) and B (6 µg/kg [recommended phase 2 dose]) are monotherapy; pts receive intravenous nemvaleukin for 5 days every 14 or 21 days. In Part C, pts receive nemvaleukin (3 or 6 µg/kg) every 21 days in combination with pembrolizumab (200 mg on day 1). We present safety and antitumor activity (RECIST v1.1, iRECIST) data as of 12/02/2020. Results: In Part A, 39 pts received nemvaleukin. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. Part B enrolled immune checkpoint inhibitor–pretreated pts into melanoma or renal cell carcinoma (RCC) cohorts. 18 pts with melanoma enrolled; 10 were evaluable, 2 (both with metastatic mucosal melanoma) achieved a partial response (PR; 1 unconfirmed). 24 pts with RCC enrolled; 1 of 16 evaluable pts achieved a PR (awaiting confirmation). 12 pts in each cohort continue on study. In Parts A and B, treatment-related adverse events in ≥40% included chills (74.4% and 52.4%, respectively) and pyrexia (74.4% and 47.6%, respectively). In Part C (83 evaluable pts), 12 objective responses (OR) were observed; an additional 5 pts had stable disease (SD) >6 months (1 pt with breast cancer, 2 with ovarian cancer, and 2 with non-small-cell lung cancer). Nemvaleukin did not demonstrate any additive toxicity to that already established with pembrolizumab alone. OR data are summarized in the table. Conclusions: Nemvaleukin was generally well tolerated and demonstrated antitumor activity as monotherapy and in combination with pembrolizumab. Pharmacodynamic studies to identify biomarkers are ongoing. Future research of monotherapy and combination therapy with nemvaleukin is warranted. Clinical trial information: NCT02799095. [Table: see text]