bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective analysis of clinical outcomes of patients with advanced non-small cell lung cancer (NSCLC) exposed to immunotherapy: The experience of the Oncology Center of Hospital Moinhos de Vento.
Authors: Venero Fernando Castilho , Andrade Helena , Roithmann Sergio , Casarotto Fernanda Cano , Lima Geraldine Eltz de , Geib Guilherme 
Published: May 2020

e21720 Background: Lung cancer has the highest mortality rate among malignant neoplasms worldwide. Most cases present an advanced stages. From the last few years, the target drugs and immunotherapy (IO) have emerged as important therapeutic options in this scenario. In Brazil, in 2018, this disease was responsible for 8.7% of cases of malignant neoplasms in men and 6.2% of cases in women. When looking at data from our state, Rio Grande do Sul, the highest rates in the country are noted, with an estimated rate of 40.22 cases for every 100 thousand men and 20.49 cases for every 100 thousand women. Although the available trials point to significant improvements in the clinical outcomes, the real impact of using such treatments on patients in our community practice, real-world scenario, is unknown. Methods: Through the detailed analysis of the institutional electronic medical record, we included patients with metastatic NSCLC, followed up on an outpatient basis at the Oncology Center of Hospital Moinhos de Vento, who had received at least one dose of nivolumab, pembrolizumab or atezolizumab, either as monotherapy or in combination therapy with chemotherapy, in any line of cancer treatment, in the period from January 2015 to June 2019. Primary endpoint was overall survival (OS) and secondary endpoints were time-to-treatment discontinuation (TTD) and treatment-related toxicity (TRT). Results: 41 patients met criteria. The sample consisted of patients with a mean age at diagnosis of 67.7 years, the majority being male (53.7%), stage IVB disease (53.7%), previously smokers (61%) and with non-squamous NSCLC (75.6%). Central nervous system (CNS) metastases were present in 26.8% of patients. About 51.3% (n = 21) received IO as second line or later treatment. At this group, nivolumab was the main IO (81%). The median OS in the first line (1L) of treatment was not reached while in second line and beyond was 10.0 months (3.4 - 16.5), with no statistical difference (p = 0.071). The median TTD was higher in patients whose received IO at 1L (17.0 months vs 7.0 months, p = 0.045). Pneumonitis was the main toxicity being present in 7.1% of patients. Colitis, thyroiditis and hepatitis were seen in one patient each. Conclusions: in general, we were able to observe that in our real-world scenario, IO is well tolerated, regardless of the treatment line. In addition, OS met the findings of the landmark clinical trials.
Impact of adherence to National Comprehensive Cancer Network (NCCN)-recommended first-line therapy on treatment duration for patients with advanced non-squamous non-small cell lung cancer (NSCLC).
Authors: John Ani K , Yang Baiyu , Shah Roma 
Published: May 2020

e21727 Background: Identification of molecular alterations can provide essential information to guide personalized treatment selection for advanced non-small cell lung cancer (aNSCLC) patients. However, in routine oncology practice, not all eligible patients receive biomarker testing and receive treatment according to the testing results following the National Comprehensive Cancer Network (NCCN) guideline. We aim to examine the impact of adherence to guideline-recommended therapy on the duration of treatment in a real-world setting. Methods: Patients diagnosed with non-squamous aNSCLC (stage IIIB and above) and received the first-line of therapy (FLOT) between 2011 and 2019 from the nationwide Flatiron Health electronic health record-derived de-identified database were included in this analysis. Adherence was defined as using any NCCN guideline-recommended FLOT consistent with a patient’s biomarker testing results (EGFR, ALK, ROS1, BRAF and PD-L1) assessed up to 90 days before and/or 14 days after the FLOT start date. Non-adherence was defined as not receiving guideline-recommended FLOT based on the above-mentioned biomarker results, or patients treated without evidence of biomarker testing. Median time to treatment discontinuation (TTD) of FLOT was calculated using Kaplan-Meier analysis. Unadjusted and adjusted Cox proportional hazards regression models were used to evaluate the association between guideline adherence and TTD. Results: A total of 17,137 eligible patients were included (67.5% adherent, 32.5% non-adherent). Mean age at diagnosis was 67 years (SD: 10 years). The majority of patients (92%) received care at a community clinic, and 73% reported having insurance plans. Overall, 87.2% had discontinuation of FLOT, including 84.9% in the adherent group and 92.0% in the non-adherent group. The median TTD was 155 days (95% CI 153-159) in the adherent group and 128 days (95% CI 125-132) in the non-adherent group. Adherent patients had a lower risk of FLOT discontinuation in the unadjusted analysis (hazard ratio [HR] 0.78, 95% CI 0.76-0.81), which remained significant after adjusting for potential confounders including age at FLOT start, sex, history of smoking, and stage at initial diagnosis (HR 0.76, 95% CI 0.74-0.79). Conclusions: Among non-squamous aNSCLC patients, the majority of patients were adherent to NCCN guidelines. Adherence was associated with lower risk of discontinuation and longer duration of FLOT.
Brain metastasis in lung cancer: Are there any predictive risk factors?
Authors: Ait Batahar Salma 
Published: May 2020

e21740 Background: Lung cancer is the first cause of death by cancer worldwide. Brain metastases in lung cancer are associated to an even poorer prognosis of this cancer. Identifying patients with a higher risk of developing brain cancer may help their prognosis by including systematic brain radiotherapy to their treatment. But what are risk factors of brain metastasis occurrence in lung cancer patients? Methods: To answer this question, we conducted a case control study comparing two groups of lung cancer patients. The cases group included 35 lung cancer patients with brain metastasis at the moment of diagnosis while the control group was made of 49 lung cancer patient with no brain metastasis at the moment of diagnosis. Many parameters were compared between the two groups such as: professional exposure, type and duration of smoking, medical history, clinical and radiological presentation as well as the histological type of the carcinoma. Results: The mean age was 56 for the cases group and 61 for the control group. Nonsmokers represented 14% in the cases group and 4% in the control group. The average smoking was 34 pack-year for the cases group and 31 pack-year for the control group and in both groups 51% of patients smoked a mixture of tobacco and Cannabis. 36% of the control group patients had an exposure to a professional carcinogen while 48% of the cases group patients had one. Digital clubbing was found in 62% of cases group patients and in 51% of the control group patients. 17% of the cases group patients had two more metastases outside the lungs and other than the brain ones while this rate was only 6% for the control group patients. The mean level of LDH (Lactate Dehydrogenase) was 340 U/L for the cases group and 342 U/L for the control group while the CRP (C- reactive protein) one was 78 mg/L for the cases group and 59 mg/L for the control group. The main histological type found in both groups was Adenocarcinoma (25% in the cases group and 18% in the control group) followed by the poorly differentiated carcinoma in the cases group and the squamous cell carcinoma in the control group. Small cell carcinoma was found in 5% of the patients with brain metastases and in 8% of the patients without brain metastases. Conclusions: Patients with brain metastases have a higher professional carcinogens exposure, a higher percentage of nonsmokers, more digital clubbing, and higher CRP levels than patients with no brain metastases. They also have more than one metastasis at the moment of the diagnosis and the predominant histological types are Adenocarcinoma and poorly differentiated carcinoma.
Interim results of prospective pilot phase II trial of concurrent anti-PD-1 and stereotactic radiosurgery (SRS) for melanoma and NSCLC patients with brain metastases (NCT02858869).
Authors: Khan Mohammad Khurram , Nasti Tahseen , Yushak Melinda Lynne , Lawson David H. , Switchenko Jeffrey M. , Wallington David , Kleber Troy , Kirmani Khadija , Owonikoko Taofeek Kunle , Ramalingam Suresh S. , Ahmed Rafi 
Published: May 2020

e22002 Background: The safety and efficacy of concurrent radiotherapy (SRS) and single agent (anti-PD-1) checkpoint inhibitor have not been established. We report the first results of an interim analysis from a prospective pilot phase II trial of cocurrent anti-PD-1 (pembrolizumab) and SRS for brain metastases Methods: Food and Drug Administration (FDA) and Institutional Review Board (IRB) approval were obtained to conduct a prospective trial with three different radiation dose arms (Arm A: 6 Gray (Gy) in 5 fractions (fx), 9 Gy in 3 fractions, and 18-21 Gy in single fraction) in combination with Pembrolizumab. Patients with not more than 10 brain metastasis who have not received prior brain radiation were eligible. Routine statistical methods were used to estimate control of brain metastases within the irradiated volume (local control, LC), anywhere intra-cranial control (AICC), progression free survival (PFS), and overall survival (OS). RECSIST 1.1 criteria were used to assess. Safety was monitored using NCI CTCAE v 4.0 criteria for toxicity assessment while intracranial and extracranial treatment response was assessed according to RECIST 1.1 criteria. Patients were enrolled from 2017-2020. Results: We report interim analysis from the first 18 patients of planned 36 patients who have completed treatments on each of the three different radiation dose arms (12 patients per arm). All patients received PD1 on day 0, immediately followed by SRS within 2-3 days. At 6 months, the LC (94.0% [CI: 65-99.1]), AICC (70.6% [CI: 43.1-86.65]), PFS (50% [24.5-71]), and OS (77.4% [50.3-90.9]) were higher than expected with either SRS alone or PD1 alone, and appear to be comparable to dual checkpoint, but with much less toxicity. No grade 4 or grade 5 toxicity was noted. The primary endpoint of safety, based on the absence of grade 3 CNS toxicity at 3 months was met with all three radiation dose arms. Overall rate of grade 1-3 toxicity was also within acceptable range. Conclusions: Preliminary prospective results of concurrent SRS and single agent pembrolizumab for brain metastases in melanoma and NSCLC supports this strategy as a safe and promising option compared with dual agent therapy. Clinical trial information: NCT02858869.
Correlation of nivolumab 480 mg Q4W with better survival than other nivolumab monotherapy schedule in metastatic melanoma patients.
Authors: Simeone Ester , Mallardo Domenico , Giannarelli Diana , Festino Lucia , Vanella Vito , Trojaniello Claudia , Vitale Maria Grazia , Palla Marco , Scarpato Luigi , Capone Mariaelena , Madonna Gabriele , Curvietto Marcello , Esposito Assunta , Hauber Federica , Sandomenico Fabio , Cavalcanti Ernesta , Caraco Corrado , Mainardi Paolo , Grimaldi Antonio Maria , Ascierto Paolo Antonio 
Published: May 2020

e22008 Background: Nivolumab (nivo) 480 mg (Q4W) flat dose has already been assessed for safety compared to other drug dose regimens in clinical trials [1]. However, few data about melanoma patients treated in real life are available. The aim of our study was to evaluate safety and efficacy in metastatic melanoma pts treated with different schedules of nivo in clinical practice. Methods: We analyzed data from n.124 metastatic melanoma patients who were treated from Jun 2016 to Oct 2019 at NCI of Naples. 83/ 124 (67%) were treated with nivo 480 mg Q4W, and 41/124 (33%) with other schedules (n.26 [63%] with 3 mg/kg, and 15 [37%] with 240 mg Q2W). All patients were stage IV, and n.44/124 (35%) were B-RAF mutated. Nivo was administered as first line in n.95 patients (77%), n. 24 [19%] as second line, and 5 (4%) as third line. Among B-RAF mutated patients, n.23/44 [52%] received a first line with a target-based regimen. According to our previous work [2] we calculated Body Mass Index (BMI). In 93/124 pts the BMI was < 25 (75%), while in 31/124 (25%) BMI was ≥ 25. In the table are summarized other clinical characteristics. Hazard Ratios and their 95% confidence intervals (95% CI) were estimated with the Cox model. Association between factors was evaluated with the chi-square test. Results: Our data suggests that nivo 480 mg (Q4W) correlates with a better OS compared with other regimens (HR = 0.48; [95% CI: 0.24-0.96; p = 0.04]). Moreover, better OS trend was also observed in pts with BMI > 25 (HR = 0.48; [95% CI: 0.33-1.74]; p = 0.51) and with B-RAF mutation (HR = 0.53; [95% CI: 0.25-1.14); P = 0.10]). The incidence of any grade toxicities did not differ according the dosage. Conclusions: This retrospective analysis showed a trend of better outcome with nivo 480. This observation warrants further investigation in a larger cohort of pts. [Table: see text]
Role of AXL in metastatic melanoma and impact of TP-0903 as a novel therapeutic option for melanoma brain metastasis.
Authors: Tizpa Eemon , Young Hannah J , Bonjoc Kimberley-Jane C. , Chang Chou-Wei , Liu Yilun , Foulks Jason M , Chaudhry Ammar 
Published: May 2020

e22021 Background: Melanoma brain metastases (MBM) are common with a median overall survival of 4-5 months. Although immunotherapies have improved clinical outcomes and have doubled overall survival in MBM, there is a high incidence rate of relapse caused by drug resistance. AXL, a receptor tyrosine kinase (RTK), is associated with drug resistance and metastasis in many cancers. The activation of AXL via trans-phosphorylation regulates multiple signaling pathways that induce tumor survival, metastasis, drug resistance, and epithelial-to-mesenchymal transition (EMT). In MBM, AXL is upregulated and associated with disease progression, promoting cell invasion and migration. This suggests that targeting AXL can be a novel strategy to overcome treatment-related resistance in MBM. TP-0903, an investigational small molecule inhibitor of AXL, has shown efficacy in reversing the mesenchymal phenotype and re-sensitizing resistant cancer cells to targeted therapies in heme malignancies, pancreatic, and breast cancer. We aim to investigate the efficacy of TP-0903 in MBM. Methods: The Cancer Genome Atlas (TCGA) data was utilized to investigate the signaling pathways downstream of AXL that are upregulated in advanced melanoma. Nine signaling molecules including AKT1, mTOR, and PAK4 were analyzed to identify any correlation between gene expression levels and overall survival. Four metastatic melanoma cell lines were used to evaluate the effect of TP-0903 on cell viability and active AXL downregulation was assessed in vitro through MTS cell viability assays and Immunoblotting. Wound closure assays were executed to understand the functional consequences of AXL downregulation. Results: In all nine genes, high expression levels confer poor survival probability. Cell viability assays of four malignant melanoma cell lines showed that TP-0903 treatment resulted in IC50 values ranging from 32 – 692 nM. Western blot analysis indicated that TP-0903 reduced the levels of phosphorylated AXL in malignant melanoma cell lines. In addition, increasing TP-0903 concentrations reduced the rate of cell migration in these malignant melanoma cell lines. Conclusions: AXL plays a role in EMT, treatment resistance, and metastasis in MBM, resulting in poor survival. Our findings suggest TP-0903 is effective in reducing cell migration, inhibit metastasis, and can be a potential therapeutic option in MBM.
Lack of evidence to support large-panel genomic testing in treatment selection for malignant melanoma.
Authors: Dimitrova Maya , Kim Min Jae , Donnelly Douglas M. , Giles Keith M. , Moran Una , Weber Jeffrey S. , Osman Iman , Jour George 
Published: May 2020

e22027 Background: Genomic profiling informs clinical decision-making for malignant melanoma (MM) as specific tumor mutations can be treated with targeted therapy (TT). However, given the range of different panel sizes available and increasing use of immune checkpoint inhibitors (ICI), the clinical significance of upfront, large-panel genomic profiling in MM remains undetermined. Herein, we investigate the impact of panel size and targetable mutational status on first-line treatment selection and outcomes of MM patients from 9 different institutions. Methods: We analyzed data for 1,341 MM patients from 3 cohorts. Cohort 1 included 169 patients enrolled at NYULH and profiled with the 50 gene Ion Torrent panel (IT). Cohort 2 included 256 patients enrolled at MSKCC, profiled with the 400-gene MSK-IMPACT panel (MSK-I). Cohort 3 included 916 patients enrolled at 7 different sites, profiled with whole exome sequencing (WES). Data for cohorts 2 and 3 were extrapolated from publicly available data using cBioPortal. We tested associations between molecular data, treatment choice and overall survival (OS), adjusting for baseline characteristics when available. Results: Treatment information was available for 100%, 25%, and 0% of patients in cohort 1, 2 and 3, respectively. Stage was available for all of cohort 1 (III, n = 68; IV, n = 101) and cohort 2 (III, n = 2; IV, n = 254), but in only 23% of cohort 3 (III, n = 184; IV n = 25). For the IT and MSK-I, BRAF and NRAS were among the top 5 most commonly mutated genes, whereas for WES only BRAF was in the top 5. In cohort 1, 36% (16/45) of BRAF MUT patients received first-line TT vs 25% (66/256) in cohort 2. There was no significant difference for BRAF MUT patients treated with ICI vs. TT in cohort 1 in OS (P = 0.19), nor for BRAF MUT patients from cohort 1 treated with ICI vs. those from cohort 2 treated with TT (OS P = 0.762). Conclusions: Publicly available datasets provide population-level data, however the heterogeneity and deficiency of reported clinical information limits their value and calls for data standardization. Without evidence of clear clinical benefit of a larger panel size, there is a rationale for adopting smaller, more cost effective panels in MM.
Access to innovation through the French Expanded-Access Program and clinical trials in patients with malignant melanoma.
Authors: Christen Claire , Belgodere Laetitia , Guillot Bernard , Kerouani-Lafaye Ghania , Brunel Liora , Turcry Florence , Monard Adrien , Grude Francoise , Guyader Gaëlle , Boudali Lotfi , Albin Nicolas 
Published: May 2020

e22030 Access to innovation through the French Expanded-Access Program and clinical trials in patients with malignant melanoma Background: The arrival of immunotherapy (IT) and targeted therapy (TT) has constituted a revolution in the treatment of metastatic melanoma (MM) since the 2010s. The major challenge was to allow these new treatments to make them available as soon as possible. France has effective tools such as clinical trials (CT) and an expanded-access program (EPA) (through temporary use authorizations (ATU) and temporary use recommendations (RTU)) allowing the use of innovative drug without marketing authorization (MA) in case of therapeutic “dead-end”. Methods: Real-time data collection of nominal and cohort ATU, RTU (between 01/09/2009 and 01/09/2019), and CT authorizations (from 01/12/2017 to 01/09/2019) filed and evaluated by the French national agency for medicines and health products safety (ANSM) in the MM from internal databases. Clinical data of the cATU come from the summary reports produced by the laboratory. Results: 45 CT were authorized in MM, including 51% in early phases and 44% in phase II/III, mainly in the metastatic stage (86%) and with an industrial promoter (73%). IT and TT (63% and 24% respectively) are the most used in experimental arms, mostly in combination. Through the EPA, 3 RTUs were authorized in the adjuvant treatment of MM, 14 drugs benefited of a nATU and 5 obtained a cATU. This has treated 6538 patients (28% of nATU and 72% of cATU). The anti-PD1 and combination therapy of BRAF and MEK inhibitors are the most used, mainly in combination. 80% of the indications are from the second line. The duration of availability of the ATU is 9,85 months before obtaining the MA. Efficacy data in patients receiving cATU of vemurafenib and combination of cobimetinib and vemurafenib showed respectively the following objective response rate (ORR): at 8 weeks of treatment, ORR = 57,7% and 54,7%; at 20 weeks, ORR = 36,7% and 54,7% (IR criteria). For pembrolizumab, at 12 weeks, ORR = 29,7% and at 24 weeks, ORR = 40% (irRC criteria). All of these drugs obtained a MA and an inscription on the reimbursement list after the health technology assessment. Conclusions: Thanks to CT and the French EPA, patients were able to benefit from innovative treatments at an early stage of MM.
Phase II study of apatinib combined with temozolomide in advanced melanoma patients after failure of anti-PD-1 therapy.
Authors: Zhou Li , Cui Chuanliang , Si Lu , Chi Zhihong , Sheng Xinan , LIAN BIN , Wang Xuan , Tang Bixia , Mao Lili , Yan Xieqiao , Bai Xue , Guo Jun 
Published: May 2020

e22043 Background: Immunotherapy is first-line therapy in advanced melanoma. Because of different subtypes and gene alterations, the efficacy of immunotherapy in Asians, mostly comprised of acral and mucosal melanoma, is lower than Caucasians. There are no standard treatment strategies after immunotherapy failure. Chemotherapy and anti-angiogenesis combination showed emerging evidence of activity in mucosal and acral melanoma. This study was to evaluate the efficacy of apatinib combined with temozolomide in advanced immunotherapy refractory melanoma patients (pts). Methods: This prospective, single-arm, phase II study recruited unresectable or metastatic melanoma pts after failure of anti-PD-1 therapy. Other treatment including targeted therapy, chemotherapy, and clinical trials were allowed. Primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). According to the dose recommended from previous phase I study, pts were given apatinib 500 mg every day and temozolomide 300mg day 1-5, 28 days for one cycle. Results: 31 pts were enrolled between Feb 2018 and Dec 2018, with 8 males, average age 55 yrs (range 24 – 69 yrs). 13 pts (41.9%) were from mucosal primaries, 9 (29.0%) acral, 5 (16.1%) cutaneous (non-acral), and 4 (12.9%) unknown primaries. One had BRAF mutation, 1 CKIT, and 3 NRAS mutations. 9 pts (29.0%) were classified as IIIc/M1a, 9 (29.0%) M1b, and 13 (41.9%) M1c. 18 pts (58.1%) had elevated lactate dehydrogenase level. All pts progressed after anti-PD-1 therapy. In addition, 29.0% pts received dacarbazine based chemotherapy, 29.0% paclitaxel or albumin-bound paclitaxel, and 3.2% had dabrafenib with trametinib. Up to Dec 2019, 30 pts can be evaluated for efficacy. Median follow-up time was 10.2 mos (2.0-23.1 mos). There were 5 confirmed PRs and 20 SDs. ORR was 16.7%, DCR 83.3%, and median PFS was 5.0 mos (95%CI 1.9-8.1 mos). Median overall survival was 10.1 mos (95%CI 4.7-15.5 mos). Common AEs were hypertension (51.6%), proteinuria (41.9%), elevated transaminase (25.8%), thrombocytopenia (16.1%), and hand-foot syndrome (16.1%). Most were grade 1-2. Grade 3-4 AEs included proteinuria (12.9%), hypertension (6.4%), and thrombocytopenia (6.4%); 10 pts required a dose reduction, and 1 had to discontinue. No treatment-related deaths were observed. Conclusions: In pts progressed after anti-PD-1 therapy, apatinib in combination with temozolomide demonstrated promising efficacy and favorable safety profile. Clinical trial information: NCT03422445.