bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoadjuvant prehabilitation therapy for locally advanced non-small-cell lung cancer: Optimizing outcomes throughout the trajectory of care.
Authors: Schmid Severin , Minnella Enrico Maria , Najmeh Sara , Cools-Lartigue Jonathan , Ferri Lorenzo , Mulder David , Sirois Christian , Owen Scott Peter , Carli Francesco , Spicer Jonathan
Published: June 2021

e20545

Background: Prehabilitation is well established for improving outcomes in cancer surgery. Combining prehabilitation with neoadjuvant treatments may provide an opportunity to rapidly initiate cancer-directed therapy while improving functional status in preparation for local consolidation. In this proof-of-concept study, we analyzed non-small-cell lung cancer patients who underwent simultaneous prehabilitation and neoadjuvant therapy. Methods: We retrospectively analyzed all patients who underwent neoadjuvant treatment for non-small-cell lung cancer followed by curative intent surgery at the McGill University Health Center between 2015-2020. Patients who were screened for the prehabilitation program were identified. Screening included assessment of physical performance, nutritional status and signs for anxiety and depression. 6-minute-walk test was used as a functional outcome parameter of prehabilitation. Results: We identified a total of 93 patients who underwent neoadjuvant therapy. Of these, 12 patients were screened to undergo a prehabilitation program. For 1 patient surgical intervention was too soon to complete the program, 1 patient dropped out after the first and another patient was deemed fit to undergo surgery without intervention. Thus, 9 patients completed full neoadjuvant prehabilitation therapy. Postoperative median length of stay was 2 days (IQR 1-5) and there were no mortalities. We found major complications in 1 patient and minor complications (prolonged air leak) in 2 cases. Patients improved their 6-minute-walk test despite undergoing neoadjuvant treatment by a mean of 35 meters (SD 39). Conclusions: Neoadjuvant prehabilitation therapy is feasible and associated with encouraging results. The performance of all measures remains a logistic challenge. With multimodal strategies for lung cancer treatment becoming key to optimal outcomes, neoadjuvant prehabilitation therapy is a concept worthy of prospective multi-center evaluation.
Assessing tumor metabolic heterogeneity of non-small cell lung cancer with total body PET-CT imaging on the uExplorer: Analysis of dynamic changes of 18F-FDG uptake.
Authors: Liu Hui , Zhang Xu , Liu Hui , Qiu Bo , Wang DaQuan , Zhou Yin , Li QiWen , Chu Chu , Liu FangJie , Chen NaiBin , Hu Nan , Ai XinLei , Guo JinYu , Fan Wei
Published: June 2021

e20549

Background: Total body positron emission tomography (PET) of uExplorer enables imaging of highly quantitative parameters beyond the standardized uptake value (SUV). The aim of this prospective study is to assess the dynamic changes of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake in characterizing tumor heterogeneity of non-small cell lung cancer (NSCLC). Methods: Sixteen NSCLC patients were prospectively enrolled in a prospective study (NCT04654234, GASTO-1067) between September 2020 and December 2020. All patients underwent a dynamic total-body 18F-FDG PET/CT scan before any treatment. The primary lung tumor, metastatic regional lymph node and inflammatory lymph node were manually delineated by a nuclear medicine physician and a radiation oncologist. Total Body PET was acquired between 0 – 60 mins after the injection of FDG from the subject’s feet. We compared lesion heterogeneity and different image-derived PET metrics including the SUV-mean, Patlak-derived influx rate constant (Ki) and distribution volume (DV). Results: The SUV-mean and Ki-mean of primary lung tumor and metastatic lymph node were significantly higher than inflammatory lymph node (p < 0.001), while there was no significantly different of DV(p > 0.05). By the scatter plot of SUV-mean and Ki-mean of primary lung tumor, 9 patients had been separated into high dynamic FDG metabolic (H-DFM) group and 7 in low DFM(L-DFM) group. The SUV-mean(p = 0.0002) and Ki-mean(p = 0.0002) of primary lung tumor were significantly higher in H-DFM group, whereas there is no difference in metastatic lymph node of both group. Interestingly, the SUV-mean and Ki-mean of primary lung tumor were higher than that of metastatic lymph node(p = 0.0002) in H-DFM group. On the contrast, the SUV-mean and Ki-mean of primary lung tumor were lower than that of metastatic lymph node(p = 0.05) in L-DFM group. There is no significant difference of DV-mean among primary lung tumor, metastatic lymph node and inflammatory lymph node in both arms. Conclusions: The results demonstrated that dynamic parameters from total body PET scan has the potential of providing complementary information of tumor heterogeneity in NSCLC than conventional static SUV imaging. The characteristics of H-DFM and L-DFM group could be taken into account for evaluation of further treatment response.
Construction and validation of an eight-gene risk prediction model for stage II-IIIA lung adenocarcinoma.
Authors: Duan Jianchun , Bai Hua , Sun Yiting , Gai Fei , Tian Shenya , Xu Wenfang
Published: June 2021

e20553

Background: Clinical characters cannot precisely evaluate long-term survival of patients with resectable lung adenocarcinoma. Genomics studies of lung adenocarcinoma (LUAD) have advanced our understanding of LUAD's biology. Thus, genomics-based robust models predicting survival outcome for patients with operatable LUAD needs to be investigated. Here, we aimed to identify new gene signatures to construct a risk prediction model via integrating Omics data from The Cancer Genome Atlas (TCGA) to better evaluate the long-term clinical outcome of LUAD patients. Methods: A cohort of one hundred and eighty-nine stage II-IIIA lung adenocarcinoma cases receiving tumor resection were screened out and downloaded from TCGA database. Tumor samples without survival information and genes with low or no expression were removed. Genes associated with cancer and immune were further narrowed down using a Master Panel Gene Set (Amoydx). Lasso-Cox regression analysis was used to screen gene-survival outcome, and then a risk prediction model was established. LUAD cases were divided into high-risk or low-risk groups as per the scores, to assess differential expressed genes and pathways. Results: A total of 8 most survival outcome related genes (CLEC7A, PAX5, XCR1, KRT7, PLCG1, DKK1, CLEC10A, IKZF3) were identified after Lasso-Cox regression analysis and used for model construction. The overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) from the subgroups within the high- and low-risk groups were assessed and showed significant prolonged in low-risk group, the hazard ratio (HR) of OS was 2.72 (95%CI: 2.04-3.61, P = 5.91e-12) in high-risk group. Hierarchical clustering analysis, gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) revealed that genes involved in immune responses were significantly suppressed in high-risk group, while as genes involved in antioxidative metabolism were activated, which gave us a hint that immune-metabolism interaction might play a vital role in determining the distal survival outcome of LUAD. Conclusions: Our risk prediction model enables precise evaluation of long-term survival for patients with LUAD. Further, it provides a novel and comprehensive understanding of biological impacts on LUAD prognosis, which offers new insights for future development of precise diagnostic and therapeutic approaches.[Table: see text]
Using predictive models to determine the presence of non-small cell lung cancer metastasis to N2 and N3 regions.
Authors: Hauptmann Edward , Batra Kiran , Kandathil Asha , Canan Arzu , Alvarado Sergio , Li Qiubai , Kukkar Vishal , Xi Yin , Kernstine Kemp H.
Published: June 2021

e20560

Background: Accurate assessment of non-small cell lung cancer (NSCLC) mediastinal involvement is key to developing treatment plans and determining prognosis. To date, there is no reliable imaging-based means to determine the presence or absence of mediastinal involvement. Current computed tomogram (CT) and fluorodeoxyglucose-positron emission tomography/ computed tomogram (PET-CT) technologies provide numerous derived automated variables have not been sufficiently evaluated to determine the presence of metastasis to the mediastinum. We have developed predictive models to determine the presence or lack of metastatic NSCLC in N2 and N3 regions. Methods: Consecutive patients from 2012-2017 with biopsy-proven NSCLC who had CT and PET-CT, as well as biopsy of the mediastinum had their images reread by a team of blinded specialty radiologists and nuclear medicine specialists. Patients with no mediastinal malignancy on biopsy were followed for 6 months from the initial evaluation to confirm lack of mediastinal malignancy.278 regions (N2 and N3) from 139 patients were included. Logistic regression models were used to build a baseline model, as well as models with additional nodal station maximum standard uptake valuve (SUVm) measurements (SUVm, SUVm-SUVmeanbloodpool and SUV lymph node/tumor (LN/T)) for N2 and N3 regions, respectively. When nodal station SUVm was not measured, SUVmeanbloodpool was used. The SUVm within each region was used. Stepwise selection was used to select variables in the baseline model. Cross-validated ROC curve and area under the curve (AUC) were reported. All analyses were done in SAS 9.4 (SAS Institute, Inc., Cary, NC). Results: 40/139 N2 regions had malignancy, 4/139 N3 regions had malignancy. Baseline models for N2 regions selected lung laterality (OR right vs left: 4.84 (1.79, 13.05)) and nodal station short-axis diameter > 1 cm (OR yes vs no: 5.49 (1.71, 17.54)) while no variables were selected for the baseline model for N3 regions due to lack of statistical power. We used the same variables for the N3 baseline model. Conclusions: We have identified models that use a more advanced analysis of predicting the presence or absence of metastatic NSCLC in both N2 and N3 regions with respect to the primary lesion. All models perform better with SUVm related measurements. From this information, we are developing a clinical application to provide practitioners a better means of assessing the presence of mediastinal involvement of NSCLC. [Table: see text]
Novel ETV1 mutation in small cell lung cancer transformation resistant to EGFR tyrosine kinase inhibitors.
Authors: Zhou Yan , Bai Hao , Cheng Lei , Han Baohui , Xiong Liwen
Published: June 2021

e20568

Background: Non-small cell lung cancer (NSCLC) patients harboring mutations in the epidermal growth factor receptor (EGFR) gene dramatically respond to EGFR tyrosine kinase inhibitors (TKIs). However, these patients inevitably developed acquired resistance to TKIs. Among them, small cell lung cancer (SCLC) transformation is a relatively rare mechanism of resistance. However, the mechanism of SCLC transformation is largely unclear. Methods: We performed a 639 cancer-relevant gene panel to detect genetic differences of tissues before and after TKIs resistance caused by SCLC transformation. In vitro experiments were conducted to study the role of ETS variant transcription factor 1 (ETV1) on SCLC transformation and TKIs resistance. Results: We present two EGFR-mutant pulmonary adenocarcinoma (ADC) patients. One with EGFR exon 19 deletion (Ex19del) accepted first-line gefitinib treatment and then received osimertinib(AZD9291) treatment due to acquisition of EGFR-T790M mutation. A novel ETV1 mutation (p.P159S) was detected in SCLC samples after SCLC transformation when not coexisting with T790M. Another patient harbored an EGFR exon 21 mutation (p.L858R) with a long-lasting response to first-line gefitinib and then transformed to SCLC. A previously unreported ETV1 mutation (p.E462Q) was detected in SCLC tissue. In vitro, ETV1 p.E462Q and p.P159S mutations participated in neuroendocrine differentiation by inducing the expression of the neuroendocrine transcription factor, achaete-scute homolog 1 (ASCL1) and promoted H69 cells proliferation. Besides, ETV1 p.E462Q and p.P159S mutations were resistant to first-generation (gefitinib) and third-generation (osimertinib) TKIs after introducing into NCI-H358 cells. Conclusions: Novel ETV1 p.E462Q and p.P159S mutations were found in SCLC tissues of TKIs resistant patients, providing novel understanding of ETV1 involved in acquired resistance to EGFR-TKIs via SCLC transformation.
Impact on second-line treatment after failure of immune checkpoint inhibitor (ICI) combination chemotherapy in extensive-disease small cell lung cancer: Experience of the Okayama Lung Cancer Study Group.
Authors: Kato Yuka , Noumi Taku , Saeki Kazuhiko , Ninomiya Kiichiro , Kubo Toshio , Fujii Masanori , Rai Kammei , Ichihara Eiki , Ohashi Kadoaki , Tabata Masahiro , Hotta Katsuyuki , Kozuki Toshiyuki , Maeda Yoshinobu , Kiura Katsuyuki
Published: June 2021

e20590

Background: For patients with extensive-disease small cell lung cancer (ED-SCLC), amrubicin monotherapy is an important therapy in the treatment of recurrence, but there has been no adequate evaluation of how effective it actually is after failure of first-line chemotherapy including immune checkpoint inhibitor (ICI). Therefore, the purposes of this study are to determine the proportion of patients who received amrubicin monotherapy in the treatment of relapse after first-line treatment with ICI (arm A) and to investigate the efficacy of amrubicin therapy after arm A compared with after chemotherapy without ICI (arm B). Methods: Consecutive 40 pts with ED-SCLC NSCLC were retrospectively assessed who underwent ICI-containing chemotherapy (n = 19) or standard cytotoxic chemotherapy (n = 21) in the 1st-line setting between 2017 and 2020. Results: In arm A, 3 of 19 patients (16%) were still on first-line ICI maintenance therapy, 2 (2/19; 11%) had ICI treatment adverse events (interstitial pneumonia, cardiopulmonary arrest), and 1 patient could not receive second-line therapy due to a decrease in performance status (PS) to 3. In arm B, 11 of 21 patients (52%) did not receive amrubicin as second-line therapy, including 1 patient with worsening PS, 1 patient with adverse events (hematologic toxicity), 1 patient refusal, and 6 patients with combination of ICI and chemotherapy. 23 patients (arm A; 13 (57%), arm B; 10 (43%)) were able to receive amrubicin monotherapy, including 7 patients (6 cases vs 1 case) were sensitive relapses, and 16 (7 vs 9 cases) were refractory relapses. There was no significant difference in either PFS or survival after first-line treatment in 16 patients with refractory relapse who received amrubicin as second-line treatment (PFS: 4.8 vs 5.2 months, p = 0.51), (median survival after first-line treatment: 9.6 vs 12.8, p = 0.75). Conclusions: Patients who received ICI in the first-line treatment were fully eligible to receive amrubicin in the second-line treatment. The recurrence pattern tended to be sensitive relapse and we found that the efficacy of amrubicin in refractory relapse was not affected by the administration of ICI in the first-line treatment.
Protein expression of programmed cell death ligand 1 and ligand 2 and their prognostic values in extensive-stage small cell lung cancer.
Authors: Zu Ke (Kirsten) , Georgsen Jeanette Bæhr , Meldgaard Peter , Deitz Anne , Ayers Mark , Pietanza Maria Catherine , Steiniche Torben
Published: June 2021

e20593

Background: The receptor-ligand interaction between programmed cell death protein-1 (PD-1) and its ligands (PD-L1 and PD-L2) plays a critical role in tumor immune evasion and has become a therapeutic target in a number of cancer types, including extensive stage small cell lung cancer (ES-SCLC). While there are some published data on PD-L1 expression in ES-SCLC, the results vary with different laboratory assays or thresholds of positivity employed. Data on PD-L2 expression is very limited in ES-SCLC. The prognostic values of these biomarkers are not well understood. The current study aims to address this data gap. Methods: A retrospective cohort study of patients with ES-SCLC receiving usual care in the clinical setting in Denmark was conducted. Formalin-fixed paraffin embedded (FFPE) tumor tissue samples and data on patient characteristics and clinical outcomes were obtained for the patient population. Protein expression of PD-L1 and PD-L2 was determined by immunohistochemistry (IHC), and a combined positive score (CPS, the percentage of tumor cells and mononuclear inflammatory cells expressing the biomarker at any intensity out of the total number of tumor cells) of ≥1 was used to define biomarker positivity. Kaplan-Meier plots and Cox proportional hazard models were employed to assess the relationship between PD-L1 and PD-L2 protein expression and overall survival (OS). Results: Among the 80 patients with ES-SCLC included in this study, 25 and 29 were positive for PD-L1 and PD-L2, respectively (Table). A total of 68 patients had concordant expression status of PD-L1 and PD-L2 (21 as double positive and 47 as double negative). There was a significant association between PD-L1 positivity and longer OS, which persisted after adjustment for age and stage at SCLC diagnosis, performance score, prior exposure to chemotherapy, and lactate dehydrogenase levels (Table). Similar results were observed for PD-L2 (Table), and the data did not suggest any additional prognostic value of PD-L2 expression independent of PD-L1 expression. Conclusions: PD-L1 and PD-L2 positivity was both observed, and highly correlated with each other, in approximately one third of the ES-SCLC tumor samples tested. Patients with PD-L1 or PD-L2 positive tumors have significantly longer OS than those with negative tumors in this study, independent of other known prognostic factors.[Table: see text]
ERO1L shapes the immune-suppressive tumor microenvironment and is a potential biomarker for immunotherapy response in lung adenocarcinoma.
Authors: Liu Lihui , Wang Chao , Li Sini , Xue Pei , Bai Hua , Wang Jie
Published: June 2021

e21006

Background: Recently, immune checkpoint inhibitors have led to a paradigm shift in treatment for patients with lung adenocarcinoma (LUAD), however, the identification of biomarkers to enable patient selection is urgently required. The endoplasmic reticulum oxidoreductin-1-like ( ERO1L) gene encodes an endoplasmic reticulum luminal localized glycoprotein known to associated with hypoxia. The role of ERO1L in the crafting of the tumor immune microenvironment (TIME) is yet to be elucidated. Methods: In this study, raw datasets (including RNA-seq, methylation, sgRNA-seq, phenotype, and survival data) were obtained from public databases. This data was analyzed and used to explore the biological landscape of ERO1L in immune infiltration. Expression data was used to characterize samples. Using gene signatures and cell quantification, stromal and immune infiltration was determined. These findings were used to predict sensitivity to immunotherapy. Results: We identified ERO1L to be an oncogene, the mRNA expression of which is significantly higher in LUAD compared with normal tissues. High expression levels of ERO1L were associated with poor prognoses in terms of overall survival (HR: 1.52, 95% CI: 1.27-1.82) and progression-free survival (HR: 1.93, 95% CI: 1.47-2.53). This overexpression was found to be a result of hypomethylation of the ERO1L promoter. Overexpression of ERO1L resulted in an immune-suppressive TIME via the recruitment of immune-suppressive cells including regulatory T cells (Spearman’s ρ = 0.199, p < 0.001) cancer associated fibroblasts (ρ = 0.286, p < 0.001), and myeloid-derived suppressor cells (ρ = 0.423, p < 0.001), and also indicated the polarization of M1-type to M2-type macrophage. On the contrary, overexpression of ERO1L was closely associated with deficiency of immune-active cells including B cells (ρ = -0.250, p < 0.001), CD8+ T cells (ρ = -0.299, p < 0.001), and NK cells (ρ = -0.258, p < 0.001). Using the Tumor Immune Dysfunction and Exclusion (TIDE) framework, it was identified that patients in the ERO1Lhigh group possessed a significantly lower response rate (31.0%) to immunotherapy compared with the ERO1Llow group (86.0%). Mechanistic analysis revealed that overexpression of ERO1L was associated with the upregulation of JAK-STAT (NES = 1.65, FDR q-value = 0.0) and NF-κB (NES = 2.03, FDR q-value = 0.0) signaling pathways, thus affecting chemokine and cytokine patterns in the TIME. Conclusions: Our study provides clear insight into the potential role of ERO1L in tumor immunology. Overexpression of ERO1L was indicative of a hypoxia-induced immune-suppressive TIME, which was shown to confer resistance to immunotherapy in patients with LUAD. ERO1L was shown to mediate cytokine and chemokine patterns in the TIME, which were resulted from activations of JAK-STAT and NF-κB signaling pathways.
Assessment of BRAF class I/II/III mutations, demographics, and treatment outcomes in NSCLC.
Authors: Marin-Acevedo Julian Andres , Hicks James Kevin , Thapa Ram , Chen Dung-Tsa , Kimbrough ErinMarie , Gray Jhanelle Elaine
Published: June 2021

e21016

Background: BRAF mutations are grouped (class I, II or III) according to kinase activity, dependence on RAS, and dimerization. BRAF class I mutations are targeted with BRAF/MEK inhibitors. The management of class II/III mutations has not been fully elucidated. We aimed to further characterize BRAF-mutant NSCLC. Methods: Moffitt patients with BRAF-mutant NSCLC were identified through retrospective review of a clinical molecular database and electronic health record from 1/1/2012 - 03/31/2020. Demographics, PD-L1 expression, responses to chemotherapy/immunotherapy, and overall survival were collected. The correlation between BRAF mutation classes and these variables was determined using a pairwise comparison of p-values and corrected for testing using the Benjamini-Hochberg method. For survival analysis, we used the Kaplan-Meier method with log-rank test. Results: 153 patients were included. Table summarizes the demographic data. 14 evaluable patients with class I mutations received anti-BRAF therapy. The DCR was 79% (11/14) and 83% when PD-L1 ≥1% (5/6). 36 response-evaluable patients received immunotherapy. The DCR was 79% (11/14) for patients with class I, 69% (9/13) for class II, and 78% (7/9) for class III mutations (p=0.89). The DCR was 73% in those with PD-L1 ≥1% (22/30) and 44% in those with PD-L1 <1% (7/16; p= 0.02). 43 response-evaluable patients received chemotherapy. The DCR was 86% (18/21) for patients with class I, 69% (9/13) for class II, and 78% (7/9) for class III mutations (p=0.49). The mOS was 26.2 months for all patients. The mOS was 31.2 months for class I, 15.6 months for class II, 28.8 months for class III, 34.8 months for AMP, and 24 months for VUS (p=0.6). Conclusions: To our knowledge, this is the largest retrospective study of patients with BRAF-mutant NSCLC. BRAFmutations were more common in patients with adenocarcinoma and those with a smoking history. PD-L1 levels ≥1% were seen more frequently in all BRAF-mutant patients. Class I mutations were significantly more common than other mutations and responded well to BRAF-targeted therapy, particularly when PD-L1 ≥1%. All BRAF-mutant classes responded similarly to immunotherapy and better responses were seen among those with PD-L1 ≥1%. Responses to chemotherapy were similar across all classes. Improved OS in class I-mutant disease was seen. These findings were not statistically significant. Additional research is needed to better characterize these patients to individualize management and improve outcomes.[Table: see text]
Increased PD-1 and EGFR expression levels of T lymphocytes in patients with non-small cell lung cancer.
Authors: Ceylan Ayca , Artac Mehmet , Artac Hasibe
Published: June 2021

e21018

Background: Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) are proteins that negatively regulate immune responses. Increased expression of PD-L1 in cancer cells leads to inhibition of the immune response against cancer, and causes cancer development and metastasis. Epidermal growth factor receptor (EGFR) activation upregulates PD-L1 expression in lung cancer cells and contribute to escape from immune response. In this study, we aimed to investigate the circulating T lymphocyte subsets and, PD-1 and EGFR expression levels of these cells in non-small cell lung cancer (NSCLC) progression. Methods: 40 NSCLC patients with 63.8 ± 8.0 mean age and 40 healthy controls with 60.9 ± 14.6 mean age were included in the study. In the peripheral blood samples of the patients taken at the time of diagnosis and controls, CD4+ T helper (Th) subsets (Th1, Th2, Th9, Th17, Th1Th17, CD4+ follicular T [Tfc] and peripheral T cells [Tpcs]), CD8+ cytotoxic T cell (CTL) subsets (CD8+ Tfcs and Tpcs), EGFR and PD-1 expression levels of T cells were determined by flow cytometric analysis. Results: Total lymphocyte ratio was decreased in patients with NSCLC compared to control (11.5 ± 5.2 in patients and 17.6 ± 6.1 in controls, p = 0.001), but there was no significant difference in CD3+ total T, Th and CTLs as well as their subsets (p < 0.05). Increased PD-1 expression level (mean fluorescence intensity-MFI) on total lymphocyte (p = 0.001), CD3+ T (p = 0.001), CD4+ Th (p = 0.001), CTL (p = 0.016), CD4+ Tpc (p = 0.002) and CD8+ Tpc subsets (p = 0.017) were determined in the patients compared with controls. EGFR expressions were also increased on total lymphocyte, CD3+ T, Th and Th2 cells (p = 0.034, p = 0.020, p = 0.030, respectively). 19 NSCLC patients were metastatic, while 21 patients were non-metastatic. There was no significant difference in mean age between metastatic and non-metastatic NSCLC patients. Reduced total lymphocytes and Th cells, increased Th1Th17 cells were found in metastatic NSCLC patients (p = 0.003, p = 0.046 and p = 0.022, respectively). The percentage of EGFR in CD3+ T cell and Th17 cells decreased in metastatic patients. Conclusions: This study showed the increased PD-1 and EGFR expression levels of T lymphocytes in patients with NSCLC. Cancer cells may upregulate PD-1 expression by inducing EGFR activation on lymphocytes to suppress immune responses, leading to programmed cell death of lymphocytes and a decrease in the percentage of these cells in NSCLC. Therapeutic approaches focused on changing EGFR need to be considered for the distribution of T cell subsets and EGFR expressions.
Differential responses to therapy in Hispanic NSCLC patients with EGFR, KRAS, or TP53 mutations.
Authors: Basher Fahmin , Saravia Diana , Lopes Gilberto
Published: June 2021

e21027

Background: Hispanic (H) patients with non-small cell lung cancer (NSCLC) tend to have more advanced disease at time of diagnosis and less likely to receive treatment compared to non-Hispanic white (NHW) Americans. While survival outcomes do not differ greatly, Hispanic patients tend to have lower response rates to immunotherapy and to targeted therapy with known EGFR mutations. We sought to determine if Hispanic patients with other common mutations present in NSCLC also demonstrate suboptimal responses to therapy compared to NHW patients. Methods: We performed a retrospective review of 468 patients with advanced stage NSCLC at the University of Miami / Sylvester Comprehensive Cancer Center who underwent next-generation sequencing (NGS) for whom treatment outcomes could be identified. Genomic results were obtained from Guardant360 and Foundation One testing in blood or tissue, respectively. Results: In our cohort, 154 patients (33%) were of Hispanic ethnicity, while 279 patients (60%) were NHW. Median age at time of diagnosis was 59, and 50% were male. PD-L1 status was known for 217 patients, with 110 expressing some level of PD-L1. EGFR mutations were present in 25% of all patients, KRAS mutations in 25%, and TP53 mutations in 61%. Average tumor mutational burden was 4.0 in Hispanic patients and 3.6 in NHW patients. We compared outcomes in patients receiving any therapy as well as those specifically receiving immune checkpoint inhibitors (ICI). No differences in OS were observed in our overall patient cohort between H and NHW patients. However, when stratifying patients with EGFR or KRAS mutations, Hispanic patients exhibit significantly shorter OS than their NHW counterparts. In patients with TP53 mutations, we observed no differences between H and NHW outcomes considering all therapy, but Hispanic patients exhibited improved OS with the use of ICI. Conclusions: Our data suggest that the presence of certain mutations in Hispanic patients with advanced NSCLC may serve some prognostic value in predicting responses to therapy, specifically the use of ICI. Further investigation is indicated to determine mechanisms leading to inferior responses after ICI therapy in Hispanic patients.[Table: see text]
Molecular characteristics of BRAF mutated non-small cell lung cancer and therapeutic outcomes: Multi-institution study.
Authors: Martos Guillermo , Pabani Aliyah , Bebb D. Gwyn , Gibson Amanda Williams , Dean Michelle Liane , Petersen Lance
Published: June 2021

e21029

Background: BRAF-mutations are uncommon, present in only 2-4% of all new non-small cell lung cancer (NSCLC) diagnoses. BRAF-mutation type has treatment implications, where the most common BRAFV600E shows sensitivity to tyrosine kinase inhibitors (Dabrafenib or Vemurafenib) with additional benefit seen in duel therapy adding MEK-inhibitors (Trametinib or Cobimetinib). Clinical responses have also been observed with immune checkpoint inhibitors in both V600E and non-V600E mutant patients. The optimal management strategy in this patient population is still unknown. Methods: Patients from the province of Alberta, Canada, with a BRAF-mutation and initiating systemic therapy between 2018 and 2020 were identified. Demographic, clinical, treatment and outcome data were extracted from the institutional Glans-Look Lung Cancer Database. Results: 31 patients with a BRAF-mutation were identified: 52% alive, 58% female, 87% ‘ever’ smokers (average: 40 pack-years). 70% ECOG > 2, 58% Stage IV at diagnosis, with the M1b (one extrathoracic metastatic site) being the most common. 87% had an adenocarcinoma histology and 64.5% carried the BRAFV600E mutation. 19% had other concurrent mutations (KRAS, PIK3CA or EGFR-L858R), 52% showed high PD-L1 expression ( > 50%). In addition, concurrent mutations also were associated with high PD-L1 positivity. 55% of the cohort received systemic treatment, with 71% still on treatment at the time of analysis. Conclusions: BRAF mutant NSCLC is associated with high PD-L1 expression and responses to both checkpoint inhibitors and BRAF inhibitor combinations. Treatment with immunotherapy appears to have a superior toxicity profile and prolonged disease control in both BRAF V600E and non-V600E mutant NSCLC and is an effective first-line strategy. Higher overall response rates are observed with BRAF inhibitor combinations in BRAF V600E patients. Further investigation is warranted to further elucidate sequencing strategies among specific subgroups.[Table: see text]
Evaluation of different MET genotypes as biomarkers for immunotherapy outcomes in NSCLC patients.
Authors: Li Xuanzong , Wang Linlin
Published: June 2021

e21032

Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.
A phase II study of vorolanib in combination with toripalimab in patients with non-small cell lung cancer.
Authors: Zhao Jun , Li Jianjie , Chen Hanxiao , Yang Xue , Zhong Jia , Zhuo Minglei , Jia Bo , An Tongtong , Wu Meina , Wang Ziping , Ding Lieming , Mao Li
Published: June 2021

e21053

Background: VEGF promotes an immunosuppressive microenvironment and contributes to resistance of immune checkpoint inhibitors in cancer treatment. VEGF inhibitors have been shown to enhance efficacy of checkpoint inhibitors in clinical studies. Vorolanib (CM082) is a multi-target tyrosine kinase inhibitor including VEGF, PDGF, c-kit, and Flt-3. Toripalimab (JS001) is a humanized IgG4 mAb against programmed death-1 (PD-1). This phase II study aims to evaluate efficacy and safety of the combination of vorolanib and JS001 in non-small cell lung cancer (NSCLC) patients who progressed with prior first-line standard therapy. Methods: This single-arm, single-center, phase II study (NCT03848611) enrolls NSCLC patients with measurable disease (RECIST 1.1) and Eastern Cooperative Oncology Group performance status ≤ 1, regardless of PD-L1 status. 15 patients received 150 mg oral CM082 daily plus 240 mg intravenous JS001 every 3 weeks while 3 patients received 100 mg oral CM082 daily plus 240 mg intravenous JS001 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR). Results: Between April 2019 and July 2020, 18 patients were enrolled. Median age was 64 years. 9 of 18 patients (50%) were adenocarcinoma and 9 of 18 patients (50%) were squamous. Males account for 83% (15/18) with 4 non-smokers among the male patients. At the data cutoff (January 11, 2021), we observed 2 (11%) confirmed and 1 (6%) unconfirmed partial response (PR), 6 (33%) stable disease (SD) and 9 (50%, including 2 PR of the target lesions) progression disease (PD). Tumor shrinkage was seen in 6 (33%) of the 18 patients. Two (11%) patients were still on the study drugs. Interestingly, all the patients with confirmed PR or PR of the target lesions were squamous histology. The most common treatment-related adverse events were proteinuria (67%), elevated ALT (60%), elevated AST (53%), hypertension (40%), and increased bilirubin (40%). Grade 3 adverse events include elevated ALT (20%), elevated AST (20%), liver function damage (13%), elevated GGT (7%), fatigue (7%), bellyache (7%), ruptured and infected tumor (7%), and dysphagia (7%). One Grade 4 adverse event was pulmonary embolism. Conclusions: Vorolanib with toripalimab showed a promising antitumor activity with acceptable safety profiles for patients with NSCLC. We hypothesized that the potential benefits of combination therapy for patients with squamous cell carcinoma may be better than those for patients with adenocarcinoma, and the study is ongoing. Clinical trial information: NCT03848611.
A phase I/II study of TQ-B2450, a PD-L1 mAb, plus anlotinib in EGFR+ advanced NSCLC patients failed to prior EGFR TKI therapies.
Authors: Shi Meiqi , Wang Li , Yu Shaorong , Yan Fei , Peng Wei , Feng Jifeng
Published: June 2021

e21062

Background: Platinum-based chemotherapy is the standard therapy for the patients(pts) with EGFR-mutation–positive advanced NSCLC failed to prior EGFR TKI therapies. However, the IMpower150 study subgroup analyses showed Atezolizumab (PD-L1) plus bevacizumab and chemotherapy improved overall survival in EGFR TKI treated NSCLC. This ongoing phase I/II study designed to assess the benefit of the chemo-free combination of TQ-B2450, a humanized PD-L1 mAb, plus anlotinib in EGFR+ advanced NSCLC pts failed to prior EGFR TKI therapies. Methods: Pts with EGFR+ advanced NSCLC who failed to prior EGFR TKI therapies were eligible. Pts with previous received platinum-based chemotherapy were excluded. Anlotinib was given orally at dose of 8mg to 12mg for 2 weeks of a 21-day cycle (days 1-14), with TQ-B2450 given at 1200mg every 3 weeks on day 1. Phase I determined RP2D. In the phase II part, pts were assessed for efficacy and tolerability. The primary endpoint for the phase II part is the progression free survival (PFS). Secondary endpoints were objective response rate (ORR) disease control rate (DCR), overall survival (OS), and safety. Assuming an expected the median PFS of 9 months (5 months in chemotherapy), and a loss to follow-up of 10%, a total of 54 pts were required to have 90% power at a two-tailed alpha of 0.05 at the phase II part. Results: As of 12 Jan 2021, 22 pts were enrolled (9 in phase 1, 14 in phase 2). 18 pts were included in efficacy and safety analysis. The median age was 64.5 years with 61% male. 50% pts harbored EGFR exon19 deletion, 44% pts had exon21 L858R mutation. While 39% pts had T790M mutation who progressed after osimertinib treatment. The dose escalation cohort included 9 pts, no dose limiting toxicity occurred. 13 pts in the phase II part were administered with dose of 12 mg for anolitinib and 1200mg for TQ-B2450. Of the evaluable pts(n = 18), ORR was 11.1%, DCR was 77.8%, median PFS was 8.0 months (95% CI 4.9 to 11.1). Most frequent TRAE included hypertension (27.8%), hand and foot skin reaction (22.2%) and proteinuria (16.7%). Grade 3 TRAE occurred in 16.7% pts(3/18 pts), all were hypertension, and no Grade 4/5 TRAE were observed. Dose delay due to TRAE occurred in 22.2% patients while no one discontinued treatment due to TRAE. Conclusions: The chemo-free combination of TQ-B2450, a PD-L1 mAb, plus anlotinib has shown a promising anti-tumor efficacy with a more favorable safety profile for pts with EGFR+ advanced NSCLC who failed to prior EGFR TKI therapies. Pts will be continuously monitored for safety and efficacy readouts (PFS, DOR and OS). Clinical trial information: ChiCTR1900026273. Clinical trial information: ChiCTR1900026273.
Efficacy and safety of low-dose albumin-bound paclitaxel plus tislelizumab as second- or further lines treatment for elderly patients with metastatic non-small cell lung cancer.
Authors: Geng Qian , Li Dongqing , Zhu Wenyu , Peng Haoliang , Jin Zhihui , Jiang Hua
Published: June 2021

e21066

Background: Lung cancer ranks first globally in morbidity and mortality rates among cancers. There are few studies focused on the different doses of chemotherapy drugs in combination with programmed cell death-1 (PD-1) inhibitors in non-small-cell lung cancer (NSCLC). Tislelizumab, a novel PD-1 monoclonal antibody, has been shown to improve antitumor activity when combined with chemotherapy as first-line treatment for patients with NSCLC. Elderly patients usually have poor physical conditions and many complications, resulted in higher risks of chemotherapy. This study aimed to preliminarily assess the efficacy and safety of low-dose chemotherapy plus tislelizumab for elderly patients with metastatic NSCLC. Methods: Eligible patients should be diagnosed as metastatic NSCLC, aged ≥65 years, and failed in one or more lines treatment. Patients with epidermal growth factor receptor (EGFR) / anaplastic lymphoma kinase (ALK) inhibitor resistance could be enrolled in the study. Participants received albumin-bound paclitaxel (130mg/m2) plus tislelizumab (200mg) every 3 weeks. Chemotherapy lasted for no more than 6 cycles. Once chemotherapy intolerance occurred or at end of 6 cycles, patients with objective response or stable disease would continue to receive tislelizumab until confirmed disease progression, death, and unacceptable toxicity. Primary endpoints were progression free survival (PFS) and safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), as well as overall survival (OS). Results: Total 23 patients were enrolled from May 2019 to March 2020: 43.5% (10/23) male, 39.1% (9/23) smokers, 26.1% (6/23) with squamous cell carcinoma and 56.5% (13/23) with ECOG 2. Median age was 71 yr (range: 65, 82). Patients had received 1 (47.8%) or ≥2 (52.2%) lines of therapy. 13 (56.5%) patients with EGFR/ALK TKI resistance participated in the study. As of data cut-off on December 1, 2020, the median PFS was 9.5 months (95% CI: 5.7–13.3 months). Nine patients achieved partial response (PR). The ORR was 39.1% (9/23) and DCR was 87.0% (20/23). Only 4 participants died in the study and the mOS was not reached. Sixteen (69.6%) patients had a decrease in tumor size as compared with baseline and the median change from baseline was −22%. 13 (56.5%) participants suffered at least one adverse event (grade 3 in 3 (13.0%) patients). The main adverse events were fatigue (17.4%), fever (17.4%), abnormal liver function (17.4%), rash (13.0%) and numbness (13.0%). No grade 4 adverse event was reported. Conclusions: Low-dose albumin-bound paclitaxel plus tislelizumab might be an optional choice for elderly patients with metastatic NSCLC after the failure of platinum-based chemotherapy or targeted therapy. Perspective clinical studies with large sample size are needed to validate our results.
Progression pattern and post-progression treatment of furmonertinib (AST2818) in EGFR T790M mutation positive NSCLC patients: A post-hoc analysis from a multicenter, single-arm study.
Authors: Hu Xingsheng , Zhang Shucai , Lv Dongqing , Wu Lin , Yu Qitao , Zhang Yiping , Liu Li , Wang Xiang , Cheng Ying , Ma Zhiyong , Niu Hongrui , Wang Dong , Feng Jifeng , Huang Cheng , Liu Chunling , Zhao Hui , Li Jingzhang , Zhang Xiaodong , Jiang Yong , Shi Yuankai
Published: June 2021

e21071

Background: Furmonertinib (AST2818) is a selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which can irreversibly inhibit both EGFR sensitizing and T790M resistant mutations. However, like other EGFR-TKIs, progression is still unavoidable when treated with furmonertinib. Methods: In a multi-center, single-arm phase IIb study (NCT03452592), non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation received furmonertinib 80mg/d treatment until disease progression, death or treatment cessations for other reasons. This is a post-hoc analysis of the progression pattern and post-progression treatment. Results: A total of 220 patients were enrolled in this study. At baseline, 105 (48%) patients had central nervous system (CNS) metastases, 84 (38%) were EGFR L858R mutated and 9 (4%) were ECOG performance status 2. At data cut-off (December 31, 2020), 179 out of 220 (81%) patients had progressed assessed by investigators (patients who died before assessed as progression were excluded). The most frequent progression site was lung (n = 106，48%), followed by CNS (n = 33, 15%), lymph node (n = 22, 10%), liver (n = 20, 9%) and bone (n = 16, 7%). CNS progression rate were 3%, 8%, 13% and 15% at 3, 6, 12 and 18 months, respectively. After progression, 52% (93/179) patients continued furmonertinib monotherapy based on the judgement of continuous benefit by investigators which was permitted in the protocol. The median post-progression treatment time of furmonertinib was 3.02 months (range 0.03-18.27). Overall, 48% (86/179) patients discontinued furmonertinib and later-line treatments were decided by investigators. The post-progression survival (PPS) was 17.3 months in the furmonertinib-continued group and 12.4 months in the furmonertinib-not-continued group (HR 0.57 [95%CI 0.40-0.80], p = 0.0048). Conclusions: Although about half patients had CNS metastases at baseline, CNS progression rate was relatively low in this study. Post-progression continuous treatment of furmonertinib monotherapy might still bring survival benefit to certain NSCLC patients with EGFR T790M mutation which need further exploration. Clinical trial information: NCT03452592.