bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-dose icotinib in advanced lung adenocarcinoma(LUAD) patients harboring EGFR exon 21 L858R mutation: Real-world (RW) experience in a single center.
Authors: Yu Yixuan , Dong Huijing , Zheng Yumin , Liu Zhening , Cui Huijuan 
Published: June 2022

e21036 Background: Non-small cell lung cancer(NSCLC) patients(pts) with epidermal growth factor receptor (EGFR) exon 19 deletion have more benefit from EGFR-tyrosine kinase inhibitors(EGFR-TKIs) compared to pts with EGFR exon 21 L858R mutation. Icotinib, which is a first-generation EGFR-TKI had been approved for use in EGFR-positive advanced NSCLC pts. A phase II trial(INCREASE trial) showed that high-dose icotinib 250mg tid(ico250) can effectively prolong the progression-free survival(PFS) of NSCLC pts with exon 21 L858R mutation without increased toxicity. However, the RW evidence is lacking. Methods: In this single-center, single-arm study, data were retrospectively collected from China-Japan Friendship Hospital. Pts with advanced LUAD, harboring EGFR exon 21 L858R mutation, and who received ico250 for more than 20 days without chemotherapy or immunotherapy were reviewed. Clinical data were analyzed for PFS, objective response rate(ORR), disease control rate(DCR), overall survival(OS), duration of treatment(DoT) and adverse events(AEs). Survival factors were evaluated by univariate and multivariate Cox regression analysis. Results: In total 40 pts(14M,26F; median age 67[46-86]; smoker:20.0%; ECOG performance status 0-1/2-3: 33/7) who received ico250 between 4/2019-11/2021 were analyzed. The median line of pre-ico therapies was 1(range 0-2). At the cut-off day, 29(72.5%) pts had discontinued ico250, and 7(17.5%) pts died. Overall, ORR was 30.0%, DCR was 80.0%, median DoT was 8.0mos (95%CI, 3.4-12.6), median PFS was 12.9mos (95%CI, 8.2-17.6) and median OS was not reached. The univariate and multivariate analysis showed that there was no significant and independent factor associated with PFS(all P> 0.05). 30(75.0%) pts experienced AEs, while the most common AEs were rash(24,60.0%), dry skin(9,22.5%), paronychia(8,20.0%) and diarrhea(6,15.0%). Grade 3/4 AEs in 6(15.0%) pts included AST/ALT elevation(3,7.5%), rash(2,5%), diarrhea(1,2.5%) and mucositis(1,2.5%)(1 suffered both rash and mucositis). 5(12.5%) pts discontinued high-dose icotinib due to AEs. Conclusions: These data add to the RW evidence that the efficacy and tolerability of ico250 in advanced LUAD pts harboring EGFR exon 21 L858R mutation. The efficacy results are consistent with the previous INCREASE trial. High-dose icotinib could be considered whatever the previous treatment and basic characteristics of LUAD pts with exon 21 L858R mutation. However, the higher incidence of grade3/4 AEs deserves special attention.
Real-world outcomes in patients with KRAS p.G12C mutant advanced non-small cell lung cancer (aNSCLC) treated with docetaxel in second-line or beyond (2L+).
Authors: Hsu Hil , Younan Diana , Suri Gaurav , Chia Victoria M. 
Published: June 2022

e21048 Background: KRAS p.G12C mutation accounts for ̃13% of non-squamous NSCLCs and recently became a druggable target. Prior standard of care (SOC) treatment options have been limited to checkpoint inhibitors and chemotherapies as a monotherapy or combination. This US-based study provides real-world clinicopathological characteristics and outcomes of patients with KRAS p.G12C mutant aNSCLC who received 2L+ docetaxel as SOC. Methods: We conducted a retrospective observational cohort study of adult aNSCLC patients with a KRAS mutation detected via molecular testing as part of real-world care, treated with 2L+ docetaxel in the nationwide, de-identified, EHR-derived Flatiron Health (FH) database and the FH-Foundation Medicine aNSCLC clinicogenomic database between January 1, 2011–March 31, 2021. Clinicopathological and treatment characteristics were described. Median real-world overall survival (rwOS) and progression-free survival (rwPFS) were separately estimated for second, third, and fourth lines of therapy, and as any line 2L+, among eligible patients (i.e., have a minimum of 6 months opportunity for follow-up and not on a clinical trial drug). Analyses were performed for cohorts of patients with KRAS p.G12C mutation and KRAS non-p.G12C mutation, separately. Results: 677 patients with KRAS mutant aNSCLC treated with 2L+ docetaxel were included, of which 295 (44%) had KRAS p.G12C mutation. Among the 295 patients with KRAS p.G12C, mean age (SD) at advanced diagnosis was 65 (+9) years and 59% were female. The majority were White (69%) and had a history of smoking (97%), an initial diagnosis with advanced disease (78%), non-squamous cell carcinoma (96%). In total, 259 patients with KRAS p.G12C mutation were eligible for outcomes assessment. Nearly 69% of these patients initiated docetaxel in 2017 or a later year. Overall, 47% received docetaxel as second line, 35% as third line, 15% as fourth line, and 6% as a fifth or later line, with 4% receiving docetaxel in more than one line. Most (59%) docetaxel regimens were combinations, primarily with ramucirumab, and 41% were monotherapy. Nearly 68% of patients received a PD-1/PD-L1 inhibitor prior to receiving docetaxel. Outcomes are summarized in the Table. Conclusions: Real-world outcomes are poor in patients with KRAS p.G12C mutant aNSCLC treated with docetaxel in 2L or beyond, with a median OS of only 6 months. Patients with aNSCLC harboring a KRAS p.G12C mutation may benefit from available targeted treatment.[Table: see text]
Intratumoral heterogeneity as a predictive biomarker in immunotherapy for advanced non-small cell lung cancer.
Authors: Xiao HaiPing , Chen Kai , Zheng Yating , Huang Mengli 
Published: June 2022

e21058 Background: Intratumoral heterogeneity (ITH) is associated with the poor prognosis in a variety of solid tumors. However, the use of ITH as a predictive biomarker for immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) is still lacking. Methods: We used the Bioconductor R package Maftools to analyze somatic variants of NSCLC from an independent cohort (Hellmman CM012 study cohort) with data from 75 patients with advanced NSCLC. We then used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and analyzed the correlation with immunogenic marker, and the prognostic effect of ITH on immunotherapy. Results: The objective response rate (ORR) and durable clinical benefit (DCB) of immunotherapy was 36.5% and 53.8% for the patients with low ITH (ITH-L), and 21.7% and 39.1% for the high ITH (ITH-H) subgroup (P = 0.0427, P = 0.3180). The ITH-L patients had significantly improved median progression free survival (mPFS) than the ITH-H group (7.98 versus 2.60 months, hazard ratio (HR) = 1.88, 95%CI 1.06−3.34, P = 0.0280). The ORR and DCB of immunotherapy was 45.9% and 59.5% for the patients with high TMB (TMB-H), and 18.4% and 39.5% for the low TMB (TMB-L) subgroup (P = 0.0354, P = 0.1077). The TMB-H patients had significantly better mPFS than the TMB-L group (8.12 versus 3.78 months, HR = 0.49, 95%CI 0.28−0.87, P = 0.0130). A pooled analysis of ITH and TMB show that mPFS and ORR in the TMB-H+ITH-L group was significantly better than that in the TMB-H+ITH-H, TMB-L+ITH-H, TMB-L+ITH-L group (P = 0.0099, P = 0.0121). A subgroup analysis of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) found that ITH-L was associated with better mPFS (ITH-L versus ITH-H = 8.71 versus 2.17, HR = 3.42, 95%CI 0.96−12.23, P = 0.0460) in LUSC, and no significantly mPFS benefit was found in the ITH-L group in LUAD (ITH-L versus ITH-H = 7.98 versus 5.09, HR = 1.69, 95%CI 0.88−3.26, P = 0.1100). There was no significant difference in TMB levels between ITH-L and ITH-H groups (13.8 Muts/Mb versus 14.2 Muts/Mb, P = 0.2139). Conclusions: ITH may serve as a positive predictor of immunotherapy in patients with advanced NSCLC, especially in LUSC and their clinical value warrants further investigation.
Correlation between PD-L1 high-expression and EGFR variants in non-small cell lung cancer.
Authors: Liu Yifei , Quan Fei , Chen Siqi , Lu Guanghua , Yang Yuan , Deng Wanglong , Ding Ran , Bu Fanfeng 
Published: June 2022

e21062 Background: In previous studies, researchers have demonstrated that activation of the epidermal growth factor receptor (EGFR)-mutant pathway induced PD-L1 expression. In this study, we explored the correlation between PD-L1 expressions and EGFR variations. Methods: This study enrolled 2417 non-small cell lung cancer(NSCLC) patients harboring diverse EGFR mutations, including exon 19 deletions(19del)(n = 1045), L858R(n = 906), G719X(n = 176), S768I(n = 62), L861Q(n = 89) and exon 20 insertions(20ins)(n = 139). The stages range from I through IV, the majority were female(n = 1452, 60.07%) and adenocarcinoma(n = 1788, 73.98%), median age was 62(range 24-92). In this study, we retrospectively analyzed variants using next-generation sequencing(NGS). PD-L1 status was determined by VENTANA PD-L1 (SP263) Assay, TPS≥50% and TPS＜1% was the cut-off value for PD-L1 high-expression and negative separately. The 95% confidence interval (CI) was used to estimate the precision of the odds ratio (OR). Results: 1) Even though we observed subtle differences of PD-L1 high-expression ratio among various subtypes(19del：9.57%, L858R: 9.27%, G719X: 12.50%, S768I: 11.29%, L861Q: 7.87%, exon 20ins: 12.23%) in total patients, that PD-L1 high-expression was more likely to shown with G719X/S768I/exon 20ins than with 19del/L858R/L861Q, there was no statistically significant between 19del and other mutation：L858R(p = 0.8224), G719X (p = 0.2319), S768I(p = 0.6563), L861Q(p = 0.5982), exon 20ins(P = 0.3247). 2)We analyzed 742 treatment-naive EGFR-mutant NSCLC patients (PD-L1 negative, n = 624; high-expression, n = 118), PD-L1 high-expression group come with higher frequency of EGFR copy number variation(CNV)(OR = 2.2364, 95%CI, 1.4576-3.4312, p = 0.0002). Importantly, the ratio of high-level EGFR CNV(CN≥6) was higher in PD-L1 high-expression group than that in the negative group(OR = 3.0668, 95% CI, 1.3745-6.8427, p = 0.0062). Conclusions: In the newly diagnosed EGFR-mutant NSCLC patients, PD-L1 high-expression patients come with more frequent high-level EGFR CNV. There is no statistical significance between PD-L1 high-expression and EGFR mutation subtypes. As for how the EGFR signal affects PD-L1 expression, the mechanism needs to be further explored. The association between driver genes and immune checkpoints is a definite interest of future investigations.
Serum liquid metabolites reveals the heterogeneity in advanced lung adenocarcinoma patients with EGFR sensitizing mutations.
Authors: Du Xinyang , Bai Hua , Wang Jie 
Published: June 2022

e21065 Background: There is a differential therapeutic efficacy of advanced lung adenocarcinoma (LUAD) patients with EGFR sensitizing mutations (mEGFR). This study aimed to explore the differences in serum liquid metabolites of EGFR mutation types and to provide further evidence for revealing the mechanism of the difference in efficacy. Methods: In total, 42 LUAD patients with mEGFR (19 deletions or 21 L858R mutations) who received EGFR-TKIs therapy were included. Prospectively collected serum samples before initial treatment were utilized to perform nontargeted liquid metabolomics profiling analyses under the application of Ultrahigh Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (UPLC-MS/MS). Multi-dimensional statistical methods such as partial least squares discrimination analysis (PLS-DA) were used to further screen and identify differential metabolites associated with EGFR mutation type. Results: The metabolic signature molecules in the metabolic profile were extracted, and a total of 1995 positive ion mode (ESI+) and 365 negative ion mode (ESI-) signature molecules were obtained. 29 metabolites displayed significant differences between the two groups, which belong to lipids including phosphatidylcholines (PCs), phosphatidylglycerol (PGs), phosphatidylethanolamine (PEs), ceramides (Cers) and sphingomyelins (SMs). Gene mutation subtypes change the proportion of saturated phospholipids and unsaturated phospholipids, with significantly higher saturated phospholipids in patients with the EGFR 21 L858R mutation. Then, pathway enrichment analysis was performed on the differential metabolites, mainly enriched in glycerophospholipid and sphingolipids metabolism pathway. Conclusions: This study not only demonstrates the heterogeneity of lipid metabolism among gene mutation subtypes, but also provides the possibility to reveal the mechanism of survival differences.
Twice-daily thoracic radiotherapy for patients with locally advanced or oligometastatic non-small cell lung cancer: A single-center observational study.
Authors: Lyu Jiahua , Liang Long , Wang Junchao , Wang Qifeng , Wu Lei , Wang Yi , Wan Gang , Jia Hongyuan , Bai Hansong , Li Tao 
Published: June 2022

e21070 Background: Radiotherapy is standard treatment for locally advanced or oligometastatic non-small cell lung cancer (NSCLC). Once-daily thoracic radiotherapy of 60～66 Gy in 30～33 fractions is considered to be the most effective schedule in the past. The aim of this study was to investigate whether twice-daily thoracic radiotherapy improves survival and reduces toxicity. Methods: Patients aged 18 years and older with treatment-naive confirmed locally advanced or oligometastatic NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. Participants received thoracic radiotherapy of 40～80 Gy(2～4Gy/fraction, bid) and 30～60 Gy (1.5～2.0Gy/fraction, bid) to the primary lung tumour and positive lymph node metastases respectively. Patients received 2-4 cycles of chemotherapy or oral targeted drugs if the driver genes is positive. Results: In total, 124 patients were included in this study between February 2016 to March 2020. The median patient age was 61 years old and 113(91.1%) patients were male. The patient group included 72 patients with stage IIB～IIIC, and 52 patients with stage IV disease. Histological diagnosis was squamous cell carcinoma in 68 patients, adenocarcinoma in 56 patients. Median follow-up was 24.8 months (range 1.5-59.7months). The 1, 2, 3-year OS were 83.1% and 70.6%, 60.6%, respectively. The incidence of ≥Grade 2 radiation pneumonitis and esophagitis were was 25.6% and 15.2%, respectively. The most common grade 3-4 adverse events were leukopenia (17 [13.7%]), thrombocytopenia (5 [4.0%]), anaemia (15[12.0%]) and lymphopenia (30[24.2%]). None of the patients experienced fatal bronchopulmonary hemorrhage or tracheal fistula. Conclusions: Twice-daily thoracic radiotherapy is feasible and well tolerated for locally advanced or oligometastatic NSCLC. It needs to be further confirmed by large randomized controlled clinical studies. Clinical trial information: ChiCTR2100055096.
Novel predictors associated with therapeutic effects of immune checkpoint inhibitors on bone metastasis of non-small cell lung cancer.
Authors: Asano Yohei , Yamamoto Norio , Hayashi Katsuhiro , Takeuchi Akihiko , Miwa Shinji , Igarashi Kentaro , Yonezawa Hirotaka , Morinaga Sei , Saito Shiro , Tsuchiya Hiroyuki 
Published: June 2022

e21071 Background: In recent years, immune checkpoint inhibitors (ICIs) have brought dramatic therapeutic effects on lung cancer. However, there are few reports regarding the therapeutic effect of ICIs on bone metastasis of non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the therapeutic effects of ICIs on bone metastases of NSCLC and to analyze the predictors associated with ICI's response to them. Methods: This retrospective study analyzed NSCLC with bone metastases who initiated ICI treatment between 2016 and 2019. Clinical data was investigated and used as variables for analyzing the therapeutic effect predictors of ICIs. Blood sampling data were used within 1 week before ICI treatment initiation. The therapeutic effect of ICIs on bone metastases was evaluated by MD Anderson criteria (MDA criteria), and overall survival (OS) after the initiation of ICI treatment was investigated. Based on the evaluation of MDA criteria, univariate analysis was performed between the response group (CR+PR) and non-response group (SD+PD), and variables with p < 0.05 were used for multivariate logistic regression analysis to investigate the predictors associated with the therapeutic effect of ICIs. Results: The 55 patients were included comprising 40 males and 15 females (mean age of 66.3±7.9 years) and the mean follow-up period was 23.2 months. The response rate of ICIs to bone metastasis was 30.9% including 3 cases in CR and 14 cases in PR. The median survival time was 9.3 months, and the 1-year and 2-year survival rates were 40.6% and 19.3%, respectively. The OS was significantly longer in the response group than in the non-response group (p < 0.01). In the blood sampling data, the cutoff value of neutrophil-to-lymphocyte ratio (NLR) determined by receiver operating characteristic (ROC) curve analysis was 2.1. The multivariate analysis based on the variables with p < 0.05 in the univariate analysis revealed significant differences in sex, treatment line of ICIs, and NLR (Table). Conclusions: Treatment with ICIs showed favorable responses to bone metastasis and better prognosis in advanced NSCLC. Moreover, this study revealed that “female, NLR < 2.1, and first-line treatment of ICIs” were independent predictors associated with favorable response to bone metastasis.[Table: see text]
Diabetes mellitus and association with outcome in pembrolizumab treated patients with non-small cell lung cancer.
Authors: Leshem Yasmin , Dolev Yardenna , Wolf Ido 
Published: June 2022

e21079 Background: Pembrolizumab and other immune check-point inhibitors became the mainstay of treatment in ample malignancies, including non-small cell lung cancer (NSCLC). Diabetes mellitus (DM) is a highly prevalent chronic metabolic disease. Though DM causes immune dysfunction, the effect of DM on immunotherapy efficacy has not been addressed. Methods: Medical records of consecutive NSCLC patients treated with first-line pembrolizumab alone or combined with chemotherapy at Tel Aviv Medical Center from January 2017 to July 2021 were reviewed. We excluded patients who received a single cycle or were lost to follow-up. Results: Of 234 patients reviewed, 203 were included in the analysis. The median age was 69 years, 128 were men (63%), 152 had adenocarcinoma (75%), 105 received monotherapy pembrolizumab (52%), and 51 patients had DM (25%). Diabetic patients were older (73 vs. 67, p < 0.001) and had a higher mean body index (27 vs. 24, P < 0.001). Median progression free survival (PFS) and overall survival (OS) were significantly shorter in diabetic compared to non-diabetic patients (5.9 vs. 7.1 months, respectively, p = 0.004, and OS 12 vs. 21 months, respectively, p = 0.006). The difference in OS was more pronounced for patients receiving pembrolizumab alone (12 vs. 27 months, p = 0.03), than for those receiving pembrolizumab together with chemotherapy (14.3 vs. 19.4 months, p = 0.06). This suggests that DM is mainly determinantal to anti-tumor immunity and not to the cytotoxic effect of chemotherapy. Multivariate analysis indicated DM as an independent risk factor for inferior PFS (HR 1.7, 95% CI 1.11-2.5, p = 0.014) and OS (HR 1.7, 95% CI 1.09-2.76, p = 0.02). Conclusions: Here we show a potential deleterious effect of DM on the efficacy of pembrolizumab in metastatic NSCLC patients. If further validated, the administration of single agent pembrolizumab in this setting should be reconsidered.
Clinical and laboratory parameters associated with rapid progression in advanced NSCLC patients treated with second or third-line single agent immune checkpoint inhibitors (ICIs).
Authors: Randall Megan , Bonomi Philip D. , Basu Sanjib , Borgia Jeffrey Allen , Moudgalya Hita , Kollipara Revathi , Batus Marta , Fidler Mary Jo J. 
Published: June 2022

e21087 Background: While laboratory parameters including PDL1 expression and NLR are associated with outcomes in patients with metastatic NSCLC treated with ICIs, these measures have not identified patients with rapid progression (RP) defined as progressive disease within 30 days. Clinical factors including patient age and weight loss have been associated with cancer outcomes in general. Identifying clinical correlates for NSCLC patients who experience RP on ICI therapy would be useful. Methods: The objective of this retrospective study was to evaluate relationships between pre-treatment cachexia and inflammation and RP in NSCLC patients who received 2nd- or 3rd- line single agent ICIs. Associations of age, race, gender, smoking status, and longitudinal changes in weight and NLR (from at least 6 weeks prior to treatment initiation) with RP were analyzed by univariate and multivariate statistical (Kaplan-Meier and related) methods. Results: 195 patients were included: 59% female, 18% Black, and 78% current or former smokers. 14% of patients had RP. Black race was associated with RP (HR = 2.32, p = 0.03). 191 patients had pretreatment weight available. 63% had weight loss prior to ICI, 25% with > 5% loss. Any weight loss and weight loss > 5% over the time period ≥6 weeks prior to treatment initiation were associated with RP (HR = 3.19 and 6.40, p = 0.03 and < 0.01). 188 patients had pretreatment NLR values, 63% and 42% had NLRs > 3.5 and > 5, respectively. Pre-treatment NLR > 5 and higher baseline NLR were associated with increased risk of RP (p = 0.03 and p < 0.01). In multivariate analysis adjusted by age, smoking status and weight change, higher pre-treatment NLR is found to differentially increase RP risk for black patients (interaction HR = 1.27, p = 0.03). A model with these 5 variables provided 84.5% AUC of ROC curve (80% sensitivity, 75% sensitivity) for prognosticating RP. Conclusions: This retrospective study identified clinical variables including pre-treatment NLR > 5, weight loss > 0% & > 5%, black race, smoking status, and age that were associated with RP in previously treated advanced NSCLC patients receiving single agent ICIs. Though this requires validation with racially diverse data sets, these clinical parameters may be useful in identifying patients at high risk of RP on 2nd or 3rd line ICI therapy. Future directions include evaluating clinical characteristics and laboratory parameters in NSCLC patients treated with ICIs combined with chemotherapy and novel immunotherapy regimens, as well as single agent ICIs in the first line setting. If these clinical characteristics are associated with frequent RP in the setting of first line ICI treatment, it would be reasonable to consider novel immune strategies in this patient subset.