bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of plasma-based molecular testing in patients with newly diagnosed advanced NSCLC on initiation of targeted agents in patients with targetable genomic alterations: A real world experience from the Middle East.
Authors: Joel Anjana , Al-Hashami Zamzam , Khan Shafquat Ali , Deshpande Prashant Ajit , Telugu Ramesh Babu , Khreis Abdallah Bilal , Nair Jayakrishnan , Bennji Sami M.
Published: July 2024

e20514

Background: The treatment of metastatic non-small cell lung cancer ( m-NSCLC) is personalized and driven by mutational profiling of the tumour tissue at diagnosis. This study evaluates the additional clinical utility of plasma based molecular testing towards shortening time to initiation of treatment and detection of targetable mutations in a cohort of patients with newly diagnosed m-NSCLC. Methods: This is a retrospective analysis of patients with newly diagnosed advanced NSCLC referred to the Thoracic Oncology Program between September 2021 to December 2023, who underwent “paired” plasma based circulating tumour ( ct-DNA ) and tissue based next generation sequencing (NGS) testing (done less than 4 weeks apart). ct-DNA testing was performed using the Oncomine Pancancer NGS Assay (Thermo Scientific) that screens for single nucleotide variants (SNV) in hotspot regions of 52 and common fusions involving 12 genes respectively. Tissue NGS testing was performed using Oncomine Comprehensive Assay Plus (Thermo Scientific); a panel covering ~500 genes capable of identifying all single nucleotide variants, indels, fusions and copy number variants (CNV). Patient demographics and clinicopathological characteristics were collected by retrospective review of electronic medical records (EMR). Results: Among 36 patients, the median age was 66.0 years (range: 32-66), 25 (69.4%) were males, and 16 (44.4%) were never smokers. Thirty (83.3%) had adenocarcinoma and 33 (91.67%) had stage IV NSCLC. The mutation detection rate of ct-DNA was 66.7% with a concordance of 58.3% between ct-DNA and tissue NGS testing. The median turnaround time (TAT) from sample collection to reporting were12 days (IQR:8-15) and 14 days (IQR:9-24.50) for ct-DNA and tissue NGS testing respectively. Among 31 patients who started treatment, the median time to initiation of 1st line treatment was 26 days from date of first visit (IQR:18-42). Fifteen(41.7%), 6(16.7%) and 10(27.8%) started first line targeted therapy, chemotherapy and chemoimmunotherapy respectively. Twenty-three(63.89%) had targetable mutations (EGFR Exon 19 or 21, EGFR Exon 20 insertion, ALK, ROS1, MET Exon1 4 skipping, ROS1 or KRAS12C detected either in ct-DNA or tissue). Fifteen (65.21%) out of these 23 started targeted therapy as their 1st line treatment and of these 8 (53.3%) were initiated on targeted agents prior to availability of tissue NGS reports. Conclusions: Though our TAT for ct-DNA and tissue based NGS testing was similar, ct-DNA based NGS testing enables earlier initiation of targeted treatment for newly diagnosed advanced NSCLC patients with targetable mutations. In the real world, this increases access to targeted agents and may translate to a subsequent improvement in survival outcomes.
Correlation of gut dysbiosis biomarkers and peripheral thyroid hormones conversion in patients with (pts) advanced lung cancer.
Authors: Bonato Adele , Belluomini Lorenzo , Silva Carolina Alves Costa , Fidelle Marine , Birebent Roxanne , Gattazzo Federica , Parisi Claudia , Remon Masip Jordi , Lavaud Pernelle , Planchard David , Aldea Mihaela , Besse Benjamin , Barlesi Fabrice , Loupakis Fotios , Zitvogel Laurence , Derosa Lisa
Published: July 2024

e20517

Background: Changes in gut microbiota may affect benefit from immunotherapy (IO). Gut dysbiosis can be identified by a fecal metagenomic signature (TOPOSCORE SIG1+ vs SIG2+), and/or by low levels of sMAdCAM-1. Recent studies showed that peripheral thyroid hormones conversion (fT3/fT4 ratio) has a strong prognostic role in various cancers, with low fT3/fT4 ratio predicting worse outcomes. Correlation between gut dysbiosis and metabolic stress, such as altered fT3/fT4 conversion, has not been investigated yet. Methods: A total of 77 lung cancer pts treated at Gustave Roussy Cancer Center with IO-based treatment with available measurement of baseline fT3/fT4 ratio, metagenomic data defined by TOPOSCORE category SIG1+ vs SIG2+, and/or level of sMAdCAM1 (low vs high according to the median) from the ongoing ONCOBIOTICS multicentric prospective study (NCT04567446) were selected. fT3/fT4 low vs high groups were defined adopting the median value as cut-off. Correlation between the fT3/fT4 ratio categories with TOPOSCORE and sMAdCAM1 were tested by means of a 2-sided chi-square test. Results: Baseline fT3/fT4 ratio and TOPOSCORE and/or sMAdCAM-1 data were available for 62 and 57 patients, respectively. A significant correlation was observed between fT3/fT4 ratio and TOPOSCORE category, with a higher proportion of SIG1+ pts (64.5%) vs SIG2+ (35.5%) in fT3/fT4 low group, and higher rate of SIG2+ (61.3%) vs SIG1+ (38.7%) pts in fT3/fT4 high group (p = .042). Similarly, a significant association was observed between low levels of sMAdCAM-1 and the fT3/fT4 low group (p = .047). In a independent dataset of 42 NSCLC treated with 2nd line IO, pts with low fT3/fT4 ratio had a mPFS of 1.7 mos and a mOS of 2.4 mos compared to 6.8 and 18.7 mos respectively for fT3/fT4 high pts (PFS HR = 0.56, 95%CI 0.30-1.05, p = .040; OS HR = 0.50, 95%CI 0.26-0.99, p = .030). Conclusions: Our data confirm the prognostic value of fT3/fT4 in progressing metastatic NSCLC and its correlation with gut dysbiosis markers. These findings open the way to further research for exploring specific therapeutic applications, such as tailored nutritional support and microbiota-driven interventions. Clinical trial information: NCT04567446 .
Ubiquitin ligase subunit FBXO9 inhibits V-ATPase assembly and lung cancer metastasis.
Authors: Liu Liang , Chen Xiaodong , Huang Kaizong , Wang Zhenyi , Zheng Yaolin , Zheng Cheng , Zhang Zhenshan , Wei Dongping , Yaping Xu
Published: July 2024

e20520

Background: The evolutionarily conserved protein FBXO9 acts as a substrate receptor for the SKP1-cullin-1-RBX1 ubiquitin ligase and is implicated in cancer, exhibiting either tumor-suppressive or oncogenic effects depending on the specific tumor type. However, their role in lung cancer metastasis remains unclear. Methods: Lentiviral vectors carrying miRNA-based shRNA sequences for gene-specific knockdown were generated, and Lenti-CRISPR-Cas9 vectors containing gene-specific sgRNA sequences were designed. Gene overexpression was achieved using doxycycline-inducible lentiviral constructs, while gene knockdown or knockout cells were generated using shRNA and CRISPR-Cas9, respectively. Functional assays included migration, clonogenic survival assays, tumor sphere assays, and protein interaction studies using mass spectrometry, immunoprecipitation, and immunoblot analysis. Results: This study identified FBXO9 as a crucial regulator that suppresses lung cancer cell migration, tumor sphere growth and restricts metastasis. We showed that FBXO9 facilitates the ubiquitination of the catalytic subunit A (ATP6V1A) of the Vacuolar-type H+-ATPase (V-ATPase), resulting in its interaction with the cytoplasmic chaperone HSPA8 and subsequent sequestration within the cytoplasm. This process hinders the assembly of functional V-ATPase, resulting in reduced vesicular acidification. In contrast, depletion of FBXO9 reduced ATP6V1A ubiquitination, resulting in increased V-ATPase assembly and vesicular acidification, thus promoting pro-metastatic Wnt signaling and metastasis of lung cancer cells. Furthermore, we demonstrated the effectiveness of inhibitors targeting V-ATPase in inhibiting lung cancer metastasis in a mouse model. Finally, we established a correlation between lower FBXO9 levels and poorer survival outcomes in patients with lung cancer. Conclusions: These findings collectively elucidate the critical role of FBXO9 in regulating V-ATPase assembly and provide a molecular basis for FBXO9's function in inhibiting lung cancer metastasis. This highlights the potential therapeutic opportunities of FBXO9 supplementation.
Implementing personalized lung cancer care with spatial profiling, patient derived organoids, and rationally designed drug testing.
Authors: Pine Sharon R. , Watson Alexander S. , Patil Tejas , Schenk Erin L. , Merrick Daniel , Camidge David Ross , Sabaawy Hatim E.
Published: July 2024

e20521

Background: Lung cancer (LC) remains the leading cause of cancer-related death in 2024, with most LC diagnoses with non-small cell lung cancer (NSCLC) subtype. Tyrosine kinase inhibitors (TKI) and targeted therapy against oncogenic drivers (KRAS, EGFR, or ALK fusions, others) are effective initial therapies; however, nearly all treated patients eventually develop resistance to therapy. Key reasons are the focus on limited predictive biomarkers and lack of patient derived LC models that reflect the underlying heterogeneity and the various phenotypic cell states among subclones within and between patients. Methods: We report the establishment of a novel platform for personalized LC care by refining the resolution of molecular interrogation of diagnostic and resistance biopsies to the single cell level, and with spatial profiling using single cell spatial multiomic (scSpMO) and coupling these enhanced diagnostic tools with functional validation with rational designed drug screens in patient-derived organoids (PDOs). Results: For deriving LC PDOs in epithelial and tumor microenvironment (TME) conditions to faithfully maintain the histological and genetic features of their respective LC tissues, we developed enrichment conditions for LC PDOs guided by tumor mutation variants and activated pathways. PDOs are maintained under the same treatment condition in the clinic (e.g., Lorlatinib) and drug testing is tailored to identify potentially most effective next lines of therapy. With nine patients enrolled and others in ongoing studies, single cell PDOs (at > 80% establishment rate) were used to determine activated pathways, lineage plasticity and acquired resistance. Functional assays for acquired resistance such as PI3K/AKT signaling, Src kinase, BRAF fusion and MET hyperactivity allow the identification of potentially novel lines of therapy and treatment sequence and/or combinations for each patient, through the compassionate care program and/or trial participation. Conclusions: Our platform when empowered by combining datasets from scRNA-seq and scSpMO signatures, with validated functional drug responses in PDOs, offers the ability to perform high-content assays, predict and/or act on resistance to therapy for each patient, and provides a path for precision medicine-guided impact on patient care.
Using machine learning approach based on gene expression profiling to predict the risk of bone metastasis in lung cancer.
Authors: He Tao
Published: July 2024

e20522

Background: Bone metastasis (BM) occurs in about 30% of patients with advanced lung cancer, and the prognosis of BM patients is very poor, with a median survival of 6-10 months. Therefore, we attempted to use machine learning methods based on gene expression profiles to construct a model to predict BM. Methods: Gene Expression Omnibus (GEO) database were searched, then these datasets (GSE10096, GSE29367, GSE29391, GSE76194, GSE175601) were included for analysis. Batch effects were removed using the ComBat function from the R package sva (v3.44.0). edgeR was used for differential expression analysis, and genes that had an absolute log2 fold change > 1 and adjusted p-value < 0.05, were selected as differentially expressed genes (DEGs) for modeling. Random forest (RF) modeling was performed using the R package random Forest (v4.7-1.1), and support vector machine (SVM) modeling and SVM Recursive Feature Elimination (SVM-RFE) were performed using the R package e1071 (v1.7-13). Survival curves were generated using the GEPIA2 R packages. Models performance was evaluated using the area under the receiver operating characteristics curve (AUC). Results: A total of 48 qualified cases were subjected to analysis, including 22 BM and 26 non-BM patients. Differential expression analysis revealed that a total of 327 DEGs were identified in the BM group. We divided the sample dataset into a training set and a test set. In the first approach, we attempted to use all 327 DEGs features to train the models. Among the evaluated models, the RF algorithm performed best with an AUC of 0.753, while the SVM algorithm had an AUC of 0.938. The second approach, we applied the SVM-RFE algorithm for feature selection, which ranked the features according to their importance, and the top 10 genes/features (TMC5, S100A4, EEF1A2, CLDN1, RALY, MYH10, MAGEC2, ALDH1A1, PI3, SALL1) were used to build a classification model (in the test set, sensitivity was100%, specificity: 81.8%, AUC:0.909). In addition, TCGA survival analysis of 10 genes was performed and found that the expression levels of five genes, including ALDH1A1, MYH10, RALY, CLDN1 and MAGEC2, were significantly associated with prognosis (p < 0.1). Conclusions: Our study suggests that we have identified ten key genes associated with BM of lung cancer which could be potential therapeutic targets.
The efficacy and safety of furmonertinib in patients with advanced EGFR-mutated NSCLC and leptomeningeal metastases.
Authors: Han Huan , Tang Hong
Published: July 2024

e20525

Background: Leptomeningeal metastasis (LM) is a common and fatal complication in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor ( EGFR) mutation. This retrospective study aimed to evaluate the efficacy and safety of furmonertinib in patients with advanced EGFR-mutated ( EGFRm) NSCLC and LM. Methods: Eligible patients with confirmed advanced EGFRm NSCLC and LM were treated with furmonertinib. The primary endpoints were LM response rate and progression-free survival (PFS). Secondary endpoints were overall survival (OS) and adverse events (AEs). Results: This retrospective study analyzed the efficacy and safety of 31 EGFRm advanced NSCLC patients with LM at two hospitals between February 2020 to March 2023. The median age was 56 years (rang: 31-75), 22 (71.0%) were females. 19 (61.3%) patients had ECOG PS≥2 and all 31 patients (100%) had adenocarcinoma histology. For the treatment of LM, 19 (61.3%) patients received furmonertinib as first-line treatment, 8 (25.8%) patients as second-line treatment. 16 (51.6%) patients were treated with 240 mg of furmonertinib and 12 (38.7%) patients with 160 mg of furmonertinib. The median follow-up duration was 16.80 months (95% CI 12.71-20.89 months). LM objective response rate (ORR) was 75.0% and LM disease control rate (DCR) was 95.0% according to RANO-LM radiologic criteria. Overall ORR was 22.6% and DCR was 96.8%. Median LM duration of response (DoR) was 12.00 months (95% CI 7.40-16.60 months) and median overall DoR was 7.20 months (95% CI 3.60-10.80 months). 23 (74.2%) of the 31 patients had progressed or died by data cutoff. The median PFS was 11.70 months (95% CI 9.48-13.92 months) and the median OS was 18.40 months (95% CI 12.49-24.21 months). There was no significant difference in survival (median PFS: 11.70 months vs 10.90 months, p = 0.335; median OS: 18.40 months vs 13.50 months, p = 0.196) between the 19 patients who treated with furmonertinib as first-line therapy and those who treated with furmonertinib as second-line therapy. Although data on cerebrospinal fluid (CSF) clearance were not available, we observed improved neurologic function in 18 (75%) of 24 patients with baseline neurologic abnormalities. Logistic regression analysis showed that the therapeutic dose of furmonertinib was a positive predictor of OS in NSCLC patients harboring EGFR mutation with LM [HR: 2.679 (1.004-7.147), P = 0.049]. The most common AEs were rash, diarrhea and decreased appetite. However, most AEs were grade 1-2. Conclusions: Our study provides real-world clinical evidence that furmonertinib shows an encouraging efficacy and a manageable safety profile in patients with EGFRm NSCLC and LM.
Decision model for durable clinical benefit from front- or late-line immunotherapy alone or with chemotherapy in large population of non-small cell lung cancer.
Authors: Zhao Jie , Wang Lu , Wen Shidi , Zhou Anda , Fang Wenfeng , Zhang Li , Duan Jianchun , Bai Hua , Zhong Jia , Wan Rui , Sun Boyang , Zhuang Wei , Lin Yiwen , He Danming , Wang Zhijie , Wang Jie
Published: July 2024

e20533

Background: Predictive biomarkers and models of immune checkpoint inhibitors (ICI) have been extensively studied in NSCLC. However, evidence for many biomarkers remains inconclusive, and the opaqueness of machine learning models hinders their practicality. We aimed to provide compelling evidence for biomarkers and develop a transparent decision-tree model. Methods: We consolidated data from ICI-treated patients with NSCLC (n = 3,288) across real-world multicentre studies, public cohorts, and the Choice-01 trial (NCT03607539). Over 50 features were gathered to examine the predictive capacity of durable clinical benefits (DCB) from mono-ICIs and ICIs plus chemotherapy. Noteworthy biomarkers were identified to establish a decision tree model. We also explored the tumour microenvironment and peripheral PD-1+ CD8+ T-cell receptor profiles. Results: Multivariate logistic regression analysis identified tumour histology, PD-L1 expression, tumour mutational burden, line, and regimen of ICI treatment as significant factors. Mutation subtypes of EGFR, KRAS, KEAP1, STK11, and disruptive TP53 mutations demonstrated significant association with DCB. The decision-tree (DT10) model, using the aforementioned five clinicopathological markers and five genomic mutations, predicted DCB with superior performance in the training set (N = 286, AUC = 0.82), and consistently outperformed the logistic regression, random forest, and support vector machine models, as well as FDA-approved biomarkers of PD-L1 and TMB in the internal and three external test sets (Table). We visualized the decision routes for DCB from ICI-based treatment based on the DT10 model, which was interpretable for clinical use. Furthermore, DT10 predicted-DCB patients manifested significantly longer progression-free survival and overall survival than -NDB patients across the train and test tests (HR < 1, p < 0.05). Additionally, the DT10 predicted-DCB group presented an enriched inflamed tumour immune phenotype (67%) and higher peripheral TCR diversity, whereas the -NDB group showed an enriched desert immune phenotype (86%) and higher peripheral TCR clonality. Conclusions: Based on the large population, we provided persuasive evidence for the predictive reliability of biomarkers in NSCLC. The development of the DT10 model introducing an easily interpretable, visually engaging, and clinically relevant model, which assisted the decision making in varied clinical scenarios. [Table: see text]
First-line treatment of EGFR mutation adenosquamous carcinoma of the lung with aumolertinib: A multicenter, single-arm, prospective study (ARISE Study).
Authors: Lin Gen , Huang Long , Chu Qian , Huang Dingzhi , Liu Zhe , Yu Yongfeng
Published: July 2024

e20541

Background: Adenosquamous carcinoma of the lung (ASC), which composed of squamous cell carcinoma and adenocarcinoma, is a rare lung cancer. In Asian population, the mutation rate of epidermal growth factor receptor (EGFR) in ASC is approximately 15.4% to 44%. There were no large prospective clinical studies using EGFR tyrosine kinase inhibitors (TKI) to treat ASC. Methods: We conducted a prospective, multicenter, single-arm clinical trial, designed to evaluate the efficacy and safety of Aumolertinib for ASC patients with EGFR mutations without prior systemic therapy (originally designed as a randomized controlled study versus chemotherapy; the protocol was revised to single-arm study due to insufficient enrollment; Clinical Trial Registry No. NCT04354961). Eligible participants of stage IIIB/IV ASC with EGFR mutations from six Chinese medical centers received Aumolertinib 110mg orally once daily. Follow-up were performed every 6 weeks conducted by independent central review (ICR), based on the RECIST 1.1 criteria. Primary endpoints was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: Of the 18 patients recruited, 12 were evaluated for efficacy and safety. The median follow-up was 13.3 months, with 17 (range 4-26) doses of Aumolertinib treatment. The median PFS was 6.2 months (95% CI 5.0-8.2), while the median OS has not been reached. Of the 12 patients, 7 (58.3%) achieved PR, 3 (25.0%) achieved SD, and 2 (16.7%) were PD. The ICR-confirmed ORR and DCR were 58.3% (95% CI: 62.6%-74.6%) and 83.3% (95% CI: 89.6%-96.2%), respectively. A total of 9 patients (75%) experienced at least one treatment-related adverse events (TRAEs). the most common TRAEs were anemia (27.3%) and elevated aminotransferase (18.2%). three patients (25%) experienced grade 3-4 TRAEs in the form of paralysis, neutropenia and hypokalemia. No treatment-related deaths occurred. Conclusions: This is the first prospective clinical study showing that Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for ASC with EGFR mutations, with favorable ORR and general PFS. In future, head-to-head comparisons of EGFR TKI with chemotherapy and combination therapy would be needed to be explored. Clinical trial information: NCT04354961 .
Efficacy and safety of time-of-day infusion of pemetrexed plus platinum and paclitaxel plus platinum for patients with advanced non-small cell lung cancer: A retrospective study.
Authors: Sun Li-Yue , Xu Quan-An , Xu Xian , Xian Ke-Xin , Zeng Xin-Xin , Li Hua-Gen , Zhang Xu-Hui
Published: July 2024

e20557

Background: Retrospective studies suggest that administering chemotherapy infusions in the morning can enhance treatment efficacy and mitigate side effects in non-small cell lung cancer (NSCLC) patients. However, the effectiveness of chronotherapy using pemetrexed plus platinum (AP) and paclitaxel plus platinum (TP) in advanced NSCLC chemotherapy remains unexplored. This study aims to evaluate the impact of AP and TP chrono-chemotherapy (CCT) on treatment response and adverse events in advanced NSCLC patients. Methods: We retrospectively analyzed 78 advanced NSCLC patients treated with AP (AP cohort) and 50 advanced NSCLC patients treated with TP (TP cohort) at Guangdong Second Provincial General Hospital from 2018 to 2021. Based on previous research, we classified patients who received chemotherapy infusions more than twice after 2:00 PM as the afternoon (PM) group, while the rest were categorized as the morning (AM) group. Treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors Criteria V.1.1. The primary endpoint was progression-free survival (PFS). All adverse events were identified and graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0. Results: In the AP cohort, the AM group exhibited a longer PFS compared to the PM group (AM vs. PM, n = 26 vs. n = 52, 43.0 vs. 13.0 months, p = 0.001). However, no significant difference was observed in PFS in the TP cohort (AM vs. PM, n = 23 vs. n = 27, 11.0 vs. 22.0 months, p = 0.501). Subsequent subgroup analysis in the AP cohort favored the AM group across all major subgroups for PFS treatment effect. In contrast, the TP cohort subgroups showed a PFS benefit only in the smoking patients of the PM group. Furthermore, the analysis of adverse reactions revealed similar incidences of any treatment emergent adverse events (TEAE) in both AP and TP cohorts (AM vs. PM, 92.3% vs. 86.5% in AP cohort and 95.7% vs. 100.0% in TP cohort), and grade 3 TEAEs (AM vs. PM, 34.6% vs. 21.2% in AP cohort and 39.1% vs. 29.63% in TP cohort). The most common adverse events were anemia (73.1%), leukopenia (57.7%), and elevated ALT (46.2%) in AP cohort and anemia (100%), leukopenia (65.2%), and hypoalbuminemia (47.8%) in TP cohort. Univariate and multivariate analyses indicated that afternoon infusion of AP chemotherapy (p = 0.009) was an independent prognostic factor for NSCLC. Conclusions: AP treatment administered in the morning may enhance PFS in advanced NSCLC, while TP remains unaffected. This suggests that CCT could potentially enhance the efficacy of individualized chemotherapy in advanced NSCLC.
5-hydroxymethylcytosine in cell-free DNA as liquid biomarker for immune checkpoint inhibitor therapy in non–small cell lung cancer.
Authors: Ajmal Zainub , Shao Jianming , Olsen Randall , Kasparian Saro , He Chuan , Bernicker Eric , Li Zejuan , Zhang Jun
Published: July 2024

e20563

Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1), and its ligand (PD-L1) are the mainstay of treatment for metastatic non-small cell lung cancer (NSCLC) in patients lacking targetable driver mutations. However, optimal predictive biomarkers are lacking. We used a plasma cell-free DNA (cfDNA) 5-hydroxymethylcytosine (5hmC) signature-based predictive model to assess treatment response and potentially select patients eligible for ICI monotherapy. Methods: 40 plasma samples were collected from adult patients with stage III or IV lung cancer at Houston Methodist Hospital between 2019 and 2022. These were divided into a training (n = 24) and validation (n = 16) set. By identifying genes associated with progression free survival (PFS), a 16-gene signature was used to develop a 5hmC predictive model. A weighted predictive score (wp-score) based on the model was calculated for each patient and grouped into low and high wp-scores. Results: Low wp-scores were associated with higher objective response rate(ORR) in both training and validation set and better correlated with response rates compared to PD-L1. In the training set, PFS was longer in low wp-scores compared to high wp-scores (median 12.3 versus 3.0 months; p = 3.5x10-6; hazard ratio (HR) 4.6x10-10). This was also seen in the validation set (median 7.6 versus 1.8 months p = .0012; HR 0.12). Contrarily, high ( > 1%) or low ( < 1%) PD-L1 was not associated with PFS (median 6.8 versus 6.0 months; p = .40; HR 0.70; 95% CI, 0.30–1.60) or overall survival (OS) (median 10.1 versus 12.0 months; p = .38; HR 0.56; 95% CI, 0.15–2.10). 15 out of the 40 total patients received ICI monotherapy. Among these, low wp-scores (n = 8) were significantly associated with longer PFS compared to high wp-scores (n = 7), (median 19.6 versus 2.8 months; p = .00073; HR: 0.059). OS although longer, was not significant among the two groups (median 38.1 versus 10.5 months; p = .12). Conclusions: Our study provides a proof of concept that cfDNA 5hmC signature can be used to predict response to ICI therapy and select patients appropriate for monotherapy. It is a more sensitive and specific biomarker to PD-L1. Larger studies are underway to further validate cfDNA 5hmC based-signature predictive model. [Table: see text]
Stage IV non-small cell lung cancer in Veterans undergoing lung cancer screening who were not prescribed statins despite U.S. Preventative Services Task Force recommendations.
Authors: Elfessi Zane , Dell Catherine , Rubinstein Israel
Published: July 2024

e20583

Background: It is well established that Veterans eligible for lung cancer screening (LCS) are also at risk of atherosclerotic cardiovascular disease (ASCVD) due to smoking. Current concepts suggest that statins could play a role in lung cancer prevention and treatment. Accordingly, the purpose of this retrospective, quality improvement project was to determine whether newly diagnosed stage IV non-small cell lung cancer (NCSLC) rate is higher in Veterans undergoing LCS who were not prescribed statins despite U.S. Preventative Services Task Force (USPSTF) recommendations. Methods: Electronic health records of Veterans undergoing LCS and subsequently diagnosed with NSCLC at the Jesse Brown VA Medical Center, Chicago, Illinois between 2021 and 2023 were reviewed. In each case, pertinent demographic, clinical, pathological, and pharmacy data were retrieved. The American College of Cardiology’s ASCVD Risk Estimator was used to assess the Veteran’s 10-year risk for a first ASCVD event. Data are presented as means ± SD. Statistical analysis was performed using Student’s t- and chi-squared tests as indicated. P < 0.05 was considered statistically significant. Results: Out of 57 Veterans diagnosed NSCLC, 33 (all males; 71±6 years; 28 African Americans) were prescribed and 24 (21 males, 3 females; 70±7 years; 18 African Americans) were not prescribed statins. Body mass index was similar in both groups (26.6±6.0 and 26.0±6.0 kg/m2, respectively; p = 0.73). Twenty one out of 24 Veterans (88%) not prescribed statins were eligible according to USPSTF recommendations (10-year calculated risk, 15.23%±6.9%). Stage IV NSCLC was diagnosed in 7/33 (21%) Veterans prescribed statins and in 10/21 (48%) USPSTF-eligible Veterans not prescribed statins (p < 0.05). Conclusions: Clinicians should assess the needfor a statin for primary prevention of ASCVD in each Veteran undergoing LCS. Stage IV NSCLC is more prevalent in Veterans with ASCVD risk who were not prescribed statins despite USPSTF recommendations. A larger, multi-site study is warranted to support or refute these initial observations.
Cost-efficiency and expanded access modeling of toripalimab versus pembrolizumab in locally advanced or metastatic nonsquamous non-small cell lung cancer.
Authors: MacDonald Karen , Pondel Marc , Abraham Ivo
Published: July 2024

e20590

Background: Toripalimab, a novel anti-PD-1 antibody, demonstrated significant PFS and OS benefit in combination with pemetrexed and platinum (toripalimab+PemPlat) in advanced nonsquamous non-small cell lung cancer (nsNSCLC) over placebo+PemPlat in the CHOICE-01 trial (median PFS: 9.7 vs 5.5 months; median OS: NE vs 17.0 months), though not currently approved for this indication. FDA-approved pembrolizumab+PemPlat was similarly found to extend PFS and OS over placebo+PemPlat in metastatic nsNSCLC patients in KEYNOTE-189 (median PFS: 9.0 vs 4.9 months; median OS: 22.0 vs 10.7 months). The current wholesale acquisition cost (WAC) of pembrolizumab is $11,115 per dose. The WAC of toripalimab, recently approved for nasopharyngeal carcinoma, is 80% of pembrolizumab. In this simulation we modeled the cost-efficiency of the toripalimab regimen versus pembrolizumab in nsNSCLC and the budget-neutral expanded access to additional toripalimab enabled by savings. Methods: Utilizing WAC drug costs and treatment administration costs, we estimated the cost-efficiency of the toripalimab regimen for the median PFS 9.7 months observed in CHOICE-01 versus the pembrolizumab regimen for the median PFS 9.0 months observed in KEYNOTE-189. We assumed that 14 cycles of toripalimab+Pem (with carboplatin in cycles 1-4) are administered over 9.7 months and 13 cycles of pembrolizumab+Pem (with carboplatin in cycles 1-4) are administered over 9.0 months. From the differential, we estimated the potential expanded access to additional toripalimab treatment on a budget-neutral basis. The model was replicated utilizing an ex ante toripalimab average sales price (ASP) of 80% of pembrolizumab ASP. Results: The pembrolizumab regimen costs $176,705 over 9.0 months (13 cycles) while the toripalimab regimen costs $159,136 over 9.7 months (14 cycles) at the respective WACs, for savings of $17,569 per patient. This would enable the purchase of 1.6 additional toripalimab+pemetrexed maintenance cycles on a budget-neutral basis for every patient treated. For every 9 patients treated with toripalimab instead of pembrolizumab, one additional patient could be treated with the full toripalimab regimen (all agents) for 9.7 months. Extrapolated to the US incident nsNSCLC population of 49,647 patients, if only 5% of patients are treated with toripalimab instead of pembrolizumab estimated savings of $43,611,849 provide access to 3,849 additional toripalimab+pemetrexed maintenance cycles or 274 full toripalimab regimens (all agents for 9.7 months) budget-neutrally. Similar results were seen in the ex ante ASP model. Conclusions: If approved for use in advanced nsNSCLC, toripalimab is estimated, at its market-entry WAC, to save $17.6 thousand per patient over a median PFS 9.7 months treatment duration compared to the pembrolizumab regimen over a median PFS 9.0 months of treatment.
Prediction of oncogene mutation status in non-small cell lung cancer leveraging radiomics from CT scans: A systematic review and meta-analysis with a special focus on artificial-intelligence-based methods.
Authors: Fuster-Matanzo Almudena , Picó Peris Alfonso , Bellvís Bataller Fuensanta , Jiménez Pastor Ana , Weiss Glen J. , Martí-Bonmatí Luis , Lázaro Sánchez Antonio David , Banna Giuseppe Luigi , Addeo Alfredo , Alberich-Bayarri Angel
Published: July 2024

e20603

Background: In non-small cell lung cancer (NSCLC), alternative strategies to determine patient oncogene mutation status are essential to overcome some of the drawbacks associated with current methods. We aimed to review the use of radiomics alone or in combination with clinical data and to evaluate the performance of artificial intelligence (AI)-based models on the prediction of oncogene mutation status. Methods: A PRISMA-compliant literature review was conducted. The Medline (via Pubmed), Embase, and Cochrane Library databases were searched for studies published through June 30, 2023, predicting oncogene mutation status in patients with NSCLC using radiomics. Independent meta-analyses evaluating the performance of AI-based models developed with radiomics features or with a combination of radiomics features plus clinical data for the prediction of different oncogenic driver mutations were performed. A meta-regression to analyze the influence of methodological/clinical factors was also conducted. Results: Out of the 615 studies identified, 89 evaluating models for the prediction of epidermal growth factor-1 (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma virus (KRAS) mutations were included in the systematic review, including a total of 32,084 patients. A total of 38 met the inclusion criteria for the meta-analyses (encompassing 17,066 patients). The AI algorithms' sensitivity/false positive rate (FPR) in predicting EGFR, ALK, and KRAS mutations using radiomics-based models was 0.753 (95% CI 0.721–0.783)/0.346 (95% CI 0.305–0.390), 0.754 (95% CI 0.639–0.841)/ 0.225 (95% CI 0.163–0.302), and 0.744 (95% CI 0.605–0.846)/0.376 (95% CI 0.274–0.491), respectively. A meta-analysis of combined models was only possible for EGFR mutation, revealing a sensitivity/FPR of 0.800 (95% CI 0.767–0.830)/0.335 (95% CI 0.279–0.396). No statistically significant results were obtained in the meta-regression. Conclusions: Radiomics with a specific focus on CT-based models may represent valuable non-invasive tools for the determination of oncogene mutation status in NSCLC. Further investigation is required to analyze whether clinical data might boost their performance.
Impact of radiation dose to the immune cells in stage IV non-small cell lung cancer in the era of immunotherapy.
Authors: He Junyi , Liu Yingxin , Li Butuo , Yu Jinming , Wang Linlin
Published: July 2024

e20608

Background: Thoracic radiotherapy now is widely accepted in advanced lung cancer. It is not only been used as palliative therapy but also been involved in Systemic treatments in advanced lung cancer, especially in immune era. However, radiotherapy impairs immune system which can be evaluated by estimated dose of radiation to immune cells (EDRIC). Here, we sought to examine the prognostic impact of the EDRIC in advanced NSCLC in the context of immunotherapy, and to identify the factors influencing EDRIC in this population. Methods: We retrospectively enrolled patients with stage IV NSCLC who had received first-line immunotherapy and thoracic radiation therapy. EDRIC is a specific formulation using a model developed by Jin et al and improved by Ladbury et al, calculated using radiation fraction, mean lung dose (MLD), mean heart dose (MHD), and mean body dose (MBD). Spearman’s rank correlation was used to assess the correlation between variables.Associations between EDRIC [analyzed continuously and categorically (<5.7Gy vs ≥5.7Gy)] and overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and Cox proportional methods. Results: We conducted a retrospectively analysis of 152 patients with stage IV NSCLC patients. GTV (r = 0.2023, p = 0.0137), PTV (r = 0.4139, p < 0.0001) and N (r = 0.1897, p = 0.0193) stage showed a positive correlation with EDRIC. Negative correlations of lymphocyte nadir with EDRIC (r = -0.3172, p < 0.0001), during/pre lymphocyte nadir with EDRIC (r = -0.2102, p = 0.0093), during/post lymphocyte nadir with EDRIC (r = -0.2750, p = 0.0006) were found. Median PFS was shorter among the EDRIC ≥5.7Gy group (10.2months vs 18.6months; p < 0.0001). Median OS was also shorter among the EDRIC ≥5.7Gy group (19.8 months vs 30.2months; p = 0.024). For ORR (38% vs 46%; p = 0.413) and DCR (84% vs 92%; p = 0.304), there was no statistical significance between EDRIC≥5.7Gy and EDRIC < 5.7Gy. Analyzed as a continuous variable, EDRIC was the only factor associated with worse PFS (HR = 1.001, p = 0.018) and OS (HR = 1.002, p = 0.001) in multivariate analysis. Conclusions: In the era of immunotherapy, EDRIC is an independent predictor for PFS and OS in advanced NSCLC, warranting investigation into techniques to optimize radiation dose to the immune compartment.
Mutation pattern of EGFR gene in Peruvian patients with non-small cell lung cancer.
Authors: Ruiz Rossana , Galvez-Nino Marco , Santos Marco , Doimi Franco , Mas Luis , Belmar-Lopez Carolina
Published: July 2024

e20615

Background: The correct characterization of EGFR mutations is crucial to the proper management of NSCLC patients due to the possibility to treat these patients with specific targeted therapies. Herein we report the incidence, mutation pattern and novel mutations of EGFR mutation in Peruvian NSCLC patients. Methods: Between 2016 and 2023 a total of 1489 NSCLC patients from public and private centers were referred to ONCOGENOMICS laboratory for somatic mutation testing. Next Generation Sequencing (NGS) was performed using the Ampliseq for Illumina FOCUS or Custom panel and run on the Illumina MiSeq. Raw data were processed automatically on the BaseSpace Sequence Hub (Illumina) and aligned to the hg19 reference genome The default limit of detection (LOD) was set at 5% allelic frequency (VAF) in tissue samples and 0.5% VAF in cfDNA samples. Results: The study included 1401 NSCLC patients, 61.8% were women. Clinical stages were distributed III (22.5%), IV (77.5%). All tumors were adenocarcinoma. Incidence of EGFR-mutated NSCLC was 33.4% (450), 68.9% were women. We found 519 EGFR mutations in 450 tumors. Classical or common EGFR mutations; L858R or ex19del corresponded to 86.4% with 331 and 383 cases, respectively and L858R or ex19del + T790M corresponded to 13.6% with 2 cases onset and 50 cases in progression. EGFR T790M de novo mutations were found in 4 cases onset. In one case at diagnosis was detected a T790M-like 3R mutant EGFR p.(C797S); c.2390G > C, a drug resistance point mutation in ex20.Non-classical or atypical EGFR mutations corresponded to 14.0% (63/450) of cases. Non-classical EGFR mutations were categorized as follows according to Janning et al.: (i) More frequent uncommon EGFR mutations - 39.7% (25/63) including G719X, S768I, E709X and L861Q (22/25); G719X + S768I (1/25); and combinations with classical EGFR mutation L858R + S768I (2/25). (ii) EGFR exon 20 insertions - 44.5% (28/63), including a novel mutation EGFR p.(769_770VDinsGFV);c.2308_2309ins. All were located in the loop following the C-helix. And (iii) very rare mutations - 15.9% (10/63) including very rare point mutations in ex19 (1/10), ex18del (4/10), ex19ins (1/10) and complex mutations (ex19del + very rare point mutation in ex19 (4/10).Two point mutation no reported previously were found, EGFR, ex19, p.(S752F);c.2255C > T and EGFR, ex19, p.(T751P);c.2251A > C, both as co-mutations with classical EGFR ex19del mutation. Conclusions: The present study underscores the value of NGS to optimally address EGFR mutations, specially the rare and novel ones due to its higher sensitivity and specificity compared to other techniques. This approach is particularly important for the Latin American population which is underrepresented in genomic databases. Clinical correlation of this genomic findings is ongoing.
Enhanced dacarbazine efficacy in advanced melanoma patients previously treated with immune checkpoint inhibitors in Korea.
Authors: Lee Soo Jung , Na Jihyun , Lee In Hee , Lee Jeeyeon , Lee Seok-Jong
Published: July 2024

e21528

Background: Immune checkpoint inhibitors (ICI) have revolutionized advanced malignant melanoma treatment. But the lack of effective options post-ICI failure presents a significant challenge. Despite its modest efficacy, chemotherapy with dacarbazine remains practical choice in metastatic melanoma patients after ICI failure. Researchers suggested an increased efficacy of chemotherapy in melanoma patients previously treated with ICI. In this study, we aimed to assess the efficacy of dacarbazine of patients with or without prior ICI treatment. Methods: 71 patients with histologically confirmed malignant melanoma, who diagnosed and underwent chemotherapy between 2011 and 2023 at the Kyungpook National University Chilgok Hospital (Daegu, Korea) were included in this retrospective study. We included patients who had received either dacarbazine single or CVD(Cisplatin, Vinblastine, Dacarbazine) regimen for an unresectable stage IIIC, IIID or IV acral, cutaneous, mucosal melanoma according to American Joint Committee on Cancer(AJCC) 8th edition. Results: Among a total of 71 individuals, there were 16 patients who had not previously received pembrolizumab treatment (DTI-only group). There were 55 patients in the pembrolizumab (pem-DTI group) experienced group. The median PFS was 2.3 months in the DTI-only group and 3.9 months in the pem-DTI group, reflecting a significant PFS difference of 1.6 months. And the median OS was 6.8 months in the DTI-only group and 19.0 months in the pem-DTI group, demonstrating a statistically significant difference. In the univariate and multivariate analysis for PFS, the use of pembrolizumab was advantageous compared to non-use (HR 0.246, 95% CI 0.106-0.576, p= 0.001). The only favorable condition in the univariate analysis for OS was the use of pembrolizumab compared to non-use (HR 0.198, 95% CI 0.068-0.574, p= 0.003). The mean duration of response for the DTI-only group was 4.64 months, while for the pem-DTI group, it was 8.11 months, indicating that the pem-DTI group exhibited a longer duration. Conclusions: We have demonstrated superior PFS and OS in the group of metastatic melanoma patients who received dacarbazine after prior treatment with pembrolizumab compared to those treated with dacarbazine alone. Dacarbazine may still be a valid option after failure of ICI +/- targeted treatment. Future studies should focus on the immunomodulatory effects of dacarbazine on the tumor microenvironment, which could be harnessed to potentially enhance sensitivity to immune checkpoint-based therapy.
Comparison of adjuvant targeted and anti-PD1 immunotherapy in BRAF-mutated stage III cutaneous melanoma: Retrospective, single center cohort study.
Authors: Akhmetianova Angelina , Orlova Kristina V. , Nazarova Valery V. , Baryshnikov Kirill A. , Samoylenko Igor , Ivanilov Kirill , Demidov Lev V.
Published: July 2024

e21558

Background: Targeted therapy (TT) and anti-PD1 immunotherapy (IT) are standard of adjuvant stage III melanoma treatment. However, no comparative prospective randomized trials (head-to-head) were conducted. Data limited to a few retrospective studies. Both treatment regimens were registered in Russia in 2019. We aimed to compare adjuvant options in Russian melanoma pts. Methods: We conducted a single-center retrospective observational study approved by the IRB. We included all pts age 18 and older (one patient, female, was 14) with BRAF-mutated stage III melanoma who were treated at the N.N.Blokhin NMRC of Oncology MoH and received adjuvant therapy between Jan 2019 and Dec 2022. The primary endpoint was RFS, the secondary endpoint - OS. Cox regression analysis was used to identify prognostic factors for RFS (including substage, thickness and ulceration of primary tumor). Results: A total of 209 pts were included, mostly BRAF V600E/K, 92 (44%) male and 117 (56%) female. Median age was 50,6 years (range: 14-81). 93 (44,4%) pts received TT, 103 (49,3%) pts received IT and 13 (6,3%) didn’t receive adjuvant therapy (observation only). The observation group wasn’t analyzed due to a small number of pts. At a median follow-up of 27 mo, median RFS was 30 mo (95% CI 23-56) in TT group and wasn’t reached in IT group; median OS wasn’t reached in both groups. There weren’t statistical differences between TT and IT groups in RFS (HR 0,84, 95% CI 0,53-1,34, p = 0,47) and OS (HR 0,59, 95% CI 0,26-1,34, p = 0,21), even though at 12 mo, the rate of RFS was higher in the TT group (91.4%) compared IT group (67%), at 18 mo – 79,5% and 63,1%, 24 mo – 68,8% and 61,1% respectively. TT group had numeric but not significant RFS benefit in most subgroups. HR values for substage, thickness and ulceration are presented in the table below. Tx+T0 pts (TT, n = 7; IT, n = 13) and unknown status of ulceration (TT, n = 7; IT, n = 16) was not presented for some pts. Conclusions: Differences between TT and IT wasn't reached at a median follow-up of 27 mo. But IT-treated pts had more and earlier recurrences than TT pts. In BRAF mutated pts, adjuvant TT might prevent early recurrences more effectively than IT. These results need to be interpreted with caution given its retrospective and non-randomized nature and potential selection biases. Additional time to follow-up and biomarker analysis was planned. [Table: see text]