bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-arm, phase II study of pyrotinib in advanced non-small cell lung cancer (NSCLC) patients with HER2 exon 20 mutation.
Authors: Gao Guanghui , Li Xingya , Wang Qiming , Zhang Yiping , Chen Jianhua , Shu Yongqian , Hu Yanping , Fan Yun , Fang Jian , Chen Gongyan , Zhao Jun , He Jianxing , Wu Fengying , Zou Jianjun , Zhu Xiaoyu , Zhou Caicun 
Published: March 2020

9089 Background: HER2 exon 20 mutation is a well-known oncogenic driver in non-small cell lung cancer (NSCLC) and its testing is recommended by NCCN guidelines for NSCLC patients. However, up to now, there has been no approved targeted therapy for this patient population. Pyrotinib is an oral, irreversible pan-Her tyrosine kinase inhibitor (TKI) against HER1, HER2 and HER4, which, combined with chemotherapy, has recently been approved in China for HER2 positive advanced breast cancer. Methods: Stage IIIB or IV NSCLC patients with HER2 exon 20 mutation (confirmed in a central lab) and previously treated with at least one platinum-based chemotherapy were enrolled in this open-label, multi-center, single-arm phase II study. Patients with active brain metastases or prior use of HER2 TKI agents were excluded. Eligible patients received pyrotinib 400 mg once daily until disease progression, intolerable toxicity or withdrawal of consent. The primary endpoint was objective response rate (ORR) according to RECIST 1.1. Secondary endpoints included safety, progression-free survival (PFS), time to disease progression (TTP), duration of response (DOR) and overall survival (OS). This trial is registered on ClinicalTrials.gov (NCT02834936). Results: Between October 20, 2016 and December 10, 2018, 60 patients (33 female, 27 male) were enrolled. The median age was 57 years (range: 40, 72). A majority were stage IV patients (95%). Over 58% of patients have been treated with two or more prior chemotherapy regimens. As of Jan 21, 2019, the ORR as evaluated by investigators was 31.7% (95% CI 20.3%, 45.0%). Median DOR was 7.0 months (95% CI 5.5, 11.0) and median PFS was 6.8 months (95% CI 4.1, 8.3). 26.7% patients reported treatment-related grade 3 AEs. Diarrhea (20.0%) was the only treatment-related grade 3 AE that occurred in ≥ 2 patients. Treatment-related grade 4 AE was reported in 1 subject (elevated gamma-glutamyl transferase). The anti-tumor activities of pyrotinib was shown in various mutation types. Conclusions: Pyrotinib as a single agent demonstrated promising anti-tumor activity and acceptable safety profile in heavily pretreated HER2 mutant NSCLC patients. Clinical trial information: NCT02834936.
Preliminary immunogenicity, safety, and efficacy of JNJ-64041757 (JNJ-757) in non-small cell lung cancer (NSCLC): Results from two phase 1 studies.
Authors: Brahmer Julie R. , Johnson Melissa Lynne , Dols Manuel Cobo , Viteri Ramirez Santiago , Coves Juan , Sukari Ammar , Awad Mark M. , Salgia Ravi , Papadimitrakopoulou Vassiliki , Rajan Arun , Allred Alicia Jones , Wade Mark , Mason Gary , Zudaire Enrique , Knoblauch Roland Elmar , Stone Nicole L. , Lorenzi Matthew V. , Hassan Raffit 
Published: March 2020

9093 Background: The immunogenicity, safety, and efficacy of JNJ-757, a live attenuated, double-deleted Listeria monocytogenes-based immunotherapy expressing human mesothelin (MSLN), were evaluated in patients (pts) with advanced NSCLC (adenocarcinoma) as monotherapy (phase 1) and in combination with nivolumab (phase 1b/2). Methods: Adult pts with Stage IIIB/IV NSCLC who had received prior systemic therapy (including 1 platinum-based chemotherapy, prior PD-1/PD-L1 therapy allowed) were included. Dose-limiting toxicities, adverse events (AEs), tumor response, T cell response, and JNJ-757 bacterial shedding profile were evaluated in pts treated with JNJ-757 (108 or 109 colony forming units [CFU]) alone or JNJ-757 (109 CFU)+nivolumab 240 mg combination therapy until progression. Results: In the monotherapy trial, 18 pts (median age 63.5 years; women 61%) were treated with JNJ-757 108 or 109 CFU with a median duration of 1.4 months (range 0-29). Most common AEs were pyrexia (72%) and chills (61%), which were usually mild and resolved within 48 hours, suggesting transient activation of an innate immune response to JNJ-757. Treatment-related grade ≥3 AEs were infrequent (4 [22%]). Induction of peripheral proinflammatory cytokines and lymphocyte activation was observed post-treatment with transient MSLN-specific T cell responses in 10/13 evaluable pts, consistent with the mechanism of action of JNJ-757. With monotherapy, 4/18 response-evaluable pts had stable disease (SD) ≥16 weeks, including 1 pt with a 53% reduction in target lesions. In the combination therapy study, 12 pts were enrolled (median age 63.5 years; women 33%). The most common AEs were pyrexia (67%) and chills (58%); 6 pts had grade ≥3 AEs including 2 cases of treatment-related fatal pneumonitis. Best overall response for the combination was SD in 4/9 evaluable pts. JNJ-757 in combination with nivolumab suggested increased risk of pneumonitis. Conclusions: As monotherapy, JNJ-757 was tolerable with mild infusion-related fever and chills supporting the initiation of the combination therapy study. However, the risk-benefit profile of JNJ-757+nivolumab, did not support proceeding to phase 2. Clinical trial information: NCT02592967, NCT03371381.
Deep learning-based predictive biomarker for immune checkpoint inhibitor response in metastatic non-small cell lung cancer.
Authors: Park Sehhoon , Ahn Chang Ho , Jung Geunyoung , Lee Sarah , Paeng Kyunghyun , Shin Jiwon , Yoo Inwan , Jung Hyun Ae , Sun Jong-Mu , Ahn Jin Seok , Ahn Myung-Ju , Park Keunchil , Choi Yoon La , Song Sang-Yong , Lee Se-Hoon 
Published: March 2020

9094 Background: In the era of immunotherapy, immune checkpoint inhibitor (ICI) has changed the treatment paradigm in metastatic non-small cell lung cancer (NSCLC). Along with clinical trials, there is an ongoing investigation to discover the predictive biomarker of ICI which so far has unsatisfactory reliability. As an effort to enhance the predictive value of ICI treatment, we applied deep learning and developed artificial intelligent (AI) score (range from 0 to 1) to analyze the specific context of immune-tumor microenvironment (TME) extracted by scanned images from H&E slides. Methods: As a ground work, deep learning-based H&E image analyzer, Lunit SCOPE, has been trained with H&E images (n = 1824) from ICI naive NSCLC samples. For the calculation of AI score, training was conducted using responder/non-responder labeled ICI treated samples from the exploratory cohort. The ICI responder was defined as the patient with a best overall response of partial or complete response and stable disease for more than 6 months. The positivity of PD-L1 immunohistochemistry (IHC) was assessed manually by pathologists. Results: The exploratory cohort is composed of NSCLC patients treated with ICI (n = 189) in Samsung Medical Center, and response to ICI was observed in 72 (38.1%) patients. Median follow-up duration was 6.8 months (6.6~8.2). Samples with PD-L1 IHC positive, defined by ≥ 1%, was observed in 138 (73.0%) patients. AI score was significant higher in the responder group (median: 0.391 vs 0.205, P = 6.14e-5), and the patients with AI score above the cut-off (0.337) showed a better response to ICI (odds ratio [OR] 3.47 P = 7.34e-5) which is higher than patients with PD-L1 ≥ 1% (OR 1.92, P = 0.069). High AI score group (n = 83) showed significantly favorable PFS compared to low AI score group (n = 106, median PFS: 5.1m vs 1.9m, hazard ratio [HR] 0.51, P = 9.6e-5) and this outcome was independent with PD-L1 status (P = 6.0e-5). In subgroup analysis, PFS of PD-L1 high / AI score high group (n = 63) had longer median PFS (6.7m) compared to both PD-L1 high / AI score low group (n = 70, 4.0m, P = 0.001) and PD-L1 low/AI score low group (n = 35, 1.9m, P = 4.0e-6). Tumor infiltrating lymphocyte (TIL) density of cancer epithelium was significantly correlated with AI score (Pearson’s r = 0.310, P = 1.43e-5), which suggests that AI score may partly reflect TME represented by TIL. Conclusions: The AI score by machine-learned information, extracted from H&E images without additional IHC stain, could predict responsiveness and PFS of ICI treatment independent of PD-L1 IHC positivity.
Phase 1 dose-expansion study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1 (ASS1)–deficient non-squamous non-small cell lung cancer.
Authors: Wimalasingham Akhila Ganeshi , Phillips Melissa Mary , Lim Louise , Rashid Sukaina , Hall Peter Edward , Khadeir Ramsay , Steele Jeremy P. C. , Conibear John , Feng Xiaoxing , Ellis Stephen , Chan Pui Ying , Thomson Jim , Johnston Amanda L. , Bomalaski John S. , Pacey Simon , Sheaff Michael , Szlosarek Peter Wojciech 
Published: March 2020

9097 Background: Pegylated arginine deiminase (ADI-PEG20) targets ASS1-ve tumors, including non–small-cell lung cancer (NSCLC), by potentiating pemetrexed cytotoxicity via arginine depletion. In Beddowes et al (JCO 2017) we showed a 100% disease control rate in thoracic cancers treated with ADI-PEG20, cisplatin and pemetrexed (ADIPemCis). Thus, we tested ADIPemCis in a phase I dose-expansion cohort study of patients (pts) with non-squamous NSCLC. Methods: Good performance (ECOG 0-1) advanced non-squamous NSCLC pts were enrolled at the maximum tolerated dose (MTD) of ADIPemCis, using tumoral ASS1 loss as a selection biomarker. Pem (500mg/m2) and Cis (75mg/m2) were given every 3 weeks with weekly IM ADI-PEG20 (36mg/m2) for up to 4 cycles with maintenance ADI-PEG20 or Pem in responding pts. Primary endpoint was tumor response rate (RR by RECIST 1.1), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and toxicity. We also measured plasma [arginine] and [citrulline], anti-ADI-PEG20 antibodies, and PD-L1 expression. Results: 21 of 70 screened pts (median age 60.1) were enrolled between April 15 and August 17. A confirmed partial response (PR) was observed in 55.6 % (n = 10/18 evaluable pts). Median PFS and OS were 4 months (95% CI 2.9-4.8) and 7.2 months (95% CI 5.1-18.4), respectively. 9% (n = 2/21) remain alive on subsequent therapies. 43% (n = 9/21) experienced grade 3/4 treatment-related toxicities, commonly non-febrile neutropenia. Plasma [arginine] declined rapidly and [citrulline] increased; both changes persisted at 16 weeks. 55% of pts’ tumors (n = 6/11 ) were PD-L1 < 1% by immunohistochemistry. Conclusions: The ADIPemCis regimen is active and safe in ASS1-ve NSCLC pts almost doubling the expected RR. However, the short survival compared with ASS1-agnostic historical controls indicates that ASS1 (and frequent PD-L1) loss selects for a biologically more aggressive and immunorefractory NSCLC phenotype. The iTRAP study opening Q2 of 2019 will assess the safety and tolerability of ADIPemPlatinum(Carbo) with atezolizumab in pts with ASS1-deficient non-squamous NSCLC. Clinical trial information: NCT02029690.
Early mortality in metastatic lung cancer: A SEER population data analysis.
Authors: Globus Opher , Bar Jair , Onn Amir , Uri Inbal , Lieberman Sivan , Weidenfeld Jonathan , Manu-Sitton Rakefet , Eshet Yael , Lawrence Yaacov Richard , Urban Damien 
Published: March 2020

9103 Background: Millions of dollars invested in improving outcomes for metastatic lung cancer patients are essentially aimed at extending long term survival, with significant benefits being achieved over the last decade. However, little is known about lung cancer patients who die rapidly after diagnosis, potentially being deprived of these advances. We analyzed population-based data to describe real-world outcomes in metastatic lung cancer patients focusing on patients with early mortality. Methods: Using the Survival, Epidemiology and End Results (SEER) Database we analyzed adult metastatic lung cancers diagnosed between 1994-2014. This period was divided into 3 equal time periods: 1994-2000 (TP1), 2001-2007 (TP2) and 2008-2014 (TP3). Early mortality was defined as death within 2 months of diagnosis. Correlations between categorical variables were analyzed with chi squared tests and survival was analyzed using the Kaplan-Meier method. Results: Of 276,527 patients diagnosed with metastatic lung cancer, median age was 67 (range 20-105) and 154,465 (56%) were males. Thirty eight percent (103,830) of all patients died within 2 months of diagnosis. Of these early deaths, 96,344 (92.8%) were due to lung cancer. While the 2-year survival almost doubled from TP1 compared to TP3 (6% vs 11%, p < 0.001), the percentage of patients who died within 2 months only marginally improved (39.7% vs. 36.2% in TP1 vs TP3, respectively). For patients surviving at least 2 months, 2-year survival increased from 10% to 18% in TP1 vs TP3 (p < 0.001). Factors associated with early mortality include age > 65 (45% vs 31%), unmarried status (42% vs 34%), male sex (39% vs 36%), liver metastases (47% vs 32%) and large cell carcinoma vs adenocarcinoma (44% vs 36%) (all p < 0.001). Conclusions: While there has been a steady improvement in the long-term overall survival of patients with metastatic lung cancer, over one third of patients still die within 2 months of diagnosis. This has only marginally improved in the last 20 years. Research is urgently needed to identify causative and treatable factors.
Randomized phase I/II trial of pembrolizumab with and without radiotherapy for metastatic non-small cell lung cancer.
Authors: Welsh James William , Menon Hari , Tang Chad , Verma Vivek , Altan Mehmet , Hess Kenneth R. , de Groot Patricia , Nguyen Quynh , Simon George R. , Skoulidis Ferdinandos , Chang Joe Y. , Papadimitrakopoulou Vassiliki , Heymach John 
Published: March 2020

9104 Background: We present findings of a randomized phase I/II trial studying PD-1 blockade with and without radiotherapy to lung lesions in patients with metastatic NSCLC. Methods: Patients with metastatic NSCLC were randomized to receive pembrolizumab with or without lung-directed radiotherapy (RT). RT referred to stereotactic body radiation therapy (SBRT, 50 Gy in 4 fractions or 70 Gy in 10 fractions) or traditional fractionation (45 Gy in 15 fractions). Pembrolizumab (200mg IV) was started on day 1 and given every 3 weeks for up to sixteen cycles. The primary endpoint was out-of-field response rate (RR), which refers to complete (CR) or partial response (PR) per irRC criteria. Results: Of 124 enrolled patients, 103 received treatment, 5 withdrew consent, 15 screen failures, and 1 was not financially cleared. Twenty-one patients completed 16 cycles of pembrolizumab; 16 patients received SBRT and 20 received traditional RT. Seven patients received salvage RT after progression on pembrolizumab alone and 15 patients received RT six months before starting the trial. In the combined-modality arm, there were 2 grade 4 toxicities and 9 grade 3 toxicities related to treatment. In the pembrolizumab arm, there were zero grade 4 toxicities and five grade 3 toxicities. At the present time, 72 patients were evaluable for response, 36 in both arms; median follow-up was 15.4 months (range: 1.4-125.2 months). RR for out-of-field lesions was 22% and 25% for the pembrolizumab + RT vs pembrolizumab respectively (p = 1.00); median PFS was 10.9 months (95% CI, 8.1-15.3 months) and 8.4 months (95% CI, 3.9-17.1 months) respectively (p = 0.83). When comparing the SBRT vs traditional fractionation sub-cohorts, non-irradiated RR was 38% and 10% respectively (p = 0.10); median PFS was 21.1 and 6.8 months respectively (p = 0.03). Within the pembrolizumab arm, comparing patients who received prior RT vs those that did not, RR was 33% and 19% respectively (p = 0.26). Conclusions: RT, while safe, did not increase the out-of-field response rate in NSCLC patients treated with pembrolizumab. Exploratory analysis suggests responses may be enhanced by SBRT, but not traditional fractionation, which warrants further investigation. Clinical trial information: NCT02444741.
Viagenpumatucel-L (HS-110) plus nivolumab in patients with advanced non-small cell lung cancer (NSCLC) after checkpoint inhibitor treatment failure.
Authors: Morgensztern Daniel , Sanborn Rachel E. , Bazhenova Lyudmila , Waqar Saiama Naheed , McDermott Lori , Hutchins Jeff , Rimm David L. , Raez Luis E. , Langer Corey J. , Cohen Roger B. 
Published: March 2020

9109 Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma cell line transfected with the gp96-Ig fusion protein that functions as an antigen chaperone for cross presentation and dendritic cell activation. DURGA is a multi-cohort study evaluating the combination of HS-110 and anti-PD-1 monoclonal antibodies in patients with advanced NSCLC. We report on Cohort B, consisting of patients with progressive disease (PD) after receiving a minimum of 4 months of treatment (tx) with a checkpoint inhibitor (CPI) at any time prior to study entry. Methods: Patients (pts) with previously treated NSCLC received weekly HS0110 (1 X 107 cells) intradermally for 18 consecutive weeks and nivolumab IV 240 mg every 2 weeks until intolerable toxicity or PD. Tissue was tested at baseline for PD-L1 expression (≥ 1% or < 1%) and tumor infiltrating lymphocytes (TILs). TIL high was defined as > 10% CD8+ lymphocytes in the tumor stroma. The primary endpoint was objective response rate by RECIST 1.1. Results: As of the September 2018 data cut-off, 20 pts were enrolled. 18 pts (90%) had PD after both chemotherapy and CPI, and 14 (70%) had CPI as their most recent line of tx. The median number prior tx lines was 2 [range 1 to 6]. 3 pts (15%) achieved partial response and 8 pts (40%) had stable disease. Disease control rate was 55%. Progression-free survival (PFS) was 2.7 months (95% CI, 1.8 – 4.0 months) with a median follow up of 6 months. Pts experiencing injection site reactions (ISR) had improved PFS (median NR vs 2.2 months; HR 0.23, p = 0.063) compared to those without ISR. Of 3 patients with confirmed response, 2 were TIL low/PD-L1 positive, and one was TIL high/PD-L1 negative. All pts experienced at least one adverse event (AE), 80% of which were grade 1 or 2. The most common AEs were fatigue (42%), cough and dyspnea (22.6% each) and anemia (16.1%). There were no grade 5 AEs. Conclusions: The combination of HS-110 and nivolumab is well tolerated. Pts continue to be enrolled in this cohort and early data suggest that the addition of HS-110 to nivolumab may restore responsiveness after tumor progression on prior CPI therapy. Clinical trial information: NCT02439450.
Combination therapy with CpG oligodeoxynucleotide and imatinib can reverse the drug resistance when applied alone through promoting BAX activation and overcoming BCR-ABL1-independent PI3K/AKT activation.
Authors: Bai Ling , Chen Wei , Li Wei , Zhou Lei , Niu Chao , Chen Jingtao , Han Wei , Cui Jiuwei 
Published: March 2020

e18502 Background: Philadelphia chromosome is an independent prognostic factor in B-cell acute lymphoblastic leukemia (B-ALL). Due to the emergence of TKIs resistance such as imatinib, new methods are yet to be explored. Toll-like receptor 9 (TLR9) agonists have been used in many cancers as immune adjuvants, due to the immune effects as well as direct effects. However, the effect of TLR9 agonists on Ph(+) B-ALLs remain unknown. Methods: Expression levels in primary B-ALL cells from 41 patients in our hospital were determined by real-time quantitative PCR and correlated to clinicopathological factors. WST-1 cell viability assay and flow cytometry were used to confirm the biological behaviors of proliferation, cell cycle arrested, apoptosis, and surface molecules expression in Ph(+) B-ALL cell line. GST pull-down, western blot, and relevant inhibitors were used to detect the mechanism of the monotherapy and combination therapy. All data were analyzed using SPSS 24.0 software. Results: Expression of TLR9 in 19 patients with Ph chromosome was higher than that in 22 patients with the normal chromosome (Median: 0.10 vs. 0.03, P= 0.047). Sup-B15, one of imatinib resistance Ph(+) B-ALL cell line, showed no proliferation suppression, no cell cycle arrested and no apoptosis after CpG 685 stimulation. However, the combination use of CpG 685 and imatinib significantly increased apoptotic cells and upregulated the expression of CD40, MHC class Ⅰ and PD-L1. By comparing the downstream signaling pathway of TLR9 in B-ALL cell lines, Sup-B15 also promoted apoptosis through P38/P53/BAX signaling pathway as other B-ALLs. After imatinib pre-treatment, the inhibition of BAX activation by BCR-ABL kinase as well as C-MYC was exposed, and the resistance of CpG 685 was reversed. In addition, CpG 685 downregulated miR-21, further upregulated PTEN, and ultimately reversed the drug resistance of imatinib which caused by BCR-ABL1-independent AKT phosphorylation in Ph(+) B-ALL. Conclusions: The combinational use of imatinib and CpG 685 to treat B-ALL cells can reverse the drug resistance when applied alone. This method can not only kill Ph(+) B-ALL directly, but also increase the immunogenicity and enhance the recognition by CD8+ T cells. Besides, due to the increasing of PD-L1, adding PD-L1 antibody with imatinib and CpG ODNs in Ph(+) B-ALL warrants more data before moving into clinical practice.
Comparison of PEG-rhG-CSF and common rhG-CSF after induction chemotherapy in patients with newly diagnosed acute myeloid leukemia.
Authors: Liu Kaiqi , Wei Hui , Wang Ying , Mi Yingchang , Wang Jianxiang 
Published: March 2020

e18507 Background: To compare the PEG-rhG-CSF (brand name:jinyouli) with ordinary rhG-CSF in the myelosuppressive phase after induction chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients promotes the recovery of neutrophils. At the same time, the effects of the two drugs on the incidence of infection and hospitalization were compared. Methods: A prospective randomized controlled trial was conducted in which patients with newly diagnosed AML who met the enrollment criteria were randomized into 1:1 groups: 1. PEG-rhG-CSF group: patients ≥45 kg for 6 mg/time, <45 kg for 3 mg/time, subcutaneous injection once on the 5th day after stopping chemotherapy; 2. rhG-CSF group: 5 μg/kg/day until neutrophils count ≥0.5×109/L and/or leukocytes count ≥1.0×109/L. The neutrophil recovery time (duration from day 1 of chemotherapy to neutrophils count ≥0.5×109/L and/or leukocytes count ≥1.0×109/L), infection rate and hospitalization time were collected from the two groups, and the two groups were analyzed and compared using SAS 9.4. Results: From August 2014 to December 2017, 60 patients with newly diagnosed AML were enrolled: 30 patients in the PEG-rhG-CSF group and 30 patients in the rhG-CSF group. Except for the gender composition (P=0.018), there were no significant differences in age, chemotherapy regimen, neutrophils count before chemotherapy, leukocytes count before chemotherapy, and induction efficacy between the two groups. The median time (range) of neutrophils recovery in patients with PEG-rhG-CSF and rhG-CSF was 19 (14-35) days and 19 (15-26) days, P=0.36. The number of patients (ratio) with infection during neutropenia in the PEG-rhG-CSF group and the rhG-CSF group were 27 (90.0%) and 28 (93.3%), P=1. The median length of hospitalization (range) was 20.5 (17-49) days and 21 (19-43) days, P=0.53. Conclusions: In patients with AML induction chemotherapy, there was no significant difference between the application of PEG-rhG-CSF and daily rhG-CSF in neutrophil recovery time, infection incidence and hospitalization time.