bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between lung immune prognostic index, microbiome, and immunotherapy outcomes in non–small cell lung cancer.
Authors: Auclin Edouard , Nolin-Lapalme Alexis , Richard Corentin , Malo Julie , Tonneau Marion , Benlaifaoui Myriam , Ponce Mayra , Messaoudene Meriem , Okuma Yusuke , Hakozaki Taiki , Routy Bertrand 
Published: June 2022

9050 Background: Host-related inflammatory biomarkers and gut microbiome are two major prognostic factors for non-small cell lung cancer (NSCLC) patients (pts) treated with immune checkpoint inhibitors (ICI). In this study, we aimed to assess an association between the Lung Immune Prognostic Index (LIPI) and the microbiome composition on ICI outcomes in two independent cohorts of NSCLC pts. Methods: We included 205 patients with advanced NSCLC treated with ICI (monotherapy or in combination with chemotherapy) from two independent cohorts. Metagenomics microbiome profiling was performed on the Canadian discovery cohort of 72 pts while 16S rRNA microbiome sequencing was used in the Japanese validation cohort of 133 pts. The LIPI score was calculated using the dNLR (neutrophils/[leucocytes-neutrophils]) and lactate deshydrogenase (LDH). Pts were classified as Good (G: 0 high factor), Intermediate (I: 1 high factor) and Poor (P: 2 high factors). Median overall survival (OS) was estimated using the Kaplan-Meier method. Microbiome diversity indexes and bacterial relative abundances were compared according to LIPI groups. Results: Among the 72 pts included in the discovery cohort, the median follow-up of 20.6 months (mos). The LIPI was distributed as follows: G (n = 31, 43.1%), I (31, 43.1%), P (10, 13.8%) and baseline characteristics were well balanced between the 3 groups. When segregating pts according to LIPI, the OS was 25.6 mo, 19.8 mo, and 5.7 mo in the G, I (HR: 1.71, 95%CI: 0.80-3.65) and P (HR: 3.97, 95%CI: 1.60-9.82) groups, respectively (p = 0.003). The microbiome alpha diversity was lower in the P group compared with the G group (p = 0.03), and there was a trend towards different microbiome composition in beta diversity (p = 0.055) between both groups. Pts in the G group had a favorable microbiome (enriched in Ruminococcus and Anaerostipes), while pts from the P group had an unfavorable microbiome (enriched in Enterobacteriaceae and Clostridium symbiosum and lavalense). Next, in the validation cohort of 133 pts, LIPI was distributed as follows: G (n = 62, 46.6%), I (51, 38.3%), P (20, 15%). Pts with G LIPI had not reached their median OS compared to pts in the I [15.7 mo HR: 1.60 (0.88-2.94)] and P [8.8 mo groups, HR: 2.02 (0.98-4.19)], p = 0.03. Similar to the discovery cohort, at the genus level, G LIPI group had enrichment of Ruminococcus as well as Anaerostipes compared with pts in the P and I groups with an overrepresentation of Hungatella. Conclusions: Host-related inflammatory biomarkers, represented by the LIPI, seemed to be associated with microbiome and ICI outcomes in pts treated with NSCLC. This observation was validated in an external validation cohort. This link could be in relation to the presence of proinflammatory bacteria in pts with poor LIPI.
A phase II trial of ALK/ROS1 tyrosine kinase inhibitor WX-0593 (iruplinalkib) in ALK-positive and crizotinib-resistant advanced non–small cell lung cancer.
Authors: Shi Yuankai , Chen Jianhua , Zhang Helong , Zhang Zhihong , Zhang Yiping , Wang Zhehai , Zhang Shucai , Zhao Jian , Liu Chunling , Wang Xiuwen , Zhao Yanqiu , Hu Changlu , Yang Lei , Hao Xuezhi , Wang Lin , Si Meimei , Ge Mingjing , Geng Huaize 
Published: June 2022

9073 Background: This single-arm, multicenter phase II trial aimed to evaluate the efficacy and safety of second generation ALK/ROS1 TKI WX-0593 (iruplinalkib) in advanced ALK/ ROS1-positive non-small cell lung cancer (NSCLC). We reported the results from the crizotinib-resistant ALK-positive cohort. Methods: Patients aged ≥18 years, with histologically or cytologically confirmed ALK-positive NSCLC, progression on ≥12-week crizotinib treatment, ≥one measurable lesion according to RECIST v1.1, and ECOG PS of 0 to 2 were eligible. Patients received oral WX-0593 180 mg once daily (with a 7-day lead-in period at 60 mg once daily). The primary endpoint was confirmed overall response rate (ORR) by independent review committee (IRC) per RECIST v1.1. Secondary endpoints included confirmed disease control rate (DCR) by IRC, ORR, DCR, duration of response (DoR), progression-free survival (PFS), time to progression (TTP), intracranial ORR (iORR) per RANO-brain metastases criteria by investigator (INV), overall survival (OS), safety, and Cmax,ss. Results: Between August 7, 2019 and October 30, 2020, totally 146 patients were enrolled. The data cutoff date was March 10, 2021. The median follow-up was 9.3 months (IQR 6.3-14.1). 90 (61.6%) patients had brain metastases, of which 41 (46%) had measurable intracranial lesions and 20 (22%) received prior radiotherapy to brain. 56 (38.4%) patients received prior chemotherapy. The IRC-assessed ORR was 67.8% (95% CI 59.6%-75.3%). Efficacy data were detailed in the Table. Additionally, subgroup analyses indicated IRC-assessed ORR were slightly higher in the patients without brain metastases (79% vs 61%) or prior radiotherapy to brain (66% vs 45%). Patients with prior chemotherapy or not had similar results (71% vs 66%). The iORR was 63% (95% CI 47%-78%) in pts with measurable intracranial lesions. OS data were immature. 134 (91.8%) of 146 experienced treatment-related adverse events (TRAEs). The most common TRAEs were AST increased (60 [41.1%]), ALT increased (52 [35.6%]), and blood creatine phosphokinase increased (49 [33.6%]). Dose reduction and discontinuation due to TRAE, and serious TRAEs occurred in 15 (10.3%), three (2.1%), and six (4.1%), respectively. No treatment-related death was reported. Drug concentration reaches steady state at Day 21 (Cmax,ss =255.4 ng/mL). Conclusions: WX-0593 showed promising activity against ALK-positive NSCLC after crizotinib resistance and favorable safety profile, demonstrating WX-0593 could be a new treatment option for this patient population. Clinical trial information: NCT04641754. [Table: see text]
Quality of life (QoL) of OSE2101 in patients with HLA-A2+ non–small cell lung cancer (NSCLC) after failure to immune checkpoint inhibitors (IO): Final data of phase 3 Atalante-1 randomized trial.
Authors: Besse Benjamin , Campelo Rosario Garcia , Cobo-Dols Manuel , Quoix Elisabeth Anne , Madroszyk Anne , Felip Enriqueta , Cappuzzo Federico , Denis Fabrice , Hilgers Werner , Romano Giampiero , Debieuvre Didier , Galetta Domenico , Baldini Editta , Viteri Ramirez Santiago , Phan Minh Duc , Schuette Wolfgang , Zer Alona , Vasseur Berangere , Dziadziuszko Rafal , Giaccone Giuseppe 
Published: June 2022

9094 Background: OSE2101 (Tedopi) is an anticancer vaccine increasing overall survival (OS) versus Standard of Care (SoC docetaxel or pemetrexed) in HLA-A2+ NSCLC patients with secondary resistance after sequential Chemo (CT)-IO (ESMO 2021 #47LBA). Here we present the QoL analysis. Methods: EGFR and ALK negative NSCLC patients who failed prior IO, ECOG PS 0-1 were randomized 2:1 to receive either OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was OS; secondary endpoints included time to ECOG PS deterioration and QoL by EORTC QLQ-C30/LC13 questionnaires at baseline and before each treatment administration until the end of treatment (EOT). Changes in QLQ-C30/LC13 scores from baseline to EoT were assessed using mixed-effects model for repeated measures (MMRM). Overall treatment effect and associated p value were estimated using MMRM. Results: 95 out of 118 (81%) patients with secondary resistance to IO completed baseline and ≥ one follow-up questionnaire. Median OS was 11.1 mo for OSE2101 vs 7.5 mo for SoC [HR 0.59; p = 0.02]. Median time to ECOG PS deterioration was 9.0 mo for OSE2101 vs 3.3 mo for SoC [HR: 0.43; p = 0.004]. Global Health Status remained stable with OSE2101 whereas it deteriorated from the 1st cycle with SoC (p = 0.045). Most pronounced effects were observed in the physical (ability to perform activities that require physical effort; p = 0.07) and the role (ability to work and carry out daily activities; p = 0.03) functioning scores (refer table below). Patients had less mouth soreness (p = 0.01), dysphagia (p = 0.01), peripheral neuropathy (p = 0.03), alopecia (p < 0.001) and fatigue (p = 0.06) with OSE2101 than with SoC. The change from baseline of dyspnea, coughing, hemoptysis, and pain were not significantly different between the 2 groups. Conclusions: In advanced HLA-A2+ NSCLC patients with secondary resistance to IO after sequential CT-IO, OSE2101 improves OS and maintains QoL vs. SoC, especially global health status, physical and role functioning scores. Patients presented fewer symptoms typically related to adverse effects of chemotherapy as compared to SoC. Clinical trial information: NCT02654587. [Table: see text]
Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic non–small cell lung cancer (mNSCLC): Treatment (tx) beyond progressive disease (PD) in platinum-pretreated patients (pts) with and without intracranial PD.
Authors: Janne Pasi A. , Ramalingam Suresh S. , Yang James Chih-Hsin , Riely Gregory J. , Bunn Veronica , Jin Shu , Zhou Caicun , Camidge D. Ross 
Published: June 2022

9099 Background: Mobocertinib is a potent, irreversible, oral tyrosine kinase inhibitor selectively targeting EGFR ex20ins in NSCLC. Mobocertinib demonstrated clinical efficacy in 114 platinum-pretreated pts (PPP) with EGFR ex20ins+ mNSCLC in a phase 1/2 study. Methods: In this study (NCT02716116), pts with ECOG status 0–1 and ≥1 prior therapy line for locally advanced/metastatic EGFR ex20ins+ NSCLC received mobocertinib 160 mg QD. Pts were allowed to continue tx beyond PD at the discretion of the investigator (INV) if evidence of clinical benefit existed. We present data on continuation of mobocertinib tx beyond PD in the PPP cohort by site of first PD (brain vs extracranial). Results: At the November 1, 2020, data cutoff, among PPP (n=114; median age 60 y, 66% female, 60% Asian), 59% had ≥2 prior systemic anticancer lines; 35% had baseline brain metastases (Zhou C, et al. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021). Confirmed objective response rate (cORR) per independent review committee (IRC) was 28%; median duration of response was 17.5 mo. IRC-assessed cORR was 34% among PPP with no baseline brain metastases versus 18% among PPP with baseline brain metastases (Zhou C, et al. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021); median progression-free survival was 9.2 and 3.7 mo, respectively. Per INV assessment, 64 pts had PD. Duration of mobocertinib tx beyond PD is summarized in the Table. Among pts with first site of PD in brain per INV (n=21), 17 (81%) pts remained on mobocertinib tx beyond PD; 7 (33%) received radiotherapy to brain and remained on mobocertinib tx, of whom 3 pts remained on mobocertinib tx for ≥6 mo and 1 pt for ≥12 mo. Among pts with first site of PD outside the brain per INV (n=43), 28 (65%) pts continued tx beyond PD and 4 (9%) pts remained on mobocertinib tx for ≥6 mo. Conclusions: These results suggest that mobocertinib may have limited intracranial activity given the high frequency of first PD in brain (25%) and numerically lower IRC-assessed cORR in pts with baseline brain metastases. Per INV assessment, pts may derive ongoing systemic benefit from mobocertinib. Duration of time to next progression based on local therapy continues to be investigated. Clinical trial information: NCT02716116. [Table: see text]
Central nervous system efficacy of furmonertinib versus gefitinib in patients with non–small cell lung cancer with epidermal growth factor receptor mutations: Results from FURLONG study.
Authors: Chen Gongyan , Wang Xiang , Liu Yunpeng , Wu Lin , Hao Yanrong , Liu Chunling , Zhu Shuyang , Zhang Xiaodong , Li Yuping , Liu Jiwei , Cao Lejie , Cheng Ying , Zhao Hui , Zhang Shucai , Zang Aimin , Cui Jiuwei , Feng Jian , Liu Fei , Gu Chuan , Shi Yuankai 
Published: June 2022

9101 Background: Furmonertinib (AST2818) is a third-generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitor (TKI) with central nervous system (CNS) penetration. Here we report the CNS response to furmonertinib versus gefitinib as first-line therapy in EGFR-mutated non-small cell lung cancer (NSCLC) patients in the FURLONG study. Methods: FURLONG was a randomized, double-blind, multi-center phase III study. Patients were randomized 1:1 to receive first-line furmonertinib 80mg/d or gefitinib 250mg/d. Brain scan was mandatory at screening. Patients with asymptomatic CNS metastases who did not require steroid treatment for 28 days or more were enrolled. A pre-planned CNS efficacy analysis was done using RECIST v1.1 in patients with measurable or non-measurable CNS lesions (cFAS) and patients with only measurable CNS lesions (cEFR). Results: Of 358 enrolled patients in the FURLONG study, 133 (37%) patients were defined as cFAS and 60 (17%) were defined as cEFR according to baseline brain scan judged by a blinded independent review committee (IRC). At the cut-off date of Sep 15, 2021, CNS progression-free survival (PFS) assessed by IRC in the cFAS population was significantly longer in the furmonertinib group than in the gefitinib group (20.8 vs 9.8 months, HR 0.40 [95% 0.23-0.71]; p = 0.0011). CNS PFS rate at 6, 12, 18 months were 91%, 77%, 63% in the furmonertinib group, and 76%, 46%, 34% in the gefitinib group. In the cEFR set, confirmed CNS objective response rate was 91% in patients with furmonertinib and 65% in patients with gefitinib (p = 0.0277), and CNS disease control rate were 100% vs 84% (p = 0.9420), respectively. The mean best percentage change in the sum of target CNS lesion size from baseline in cEFR was -61.8% in the furmonertinib group versus -38.7% in the gefitinib group (p = 0.0011). Conclusions: Furmonertinib showed CNS efficacy as first-line therapy in EGFR-mutated NSCLC patients with CNS lesions. Patients treated with furmonertinib had a reduced risk of CNS progression or death, a higher CNS ORR and a deeper CNS response compared with gefitinib. Clinical trial information: NCT03787992.
Afatinib (Afa) + bevacizumab (Bev) versus afatinib alone as first-line treatment of patients with EGFR-mutated advanced non-squamous NSCLC: Primary analysis of the multicenter, randomized, phase II study—AfaBev-CS study.
Authors: Ishikawa Nobuhisa , Ninomiya Takashi , Kozuki Toshiyuki , Kuyama Shoichi , Inoue Koji , Yokoyama Toshihide , Kanaji Nobuhiro , Yasugi Masayuki , Shibayama Takuo , Aoe Keisuke , Ochi Nobuaki , Fujitaka Kazunori , Kodani Masahiro , Ueda Yutaka , Watanabe Kazuhiko , Bessho Akihiro , Sugimoto Keisuke , Oze Isao , Kiura Katsuyuki 
Published: June 2022

9112 Background: Adding Bev to erlotinib prolonged PFS in NEJ026 and CTONG1509 trials, but limited data are available adding Bev to a second-generation EGFR-tyrosine kinase inhibitor. AfaBev-CS is a Japanese no-profit, randomized, open-label, multicenter phase II trial of Afa plus Bev vs Afa alone as first-line treatment for EGFR-mutated advanced NSCLC. Methods: This study enrolled untreated pts of advanced non-squamous NSCLC harboring EGFR sensitizing mutation (Del19 or L858R) and without symptomatic brain metastases. 100 eligible pts were randomized in a 1:1 ratio to receive either Afa (30 mg, daily) plus Bev (15 mg/kg, every 3 weeks) (AfaBev arm) or Afa (40 mg, daily) monotherapy (Afa arm), and stratified according to stage, EGFR mutation status and institution. The primary endpoint was PFS and the secondary endpoints were OS, tumor response and time to treatment failure. The sample size was set in terms of feasibility. The power is greater than 50% under the assumptions of a median PFS of 12 months for the Afa arm and HR of 0.6 for the AfaBev arm, with an accrual of 2.5 years and a minimum planned follow-up period of 2 years with the type 1 error of 0.05 (two-sided). Results: Between August 2017 and September 2019, 100 pts were enrolled (each arm, 50 pts). At a median follow-up of 31.3 months for all randomized pts, total 69 events occurred. Median PFS was 16.3 months for AfaBev arm and 16.1 months for Afa arm, with a hazard ratio (HR) of 0.865 (95%CI, 0.539 – 1.388; loglank p = 0.5476). In subgroup analysis, pts < 70 years old (HR 0.347) and pts with brain metastasis (HR 0.353) showed better trend of PFS in AfaBev arm. On the other hand, pts ≥ 70 years old (HR 1.738) and pts without brain metastasis (HR 1.196) did not show better trend in AfaBev arm. In terms of OS, result was immature because number of events was still small. Objective response rate was 77.6% in AfaBev arm and 72.0% in Afa arm. Severe adverse events were observed in 11 pts for each arm. Grade 3 or more diarrhea, hypertension, rash acneiform, paronychia and stomatitis were frequently observed in AfaBev arm. Pneumonitis was not observed for AfaBev arm and observed in 3 (6.0%) for Afa arm, and grade 3 in one patient. Conclusions: This study failed to show the efficacy of AfaBev arm for improving PFS in untreated pts with EGFR mutated non-squamous NSCLC. In pts < 70 years old, Afa plus Bev might be promising. Clinical trial information: jRCTs061180006.
Updated study results of pelcitoclax (APG-1252) in combination with osimertinib in patients (pts) with EGFR-mutant non–small cell lung cancer (NSCLC).
Authors: Zhang Li , Zhao Hongyun , Zhao Yanqiu , Cheng Ying , Cui Jiuwei , Ma Yuxiang , Yang Chen , Zhang Jie , Xu Liang , Yu Juan , Men Lichuang , LIANG ZHIYAN , Yang Dajun , Zhai Yifan 
Published: June 2022

9116 Background: Investigational agent pelcitoclax is a dual BCL-2/BCL-xL inhibitor, which enhanced antitumor effects of osimertinib in preclinical models. A report presented at International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer demonstrated that the combination of pelcitoclax and osimertinib at the recommended phase 2 dose (RP2D) was safe, and preliminary efficacy was observed in some patients whose disease failed prior osimertinib or other third-generation EGFR-TKI treatments. Here, we further provide safety and efficacy results of this combination therapy. Methods: After RP2D was determined to be pelcitoclax 160 mg per week plus osimertinib 80 mg QD, pts were enrolled into 3 expansion cohorts of 20 pts each: Cohort 1 (EC-1) included those with disease resistant to third-generation EGFR-TKIs; Cohort 2 (EC-2) included those with osimertinib-naïve, EGFR-sensitive or T790M-positive mutations; and Cohort 3 (EC-3) included those with the EGFR exon 20 insertion mutation. Results: At the data cutoff date of January 6, 2022, 61 pts (median age, 56 years [69% female]) had been treated with pelcitoclax plus osimertinib. Among them, 13 were in dose escalation cohorts, 20 in EC-1, 20 in EC-2, and 8 in EC-3. Sixteen pts in EC-2 were EGFR-TKI naïve, and 4 were T790M positive with prior TKI treatment. All pts in EC-2 experienced treatment-related adverse events (TRAEs) but only 4 (20%) had grade ≥ 3. Common TRAEs included increased aspartate aminotransferase (90%) and alanine aminotransferase (85%) levels, reduced platelets (40%), diarrhea (40%), and increased lipase (35%). Among 20 evaluable pts, 17 PRs (85%) were observed and 16 (80%) confirmed. The median (range) time to response was 1.4 (1.2-7.0) months, and the median duration of response (DOR) was not reached. The DOR rate at 9 months after first response was 71.4% (95% CI 25.8-92.0). Seven pts had brain metastases at baseline in EC-2; 2 CRs and 3 PRs were observed intracranially. Conclusions: Osimertinib in combination with targeted therapies has been of clinical interest to improve the outcomes of patients with EGFR-mutant NSCLC. Pelcitoclax plus osimertinib was well tolerated and showed comparable efficacy in TKI-naïve pts. Further randomized control trials are warranted to elucidate the role of pelcitoclax when combined with osimertinib. Clinical trial information: NCT04001777.
Analysis of MET exon 14skippingmutations in non–small cell lung cancer (NSCLC) by histology and specific mutation.
Authors: Marks Jennifer Aline , Yin Jun , Halmos Balazs , Bazhenova Lyudmila , Ramalingam Suresh S. , Marmarelis Melina Elpi , Xiu Joanne , Walker Phillip , Oberley Matthew James , Ma Patrick C. , Liu Stephen V. 
Published: June 2022

9119 Background: MET exon 14 skipping mutations (METex14) join a growing list of viable therapeutic targets in advanced NSCLC. Several unique features distinguish METex14 from other established targets. METex14 has been characterized as a tumor-agnostic genomic alteration, though most frequently reported in lung adenocarcinoma. However, METex14 represents a family of mutations (mt), not a single alteration, and there is notable heterogeneity in histology. The degree and significance of heterogeneity within METex14 have not been well characterized. Methods: NSCLC tissue samples were analyzed with DNA-based next-generation sequencing (NGS; 592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-based whole transcriptome sequencing (WTS, NovaSeq), and immunohistochemistry (IHC) at Caris Life Sciences (Phoenix, AZ). PD-L1 expression utilized the 22C3 clone (Dako); TMB-high was defined as ≥ 10 mt/Mb. Wilcoxon or Fisher’s exact were used to determine statistical significance (p without and q with multi comparison correction). Immune cell fraction (QuanTiseq) and pathway analysis (ssGSEA) were informed by WTS analysis. Results: A total of 440 METex14 cases were identified: 49 (11.1%) with squamous histology, 381 (86.6%) with non-squamous histology, and 10 (0.2%) with adenosquamous histology. A total of 147 distinct METex14 mutations were detected. The most common METex14 mutations were D1028H (8.4%), D1028N (7.0%), c.3082+2T > C (5.7%), D1028Y (5.2%), and c.3082+1G > A (4.5%). Co-mutations in TP53 were common (43.9%) but varied by specific METex14 mutation; TP53 co-mutations were observed in 53.9% of c.3082+3A > T but only 21.1% of c.3082+1G > T. Among all METex14 cases, 8.6% were TMB-high, but this varied by specific mutation with a median TMB of 2 mt/Mb in MET c.3082+2T > A and a median of 7 mt/Mb in MET c.3082+1G > C (q < 0.05). PD-L1 expression ≥ 1% was present in 82.2% of METex14 samples but also varied by specific METex14 mutation with a median PD-L1 tumor proportion score (TPS) of 97.5% in MET c.3082+1G > C and a median TPS of 0% in MET c.3082+3A > G (q < 0.05). Co-mutations varied by histology: in squamous METex14, 90.4% had TP53 mt (p < 0.001), 17.9% had KMT2D mt (p < 0.05), and 10.7% had PIK3CA mt (p < 0.05), while in non-squamous METex14, 60.7% had TP53 mt, 2.7% had KMT2D mt, and 4.3% had PIK3CA mt. Survival was numerically shorter in squamous METex14 NSCLC compared to non-squamous (HR 1.22, p = 0.47, mOS 336 vs.1106 days). Conclusions: There is significant heterogeneity within METex14 NSCLC with differences in co-mutations, TMB, and PD-L1 expression noted among different METex14 mutations. While METex14 is detected in both squamous and non-squamous NSCLC, there are differences in enrichment of oncogenic pathways. The clinical impact of these differences warrants further investigation.