bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic alteration profiling of Chinese lung adenocarcinoma: A targeted and immunotherapy biomarker analysis.
Authors: Zou Zhiqiang , Nguyen Thi Phuong Anh , Xia Chaoran , Ding ShouTai , Luo Peng
Published: June 2022

e20572

Background: Lung adenocarcinoma is the most common primary lung cancer, comprises about 30% of lung cancers. So far, little is known about an in-depth molecular characterization for lung adenocarcinoma in Chinese patients. The genomic characteristics, microsatellite instability (MSI) status, programmed cell death-1 (PD-L1) and tissue tumor mutational burden (tTMB) in Chinese lung adenocarcinoma patients will benefit to understanding drug resistance-related mechanisms. Methods: 591 Formalin-Fixed Paraffin-Embedded (FFPE) lung adenocarcinoma samples were collected and detected by Next Generation Sequencing 603-gene panel. The biomarkers of immunotherapy (TMB-High [≥10/Mb], MSI-High, and PD-L1 22C3 [TPS] were also calculated. Results: Of 591 patients, 312 patients (52.8%) were male and 279 (47.2%) patients were female. The median age of the patients was 60.7 (range 28-99). The most commonly mutated genes were EGFR (45.5%), TP53 (22.1%), KRAS (7.8%), PIK3CA (5.3%), ERBB2 (2.5%), BRAF (2.2%), CTNNB1 (1.5%), SMAD4 (1.5%),NRAS (1.0%), SMAD4 (1.5%), NRAS (1%), ATM (1%), RB1 (1%), NF1(1%), IDH2 (0.67%). Three genes mutations (EGFR, TP53, KRAS) were identified significantly different between male and female. EGFRmutations were significantly more frequent in females (54.12%) than in males (37.5%;p = 0.000051). In contrast, TP53 mutations were significantly more frequent in males (11.53%) than in females. KRASmutations were significantly more frequent in males (25.6%) than in females (17.9%;p = 0.023). (3.6%;p = 0.0003). The aging of patients was associated with a higher PTEN mutations (< 50 years-old, p = 0.039), RAF1 mutations (> 76 years-old, p = 0.038), BRCA1 mutations (< 42 years-old, p = 0.032). The average of TMB was 5.3 mut/Mb (range 0-54.8). Immunotherapy markers were presented in 36.4% of cases (TMB-High in 15.91%, PD-L1+(TPS > 1%) in 47.12%,PD-L1+(TPS > 50%) in 5.17%, MSI-High in 0.17%). PD-L1 expression and TMB score were not significantly correlated in lung adenocarcinoma. The TMB score was associated with a higher TP53 mutations(TMB > 6.6, p < 0.0001), KRAS(TMB > 6.1, p = 0.034), NF1(TMB > 9.8, p = 0.0018), IDH2(TMB > 11.3, p = 0.0028). Conclusions: These findings may be helpful for identifying therapeutic targets strategies in lung adenocarcinoma patients that were previously unavailable to clinicians in China.
Single-cell profiling of immune cells associated with response to neoadjuvant chemoimmunotherapy in IIIA non-small cell lung cancer (NSCLC).
Authors: Hui Zhenzhen , Zhang Jiali , Ren Yulin , Li Xiaoling , Yu Wenwen , Wang Tao , Zheng Liuqing , Xiao Shanshan , Chen Yu-Long , Wei Feng , You Jian , Ren Xiubao
Published: June 2022

e20584

Background: The combination of immune checkpoint inhibitors (ICIs) with chemotherapy (chemoimmunotherapy) in the neoadjuvant setting have achieved favorable clinical benefits in non-small cell lung cancer (NSCLC), but the underlying molecular mechanism has not been fully elucidated. Methods: To identify factors associated with the clinical outcome, single-cell RNA/TCR sequencing was performed using 10x Genomics on CD45+ immune cells isolated from tumor and multiple immune-relevant tissues and peripheral blood of four treatment-naïve and eight neoadjuvant chemoimmunotherapy treated IIIA NSCLC patients (responders versus non-responders). Bioinformatics analysis was used to screen immune cell factors associated with therapy response in single-cell sequencing profiles, and results were verified at protein level by flow cytometry, multiplex fluorescent immunohistochemistry (mIHC) and ELISA. Results: A total of 186,477 immune cells from 48 samples were acquired after quality-control filtering. The synergistic increase of B cells and CD4+ T cells are associated with positive therapeutic response of neoadjuvant chemoimmunotherapy. B cell class switching to IgG1 and IgG3 plays a critical role in anti-tumor immune response in tumor lesion, and this process is driven by increased IL-21 protein secreted by infiltrated T follicular helper (Tfh) cells after neoadjuvant chemoimmunotherapy. Several critical events lead to the positive clinical outcome during neoadjuvant chemoimmunotherapy, including the diminished activated TNFRSF4+ regulatory T cells (Tregs), increased LAMP3+ dendritic cells (DCs), high pretreatment peripheral blood T-cell diversity, and the expansion of intratumoral CD4+ T clones and peripheral CD8+ T clones. A validation cohort of 26 treatment-naïve and 30 neoadjuvant chemoimmunotherapy treated IIIA NSCLC patients verified these findings. Conclusions: Single-cell profiling of the immune response to neoadjuvant chemoimmunotherapy uncovered several critical factors of anti-tumor immune response and provided insight of potential novel predictive factors and therapeutic targets for improving the efficacy of treatment in NSCLC.
Risk factors and clinical characteristics of pneumonitis among patients with ALK-rearranged non-small cell lung cancer who received alectinib and thoracic radiotherapy.
Authors: Xu Yiyue , Qie Wenting , Yu Jinming , Wang Linlin
Published: June 2022

e20591

Background: Alectinib and thoracic radiotherapy (TRT) are important modalities in the management of ALK-rearranged non-small cell lung cancer. We therefore aimed to assess the incidence and risk factors of pneumonitis when these two treatments were combined. Methods: Patients with ALK-rearranged non-small cell lung cancer, receiving alectinib and TRT from January 2018 to December 2020 were reviewed, and the clinical and dosimetry data were collected. Logistic regression analyses were performed to evaluate risk factors associated with treatment-related pneumonitis (TRP). The prediction ability of dosimetry parameters for pneumonitis were examined by receiver-operating characteristic (ROC) curve analyses. Results: Of the 25 enrolled patients, 16 (64%) developed pneumonitis, and 12 (48%) developed grade 2 or higher pneumonitis. Logistics regression analyses revealed chemotherapy (OR = 8.750, 95% CI 1.207 - 63.428, p = 0.032), higher ipsilateral V5 (OR = 1.060, 95%CI 1.002 - 1.122, p = 0.043) and total lung V5 (OR = 1.083, 95%CI 1.000 - 1.174, p = 0.05) to be risk factors for TRP. Total lung V10, total lung V5, and ipsilateral V5 were strong predictors of TRP among the dosimetry parameters (AUC = 0.800, 0.786 and 0.781, respectively). After developing pneumonitis, 52% of patients recovered or improved, but one patient died due to respiratory failure. Conclusions: The combined use of alectinib and TRT significantly increased the risk of pneumonitis. Clinicians should consider the elevated risks and related dosimetric factors when deciding on combination treatment for ALK-rearranged NSCLC patients.
T-cell infiltration in matched samples from malignant pleural mesothelioma (MPM) during evolution of disease.
Authors: Cedres Perez Susana , Serna Garazi , Assaf Pastrana Juan David , Iranzo Patricia , Callejo Ana , Pardo Nuria , Navarro Alejandro , Martinez-Marti Alex , Cabrera Galvez Carlos , Gonzalez-Medina Alberto , Fasani Roberta , Guardia Xavier , Gonzalo Javier , Carbonell Caterina , Frigola Joan , Amat Ramon , Vivancos Ana , Nuciforo Paolo , Felip Enriqueta
Published: June 2022

e20595

Background: MPM is an aggressive cancer associated with asbestos exposure. Chemotherapy has been a mainstay of therapy and recently immunotherapy has been associated with survival improvements. Chemotherapy and immunotherapy influence the tumor microenvironment and some reports have shown increased of TIL after chemotherapy in MPM. The purpose of this study was to determine dynamic changes in the tumor immune environment during mesothelioma evolution and after systemic therapies in paired samples. Methods: We examined 20 matched formalin-fixed paraffin embedded tissue samples from 10 patients (p) with MPM taken at diagnosis and at disease progression (follow-up), including untreated and treated with chemotherapy or immunotherapy. Tissue densities (number of cells/mm2) of key immune effector cells such as total lymphocytes (CD3), cytotoxic T cells (CD8), regulatory T cells (FOXP3) and monocytes/macrophages (CD163) were quantified by image analysis using multiplexed immunohistochemistry (IHC). PD-L1 expression in both tumor cells and immune cells was analysed by singleplex IHC and quantified using the CPS score. Results: Median age was 62 years (range 53-84), 7 p were male and all p presented epithelioid histology. Three matched samples belong to patients that did not receive any systemic treatment between biopsies and the other 7 pair of samples belong to patients treated with chemotherapy +/- immunotherapy. The median interval between paired biopsies was 12 m (3-33 m). Median overall survival was 27.8 months (1 m-NR). Median densities of T cells and macrophages in diagnostic and matched follow-up samples were: CD3+:982 vs 712; CD8+:422 vs 334, FOXP3+: 22 vs 25 and CD163+: 2086 vs 1706. Median PD-L1 CPS was 2.5 and 4 in diagnostic and follow-up samples, respectively. In p receiving treatment between sample pairs, the median densities in diagnostic and follow-up matched samples were: CD3+:979 vs 407; CD8+:467 vs 225, FOXP3+: 25 vs 15, CD163+: 1583 vs 1508, and PD-L1: 2 and 1. In p without any systemic treatment between sample pairs, the median densities were CD3+:1645 vs 2397; CD8+:376 vs 1605, FOXP3+: 19 vs 121, CD163+: 2102 vs 2377, and PD-L1: 3 vs 25. Conclusions: In our small series with paired samples from MPM p, we observed immune cells infiltration changes during MPM evolution with a trend towards a decrease after systemic therapy. Further investigation in tumor microenvironment in MPM to define the most appropriate time for immunotherapy is needed.
Efficacy and safety of low-dose radiotherapy (LDRT) concurrent atezolizumab plus chemotherapy as first-line therapy for ES-SCLC : Interim analysis of Phase II MATCH trial.
Authors: Zhou Lin , Sun Jianguo , Xie Conghua , Gong Youling , Huang Meijuan , Yuan Zhiyong , Wu Lin , Wang Hui , Bi Nan , Yaping Xu , Zhu Jiang , Zhang Yan , Fan Min , Zou Bingwen , Yu Min , Na Feifei , Xiu Weigang , Zhang Xuanwei , Xue Jianxin , Lu You ,   MATCH Study Group
Published: June 2022

e20611

Background: The IMpower 133 trial represents the current SoC in the 1L setting for pts with ES-SCLC but still needs further efficacy improvement such as objective response rate (ORR, ̃60% in both arms) which may lead to survival benefit. LDRT could play a key role in the priming effect of immune system by acting as an immune adjuvant and having sensitive cytotoxic activity to SCLC. We have reported that LDRT plus ICIs in pretreated ES-SCLC was well tolerated with an improved efficacy. Here we conducted MATCH study to investigate the clinical benefits of adding LDRT to Atezo plus chemotherapy in ES-SCLC pts as 1L therapy. Methods: The MATCH study was a single-arm phase II trial conducted in eight centers across China. A Simon’s minimax two-stage design was adopted. Pts with measurable disease per RECIST v1.1 at baseline with ECOG 0-1 were eligible. Atezo (1200 mg IV, D1) + Cisplatin (75 mg/m2 IV, D1)/Carboplatin (AUC = 5 IV, D1) +Etoposide (100 mg/m2 IV, D1-D3) were administrated on a 21-day cycle for four cycles. Concurrent LDRT (15 Gy/5f) were conducted from D1-D5 in the first cycle. Then pts received Atezo maintenance until loss of clinical benefit or unacceptable toxicity. The primary endpoint was ORR confirmed by investigators after two consecutive evaluations ≥ 4 weeks apart. The secondary endpoints included disease control rate (DCR) and safety. Results: This is the report on the completed 1st phase of the trial. By the cutoff date of 26th August 2021, of the first 21 evaluable pts, 20 were males; mean age was 60.2 y and 85.7% pts had ECOG PS of 1. Previous smokers were 85.7%. Most pts were staged T4 (n = 15, 71.4%), N3 (n = 18, 85,7%) and M1(n = 17, 81.0%). The most common sites of metastasis were bone (47.1%) and liver (11.8%). Median follow-up was 4.0 m (range: 2.6-8.0 m). The confirmed ORR was 95.2% (95% CI, 76.2%-99.9%), among whom all pts were PR. DCR was 100%. The safety profile was consistent with the previous reports. Neutrophil count decreased (66.7%), white blood cell count decreased (42.9%) and anaemia (38.1%) were the most common grade 3-4 adverse events. No grade 5 AE occurred. Two pts experienced AEs leading to treatment withdrawal. IrAEs by preferred term were reported in 3(14.3%) pts: 2 were immune-mediated hyperthyroidism (grade 2) and 1 was immune-mediated enterocolitis (grade 3). No radiation pneumonitis occurred. Conclusions: The study met the response criteria for 1st phase. The combination of LDRT and Atezo plus chemotherapy showed promising benefit and was tolerable in pts with ES-SCLC. The 2nd phase is ongoing. Clinical trial information: NCT04622228.
Outcomes in non-small cell lung cancer (NSCLC) patients treated with second-line therapy after progression or recurrence after initial first line immune checkpoint-based therapy.
Authors: Muhsen Ibrahim , Mylavarapu Charisma , Sarfraz Humaira , Mathur Sunil , Bernicker Eric
Published: June 2022

e21027

Background: The use of immune checkpoint inhibitors (ICI) based therapies, including in combination with platinum-based or as monotherapy, is currently the standard of care in stage IV NSCLC patients as a first line therapy. However, there is limited data on the options and outcomes of NSCLC patients if they progress after first-line therapy. This study aims to investigate the clinical outcomes to second lines of treatment for these patients. Methods: This is a retrospective study conducted at Houston Methodist Hospital involving adult patients (> 18 years old) with metastatic stage IV NSCLC who received ICI based therapy (combination or monotherapy) for the treatment of NSCLC and subsequently progressed or recurred and received a second line of therapy between 11/1/2016 and 12/31/2019. We excluded patients with targetable driver mutations (except KRAS) and patients with a concurrent cancer diagnosis. We collected information on the second line of therapy received and evaluated outcomes including progression-free survival (PFS), overall survival (OS) and overall response rate (ORR). PFS was defined from time of second-line therapy initiation to time of documented recurrence/progression. ORR was defined as patients who achieve partial response (PR) or complete response (CR). The Kaplan Meier method was used for survival analysis. Results: Among patients who received ICI-based first line therapy, 32 patients were identified to meet the inclusion criteria. Twenty-seven (84%) patients had adenocarcinoma and 17 patients had negative PD-L1 stain. Twenty-seven (84%) patients received a combination of carboplatin, pembrolizumab, and pemetrexed, whereas five (16%) patients received ICI monotherapy (3 pembrolizumab, 1 nivolumab and 1 durvalumab). Thirteen patients had an initial response to first-line therapy (11 PR, 2 CR). After progression/recurrence, various therapies were administered as second-line with the most common being the use of ICI + chemotherapy combination (6 pts, 19%) or ramucirumab + taxotere combination (6 pts, 19%). The remaining patients received other types of chemotherapy, targeted therapy, ICI, or were enrolled in a clinical trial. Nine patients (28%) had a response after 2nd line therapy [4 CR and 5 PR], 16 (50%) had progressive disease, and 5 (16%) had mixed response/stable disease. The cohort median PFS after 2nd line of therapy was 16.9 weeks (95% CI: 14.4-19.3). Conclusions: These findings reflect the variability in practices in stage IV NSCLC patients who progress after receiving ICI-based first line therapy. Outcomes of patients who progress after their first line remain suboptimal with short-lived responses. Further studies are needed to investigate the efficacy and safety of different second line treatment options.
Preliminary clinical investigations of high-dose furmonertinib in NSCLC with EGFR Exon 20 insertions (20ins).
Authors: Lin Ying , Hu Zhihuang , Zhang Yao , Sun Si , Yu Hui , Zhao Xinmin , Wu Xianghua , Wang Huijie , Wang Jialei
Published: June 2022

e21029

Background: Currently neither chemotherapy nor approved EGFR TKIs have satisfactory efficacy in most EGFR 20ins mutations. Activity of high-dose furmonertinib, a novel 3rd generation EGFR TKI, against EGFR 20ins was assessed in preclinical models and a phase lb study. This study aimed to retrospectively investigate the efficacy of high-dose furmonertinib against EGFR 20ins in the real world. Methods: Retrospective search identified 14 metastatic NSCLC patients (pts) with EGFR 20ins treated with high-dose furmonertinib (160mg qd) in Fudan University Shanghai Cancer Center. The clinical efficacy and safety were investigated. Results: Median age was 60 years old (range 40-75) in this cohort with 28% female. At data cutoff date of January, 2022, 9 pts had ≥1 disease assessment. 5 out of 9 pts achieved PR, and 3 patients achieved SD. No CR was observed and 1 patient PD at first assessment. The most common adverse events (AE, ≥20%) were diarrhea, paronychia, skin fissures, anorexia, pain in extremity, rash and stomatitis. No grade ≥3 AE was observed. Conclusions: High-dose furmonertinib has shown encouraging anti-tumor activity in NSCLC with EGFR 20ins.
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.
Efficacy of osimertinib in patients with EGFR mutant lung cancer harboring the uncommon exon 19 deletion, L747_A750>P.
Authors: Grant Michael J , Aredo Jacqueline V , Starrett Jacqueline , Wurtz Anna , Piotrowska Zofia , Piper-Vallillo Andrew , Yu Helena Alexandra , Falcon Christina , Patil Tejas , Nguyen Christina , Aggarwal Charu , Scholes Dylan G. , Li Fangyong , Phadke Manali , Neal Joel W. , Walther Zenta , Politi Katerina A. , Goldberg Sarah B.
Published: June 2022

e21112

Background: EGFR exon 19 deletions (del19) are largely considered to have uniform sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Approximately 70% of del19 tumors harbor the most common deletion, E756_A750del; however, many “uncommon” variants comprise the remainder of this group. In preclinical studies, the uncommon del19, L747_A750 > P, demonstrates diminished sensitivity to the third generation TKI, osimertinib [. Identifying differences in clinical outcomes with osimertinib treatment could have therapeutic implications for patients (pts) with EGFR del19 non-small cell lung cancer (NSCLC). Methods: We conducted a multi-center retrospective cohort study of pts with metastatic EGFR del19 NSCLC treated with osimertinib. We compared progression free survival (PFS, time from TKI initiation to clinically significant growth of existing lesions or new lesions on imaging or death) and overall survival (OS) of pts with tumors harboring E746_A750del and L747_A750 > P who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L). The Kaplan Meier method and Cox model were used to estimate PFS and OS, and multivariable logistic regression was used to estimate the odds of achieving PFS > 12 months. Multivariable analyses adjusted for baseline covariates- age, sex, race, and smoking. Results: From March 2013 to December 2021, 86 pts with EGFR E746_A750del and 36 with L747_A750 > P were treated with osimertinib. For 1L osimertinib, E746_A750del was associated with significantly prolonged PFS vs. L747_A750 > P (median 21.3 months (95% CI 17.0-31.7) vs. 11.7 months (10.8-29.4)) in the adjusted analysis (hazard ratio [HR] 0.52 [95% CI, 0.28-0.98, p = 0.043]). Pts with the common del19 mutation were more likely to achieve PFS > 12 months with 1L osimertinib than those with the L747_A750 > P mutation (Odds Ratio 4.14 (1.41-12.15), p 0.0097). OS exhibited a similar trend with a median OS that that was not reached (NR) at 40 months of follow-up among those with E746_A750del vs 26 months for L747_A750 > P (adjusted HR 0.52 [95% CI, 0.23-1.19], p = 0.120). For pts treated with ≥2L osimertinib, there was also a trend towards favorable PFS and OS for pts with tumors harboring E746_A750del. Conclusions: The del19 mutation L747_A750 > P is associated with inferior PFS compared to the common E746_A750del mutation in pts treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR del19 subtypes could alter management of these pts in the future.[Table: see text]
The efficacy of afatinib combined with bevacizumab in first-line treatment of EGFR-mutated advanced non-small cell lung cancer.
Authors: Liu Yangli , Chen Haihong , Liang Wei , Kuang Yukun , Guo Yubiao , Tang Ke-Jing
Published: June 2022

e21124

Background: The addition of bevacizumab to first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) has shown promising efficacy in delaying TKI resistance and prolonging PFS in treating EGFR-mutated advanced lung cancer. However, data on the afatinib-bevacizumab combination therapy are limited. Methods: A total of 47 patients with EGFR-mutated advanced lung cancer were retrospectively analyzed, including 21 patients treated with afatinib combined with bevacizumab and 26 patients treated with afatinib monotherapy. Clinical data, survival outcomes and toxic effects were evaluated. Results: There was no significant difference in basic clinical features between the combination and monotherapy groups. The overall response rate (ORR), median progression-free survival (PFS) and overall survival (OS) in the combination group (afatinib 40 mg/day combined with bevacizumab 7.5 mg/kg every 3 weeks) were 42.9%, 16.5 months and 35.2 months, respectively, while the ORR, PFS and OS in the afatinib group was 53.8%, 13.8 months and 33.8 months, respectively. No significant difference was noted in ORR, PFS or OS between the two groups ( p＞0.05). However, among the subgroup with concurrent genetic mutations, combination therapy provided a significant PFS benefit (18.2 months, [95% CI 7.1-29.3] vs. 11.0 months [95%CI 7.5-14.5], p= 0.036). Although there was a longer trend in OS, no statistical difference was presented (35.2 months [95% CI 29.8-40.6] vs. 27.5 months [95% CI 13.1-41.9], p= 0.138). The safety of the combination therapy was acceptable and manageable. Conclusions: Afatinib-bevacizumab combination therapy could provide superior PFS benefit over afatinib alone in the subset of patients with concomitant genetic mutations in EGFR-mutated advanced NSCLC, and the safety of the combination therapy is acceptable.[Table: see text]
Blood gene expression changes in metastatic lung cancer under first-line immunotherapy according to clinical response.
Authors: Lusky Fabienne , Schindler Hannah , Elshiaty Mariam , Gaissmaier Lena , Daniello Lea , Bozorgmehr Farastuk , Kuon Jonas , Shah Rajiv , Schneider Marc A , Eichhorn Florian , Baum Philip , Trudzinski Franziska , Angeles Arlou , Janke Florian , Kirchner Martina , Kazdal Daniel , Stenzinger Albrecht , Sültmann Holger , Thomas Michael , Christopoulos Petros
Published: June 2022

e21141

Background: First-line pembrolizumab monotherapy is a standard treatment for metastatic non-small-cell lung cancer (NSCLC) with high PD-L1 expression (TPS ≥50%). However, many patients do not respond, and reliable biomarkers are lacking. Methods: Blood samples of 33 patients with metastatic NSCLC were analyzed at baseline (BL) and after four cycles of pembrolizumab monotherapy (FU). The expression of 12 genes involved in tumor-specific immune responses ( FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, MKI67, TBX21) in whole blood RNA was quantified by RT-PCR in absolute terms using plasmids as standards. Results: Gene expression was significantly higher after immunotherapy for 11/12 genes analyzed ( FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, TBX21 with fold changes [FC] 1.99 – 5.45; all p < 0.001). Blood neutrophil and total leukocyte counts were significantly decreased (ANC BL:7.65/nl vs. FU:5.36/nl, p = 0.024; Leu BL:10.65/nl vs. FU:7.78/nl, p = 0.032), while lymphocyte counts did not change (ALC BL:1.41/nl vs. FU:1.47/nl, p = 0.267). Increases in the expression of RORgt, FASLv1, PRF1, PD1, CD247, GZMB and TBX21 remained significant (FC 1.9 – 3.7; all p < 0.001) even after correction for the blood lymphocyte/leukocyte ratio (Ly/Lc BL:0.151 vs. FU:0.197, p = 0.003). Patients with long-term response (LTR, i.e. lasting > 6 months) had significantly higher increases in the expression of 8 genes ( RORgt, FOXP3, IFNγ, FASLv1, GATA3, PD1, CD247, TBX21) compared with patients with rapid disease progression within 3 months (RP) (FC 2.34 – 4.62, all p < 0.05). There were no significant differences (FU-BL) between LTR and RP regarding ANC (RP:-1.00/nl vs. LTR:-2.63/nl, p = 0.50), ALC (RP:-0,14/nl vs. LTR:+0,12/nl, p = 0,33) or Ly/Lc (RP:0.015 vs. LR:0.0542, p = 0.259). Conclusions: Pembrolizumab monotherapy of metastatic NSCLC causes significant increases in the blood expression for several genes including FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, TBX21, as well as a decrease in circulating neutrophiles and total leucocytes. Long-term responders have more pronounced blood gene expression changes, which appear to correlate with long-term benefit, in contrast to blood count changes, which are not indicative. These results are currently being validated in a larger prospective study.