bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutational landscapes and PD-L1 expression in non-small cell lung cancer.
Authors: Zhang Kang , Wang Guanghui , Guo Chao , Chen Xinyu , Zhang Shiyue , Wang Wenjing , Yao Ming , Liu Angen 
Published: March 2020

8541 Background: Programmed death-ligand 1 (PD-L1) serves as a major predictive biomarker for immune checkpoint inhibitors in non-small cell lung cancer (NSCLC). However, the relationship between PD-L1 expression and genetic features of NSCLC remains unclear. The aim of this study was to explore the correlation between genetic profiles and PD-L1 expression in NSCLC. Methods: FFPE tumor and matched blood samples from 568 NSCLC (487 adenocarcinomas (ACAs) and 81 squamous carcinomas (SCAs)) patients were collected for NGS-based targeted panel sequencing. Genomic alterations including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. Tumoral PD-L1 expression was evaluated by immunohistochemical analysis (Dako 22C3 and 28-8). Results: The prevalence of PD-L1 expression was 9.9% with a ≥50% cutoff and 27.5% with a ≥1% cutoff. High PD-L1 expression (using a ≥1% cutoff) in tumor cells was significantly associated with mutations of MET (p < 0.001), RET (p = 0.036), ROS1 (p < 0.001), TP53 (p = 0.0013) and 11q13 amplification (p = 0.004), and was inversely correlated with EGFR mutations (p = 0.011). SOX2 and KLHL6 mutations were more frequent in SCAs (33.3% and 28.4%, respectively) than in ACAs (0.4% and 1%, respectively) and were adversely associated with PD-L1 expression in SCAs (p = 0.01, p = 0.004). Gene set 1 (GS1) mutations included EGFR, ALK, KRAS, BRAF, MET, RET, ROS1 and ERBB2 and gene set 2 (GS2) mutations included TP53, RB1, PTEN, APC and MYC. According to the mutation status of GS1 and GS2, 18 patients were classified as type I (GS1-, GS2-), 92 as type II (GS1-, GS2+), 202 as type III (GS1+, GS2-) and 256 as type IV (GS1+, GS2+). PD-L1 expression was higher in Type IV tumors than in type III (33.2% vs. 14.4%, respectively, p < 0.001). Conclusions: We highlighted the genomic heterogeneity of NSCLC according to the mutation status of different gene sets. Our results indicate that patients with GS1 and GS2 gene mutations might correlate with higher PD-L1 expression. Our results help to understand the relationship between genomic features and PD-L1 expression and may be a potential guide for immunotherapy.
Radiological response patterns in the phase 2 STELLAR trial of TTFields with chemotherapy for first-line treatment of malignant pleural mesothelioma (MPM).
Authors: Grosso Federica , Ceresoli Giovanni Luca 
Published: March 2020

8551 Background: Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable, medical device. TTFields have significantly extended survival of patients with glioblastoma. In-vitro, human MPM cells were highly susceptible to TTFields. In the STELLAR study, patients with unresectable MPM treated with first line chemotherapy in combination with TTFields had a significantly higher median overall survival compared to historical controls (18.2 vs. 12.1 months). We report on analysis of radiological data from STELLAR patients whose tumors responded while receiving the combined therapy. Methods: The STELLAR trial accrued 80 patients with unresectable, previously untreated mesothelioma. Patients were treated with continuous 150 kHz TTFields (>18h/day) in combination with pemetrexed and cisplatin or carboplatin (at standard dosing). Inclusion criteria included ECOG PS of 0-1, pathologically proven mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients were followed q3w (CT scan q6w) until disease progression. Radiological assessments were done at each study site. Results: Partial responses (PRs) were seen in 40.3% of evaluable patients and clinical benefit (PR+SD) was seen in 97.2% of these patients. The median time between treatment start and PR was 1.8 months (range: 1.4-4.4 months). All patients presenting with PR during the STELLAR study had continuous reduction in the total sum of lesion diameters, suggesting no initial / pseudo-progression. 83% of the patients who responded to the combined therapy finally had disease progression within a median response duration of 5.7 months (range: 1.4-13 months), per Kaplan-Meier Estimator. One patient did not progress for more than 27 months. Conclusions: The STELLAR study met its primary endpoint of significant survival extension for previously untreated mesothelioma patients. Response rates were similar to the ones reported for the current standard of care treatment, but lasted longer with the addition of TTFields. Clinical trial information: NCT02397928.
Efficacy and safety of apatinib in extensive stage small cell lung cancer patients failed from two or more lines of chemotherapy.
Authors: Liu Yutao , Hu Xingsheng , Jun Jiang , Yang Lin , Zhou Shengyu , Liu Peng , Li Junling , Wang Yan , Hao Xuezhi , Shi Yuankai 
Published: March 2020

8553 Background: Information on the optimal therapy beyond the second-line treatment of small cell lung cancer (SCLC) is very limited and controversial. Inhibiting the components of the VEGF signaling pathway is an attractive treatment option for SCLC patients. Apatinib, a selective inhibitor of VEGF receptor-2 (VEGFR-2) tyrosine kinase, has been proven to be safe and effective for the treatment of a broad range of advanced solid tumors. In our prospective clinical study, we aim to evaluate the efficacy and safety of single-agent apatinib as treatment of extensive-stage (ES) SCLC patients after failure from at least two prior chemotherapy regimens. Methods: Twenty-two ES-SCLC patients treated with single-agent apatinib after failure from at least two prior chemotherapy regimens in our institution between November 2016 to August 2018 were enrolled in the clinical study. Apatinib mesylate was orally administered at a dose of 500 mg once daily on a 28-day cycle until evaluation of disease progression (PD) or the occurrence of unacceptable toxicity. Dosage reduction to either 425 mg or 250 mg once daily were permitted based on the evaluation of toxicities. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and adverse events (AE). Results: The median age was 56 years, ranging from 36 to 70 years. A majority (63.6%, 14/22) received apatinib as third-line treatment, while 22.7% (5/22) and 13.6% (3/22) received it as fourth or fifth-line treatment, respectively. Partial response (PR) was achieved by 3 (13.6%) patients and stable disease exhibited by 18 (81.8%) patients. The median PFS and OS were 5.4 and 10.0 months, respectively. Apatinib demonstrated a manageable toxicity profile, with grade I-III secondary hypertension and proteinuria as the most common AE. Grade III adverse events were only observed in 3 (13.6%) patients with either hypertension (1 patient) or proteinuria (2 patients). Except for these 3 patients, all the other patients experienced grade I-II adverse events. No grade IV and V AE were observed among the patients. Multivariate analysis revealed secondary hypertension as an independent predictor of OS ( p= 0.047). Conclusions: Apatinib is safe and effective in the management of ES-SCLC patients and can be considered as a treatment option after failure from at least two prior chemotherapy regimens. Secondary hypertension can be a potential prognostic factor for apatinib treatment. Clinical trial information: NCT02995187.
RESILIENT: Study of irinotecan liposome injection (nal-IRI) in patients with small cell lung cancer—Preliminary findings from part 1 dose-defining phase.
Authors: Paz-Ares Luis G. , Spigel David R. , Zielinski Christoph , Chen Yuanbin , Jove Maria , Juan Vidal Oscar , Chu David , Rich Patricia , Hayes Theresa M. , Gutierrez Calderon M Vanesa , Bernabe Caro Reyes , Navarro Alejandro , Dowlati Afshin , Zhang Bin , Moore Yan , Wang Haofei Tiffany , Nazarenko Natalya , Ponce Aix Santiago , Bunn Paul A. 
Published: March 2020

8562 Background: Nal-IRI is investigated as monotherapy in patients with SCLC who progressed on or after platinum regimen. The RESILIENT study is a Part 1 study of a Phase 2/3 trial to assess safety, tolerability, and efficacy of Irinotecan Liposome Injection in patients with SCLC. Methods: Nal-IRI is evaluated in patients ≥18 yrs with advanced SCLC with an ECOG performance status ≤1 and adequate organ function; prior exposure to immunotherapy is allowed. Safety and tolerability at dose levels of 85 mg/m2 and 70 mg/m2 are the primary endpoints, with assessment of exploratory efficacy signal. Results: At 24 Dec 2018 safety cutoff 12 patients in Part 1 received ≥1 dose of nal-IRI (Cohort 1 [C-1] at 85 mg/m2 dose n=4; Cohort 2 [C-2] at 70 mg/m2 dose n=8; median age 60.0 yrs; range 49–73 yrs). Three patients experienced ≥1 DLT (Cohort 1 n=3/4; Cohort 2 n=0/8). Most frequent treatment-emergent adverse events (TEAE) were gastrointestinal (GI) disorders (any grade): diarrhea (91.7%), nausea (58.3%), vomiting (41.7%), decreased appetite (58%), abdominal pain (33%) manageable by antidiarrheal regimen and antiemetics; as well as fatigue (50%) and asthenia (37.5%). Overall, hematologic toxicity was neutropenia (any grade) at 16.7% and anemia (any grade) at 16.7%. At 11 Dec 2018 efficacy cutoff the best objective response was partial response (PR) at 33.3% in 4/12 patients (C-1 n=1/4; C-2 n=3/8), median time to response was 6 wks. Overall disease control rate (DCR) was 58.3%; progressive disease (PD) was observed in 2 patients (16.7%), and 3 patients were non-evaluable (25%). Conclusions: Initial assessment suggests that nal-IRI at 70 mg/m2 dose given bi-weekly is well-tolerated and has promising antitumor activity in patients with SCLC who progressed on or after platinum regimen. Part 1 dose expansion is ongoing. Clinical trial information: NCTN03088813. [Table: see text]
Clinical application of circulating cell-free DNA for monitoring the biological course of thymic epithelial tumors.
Authors: Ottaviano Margaret , Giuliano Mario , Tortora Marianna , Terracciano Daniela , Formisano Pietro , Liotti Antonietta , De Rosa Nicoletta , Botti Gerardo , Campione Severo , Staibano Stefania , La Civita Evelina , Curcio Carlo , Guggino Gianluca , Mucci Brigitta , Picozzi Fernanda , Habetswallner Francesco , Di Lauro Vincenzo , De Placido Sabino , Palmieri Giovannella 
Published: March 2020

8566 Background: Thymic epithelial tumors (TETs) are rare thoracic malignancies. Widely recognized as different histopathological entities, thymoma (T) and thymic carcinoma (TC), show a different biological behavior with a higher tendency to hematogenous dissemination for TC and thoracic recurrence for T, sharing, however, a poor prognosis when characterized by high tumor burden. Up to date, there are no specific biomarkers for monitoring the biological course of these rare tumors. Analysis of circulating cell-free DNA (cfDNA) has potential applications throughout the natural course of cancer development, diagnosis and treatment, never the less several studies have suggested that cfDNA levels closely parallel overall tumor burden. For the first time the detection and the correlation of cfDNA levels with tumor burden and histological subtype of TET, has been carried on in this monocentric study. Methods: Starting from July 2018, serum samples from 19 patients with TET, 4 with completely resected TET (rTET) and 15 with advanced (aTET), were prospectively obtained before the initiation of therapy. Serum samples from 15 healthy donors were used as control. Five ml of blood was collected and processed within one hour or less, followed by centrifugation at 3000g for 10 minutes and storage at -80°C. The serum samples were processed for QiAamp MinElute cell-free DNA mini kit extraction (Qiagen). cfDNA quantification was assessed using Qubit Fluorometric Quantitation (Thermo Fisher Scientific). Clinical, and histo-pathological features of TET were assessed. Results: A median cfDNA amount in healthy donors of 0.108 ng/µl (0.083-0.868) was registered. A median cfDNA of 0.512 ng/µl (0.178-1.42) resulted for the rTET, including the value of 0.178 for the resected TC. A median cfDNA of 2.53 ng/µl (1.20-6.11) resulted for the aTET, with respectively a median of 2.845 ng/µl (1.3-5.24) and of 1.5 ng/µl (1.2-6.11) for TC and T. The highest registered level for both group of thymoma (6.11 ng/µl) and thymic carcinoma (5.24 ng/µl) correlates with the highest tumor burden. Conclusions: To the best of our knowledge, this is the first study that explore detection and quantification of cfDNA in TET. Higher baseline levels than the control group and the rTET group have been registered for both advanced T and TC. Highest levels of cfDNA may be associated with high tumor burden despite the histological subtype. We envision that further valuable information will be obtained with mutational analysis.
JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC).
Authors: Haura Eric B. , Cho Byoung Chul , Lee Jong Seok , Han Ji-Youn , Lee Ki Hyeong , Sanborn Rachel E. , Govindan Ramaswamy , Cho Eun Kyung , Kim Sang-We , Reckamp Karen L. , Sabari Joshua K. , Thayu Meena , Bae Kyounghwa , Knoblauch Roland Elmar , Curtin Joshua , Haddish-Berhane Nahor , Sherman Laurie Jill , Lorenzi Matthew V. , Park Keunchil , Bauml Joshua 
Published: March 2020

9009 Background: JNJ-372 binds EGFR and cMet to block ligand binding, promote receptor degradation, and trigger antibody-dependent cellular cytotoxicity in models of EGFR-mutated (EGFRm) NSCLC. Here we describe the ongoing phase 1 safety, pharmacokinetics (PK), and activity of JNJ-372 in patients (pts) with NSCLC, including 3rd generation tyrosine kinase inhibitor (3GTKI)-relapsed EGFRm NSCLC and EGFR Exon20ins disease. Methods: Pts received JNJ-372 (140–1400 mg) IV weekly for the first 28-day cycle and biweekly thereafter. 1050–1400 mg doses are being explored in dose expansion. Blood samples were collected for PK analyses. Efficacy by investigator per RECIST v1.1 in pts with EGFRm NSCLC treated at ≥700 mg is presented. Tumors were characterized by next-generation sequencing of circulating tumor (ct)DNA and/or tumor tissue. Results: As of 17 Jan 2019, 116 enrolled pts with NSCLC were treated. Median age was 63 years, 38% were male, 77% were Asian, and 97% had EGFR mutations. Mean duration of treatment was 3.8 months, longest exposure was 20 cycles. The PK data set included pts from Korea (77%) and the US (23%). At the 1050 mg dose, 72% of pts achieved average concentrations above the EC90 based on preclinical models. Adverse events (AEs; ≥20%) were rash (59%), infusion related reaction (58%), paronychia (28%), and constipation (22%). Additional EGFR/cMet-related AEs include stomatitis (17%), pruritis (15%), peripheral edema (11%), and diarrhea (7%). Grade ≥3 AEs were reported in 34% (8% treatment-related) with dyspnea (6%) and pneumonia (3%) most frequently observed. Among response-evaluable pts, 25/88 (28%) achieved best timepoint response of partial response (PR). 10/47 pts with prior 3GTKI therapy had best timepoint response of PR (6 confirmed), including 4 with C797S, 1 with cMet amplification, and 5 without identifiable EGFR/cMet-dependent resistance. 6/20 pts with Exon20ins had best timepoint response of PR (3 confirmed). Conclusions: JNJ-372 has a manageable safety profile consistent with EGFR and cMet inhibition. Preliminary responses were achieved in 3GTKI-relapsed disease, including C797S and cMet amplification, and Exon20ins disease; enrollment in dose expansion is ongoing. Clinical trial information: NCT02609776.
S1507: Phase II study of docetaxel and trametinib in patients with G12C or non-G12C KRAS mutation positive (+) recurrent non-small cell lung cancer (NSCLC).
Authors: Gadgeel Shirish M. , Miao Jieling , Riess Jonathan W. , Mack Philip C. , Gerstner Gregory James , Burns Timothy F. , Taj Asma , Akerley Wallace L. , Dragnev Konstantin H. , Moon James , Gandara David R. , Kelly Karen 
Published: March 2020

9021 Background: KRAS+ NSCLC remains the most common genetically defined subset of NSCLC. Despite promising pre-clinical data, MEK inhibitors have failed to provide meaningful clinical benefit both as single agents and in combination with chemotherapy in KRAS+ NSCLC patients. Pre-clinical data suggest that efficacy of MEK inhibitors in KRAS+ NSCLC differs based on specific KRAS mutations such as G12C and by status of p53 or LKB1 mutations. We conducted a phase II study to assess the efficacy of docetaxel plus trametinib in KRAS+ NSCLC patients and in specific genetic subsets. Methods: KRAS+ NSCLC patients who had progressive cancer following 1 or 2 prior regimens were eligible. Docetaxel was given at 75 mg/m2 every 3 weeks and trametinib orally at 2 mg daily. The study was 2-stage design to rule out a response rate (RR) of 17% at the 3% level with 90% power if the true rate were 37%. The study required 45 pts with a futility analysis at 30 pts; 13/45 responses would indicate a success. RR was also assessed in G12C and non-G12C cohorts and will be assessed according to presence of co-mutations in p53 and LKB1. Progression free survival (PFS) and overall survival (OS) were secondary endpoints. Multivariate analysis including age, sex, number of prior treatments, prior immunotherapy (IO) and G12C status was conducted. Results: The study enrolled 54 evaluable pts (19 G12C, 9 G12D, 9 G12A); median age 65 years; female 57%; never smokers 7%; adenocarcinoma 89%; liver metastases 31%; 2 prior regimens 70%; prior IO 57%. Outcomes are summarized in Table. Median duration of therapy was 2.2 months and most common toxicities were fatigue (78%), diarrhea (68%), nausea (57%) and vomiting (28%). One patient died of treatment related respiratory failure. There was a trend for worse PFS (HR- 1.86, p = 0.06) and survival (HR- 1.80, p = 0.14) in G12C patients. Analysis of efficacy data according to co-mutations in p53 or LKB1 is ongoing. Conclusions: Docetaxel plus trametinib met the primary endpoint of the study, with a RR of 33% and median survival of 11.1 months in patients with KRAS+ NSCLC, 70% of whom had received 2 prior regimens. Although, there was no statistical difference between KRAS+ subtypes, these data suggest that outcomes may differ between G12C and non-G12C patients. Clinical trial information: NCT02642042. [Table: see text]
Preliminary results of single arm phase 2 trial of brigatinib in patients (pts) with progression disease (PD) after next-generation (NG) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in ALK + non-small cell lung cancer (NSCLC).
Authors: Stinchcombe Tom , Doebele Robert Charles , Wang Xiaofei F. , Gerber David E. , Horn Leora , Camidge D. Ross 
Published: March 2020

9027 Background: NG ALK TKIs are the standard first-line therapy for patients with advanced ALK + NSCLC. Brigatinib has activity against ALK resistance mutations and has CNS activity. The efficacy of brigatinib after NG ALK TKI is undetermined. Methods: Pts with stage IIIB/IV ALK + NSCLC, and PD after NG ALK TKI’s were eligible. Pts were required to have measurable disease, performance status 0-2, and adequate organ function. Pts were required to undergo tumor biopsy ≤ 60 days of enrollment; ctDNA was collected at baseline, at time of imaging, and PD. Brigatinib treatment was 90 mg daily for 7 days and then 180 mg daily (1 cycle = 28 days). Primary objective was objective response rate (ORR), and ORR of 20% was determined to be worthy of further investigation. Response was assessed every 2 cycles. A 2-stage design was used; if > 2 responses in 20 pts in the 1st stage, study proceeded to 2nd stage; if ≥ 5 responses in 40 pts therapy considered active. Results: Between 3/2017 and 11/2018, 20 pts were enrolled in the 1st stage. Pt characteristics were: median age 55 years (range 32 to 71), median number of prior therapies 3 (range 1 to 6), 12 had CNS disease at the baseline (8 pts had CNS PD). ALK resistance mutation detected in 3 of 8 pts on standard of care molecular testing. ORR results were confirmed partial response (n = 8), stable disease (n = 7), PD (n = 3), unconfirmed response (n = 1), and non-evaluable due adverse events (AE’s) (n = 1). The grade 3 or 4 AE’s were: pneumonitis (n = 2); 1 of each: acute renal failure, respiratory failure, sepsis, hypertension, CPK elevation, and headache. With median follow-up of 6.7 months (11 PFS events), the median PFS was 6.4 months (95% CI: 4.6 to NE). Overall survival data is immature. 3 of 3 pts with a known ALK mutation (F1174C in 2 pts, I1171T in 1 pt) responded, 2 of 5 pts without ALK mutation responded. Additional study related tumor analysis and ctDNA analyses are ongoing. Conclusions: Brigatinib has activity after progression on next generation ALK TKI. The study is enrolling additional patients in the second stage. Detailed molecular and site of disease (CNS versus extra-CNS) activity analyses are underway Clinical trial information: NCT02706626.
Acquired resistance to MET inhibition in MET driven NSCLC.
Authors: Riedel Richard , Heydt Carina , Scheel Andreas H. , Tumbrink Hannah Lea , Brägelmann Johannes , Castiglione Roberta , Nogova Lucia , Abdulla Diana S.Y. , Michels Sebastian Yves Friedrich , Scheffler Matthias , Fischer Rieke Nila , Koleczko Sophia , Merkelbach-Bruse Sabine , Sos Martin , Büttner Reinhard , Wolf Juergen 
Published: March 2020

9030 Background: MET mutations ( MET∆ex14), amplifications or translocations can activate oncogenic signaling in lung cancer and are sensitive to MET inhibition. Acquired resistance to therapy with MET tyrosine kinase inhibitors (TKI) occurs inevitably. Methods: Between 2015 and 2018, eighteen patients with MET-driven NSCLC were treated with capmatinib or crizotinib as single agent at our site. Rebiopsy samples from five patients were analyzed by NGS and fluoreszenz-in-situ hybridization (FISH) at time of progression. Results: Of the five patients with rebiopsy samples at time of progression, two had initially a MET amplification (one patient with low-level and one patient with high-level amplification), two patients had a MET∆ex14 and one patient had a KIF5B-MET fusion. Patient 1 (low-level MET amplification) showed a partial response to crizotinib. The rebiopsy revealed an acquired KRAS mutation as a potential mechanism of resistance. Patient 2 (high-level MET amplification) showed stable disease as best response to capmatinib and patient 3 (MET∆ex14) showed a partial response to capmatinib. Both patients developed acquired HER2 amplifications. Patient 4 ( MET∆ex14) showed initially a partial response to crizotinib. The rebiopsy sample revealed an acquired MET kinase domain mutation (p.D1246N). As preclinical findings suggested that D1246N confers resistance to type I MET inhibitors but remains sensitive to type II inhibitors, cabozantinib was started. A CT six weeks after therapy initiation showed progressive disease. Patient 5 ( KIF5B-MET) had a partial response to crizotinib. An acquired MET p.Y1248H mutation was found at time of progression. Therapy was changed to cabozantinib. A new CT scan is pending. Conclusions: Resistance to MET inhibition is heterogeneous with on- and off-target-mechanisms occurring. We found HER2 amplification as a potential new bypass mechanism. The MET mutation D1246N conferred resistance to type I and type II inhibitors. We describe the first case of an acquired mutation of the MET tyrosine kinase domain in a patient with an oncogenic MET fusion. Further investigations are needed to collect comprehensive data to understand resistance mechanisms in MET inhibition and to develop novel therapeutic strategies.