bluuebunny/crossref_metadata_2025 huggingface dataset:
The frequency of rare ALK fusions and their clinical significance in NSCLC.
Authors: Zhu Bowen , Zhen Xinlin , Gao Zeqing , Peisu Suo , Zhang Jing , Fan Wenzhe
Published: June 2022

e21012

Background: ALK fusion is one of the key driver mechanisms in non-small cell lung cancer. In some case reports, some rare mutant forms have also been found to be active and drug-susceptible. There are few reports on the detection and verification methods of rare ALK fusions. Here, we counted the rare fusions of ALK detected by NGS and verified them by other methods. Methods: We analyzed 184 patients with NSCLC harboring ALK-rearrangement detected by NGS from January 2020 to January 2022. We counted the rare ALK fusion forms, and selected two of them for verification by RNA sequencing or immunohistochemistry. Results: Of the 184 patients with ALK fusion that we included, 105 were female and 79 were male (medium age 53). Most female were non-smokers except one while nearly 50% male were smokers. EML4-ALK fusion accounted for the highest proportion (170, 92.4%), 5 were ALK fusions with other 5’ partners ( C2orf44, KCNG3, KIF5B, KDM5A, DCTN1), 6 were intergenic region- ALK rearrangements, 2 were fusions without transcription initiation region, and 1 was LOC399815 -ALK and ALK-EML4 double fusion. Rare fusion forms accounted for less than 10%. We further verified two of these rare fusion mutations by RNA sequencing or immunohistochemistry. Interestingly, one of the patients with a KCNG3-exon1- ALK-exon20 fusion detected by DNA sequencing was confirmed to be an EML4-ALK fusion by RNA sequencing, and another patient with an intergenic region- ALK fusion was confirmed positive by immunohistochemistry. Conclusions: The vast majority of ALK fusions are EML4-ALK fusions, but there are a small number of other forms of fusions. DNA sequencing, RNA sequencing and ICH may give different conclusions for ALK fusions, which may be limited by the detection method. For some rare fusion forms, a variety of methods can be used to detect whether it is an active ALK fusion form.
Race-specific genomic determinants of therapeutic response in African American NSCLC patients.
Authors: Pilling Amanda , Li Pin , Kane Kaitlyn , Wolf Frank M. , Berry Anna B. , Gadgeel Shirish M.
Published: June 2022

e21015

Background: African American (AA) individuals are disproportionately affected by lung cancer in terms of incidence and mortality, despite lower tobacco exposure compared to Caucasian Americans (CA). Since molecular profiling is critically important to guide therapy selection in non-small cell lung cancer (NSCLC), we compared treatment-relevant molecular data in a cohort of AA and CA patients with EGFR or KRAS-driven NSCLC. Methods: This is a retrospective study using a clinicogenomic electronic medical record database from health systems in the United States designed to evaluate outcomes in advanced stage NSCLC. Eligibility criteria for analysis included a diagnosis of NSCLC between 2010 and 2020, stage III or IV, available race/ethnicity data, and identification of common KRAS or EGFR activating variant within 60 days of diagnosis. The primary objective was to define the type of EGFR or KRAS activating variant and determine the frequency of co-occurring alterations in NSCLC-associated genes by cohort (AA and CA). Secondary objectives included examining the timing of genetic testing and use of targeted therapy in these cohorts. Results: A total of 642 NSCLC patients with KRAS (15.0% AA; 81.6% CA) and 348 patients with EGFR oncogenic mutations (13.8% AA; 70.1% CA) met inclusion criteria. Mean time from diagnosis to first molecular test result was 20.9 days for AA vs. 19.9 days for CA (p = 0.5). The EGFR G719S variant was more prevalent in the AA cohort (6.3% AA v 0.4%) with no significant differences observed in the most common KRAS or EGFR variants tested (Table). A total of 100 KRAS-mutant patients (16 AA, 86 CA) had a reported result in at least one co-mutation of interest. The most frequent co-mutations were TP53 (81.3% AA v 65% CA, p = 0.92); KEAP1 (18.8% AA v 8.3% CA, p = 0.52); ATM (18.8% AA v 9.5% CA, p = 0.54); and PTEN (0% AA v 8.3% CA, p = 0.5). A total of 35 EGFR-mutant patients (4 AA, 31 CA) had a co-mutation reported in TP53 (75% AA v 65% CA, p = 0.77). EGFR targeted therapy was reported in 47.9% of AA and 52.9% of CA (p = 0.639). In the KRAS-mutant cohort, delivery of immune checkpoint inhibitors (ICIs) was reported in 29.2% of AA and 39.3% of CA (p = 0.08); chemotherapy was reported in 36.5% AA and 45.2% of CA (p = 0.14). Delivery of both ICI and chemotherapy was reported in 13.5% of AA and 21.9% of CA (p = 0.08). Conclusions: In a real-world cohort of NSCLC patients, we found similar frequencies of common KRAS and EGFR variants in AA and CA, but higher rates of EGFR G719S variant in AA patients. A more comprehensive analysis is needed to further evaluate the trends in co-mutations observed in our analysis, to determine the race-specific impact of these alterations in EGFR and KRAS-driven NSCLC.[Table: see text]
Circulating tumor cells as a biomarker for precise management in lung cancer.
Authors: Chen Juan , Li Qian , Xu Chen-yu , Qian Ying-ying , Yang Zhen-hua , Chen Dong-sheng
Published: June 2022

e21018

Background: Circulating tumor cells (CTCs) have potential utility in various clinical application for cancer management. In this study, we evaluated whether circulating tumor cells (CTCs) provide early diagnostic information and/or precisely indication of patient response to chemotherapy. Methods: 56 patients with newly diagnosed lung cancer, 42 patients with nonmalignant pulmonary disease and 27 healthy controls were enrolled in this study. CTCs were measured at baseline in all eligible subjects and after two cycles of chemotherapy in 25 advanced lung cancer patients, with a strategy of negative enrichment combined with immunostaining-fluorescence in situ hybridization (imFISH). The receiver operating characteristic (ROC) curve was plotted to determine the sensitivity and specificity of the CTC detection for diagnosis. Kaplan-Meier curve and two-sided log-rank test were used for univariate survival analyses. Results: The number of CTCs was significantly increased in lung cancer patients, compared with benign lung disease patients and healthy controls. And it reached 87.5% sensitivity and 95.7% specificity at a cutoff value of 2 cells/3.2ml (AUC = 0.975, 95%CI, 0.953-0.998, p＜0.001).Moreover, the sensitivity of CTCs was much higher than individual or the combination of serum tumor markers, especially in the early detection of lung cancer. Twenty-five advanced lung cancer patients were subsequently followed for an average of 18.2 months (range 6-36 months) ， during which all patients experienced disease progression, and 16 patients died. A change in CTC count after two cycles of chemotherapy was highly predictive for PFS (13.5 v 8.5 months; p = 0.025) and OS (27.6 v 16.8 months; p = 0.009) in favor of a reduction in CTC number compared with an increase. Interestingly, among the patients whose post-treatment computed tomography(CT) results indicated stable disease(SD), PFS (14.0 v 8.7months; p = 0.033) and OS(25.8 v 15.9 months; p = 0.018) in patients whose CTC number decreased after two cycles of treatment were still significantly longer than those whose post-treatment CTCs number increased or unchanged. Conclusions: CTCs may act as precise biomarker for early detection and therapy monitoring that could compensate for imaging.
Blood monocyte and lymphocyte counts patient outcomes in non-small cell lung cancer after immune checkpoint inhibitor therapy: Real-world data of 12,416 patients.
Authors: Goldschmidt Jerome H. , Chan Philip K , Chou Lin-Na , Chen Liwei , Robert Nicholas J. , Kinsey Joyce , Nestor Matt , Lazarus Hillard M. , Rock Edwin P.
Published: June 2022

e21023

Background: Immune checkpoint inhibitors (ICPi) are now commonly used in non-small cell lung cancer (NSCLC) treatment. Beyond PD-L1 status, no clinically validated predictive biomarkers guide therapeutic decision making regarding their use. Blood monocyte, lymphocyte counts, or their ratio might inform clinical utility of these expensive, potentially toxic agents. Methods: Adults with advanced/metastatic NSCLC receiving any ICPi after diagnosis from January 2015 to November 2020 were included. Treatment outcomes were followed until 31 May 2021. Data were sourced from structured fields of electronic health records from The US Oncology Network and non-Network practices. The primary end point was overall survival (OS), and time to treatment discontinuation (TTD) was secondary. Baseline absolute monocyte count (AMC), absolute lymphocyte count (ALC), and monocyte-to-lymphocyte ratio (MLR) were subdivided into quintiles (Q) with Q1 lowest and Q5 highest. Patient (pt) and treatment characteristics were described. Time-to-event outcomes were assessed by Kaplan-Meier methods. Univariate and multivariate Cox regression analyses described associations among baseline biomarkers, OS, and TTD. Results: For 12,416 pts with NSCLC, median OS and TTD were 13.6 months (mos) and 4.5 mos, respectively. For AMC, patients in Q2 and Q3 had the longest median OS of 15.9 mos. Median TTD by AMC was longest for Q1 and Q2 (5.1 mos), declining sequentially to 3.3 mos for Q5. For ALC, Q5 had longest median OS of 19.2 mos, as well as longest median TTD of 5.8 mos. For MLR, Q1 had the longest median OS and TTD of 22.3 and 6.2 mos., respectively. In univariate Cox regression, AMC, ALC, and MLR each associated with OS and TTD (p < 0.0001). Pts in AMC Q5, compared with AMC Q1, had an OS hazard ratio (HR) of 1.48 (95% CI 1.38-1.60). For ALC, each successive increasing quintile, compared to ALC Q1, demonstrated a lower risk of death (p < 0.0001). Pts in MLR Q5, compared with MLR Q1, had an OS HR of 2.21 (95% CI 2.04-2.39). Conclusions: This data set is the largest to date to examine interactions among baseline immune cell counts, ICPi use, and pt outcome in NSCLC. These data inform efforts to describe immune-based prognostic risk groups among NSCLC pts receiving immunotherapy.[Table: see text]
Comparative efficacy and safety of immunotherapy for advanced NSCLC: A systematic review and network meta-analysis.
Authors: Xu Bin , Zhao Chen , Zhong Hao , Lei Tianyu , Zhang Huibo , Wu Jie , Li Lan , Yao Yi , Song Qibin
Published: June 2022

e21028

Background: Advanced non-small cell lung cancer (NSCLC) patients responded differently to checkpoint inhibitors (ICIs) therapy, leading to the confuse of choosing the optimal regimens for patients. Therefore, we performed this network meta-analysis to compare different agents across clinical trials. Methods: We searched databases, including EMBASE, PubMed, ClinicalTrials and etc, for abstracts, full-text articles and minutes of the annual meetings published from database inception through Oct 01, 2021. Phase 3 randomized clinical trials (RCTs) of first-line immunotherapy or combinations for adcanced (stage III/IV or recurrent) NSCLC were included. We selected 26 trials evaluating different ICIs (Atezolizuma (atezo), Pembrolizumab (pem), Nivolumab(nivo), Durvalumab (durva), Camrelizumab (camre), Tislelizumab (tisle), Sintilimab (sint), Sugemalimab (suge), Toripalimab (tori), Cemiplimab (cemip)) and combinations based on them. Primary outcomes of interests were overall survival (OS) and progression-free survival (PFS). Secondary outcomes of interests were objective response rate (ORR), and adverse events (AEs). Hazard ratio (HRs) and 95% confidence intervals (CI) were used to represent the results of OS and PFS. The subgroup analysis (pathological type, PD-L1 expression, gender, smoking history, ECOG score, metastasis status and ethnicity) was performed and the treatments were ranked in it and overall population. Results: In our study, all ICIs-based regimens had benefit in OS and PFS compared with chemotherapy. The network meta-analysis for OS showed the combination of Camre-Chemo ranked 1st in overall population, and most of dual ICIs-based regimens, except Nivo-Ipi-Chemo, showed minor improvement in OS while possess more safety concerns compared with other regimens. Atezo-Beva-Chemo (ranked 1st in PFS, 20th in safety), has shown good efficacy but was revealed with lower safety. Sint-Chemo demonstrated promising efficacy in PFS, but it remains to be seen whether the effectiveness could be transformed into OS benefit due to the lack of related data. Pem-Chemo (ranked 1st in ORR) demonstrated the best response to tumors in all treatments regardless of PD-L1 expression. In subgroup analysis, for patients with poor health conditions (≥65 years or with ECOG = 1), multi-drug combination regimens, such as Nivo-Ipi-Chemo and Atezo-Beva-Chemo, showed better benefits in PFS and OS compared with only chemo but had no significant advantages than any other treatments. Conclusions: In our study, we provide relative comprehensive results for latest researches of first-line ICIs. Overall, Care-Chemo, Pem-Chemo, Sint-Chemo, are prior to be recommended according to our study.
Pattern of disease progression amongst veterans with stage IV non-small cell lung carcinoma (NSCLC) on immunotherapy.
Authors: Mahmood Fatima , Azem Amin , Gemoets Darren , Thalody Vimala , Mehdi Syed Arzoo
Published: June 2022

e21032

Background: Use of immune checkpoint inhibitors against advanced stage NSCLC is associated with significant reduction in overall morbidity and mortality. However, despite the survival benefit, tumors invariably relapse. We aim to study pattern of disease progression and assess baseline or tumor specific associations. Methods: We performed a retrospective review of 74 Veterans with Stage IV NSCLC who received ≥2 immunotherapy cycles between 2015-2021 at Albany Stratton VA Medical Center. IRB approval was obtained. Fisher Exact Probability Test was used to analyze data, level of significance at < 0.05. Results: Baseline characteristics of 74 male veterans revealed median age 67 years (IQR 62.5-72.5). Common tumor histology included squamous cell carcinoma (SCC; n = 38, 51.3%) and adenocarcinoma (n = 32, 43.24%), PD-L1 expression > 50% in 33.8% of population. Molecular testing positive for EGFR in 1 patient and otherwise negative for EGFR, ALK, BRAF, ROS, KRAS translocations in all patients. Treatment regimen was either immunotherapy alone or concurrent chemoimmunotherapy. Disease status prior to starting immunotherapy was classified as M1a (25.7%), M1b (50%) and M1c (24.3%). Out of total study population, progression of disease was noted in 48 patients (56.4%) further divided into progression at initial site only 20.8%, new site only 31.2%, or combined 48%. Most common sites of progression included local and distant LNs, brain, bone, and liver. Using Kaplan Meier Survival Analysis, median progression free survival (PFS) from start of immunotherapy till evidence of progression was 8.4 months. Our data revealed that progression at initial, new, and combined sites was noted in both adenocarcinoma and SCC. Use of immunotherapy as first line therapy and smoking history > 50ppd were also associated with risk of progression. Other characteristics such as ECOG score (p = 0.50), initial metastatic status (p = 0.30), type of immunotherapy (p = 0.60) and PD-L1 score (p = 0.27) did not reveal significant association. We did not find any association between baseline characteristics and improved PFS. Conclusions: We conclude that certain baseline characteristics can be associated with progression of Stage IV NSCLC on immunotherapy amongst Veteran population. We recommend further studies with a larger study population to analyze the pattern of disease progression and associated factors. This will allow physicians to modify and personalize therapy regimen to improve PFS.[Table: see text]
AI in NSCLC: PET-CT & histology model.
Authors: Batra Ullas , Nathany Shrinidhi , Nath Swarsat Kaushik , Jose Joslia T , Sinha Robin , P Preeti , Sharma Trapti , Pasricha Sunil , Sharma Mansi , Bansal Abhishek , Rawal Kamal
Published: June 2022

e21044

Background: Almost 70% of cases of lung cancer are diagnosed at advanced stage, albeit with sophisticated imaging modalities available. Of these, 35% are tiny nodules that are often missed at initial radiological screening, owing to limitations of resolution of human vision.Dramatic shift in therapeutic paradigm in the management of lung cancer in the last decade has ushered an era of stratified medicine. In India, one-third population inhabits rural lands;lack of awareness for molecular medicine poses challenges to treating oncologists. AI-based cancer detection and prediction of potential oncogenic driver at diagnosis, will help alleviate patient anxiety caused due to diagnostic delays, aiding in prompt initiation of optimal therapy.Here, a comprehensive deep-CNN based diagnosis of lung adenocarcinoma (LUAD) was implemented using both PET/CT and histopathology images of 100 patients. Methods: Data collection: 143 whole-slide images were downloaded from Dartmouth Lung Cancer Histology Dataset from Biomedical Informatics Research and Data Science website and PET/CT dataset-A Large-Scale CT and PET/CT Dataset for Lung Cancer Diagnosis (Lung-PET-CT-Dx) from The Cancer Imaging Archive. This comprises 251,135 images from 355 participants across 436 studies. Creation of Deep-CNN model: Residual Neural Network - 18 was used for histopathlogic classification followed by Detectron2’s region-based deep-CNN for detection of presence of tumours in lung PET/CT images. Properties such as size, morphology, attenuation, malignancy, and spiculation were also measured. The 18-layer deep network, ResNet-18, detected the histologic patterns using whole-slide histopathology images. Results: Results for 100 patients whose PET/CT images, histopathology images, and mutational status of three genes (EGFR, ALK, ROS) were readily available. The histologic patterns of tumour cells appear to be related to the mutational status of genes. The ResNet-18 CNN could predict various histologic patterns (Acinar, Lepidic, Papillary, Micropapillary, and Solid patterns). Conclusions: CNN models can help in early diagnosis and prompt treatment of lung cancer, if fairly accurate. Larger datasets are needed to improve the same. The final validation of the model is underway and will be reported in near future.[Table: see text]
The association between BIM deletion polymorphism and treatment efficacy of PD-1/PD-L1 inhibitors in advanced NSCLC.
Authors: Zhang Dai , Li Xuanzong , Huang Caimei , Fan Xinyu , Qin Wenru , Yang Linlin , Wang Linlin
Published: June 2022

e21055

Background: PD-L1 is a recommended biomarker for immunotherapy, but Some patients with high pD-L1 expression had poor clinical response. Considering the inconsistent correlation between PD- L1 expression and ICI efficacy, A more sensitive biomarker is needed to predict immunotherapy efficacy. B-cell lymphoma-2 (BCL2L11/BIM) belongs to the Bcl-2 family and is a key factor promoting apoptosis. BIM deletion polymorphism (BIM- del) may lead to BH3 deletion and thus hinder cell apoptosis. Loss and decreased expression of BIM may lead to resistance to tumor therapy. A study on patients with metastatic melanoma found that the high level of BIM in CD8+ T cells suggests a stronger PD-1 and PD-L1 interaction, which predicts clinical benefit in patients with metastatic melanoma receiving anti-PD-1 therapy.This study aims to evaluate the relationship between BIM deletion and PD-1/PD-L1 inhibitors efficacy in advanced NSCLC patients. Methods: Patients diagnosed with advanced stage NSCLC that treated with Immune checkpoint inhibitors (ICIs) at Shandong Cancer Hospital between March 2019 and January 2021 were enrolled in this study. Peripheral blood samples from these patients were collected to detect BIM-del by polymerase chain reaction. Cox proportional hazards models were used to analyze the clinical outcomes of patients with and without BIM-del. Results: A total of 61 patients with advanced NSCLC who received immunotherapy were enrolled, only 18.0% (11/61) patients were detected with BIM-del. Most of the patients were male (73.8%, 45/61), younger than 65 years (72.1%, 44/61), non- smokers (50.8%, 31/61), previous treatment lines 0-1 (90.2%, 55/61),had Eastern Tumor Cooperative group (ECOG) performance status (PS) 0-1 (98.4%, 60/61). There were no associations between the BIM-del and clinical characteristics. There was no difference in the objective response rate between patients with and without BIM-del (27.3% vs 30 %, p = 1.000).BIM-del is associated with shorter progression-free survival (PFS) (5.7 months vs12.0 months, p = 0.001). The median OS had not been reached. Multivariate analysis suggested that BIM-del was an negative independent prognostic factor for PFS in immunotherapy patients with non-small cell lung cancer, but not for OS. Conclusions: BIM-del may be a negative prognostic biomarker for patients with advanced NSCLC treated with immunosuppressive therapy. It is very important to find effective and accurate biomarkers to predict the PD-1/PD-L1 inhibitors Treatment efficacy, and further exploration is needed in the future.
Relationship between IFN-α, IL-1B, IL-5, IL-6 and effectiveness of the first-line with camrelizumab combined with chemotherapy in non small cell lung cancer.
Authors: Shi Jian , Duan Xiaoyang , Liu Rongfeng , Wang Zhen , Han Shan , Shan Baoen
Published: June 2022

e21059

Background: Biomarkers of combination with immunotherapy therapy remains unknown. To explore prediction of efficacy in patients(pts) with non small cell lung cancer (NSCLC) without driver genes mutations which received Camrelizumab combined with chemotherapy. Methods: From Jan, 2020 to Dec, 2021, 28 pts with NSCLC without driver genes mutations who received Camrelizumab combined with chemotherapy for 4 cycles. According to RECIST1.1, all of these patients were assessed with benefit. IFN, TNF-α, IL (IL-1B、IL-2、IL-4、IL5、IL-6、IL-8、IL-10、IL-12P70、IL-17)in peripheral blood of all pts were measured using flow cytometry. Statistical analyses were performed with SPSS 23.0 software (Pearson’s correlation). Results: Before treatment, the mean values of IFN-α, IFN-γ, TNF-α and IL in pts with partial response (PR) were higher than in pts with stable disease (SD). There was no correlation with age, sex, stage and pathological type of pts ( P > 0.05). There was significant difference of IFN- α, IL-1B, IL-5 and IL-6 increased compared with the level before treatment in 28 pts ( P＜0.05). However, pts with PR compared with pts with SD, There were no significant differences of IFN-α, IFN-γ, TNF-α, IL compared with the level before treatment (P > 0.05). The IFN-α, IL-1B, IL-5, IL-6 Spearman correlation showed that before treatment, there was a correlation between INF-α and IL-5, INF-α and IL-1B, INF- α and IL-6, IL-1B and IL-6, respectively (r = 0.786, P = 0.036 < 0.05; r = 0.889, P = 0.007 < 0.05; r = 0.929, P = 0.003 < 0.05; r = 0.778, P = 0.039 < 0.05). In self-control before and after treatment, there was a correlation between INF-α and IL-1B, INF- α and IL-6, IL-1B and IL-6, respectively (r = 0.880, P = 0.009 ＜05; r = 0.936, P = 0.002＜ 0.05; r = 0.882, P = 0.023＜ 0.05). Conclusions: First-line chemotherapy combined with Camrelizumab in NSCLC without driver genes mutations can effectively improve the levels of IFN-α, IL-1B, IL-5, and IL-6, and the combined detection has certain predictive significance for the efficacy evaluation of patients. Further study is needed.
Managing cardiotoxicity in metastatic non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs).
Authors: Sukar Nabil , Walker Damaal , Dumais Katerine , Powery Hermán Wesley , Raez Luis E. , Aung Pyi Phyo
Published: June 2022

e21072

Background: Current guidelines for prevention and monitoring cardiac dysfunction in patients with cancer state there is insufficient evidence to support surveillance strategies for TKIs alone. Furthermore, risk stratification for baseline and frequency of monitoring remains unclear for various products. This study evaluates the current practice for screening and monitoring for cardiotoxicity in patients treated for NSCLC with TKIs and the adherence rate to the standards of care. Methods: A single-center retrospective chart review of 113 patients with metastatic NSCLC who received TKIs at a large academic-community cancer center was performed. The current practice for screening and monitoring for cardiotoxicity and the adherence rate to the suggested standards recommended by the prescribing information of each drug were analyzed. Total incidence of cardiotoxicity was also evaluated. Descriptive statistics were calculated for all demographic variables and clinical outcome endpoints. Incidence of cardiotoxic adverse events were reported as percentages. Results: A total of 113 metastatic NSCLC patients were identified with the majority of patients taking osimertinib (67.3%), alectinib (8.0%), or dabrafenib/trametinib (7.1%) at baseline. Total adherence rate for screening and monitoring for cardiotoxicity as recommended by the prescribing information for all agents was 54%. Cardiotoxicity occurred in 46 (40.7%) patients, presenting most frequently as hypertension and bradycardia. Cohort cardiotoxicity events are summarized in the table below. Decreased left ventricular ejection fraction (LVEF) ≥ 10% or to < 50% occurred in 6/76 (7.9%) patients on osimertinib; however, only 12 (15.8%) patients were able to be assessed due to lack of baseline data. Osimertinib was held and/or discontinued in 3 (3.9%) patients and 1 (1.3%) death resulted due to cardiomyopathy. QTc interval prolongation occurred in 2 (33.3%) patients on afatinib, 1 (20%) patient on crizotinib, and 1 (1.3%) patient on osimertinib. Three (3.9%) patients on osimertinib were diagnosed with atrial fibrillation. Conclusions: The results reported in this study show higher rates of decreased LVEF and similar rates of QTc prolongation with osimertinib compared to prior studies. The increased rate of hypertension observed may be associated with the high rate of uncontrolled blood pressure at baseline. Low adherence rates to the recommendations provided by prescribing information may contribute to increased risk of cardiac dysfunction.[Table: see text]
Temporal trends of lung cancer burden in India in comparison to global burden from 1990 to 2019: An observation analysis.
Authors: Jani Chinmay , Jani Ruchi Tusharkumar , Kurman Jonathan , Singh Harpreet
Published: June 2022

e21081

Background: Lung cancer is the leading cause of cancer-related deaths worldwide and remains a significant health concern globally. There is limited understanding of the lung cancer epidemiology trends in India. This study compares lung cancer incidence, disability-adjusted life years (DALYs), and mortality in the Indian population with the global burden. Methods: The lung cancer incidence, DALYs, and mortality data were analyzed for males and females from 1990-2019 using the Global Burden of Disease (GBD) database. GBD is an open-source data repository managed by the Institute for Health Metrics and Evaluation research center, University of Washington. International Classification of Diseases (ICD) code C34 were used for data extraction. Temporal trends in lung cancer were evaluated using descriptive statistics. Results: India had a lower lung cancer-related disease burden than the global population. Incidence trends: In India, lung cancer age-standardized incidence rates (ASIRs) increased from 6.62/100,000 in 1990 to 7.7/100,00 in 2019. ASIRs increased from 10.36 to 11.16 in males and 2.68 to 4.49 in females. In contrast, overall and male ASIRs decreased globally from 28.39 to 27.66 and 46.22 to 40.44, respectively. But global lung cancer incidence in females increased from 13.77 to 16.83, mirroring the trends in the Indian female population. DALYs trends: In India, DALYs increased uniformly from 1990 to 2019. The overall DALYs (including males and females) increased from 166.66 to 190.16. In males, DALYs increase from 258.05 to 271.30, and in females DALYs increase from 68.80 to 112.90. Similarly, at the global level, DALYs in females increased from 311.7 to 327.57. However, overall and male’s global DALYs improved from 657.97 to 551.58 and 1053.25 to 802.86, respectively. Mortality trends: In the Indian population, there was only a slight overall increase in age-standardized mortality rates (ASMRs) from 7.04 to 8.06. A similar slight increase in mortality rates was observed in males (11.04 to 11.73). However, in females, there was a substantial increase from 2.85 to 4.70. In contrast, overall and male ASMRs decreased globally from 27.39 to 25.18 and 45.08 to 37.38, respectively. Similar females’ mortality trends in India, globally, females ASMRs increased from 13.04 to 14.96. Conclusions: Our study reports a lower lung cancer-associated health burden in the Indian population. However, there is an increase in the incidence, DALYs, and mortality in both males and females in the Indian population from 1990 to 2019. Similar worsening trends are observed in females at the global level. In contrast, there is a hint towards improvement in the incidence, DALYs, and mortality at the global level in general, primarily due to improvement in males’ disease burden. There is also a persistent gap in males and females epidemiology, where males have a higher lung cancer burden than females.
The comparison of chemotherapy and treatments according to NGS results in advanced lung adenocarcinoma patients resistant to EGFR-TKIs.
Authors: Jiang Kan , Lin Gen , Zheng Xinlong , Zheng Xiaobin , Long Feng
Published: June 2022

e21082

Background: There were no relative researches referring to optimal treatment strategy after the resistance to the first/second-generation EGFR-TKIs without T790M mutation or the third generation EGFR-TKIs as the first or second line therapy. Methods: Retrospective analysis was performed on the clinical and sequencing data obtained from 129 patients with advanced EGFR-mutant lung adenocarcinoma and disease progression on the prior EGFR-TKIs.The patients were divided into Chemotherapy group or Personalized group according the the therapies after acquired resistance to EGFR-TKIs. Results: 36 patients were enrolled in Personalized group and 93 in Chemotherapy group. Personalized group：22 patients with MET amplification received the combination therapy of EGFR-TKIs and MET inhibitors; 6 patients with SCLC transformation received EP/EC chemotherapy; 2 patients with BRAF mutation were treated with the combination of EGFR-TKIs, dabrafenib and trametinib; 3 patients with ERBB2 amplification were added Trastuzumab in the therapy; 2 patients with RET fusion were accepted LOXO-292 therapy; 1 patient had the combination therapy of the 1st and 3rd EGFR-TKIs because of T790m and C797S mutations in trans allelic context.Chemotherapy group: 79 patients received pemetrexed plus platinum therapy, 14 patients received paclitaxel plus platinum therapy. 12 patients achieved PR and 11 patients achieved SD in Personalized group, 48 PR, 25 SD in Chemotherapy group. The median PFS was 5.5 months in Chemotherapy group and 3.5 months in Personalized group, No significant differences were observed in ORR(p = 0.13), DCR(p = 0.12) and PFS(P = 0.26) between two group. Conclusions: Chemotherapy maybe is the optimal choice to patients with advanced EGFR-mutant lung adenocarcinoma and disease progression on the prior EGFR-TKI in current medical conditions.
Cost of care in EGFR mutant versus wild-type non-small cell lung cancer.
Authors: Vusqa Urwat Til , Asawa Palash , Miller Katherine , Sethi Ashish , Rodriguez Robin Raquel , Friday Andrew , Finley Gene Grant
Published: June 2022

e21084

Background: Lung cancer remains the most commonly diagnosed cancer in the United States, as well as the leading cause of cancer-related mortality. Approximately 84% of all lung cancers are non-small cell lung cancer (NSCLC). Most are diagnosed at an advanced stage when the prognosis is poorest. EGFR is the most common driver mutation in NSCLC with an incidence ranging from 20% in Caucasians, and up to 50% in Asians. Oral tyrosine kinase inhibitors (TKI) are the preferred treatment for EGFR mutant cancers as they provide better outcomes and lower toxicity than chemotherapy (Ch) or immunotherapy (ICI). Therefore, it is imperative to analyze NSCLC patients for these important driver mutations. Cancer care is expensive with the treatments and attendant costs for administration and management. We sought to compare cost of care (COC) in EGFR mutant vs wild-type NSCLC as the treatments and known toxicities differ markedly. Methods: We performed a retrospective COC analysis of NSCLC using claims data from the local BCBS affiliate Highmark (HM) members. Patients were selected based on NSCLC diagnosis codes between October 2016 and September 2018. COC was calculated from claims data to compare treatment of driver mutant NSCLC with targeted therapy versus treatment of wild-type NSCLC with ICI and/or ChT. Data used to compare COC analysis included overall medical costs defined as all medical claims incurred by a patient following start of respective therapy, oncology related medical claims, therapy costs, costs related to emergency room visits and tissue biopsies. Overall medical costs, oncology related costs and therapy costs were measured in per member per month (PMPM). We extracted cost related data at 6 months, 12 months, and 18 months into treatment. Results: Patients treated with ICI and/or ChT incurred $1000-2000 more in PMPM total medical costs than patients treated with targeted therapy. Additionally, chemoimmunotherapy patients were found to have a 5% higher emergency room admission rate along with a longer median length of stay of 1/3 day, when compared to targeted therapy patients. ICI and/or ChT patients showed a 20% higher rate of tissue biopsy and a 5-10% higher rate of repeat tissue biopsy which incurred an additional $300-$400 expense for chemoimmunotherapy patients. Conclusions: The use of targeted treatment with TKIs in EGFR mutant NSCLC patients is more cost effective than ICI and/or ChT in wild-type NSCLC. Routine screening of lung cancer patients with molecular profiling is essential, as identification of such critical driver mutations can alter the treatment plan to be more efficient, providing better care at lower cost.
Real-life experience of rare hepatoid adenocarcinomas of the lung: A large retrospective french cohort.
Authors: Favé Thomas , Quere Gilles , Robinet Gilles , Babey Hélène , Renaud Emmanuelle , Dhamelincourt Estelle , Nguyen Jessica , Simaki Amah Arnaud , Basse Victor , Descourt Renaud , Geier Margaux
Published: June 2022

e21091

Background: Hepatoid adenocarcinoma of the lung (HAL) is a rare subtype of lung cancer exhibiting common histological features with hepatocellular carcinomas (HCC). Therapeutic landscape is currently similar to lung adenocarcinoma standards. We report here the largest descriptive cohort of HAL with focus on (chemo)-immunotherapy (CT-IO) efficacy. Methods: In this single-center retrospective observational study, we selected all consecutive cases of HAL patients from January 2013 to January 2022. Eligible patients had primary lung tumor with positive immunohistochemical hepatocyte marker. HCC was eliminated with liver imaging. We provide a descriptive analysis of HAL population and describe our therapeutic experience. Results: A total of 21 patients were included. Main characteristics at diagnosis were: median age of 63 years [41-81], 80,9% of males, with 76,2% of PS 0-1. All patients had smoking history, with 8 active smokers. Twenty patients (95,2%) had stage IV disease. Median number of metastatic sites was 2; 7 (33,3%) patients had brain metastases. PD-L1 status was < 1% (n = 10), 1-5% (n = 2), ≥50% (n = 5), unknown (n = 4). Six (28,6%) patients harbored KRAS mutation: G12C (n = 4), G60D (n = 1), G12V (n = 1). One patient had Lynch syndrome with MMR deficiency. Median follow-up was 5 months. Median overall survival (mOS) since diagnosis achieved 9 months (95% CI, 3 to 21). Early palliative care concerned 6 patients. Five patients received first-line CT-IO. Best response was: partial response (n = 3), stable disease (n = 1), progressive disease (n = 1). One patient treated with first-line pembrolizumab achieved stable disease. Four patients received second-line IO but experienced early progressive disease. Conclusions: Our results highlighted the aggressive metastatic profile of HAL accounting for the poor mOS of 9 months. Patients could benefit from upfront CT-IO but further studies are warranted to confirm it.
Immunotherapy plus chemotherapy versus chemotherapy alone as first-line treatment for non-small cell lung cancer: A systematic review and meta-analysis.
Authors: Abdelazeem Basel , Abbas Kirellos Said , Labieb Fatma , Arida Abdul Karim , El-Shahat Nahla Ahmed , Shehata Joseph , Kandah Emad , Malik Bilal , Akanbi Maxwell Oluwole , Rafae Abdul , Tahir Nayha , Wahab Ahsan , Ehsan Hamid
Published: June 2022

e21092

Background: There is an emerging role of immunotherapy plus chemotherapy (ICC) in the front-line setting for the treatment of Non-Small Cell Lung Cancer (NSCLC) with reported improvement in overall survival (OS) and progression-free survival (PFS). In this review, we highlighted the efficacy and safety of combination regimens as a first-line therapy for NSCLC. Methods: A comprehensive literature search was done on PubMed, Cochrane, Embase, WOS, and Scopus until Dec-2021. The outcomes included progression free survival (PFS) and/or overall survival (OS) and treatment-related adverse events (TRAEs). The inverse variance method was used to generate hazard ratios (HR) with the corresponding 95% confidence intervals for the OS and PFS. Meanwhile, Mantle-Hazard variance was used to create risk ratios for TRAEs. Results: The total eleven randomized controlled trials (RCTs) involving 6,386 patients (pts) were included. 3,850 pts received ICC while 2536 pts received chemotherapy., Four studies each used atezolizumab and pembrolizumab while one study each used nivolumab, tislelizumab, and camrelizumab. The ICC group showed a significant improvement in both PFS (HR, 0.60; 95% CI, 0.54-0.66; p = < 0.00001) and OS (HR, 0.77; 95% CI, 0.68-0.87; p = < 0.0001). Atezolizumab combinations have better PFS and OS compared to the other combinations; HR 0.65 (0.59-0.71) and 0.82 (0.74-0.90), respectively. There was no statistically significant difference between the ICC and control groups regarding TRAEs (RR, 1.07; 95% CI, 0.99-1.16; p = 0.09). Further subgroup analysis is mentioned in the table. Conclusions: The ICC seems to be a promising front-line therapy for NSCLC with superior PFS and OS compared to chemotherapy alone and without significant increase in TRAES. [Table: see text]
Prognostic value of PIOS (Patras Immunotherapy Score) model in patients with advanced NSCLC treated with combination of immunotherapy with chemotherapy: Preliminary results from a European retrospective study.
Authors: Dimtrakopoulos Foteinos-Ioannis D. , Christopoulos Petros , Elshiaty Mariam , Daniello Lea , Pyrousis Ioannis , Kottorou Anastasia E , Makatsoris Thomas , Kalofonos Haralabos , Koutras Angelos
Published: June 2022

e21096

Background: Ιmmune checkpoint inhibitors (ICIs) have tremendously changed the daily clinical practice on the treatment of advanced non-small cell lung cancer (aNSCLC). However, clinical useful biomarkers remain an unmet need. Recently, a new score, Patras Immunotherapy Score (PIOS), has been proposed by our group proving its prognostic value in aNSCLC patients treated with ICIs monotherapy. The objective of the current study was to assess the clinical significance of PIOS formula in aNSCLC patients treated with combination of immunotherapy with chemotherapy. Methods: PIOS is a baseline formula derived by combining the following non-interventional clinical parameters, Performance Status (PS), Body Mass Index (BMI), age and Line Of Treatment (LOT) and it is calculated as PIOS = (PS×BMI)/(LOT×AGE). In the current study, 159 aNSCLC patients, treated with combination of immunotherapy with chemotherapy, were retrospectively selected, blindly to the clinical outcome, and enrolled. In addition, a second subcohort with 444 aNSCLC patients, who had been treated with chemotherapy alone, were also retrospectively included. The primary endpoint of this study was to investigate the prognostic value of PIOS in terms of progression free survival (PFS) and overall survival (OS). Results: Patients with higher PIOS score had longer PFS compared to patients with lower PIOS score (ΗR 0.575, 95% CI 0.364-0.908, p= 0.016), while multivariate analysis for PFS, adjusted for PD-L1, confirmed the clinical value of PIOS score (HR 0.561, 95% CI 0.352-0.893, p= 0.015). Moreover, PIOS score was also associated with prognosis ( p= 0.003). The median OS for the favorable group was 1067 days compared to 528 days for the unfavorable group with low PIOS score (HR 0.487, 95% CI 0.302-0.787, p< 0.001) at univariate analysis. This association remained statistically significant (HR 0.468, 95% CI 0.286-0.764, p= 0.002) after adjusting for PD-L1 expression. Specificity of PIOS formula was also confirmed in the second cohort (n = 444) of patients with metastatic disease who had been treated with chemotherapy alone, in which no prognostic significance for PIOS was observed. Conclusions: This study for the first time documents the prognostic significance of PIOS model in aNSCLC patients treated with immunotherapy/chemotherapy combination and provides adequate evidence regarding the specificity of this association, since no similar finding was observed in the patients treated with chemotherapy alone.
Clinical outcomes of immune checkpoint inhibitors in HER2-amplified non-small cell lung cancers.
Authors: DeMatteo Raymond , Goldman Debra A. , Lin Sabrina T. , Buonocore Darren J. , Gao JianJiong , Chang Jason C. , Rekhtman Natasha , Offin Michael , Yu Helena Alexandra , Isbell James M. , Jones David Randolph , Rudin Charles M. , Travis William D. , Kris Mark G. , Drilon Alexander E. , Arcila Maria E. , Ginsberg Michelle S. , Iasonos Alexia , Liu Dazhi , Li Bob T.
Published: June 2022

e21098

Background: HER2 (ERBB2) amplification is a distinct actionable oncogenic driver in 2-3% of non-small cell lung cancer (NSCLC). While HER2-targeted agents are now in development for lung cancers harboring HER2 mutations, the therapeutic landscape for patients with HER2 amplification is not well elucidated. Although immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy are widely used as treatment for NSCLC, little is known about the impact of ICIs in patients with HER2-amplified NSCLC. This study aimed to assess the efficacy of ICIs in this patient population. Methods: Patients with HER2-amplified NSCLC were identified from January 2014 to October 2021. HER2 amplification was detected by next generation sequencing (NGS) on the MSK-IMPACT platform. Clinicopathologic and molecular features, as well as response to therapy with ICIs were assessed. Patients were excluded if they harbored concurrent HER2 mutations, had localized disease, or received concurrent chemotherapy. Patient records were reviewed to evaluate overall survival (OS), progression free survival (PFS) and overall response rate (ORR). Results: Eighteen patients with metastatic HER2-amplified NSCLC who received ICI alone as first line treatment or subsequent therapy after progression met inclusion criteria. Histologic subtypes included adenocarcinoma (78%) and squamous cell carcinoma (22%). PD-L1 expression was available for 16 patients, with 69% having no expression of PD-L1. The median tumor mutation burden (TMB) was 9.2 mutations/Mb (range 3.0-35.4). The median OS was 11 months (95% CI: 4 to 37), with 6-month and 12-month survival being 67% (95% CI: 40% to 83%) and 49% (95% CI: 25% to 70%), respectively. Median PFS was 2 months (95% CI: 1 to 7). In the 15 patients that were assessed for response, the ORR was 0% (95% CI 0% to 19%), including 3 cases with PD-L1 expression of ≥ 50% and 9 cases with TMB ≥ 10 mutation/Mb. Conclusions: Patients with HER2-amplified NSCLC showed minimal response to immunotherapy, regardless of PD-L1 status and TMB. These findings underscore the importance of developing novel HER2-targeted agents for these patients with unmet medical need.
Metastatic patterns plus clinical and molecular characteristics of ROS1 aberrations in non-small cell lung cancer patients without rearrangements.
Authors: Glaser Moritz , von Levetzow Cornelia , Michels Sebastian Yves Friedrich , Nogova Lucia , Katzenmeier Marianna , Wompner Claudia , Schmitz Jaqueline , Bitter Elisabeth , Terjung Inken , Passmann Elke , Schaufler Diana , Eisert Anna , Fischer Rieke Nila , Riedel Richard , Weber Jan-Phillip , Hahne Sabine , Merkelbach-Bruse Sabine , Büttner Reinhard , Wolf Juergen , Scheffler Matthias
Published: June 2022

e21117

Background: Fusions in the ROS1 proto-oncogene are among the best treatable genetic aberrations in Non-small cell lung cancer (NSCLC). Besides the occurrence of solvent-front mutations (SFM) in acquired resistance to targeted therapy, little is known about ROS1 aberrations other than fusions. We analyzed molecular and clinical characteristics and metastatic patterns of ROS1 mutations in NSCLC patients without activating ROS1 fusions or SFMs. Methods: Next-generation sequencing (NGS) was performed on tissue samples from NSCLC patients within the National Network Genomic Medicine (nNGM). Patients with activating ROS1 fusions detected by fluorescence in-situ hybridization (FISH) were excluded. Staging and restaging procedures were performed following local standards from each partner. We analyzed the mutations’ characteristics, co-occurring mutations and metastatic patterns. Results: Of 8072 patients analyzed by NGS between 2018 and 2021, 118 (1.5%) patients harbored ROS1 mutations. Most patients were male (76.3%) and had adenocarcinoma histology (57.6%). The median age at diagnosis amounted to 68 years. Nearly all of the patients (96.5%) had a smoking history, amassing 40 pack-years on average. Besides TP53 mutations (61.0%), KRAS (25.4%), EGFR (7.6%), PIK3CA and FGFR1-4 mutations (5.9% each) co-occurred most frequently. In 12 (10.2%) patients, ROS1 mutation was the only detected aberration. The majority (59.3%) of patients had UICC stage IV whereby 27.2% of patients featured Stage III; about 7% fall upon stage I and II. The metastatic pattern of all stage IV patients shows that 22.9% of metastasis is allotted to cerebral, 12.5% to lung, 16.7% to subdiaphragmatic, 14.9% to bone and 6.3% to skin metastasis. Thereby, the patients’ subgroup with mutually exclusive ROS1 mutations (10.2%) resembles this trend: about a half of these patients had UICC stage IV, too, and the metastasis distribution featured similar characteristics. Conclusions: The cohort contrasts the clinical characteristics of patients with ROS1 fusion regarding sex, age, and histology. This evidence implies a basic clinical impact exerted by this molecular subtype. We warrant further research on the detected mutations to characterize the biological impact and the potential to act as a drug target.