bluuebunny/crossref_metadata_2025 huggingface dataset:
10-year patient journey of stage III non-small cell lung cancer patients: A single-center, observational, retrospective study in Korea real-time automatically updated data warehouse in health care (UNIVERSE - ROOT study).
Authors: Park Keunchil , Jung Hyun Ae , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Ahn Myung-Ju , Lee Joohwan
Published: March 2020

8536

Background: The current standard of care (SoC) for locally advanced stage III NSCLC is concurrent chemoradiotherapy (CCRT) but the outcomes are poor and unsatisfactory. The purpose of this study is to analyze the clinical features of patients with locally advanced lung cancer for 10 years in order to help develop future treatment strategy. Methods: This study through big data analysis retrospectively collected de-identified patient data from clinical data warehouse (CDW) using an unique algorithm with Standard Query Language (SQL). This new algorithm was developed by the close interactive collaboration between senior data scientists and medical oncologists. These algorithms include clinical natural language processing (NLP) systems that generate structured information from unstructured free text and structured data capture (SDC). We performed pre-processing work and data quality management (DQM) operation using over 700 clinical variables from 23,735 patients with NSCLC. Through data extraction, transformation, cleansing, and organization, we have developed a systematic and optimized program for lung cancer cohorts, including clinical features and molecular study and outcomes. It is also automatically updated every 24 hours in real time. Results: In the past 10 years, 23,735 patients were diagnosed with NSCLC and complete clinical data were available in 22,718 patients (95.7%). Out of total 22,718 patients 4,138 (18.2%) were diagnosed with stage III NSCLC. Among them, 2,676 patients (64.7%) received any type(s) of anti-cancer treatments or regular follow up at our institute. Of these 2,676 patients, 1,275 (47.6%) received curative surgery (+/- neo- and/or adjuvant CCRT); 685 (25.6%) patients definitive CCRT ; 220 (8.2%) patients palliative thoracic RT; 76 (2.8%) patients best supportive care. Median OS was 48.0 months for neoadjuvant CCRT followed by curative surgery, 51.8 months for curative surgery +/- adjuvant treatment, 29.4 months for unresected definitive CCRT (PFS 10.0 months (range: 9.1-10.9). Molecular profiles as well as updated clinical data will be presented. Conclusions: This unique in-house algorithm enables us to do a rapid and comprehensive analysis of the big data through CDW, which can be also automatically updated daily. This should provide clinically relevant information about real-world treatment outcomes and help implement or develop new treatment strategy in a timely manner.
EGFR L858R mutation as a possible target for individual-independent immunotherapy in Chinese population.
Authors: Chen Yu , Hao Shiguang , Guo Zeng-qing , Lin Jing , Chen Li-zhu , Chen Ling , Yu Jia-mi , Chen Gang , Zheng Xiong-wei , Yi Yuting , Guan Yan-Fang , Xia Xuefeng , Yi Xin
Published: March 2020

8538

Background: Neoantigens arise from tumor-specific mutations and potentially provoke immune responses. General vaccines targeting these peptides could be beneficial for patients suffering from common cancers, like lung cancer. Therefore, a retrospective analysis was performed on 799 non-small cell lung cancer (NSCLC) tissue samples previously profiled using our 1021-gene panel. Each sample was collected from a unique patient, from whom peripheral blood or normal tissue was also obtained as control. Methods: Sequencing data were generated and pre-analyzed according to our in-house procedures. HLA typing was done using OptiType v1.0 (required sequences were captured by 1021-gene panel) and neoantigens were predicted by netMHCpan v4.0 based on typed HLA alleles and curated non-frameshift somatic mutations with frequency > 5%, which were called in pre-analysis. A neoantigen is considered mutant-specific if IC50 mut is < 500 nM and IC50 wild is > 500 nM, and especially, it is considered a strong-binder if IC50 mut is < 50 nM. Results: HLA typing returned 141 unique alleles, with the top 3 by carrier frequency being A*1101 (39%), C*0102 (33%) and A*2402 (28%). A further investigation into HLA alleles, mutations and neoantigens revealed two mutations on EGFR as candidates for off-the-shelf vaccine development: (1) L858R mutation (19%, 151 out of 799) and (2) E746_A750del mutation (13%, 106 out of 799). Among the four neoantigens derived from EGFR L858R mutation is HVKITDFGR, which can be recognized by A*3303 (IC50 mut = 22.93 nM and IC50 wild = 12,733.96 nM) and the combination is shared by 3% of the patients (23 out of 799), despite that A*3303 is not a very frequent allele in this population (16%, 127 out of 799). Two neoantigens were derived from EGFR E746_A750del mutation, including IPVAIKTSPK, which is mainly recognized by A*1101 (IC50 mut = 158.16 nM and IC50 wild = 31,132.66 nM). This combination is shared by 5% of the patients (41 out of 799). Conclusions: (1) EGFR L858R mutation and HLA-A*3303 could be a good target for individual-independent vaccine development. (2) HLA-A*1101 is the most frequent allele in this population. However, HLA-A*1101 and E746_A750del mutation is not so ideal for off-the-shelf vaccine development.
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.
Randomized phase III study comparing carboplatin plus pemetrexed followed by pemetrexed versus docetaxel in elderly patients with advanced non-squamous non-small-cell lung cancer (JCOG1210/WJOG7813L).
Authors: Okamoto Isamu , Nokihara Hiroshi , Yoh Kiyotaka , Sugawara Shunichi , Horinouchi Hidehito , Azuma Koichi , Yoneshima Yasuto , Murakami Haruyasu , Daga Haruko , Hosomi Yukio , Atagi Shinji , Ozaki Tomohiro , Horiike Atsushi , Fujita Yuka , Okamoto Hiroaki , Ando Masahiko , Nomura Shogo , Yamamoto Nobuyuki , Ohe Yuichiro , Nakagawa Kazuhiko
Published: March 2020

9031

Background: The aim of this phase III randomized trial is to determine the efficacy of pemetrexed and carboplatin followed by pemetrexed for elderly patients (pts) with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods: Cytotoxic chemotherapy-naïve, ECOG-PS 0-1, aged 75 years or older, and advanced stage non-squamous NSCLC pts were randomized to receive either docetaxel 60 mg/m2 on day 1 every 3 weeks [DOC] or carboplatin AUC 5 mg/ml/min and pemetrexed 500 mg/m2 on day 1 every 3 weeks followed by maintenance therapy with pemetrexed 500 mg/m2 every 3 weeks after 4 cycles of carboplatin and pemetrexed [CBDCA/PEM] given until disease progression or unacceptable toxicities. The primary endpoint was OS. Non-inferiority of CBDCA/PEM arm was planned to be demonstrated if upper limit of 95% confidence interval (CI) for hazard ratio (HR) did not exceed 1.154. Results: Between August 2013 to February 2017, 433 pts with a median age of 78 years (range, 75 to 88) were randomly assigned to the DOC arm (n = 217) or the CBDCA/PEM arm (n = 216). Non-inferiority of CBDCA/PEM arm was confirmed in all enrolled patients (HR for OS, 0.850; 95% CI, 0.684 to 1.056, P < 0.01). The median OS for DOC and CBDCA/PEM arms were 15.5 months and 18.7 months, respectively. In the CBDCA/PEM arm, PFS was significantly better (HR, 0.739; 95% CI, 0.609 to 0.89) and response rate was better (28.2% vs. 36.8%; P = 0.07), and incidence of neutropenia or febrile neutropenia of grade 3 or 4 was significantly lower. Grade 3 or 4 thrombocytopenia or anemia was more common in the CBDCA/PEM arm. Four treatment-related deaths (two in each treatment arm) occurred. QOL (FACT-LCS) was favorable for CBDCA/PEM arm throughout 18 weeks after enrollment. Conclusions: Pemetrexed/carboplatin followed by pemetrexed maintenance is a valid therapeutic option for the first-line treatment of elderly pts with advanced non-squamous NSCLC. Clinical trial information: 000011460.
SHERLOC: A phase 2 study of MM-121 plus with docetaxel versus docetaxel alone in patients with heregulin (HRG) positive advanced non-small cell lung cancer (NSCLC).
Authors: Sequist Lecia V. , Janne Pasi A. , Huber Rudolf M. , Gray Jhanelle Elaine , Felip Enriqueta , Perol Maurice , Hirsch Fred R. , Tan Daniel Shao-Weng , Kuesters Geoffrey , Zalutskaya Alena , Santillana Sergio , Pipas J. Marc , Shepherd Frances A.
Published: March 2020

9036

Background: Seribantumab (MM-121) is a human monoclonal IgG2 antibody that blocks the HRG domain of HER3. Preclinical data suggest that seribantumab reverses HRG mediated drug resistance across multiple cancer models. In prior retrospective analyses, addition of seribantumab to standard of care (SOC) appeared to improve outcomes in pts with HRG+ tumors. Here we tested if seribantumab plus SOC improved progression-free survival (PFS) in pts with HRG+ lung adenocarcinoma who had received prior platinum-based therapy. Methods: SHERLOC was a randomized, open-label, multicenter, Phase 2 study in pts with advanced HRG+ adenocarcinoma of the lung. Archival or pre-treatment tumor samples were assessed for HRG+ by RNA in situ hybridization. Eligibility criteria included prior platinum-based therapy for advanced disease with ≤ 2 total prior lines of therapy (prior IO was allowed) and no EGFR or ALK mutations. Pts were randomized 2:1 to receive seribantumab 3000 mg/docetaxel 75 mg IV q3w (experimental; exp) or docetaxel 75 mg IV q3w alone (control). Primary endpoint was PFS. Key secondary endpoints were overall survival (OS), objective response rate (ORR), and adverse event (AEs) profile. Results: At a pre-specified interim analysis of 75% of total PFS events, 108 pts were enrolled (exp n = 71, control n = 37). Median age was 62y (range 34-83y); female 34%; one prior treatment only 39%. Median PFS was 3.0m for exp and 4.0m for control, HR = 1.66m (p = 0.084). Median OS was 7.9m for exp and 8.4m for control, HR = 1.50 (p = 0.235). ORR was 19.7% for exp and 5.6% for control (p = 0.052). Serious AEs were more frequent in the exp arm (40.8%) vs control (24.3%). Most common treatment emergent AEs (TEAEs) in the exp arm were diarrhea (47%), fatigue (37%), and neutropenia (27%). Based on a determination of futility at interim analysis, the study was terminated early. Conclusions: Seribantumab failed to improve PFS when added to docetaxel among previously treated advanced HRG+ NSCLC pts. A higher response rate and a higher incidence of TEAEs were observed in the exp arm. No further study of seribantumab is planned in NSCLC. Clinical trial information: NCT02387216.
Patient-reported outcomes (PROs) with first-line durvalumab (D) ± tremelimumab (T) versus chemotherapy (CT) in metastatic NSCLC: Results from MYSTIC.
Authors: Garon Edward B. , Cho Byoung Chul , Reinmuth Niels , Lee Ki Hyeong , Luft Alexander , Ahn Myung-Ju , Robinet Gilles , Le Moulec Sylvestre , Natale Ronald , Schneider Jeffrey Gary , Shepherd Frances A. , Garassino Marina Chiara , Geater Sarayut Lucien , Papai-Szekely Zsolt , Van Ngoc Tran , Liu Feng , Scheuring Urban J. , Rydén Anna , Peters Solange , Rizvi Naiyer A.
Published: March 2020

9048

Background: MYSTIC, an open-label, Phase 3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs platinum CT in mNSCLC, showed an improvement in overall survival (OS) with D vs CT in pts with tumor cell PD-L1 expression ≥25% (TC ≥25% [primary analysis population]; D vs CT, HR 0.76 [97.54% CI 0.56–1.02], p = 0.036; D+T vs CT, HR 0.85 [98.77% CI 0.61–1.17], p = 0.202). Here we summarize PROs from MYSTIC. Methods: Immunotherapy/CT-naïve mNSCLC pts were randomized (1:1:1) to D, D+T, or CT. Symptoms, function, and global health status/quality of life (QoL) were assessed using the EORTC QLQ-C30 v3 questionnaire and its lung cancer module, QLQ-LC13. A change in score from baseline ≥10 points was predefined as clinically meaningful (CM). Mean changes from baseline (over 12 mos) for prespecified symptoms were analyzed using a mixed model for repeated measures (MMRM). Time from randomization to the first CM deterioration (TTD) was analyzed. Results: Among pts with PD-L1 TC ≥25% (n = 488), there were no differences between arms in symptoms, function, or global health status/QoL at baseline. Compliance with completing the questionnaires was ≥60% to wk 120 in the D±T arms, and to wk 40 (C30) and wk 44 (LC13) in the CT arm. MMRM analysis showed significant between-arm differences in changes from baseline in favor of D for fatigue (difference vs CT −9.5) and appetite loss (−11.9; CM), and D+T for fatigue (−11.7; CM). Significantly longer TTD (median, mos) was seen with D and D+T vs CT for appetite loss (12.8 and 5.6 vs 4.5), constipation (14.6 and 9.0 vs 5.5), nausea/vomiting (16.7 and 9.7 vs 4.5), and dyspnea (10.6 and 7.4 vs 5.6); D vs CT for diarrhea (16.3 vs 9.0), insomnia (9.3 vs 6.2), and hemoptysis (not reached vs 10.3); and D+T vs CT for fatigue (5.6 vs 2.0). Significantly longer TTD (median, mos) was also seen with D and D+T vs CT for function (cognitive [9.1 and 6.6 vs 5.2], physical [9.0 and 7.4 vs 4.2], role [D vs CT only; 7.3 vs 3.7], social [12.9 and 5.4 vs 5.2]), and global health status/QoL (5.9 and 6.8 vs 5.5). Conclusions: Pts with PD-L1 TC ≥25% treated with D±T had a reduced symptom burden over time and longer TTD for symptoms, function, and global health status/QoL compared to pts receiving CT. Clinical trial information: NCT02453282.
Evaluation of clonal hematopoiesis in late stage NSCLC using a next-generation sequencing panel targeting cancer genes.
Authors: Yaung Stephanie J. , Fuhlbrück Frederike , Wu Johnny , Casey Fergal , Peterson Maureen , Zou Wei , Palma John F. , Patil Namrata S. , Jiang Yuqiu
Published: March 2020

9050

Background: Somatic mutations derived from the expansion of clonal populations of blood cells (clonal hematopoiesis of indeterminate potential, or CHIP) may be detected in sequencing of cell-free DNA (cfDNA) samples. We evaluated the potential implications of CHIP in targeted sequencing of lung cancer plasma samples using matched peripheral blood mononuclear cells (PBMC) to identify CHIP. Methods: Samples were evaluated from OAK, a phase 3 trial of atezolizumab in locally advanced or metastatic NSCLC following failure with platinum-based therapy. 94 samples from Cycle 1 Day 1 (C1D1) plasma and matched PBMC were analyzed with the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), a 198-kb next-generation sequencing panel targeting cancer genes. Plasma samples from subsequent cycles of therapy (C2D1, C3D1, and C4D1) were also sequenced with the same panel. Using median input amounts of 22.8 ng cfDNA and 50 ng PBMC DNA, we obtained median deduplicated depths of 5413 and 5070, respectively. Results: In C1D1 cfDNA, a median of 120 single nucleotide variants were detected per sample, with 5.13% of variants not identified in matched PBMC (i.e., putative tumor-derived somatic variants) versus 94.87% of variants identified in matched PBMC (i.e., germline or CHIP variants). While the majority of PBMC-matched variants were SNPs with allele frequency (AF) around 50% or 100% as expected, there was a median of 1 (range 0-8) PBMC-matched cfDNA variants per sample with AF below 10%. Consistent with CHIP, the number of PBMC-matched cfDNA variants per subject below AF 10% were positively associated with age (p-value = 0.0145), and TP53 was the most frequently mutated gene. We found similar results in plasma samples from subsequent cycles. Conclusions: Plasma and PBMC sequencing analysis identified potential mutations derived from CHIP. However, 39% of cfDNA samples had zero potential CHIP mutations identified in the study, possibly due to the specific regions targeted by the AVENIO assay. While this study suggests that only a small percentage of variants detected by the AVENIO Surveillance panel in lung cancer are derived from CHIP, further studies are warranted to assess the impact and removal of these variants.
Tracking plasma KRAS mutations (mu) in lung adenocarcinoma (LUAC) patients (p) and branching evolution.
Authors: Bracht Jillian , Karachaliou Niki , Lanman Richard B. , Dix Daniel , Faull Iris , Nagy Rebecca , López Noemí , Palmero Ramon , Viteri Ramirez Santiago , Majem Margarita , Taus Alvaro , Carcereny Costa Enric , Garde Javier , Riva Francois , Malfettone Andrea , Sampayo Miguel , Drozdowskyj Ana , Felip Enriqueta , Rosell Rafael
Published: March 2020

9055

Background: KRAS m in LUAC p are recalcitrant to therapy. In mice models and p, STK11 m confer poor prognosis. Patients with KRAS, or KRAS with TP53 m, benefit from immunotherapy (IO). We used a cell free DNA (cfDNA) sequencing platform to sub-group 53 LUAC p with KRAS m from the Spanish Lung Liquid versus Invasive biopsy Program (SLLIP, NCT03248089), according to the coexistence of TP53 and STK11 m. We evaluated the treatment outcome in the KRAS subgroups and we explored the mutational evolution at 2 weeks (w), and at the end of the study (EOS). Methods: SLLIP was a multi-center observational study in patients with treatment-naïve metastatic LUAC. Genotyping, with a clinically validated cfDNA assay (Guardant360) was performed at 3 time points: before start of treatment, at 2 w, and upon progression or at 12 months (mo). Oncoprints were constructed based on mutation status and variant allele frequency (VAF). Results: 53 p with KRAS alterations were included. 36 male; median age 59; 46 current/ex-smokers; 64% received 1st line platinum-based chemotherapy (CT), 4% platinum-based CT+IO, 8% platinum-based CT plus bevacizumab, and 24% other or no therapy. 13 p had only KRAS m (K-only group), 25 p had KRAS + TP53 m (KP group), and 15 p had KRAS + STK11 with or without TP53 m (KS group). Median progression-free survival was 3.5 mo for all 53 p, 4.8 mo for the K-only group, 4.4 mo for the KP group, and only 2.6 mo for the KS group (p = 0.05 for KS versus K-only). The average VAF for K-only, KP, and KS groups at EOS were 6.4%, 9.7%, and 46%, respectively. When looking at p with cfDNA analysis at the three time points, the following were observed: In the K-only group, 25% lost KRAS m at 2 w and 50% at EOS. 50% and 75% gained TP53 m, at 2 w and EOS, respectively. None gained STK11 at the 2 time points. In the KP group, 40% lost KRAS m at 2 w but all had KRAS m at EOS. 20% and 10% lost TP53 m, at 2 w and EOS, respectively. 10% gained STK11 m at the 2 time points. In the KS group, 33% lost KRAS m at the 2 time points. All and 33% lost STK11 m at 2 w and EOS, respectively. 66% gained TP53 at the 2 time points. Conclusions: Subgroups of KRAS m traced in cfDNA confirm dismal prognosis to 1st line therapies. These findings prompt us to tailor IO for K-only or KP subgroups. For p with STK11 m, restoration of the STK11 function is warranted. Clinical trial information: NCT03248089.
Impact of time to treatment initiation (TTI) on survival of patients with newly diagnosed non-small cell lung cancer (NSCLC).
Authors: Azzouqa Abdel-Ghani , Chen Ruqin , Lou Yanyan , Ailawadhi Sikander , Manochakian Rami
Published: March 2020

9058

Background: Lung Cancer is the leading cause of cancer related deaths in the USA. NSCLC comprises about 85% of lung cancer cases. Although timeliness of care in patients with NSCLC is considered an important aspect of quality care, there are conflicting data about its impact on clinical outcomes. The primary objective of this study is to determine if there is an association between TTI and survival in patients with NSCLC. Methods: In this retrospective study, we reviewed data from our multi-site Mayo Clinic Cancer Center registry and identified patients with newly diagnosed NSCLC from 2000 to 2016. TTI was calculated from time of diagnosis to time of first treatment (surgery, radiation therapy or systemic therapy). Analyses were performed by SAS software 9.4. Log-Rank test was used to compare survival. Cox regression multivariate model was used to evaluate the prognostic value of variables to survival. Results: 10010 patients (53% males and 47%) were reviewed. Median age at diagnosis was 70. Median TTI was 12 days for stage I, and 20 days for stage II, III and IV. We compared outcomes of patients with TTI > 20 days to TTI ≤20 days. Outcomes were stratified based on age, gender, grade, and stage. Median Overall Survival (OS) was significantly better for patients with TTI ≤20 days compared to TTI > 20 days (39.1 vs 28.6 months P-value < 0.0001). Further stratification, based on stage, showed significantly better OS for stage I and II patients with TTI ≤20 days compared to TTI > 20 days (103.4 vs. 63.9 months P-value < 0.0001 and 72.3 vs. 46.8 months P-value 0.0014 respectively). OS for stage III patients with TTI ≤20 days was not significantly different from patients with TTI > 20 days (30.6 vs. 28.5 months P-value 0.118). Interestingly, stage IV patients had worse OS if TTI ≤20 days compared to TTI > 20 days (8.3 vs. 12.8 months P-value < 0.0001). Conclusions: Our study showed an association between TTI and survival of patients with NSCLC. Shorter TTI was associated with better survival in stage I and II patients and worse survival in stage IV patients. Our study further highlights the controversy surrounding the topic of impact of timeliness of care on survival in patients with cancer, specifically NSCLC across different stages.
Identification and use of treatment (tx) options in patients (pts) with advanced non-small cell lung cancer (aNSCLC) after comprehensive genomic profiling (CGP): A real-world study.
Authors: Mascaux Celine , Bubendorf Lukas , Barlesi Fabrice , Clendening James W. , Zhang Qing , Mace Kieran , Gondos Adam , Foser Stefan , Wang Lisa I. , Paz-Ares Luis G.
Published: March 2020

9076

Background: The number of targeted txs for NSCLC is increasing. By analyzing numerous molecular alterations, CGP may open more targeted tx options than single biomarker testing. Methods: We analyzed a database linking Flatiron Health electronic health record-based clinical and Foundation Medicine, Inc. (FMI) CGP genomic alteration (GA) data in US pts diagnosed from 1/2011 with aNSCLC, primarily from community practices, and with follow-up through 6/2018. We examined the prevalence and distribution of genomic findings, and agreement between tx received and CGP-directed tx options (approved for aNSCLC/other tumors) on the FMI report as a measure of clinical utility. The latter was evaluated in a subset of pts with sufficient tx and follow-up data after FMI testing. Results: Among 5112 FMI-tested pts (first test observed 8/2012), 49% had their FMI test before starting any line of tx, 97% had ≥ 1 GA with known/likely function (median = 5), and 85% had ≥ 1 potential tx option (52% had ≥ 1 option for aNSCLC and 33% had ≥ 1 for another tumor type only). In 1366 pts evaluable for tx agreement after FMI testing, 572 (42%) received a tx listed on the FMI report and 111 (8%) were enrolled in clinical trials. Pts with a tx option approved for aNSCLC were more likely to have a tx agreeing with an option on the FMI report (67% of 754) v pts with a tx option approved in another tumor type only (8% of 612). Among the 1366 pts, 14% had EGFR/ALK/ROS1/BRAF (EARB) tx options only. The remaining 1170 had a non-EARB tx option, either as their only option (1014; 87%), or in addition to an EARB tx option (156; 13%). The non-EARB tx options included 377 pts (32%) with a tumor mutational burden-associated tx option. In these 1170 pts, 341 (29%) had an agreeing tx besides EARB, and 100 (9%) were enrolled on trials. Conclusions: FMI CGP identified potential NSCLC-specific tx options/a clinical trial opportunity for 52% of pts with aNSCLC. Of the pts evaluated for tx agreement, almost ½ received a tx agreeing with an option on the FMI report and/or were enrolled in a clinical trial. FMI CGP adds value beyond single biomarker testing by identifying txs and trial options in a meaningful proportion of pts.