bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring immunotherapy response in non-small cell lung cancer patients using 5-hydroxymethylcytosine signatures in circulating cell free DNA.
Authors: Guler Gulfem , Haan David , Ning Yuhong , Ku Jeremy , McCarthy Erin , Phillips Tierney , Antoine Michael , Bergamaschi Anna , Lloyd Paul , Scott Aaron , Ellison Chris , Levy Samuel
Published: May 2020

e21505

Background: Liquid biopsies are gaining prominence for not only cancer diagnosis but also patient monitoring. Mutational signals derived from cell-free DNA (cfDNA) show promise to assess response to cancer treatment, including immunotherapy. However, reliance of these methods on mutational data from tissue biopsies limit their applicability when a tumor biopsy is unavailable, or when mutational landscape of tumor changes under the selective pressures of cancer drug treatment. Epigenomic approaches have the potential to address these shortcomings. Methods: Blood draws were obtained from a cohort of non-small cell lung cancer (NSCLC) patients (n = 19) who went on to anti-PD1 treatment prior to therapy start and while on therapy. cfDNA was isolated from plasma and was subsequently processed to generate 5hmC genome-wide profiles. Results: We analyzed cfDNA from NSCLC patients undergoing anti-PD1 therapy to investigate whether immunotherapy response can be detected from plasma. Using a predictive model trained on lung cancer and non-cancer samples, we were able to detect changes in prediction scores in patient treated with immunotherapy that were consistent with RECIST. Patients with progressive disease (n = 3), determined by RECIST, had prediction scores that increased while they received treatment. On the other hand, majority of the patients that exhibited partial response to treatment (n = 12) had predictive scores that decreased with treatment, again consistent with RECIST. Furthermore, score changes consistent with RECIST was observed one cycle prior to the RECIST timepoint in all except one patient, where an extra blood draw after baseline was available (n = 7). Annotation of the regions that account for differential scoring identified enhancer, 5’UTR and promoter regions. Comparison of partial responders to patients with progressive disease revealed genes involved in metastasis, oncogenes and tumor suppressors that change in opposing directions between these patient groups, consistent with the underlying biology. Conclusions: Our results suggest that 5hmC profiles from cfDNA can be used to determine immunotherapy response in non-small cell lung cancer patients. Compared with mutation based liquid biopsy methods to assess response, epigenomics-based methods have the advantage of being agnostic to starting tumor mutations, and not relying on a mutational analysis from tumor biopsy. Future work will help determine applicability of this method to other kinds of therapies and cancer types.
Clinical management of lung adenocarcinoma patients with HER2 V659E mutation.
Authors: Jia Ziqi , Liang Naixin , Wang Yadong , Wang Yanyu , Ye Junyi , Wang Weiwei , Li Bing , Han-Zhang Han , Zhao Jiaxing , Zhang Xiaochun , Peng Feng , Chen Fengxia , Chen Xueqin , Lu Yan , Ying Shenpeng , Dp Wu , Zhang Xinwei , Ma Caixia , Lai Lipeng , Ma Songling
Published: May 2020

e21521

Background: ERBB2 mutations, mostly affecting the kinase domain (KD), were later found in the transmembrane domain (TMD), most frequently seen in residues V659, G660, but with a much lower prevalence. Comparing to other solid tumors, ERBB2-mutant NSCLC shows a lower response rate to HER2 inhibitors (HER2i). ERBB2 V659E has been reported to respond to lapatinib in combination with carpecitabine, afatinib, or ado-trastuzumab emtansine (TDM-1). However, since the prevalence of ERBB2 V659E is low, no study has reported the subsequent clinical management after developing resistance to HER2i. Methods: We retrospectively screened genomic profiles of 7,812 lung adenocarcinoma (LADC) patients. Molecular docking of lapatinib, afatinib and pyrotinib with the HER2 KD was simulated with AutoDock 4.2 and the binding affinity was predicted by MMPBSA.py program in AmberTools18. Results: We analyzed NGS data of 7812 LADC patients and identified 14 patients (0.18%) with HER2 TMD mutation, mostly V659E mutation (11/7812, 0.14%); other mutations included V664F, T652M, V664F; each occurred in 1 patient. In this cohort, all adenocarcinomas harbor a dinucleotide missense mutation, including 10 TT→AA and 6 TT→AG (c.1976_1977). T P53 was the most frequently co-mutated gene (n = 4) followed by HER2 (n = 2), NSD1 (n = 2) and RARA (n = 2). Treatment history of 9 advanced LADC patients were collected and analyzed. 3 of them had chemotherapy as first-line therapy. 5 patients were treated with HERi as first-line therapy, achieving a median PFS of 192 days (ranged from 60-515days), comparing to patients treated with chemotherapy (71.7±53.3days). 1 patient who was treated with different HERi sequentially in the order of lapatinib, afatinib, TDM-1, achieving an overall PFS of 515 days. Subsequently, she was treated with pyrotinib and had a PFS of 92 days. Molecular docking simulation showed the covalent inhibitors Afatinib and Pyrotinib are more favorable for blocking HER2 KD than non-covalent inhibitor Lapatinib. Between the two covalent inhibitors, Pyrotinib (∆GPyrotinib = -65.92kcal/mol) shows stronger non-covalent binding ability than Afatinib (∆GAfatinib = -59.71 kcal/mol) (p < 0.001). Conclusions: To the best of our knowledge, this is the largest-reported HER2 V659E mutation cohort. We revealed the prevalence of ERBB2 V659E in Chinese LUAD patients and elucidated the genomic profile of ERBB2 V659E mutant. This study paves avenue for the utilization of the novel HER2 inhibitors pyrotinib in ERBB2 V659E mutant LUAD patients.
Major pathologic response of EGFR mutated non-small cell lung cancer (NSCLC) on 1-3 G TKI.
Authors: Moiseenko Fedor Vladimirovich , Kryukov Kirill , Myslik Alexander , Levchenko Nikita , Ivantsov Alexander , Aleksakhina Svetlana , Volkov Nikita , Gabina Albina , Shelekhova Ksenia , Artem'eva Elizaveta , Moiseyenko Vladimir
Published: May 2020

e21528

Background: Despite impressive clinical efficacy in response rate, increase in PFS and sometimes in OS EGFR TKI rarely cure cancer patients, as all of them inevitably develop resistance. Small fractions of residual cells appear to be a reservoir of further clones with acquired resistance. For this moment morphological characteristics of “persister” population are not well defined. Methods: We screened hospital data-base containing > 200 pts for EGFRmut NSCLC who underwent cytoreductive surgical treatment during treatment with either TKI and before radiographic disease progression. We obtained 18 pairs of pretreatment biopsy and surgical specimen. 7/18 were male, median age 60.5 yo (45-79). 15/18 had ex19del; 3/18 – L858R. 12/3/2/1 received gefitinib/erlotinib/afatinib/osimertinib before surgery. Median time from treatment initiation to surgery was 8.9 mon (0.7 – 24.3). None of the pts had evidence of increase in any dimension of tumor lesions before surgery. According to RECIST 6/18 pts had SD, 12/18 – PR. 6/18 pts had complete cytoreduction, 4/18 – partial, 8/17 – metastasectomy. All pathologic responses (MPR) were graded according to Hellmann MD et al., 2014. Results: Pathologic response with > 50% of residual tumor – 2/18; 10-50% – 7/18; < 10% – 4/18; pCR – 3/18. Median observation time is 15.4 mon (8.4 – 37.2+). Disease progression after surgery was registered in 6/18 pts. No significant correlations between PFS, MPR, RR, TKI generation, time to surgery were seen. Conclusions: In our serie MPR rate ( < 10% of viable tumor cells according to Hellmann MD et al, 2014) for NSCLC treated with various TKI was 38%, that is higher than in other reports (10.2% in CTONG 1103 for example). Further characterization of the “persister” tumor cells may help to determine mechanisms of intrinsic resistance and direct more efficient antitumor activity.
Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC) patients with EGFR or HER2 exon 20 insertions.
Authors: Chen Kaiyan , Pan Guoqiang , Xu Yanjun , Fan Yun
Published: May 2020

e21540

Background: This study aimed to investigate the immune microenvironment features and efficacy of PD-1/PD-L1 blockade of NSCLC with insertions in exon 20 (Ex20ins) of EGFR or HER2. Methods: Molecular spectrum, tumor mutational burden (TMB), PD-L1 protein expression, and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) were reviewed for NSCLC patients with Ex20ins of EGFR or HER2. Results: Thirty-five patients carrying EGFR Ex20ins and 21 patients harboring HER2 Ex20ins were retrospectively enrolled between April 2016 and September 2018. The average TMB was 3.3 mutations/megabase. PD-L1 expression in patients with EGFR Ex20ins was significantly higher than those with HER2 mutations (48.6% vs. 19.0%, P=0.027). High TMB and PD-L1 expression was independently associated with considerably poor prognosis (P=0.025, P=0.045; respectively). Finally, patients harboring EGFR Ex20ins seemed to be sensitive to PD-1/PD-L1 blockage whereas it showed limited efficacy in patients with HER2 Ex20ins. Conclusions: NSCLC patients with EGFR/ HER2 Ex20ins had distinct immune features. Patients with EGFR Ex20ins had significantly higher PD-L1 expression than those with HER2 mutations, which may be the underlying reason for the different responses to PD-1/PD-L1 blockage.
Correlation between tissue PD-L1, TMB, and blood PD-L1, MSI biomarkers in patients with advanced-stage non-small cell lung cancer (NSCLC).
Authors: Nandimandalam Sujitha , Sharma Nitika
Published: May 2020

e21564

Background: Tissue biomarkers like programmed cell death ligand-1 (PD-L1), microsatellite instability (MSI) and high tumor mutational burden (TMB) are surrogates in identifying patients with non-small cell lung cancer (NSCLC) for treatment with immune checkpoint blockade (ICB) therapy. Although tissue biopsy is widely used for identifying the tumor biology, the invasive nature as well as insufficiency of tissue biopsy specimens limits its application. Liquid biopsy is a minimally invasive procedure and has gained interest in recent times for profiling cancer. We sought to study the correlation in the molecular tumor profile specifically PD-L1, MSI and TMB markers between the tissue and liquid biopsies. Methods: We conducted a retrospective review of patients with Stage 3, 4 and recurrent NSCLC that underwent tissue next generation sequencing (NGS) using Caris life sciences and liquid biopsy using Circulogene molecular diagnostics from January 2018 to December 2019 at East Carolina University. A total of 524 patients were reviewed out of which 199 patients had both liquid and tissue NGS performed at the time of initial diagnosis. TMB high was defined as greater than 10 mut/Mb whereas TMB low as less than or equal to 10 mut/Mb. PD-L1 was divided into negative (0%), 1-49% and ≥50%. The blood MSI was classified as positive or negative. We used frequency table, logistic regression and Pearson bivariate correlation for statistical analysis using SPSS platform. Results: The study cohort had 60% (n = 119) male and 40% (n = 80) female patients of which 53% (n = 105) were Caucasians and 45% (n = 89) were African Americans. A total of 87 patients (44%) had negative tissue PD-L1, 59 patients (30%) had tissue PD-L1 ≥ 50%. A linear correlation was seen between negative tissue PD-L1 and negative blood PD-L1 in 92% of patients (n = 80). However, only 15.3% (n = 9) had correlating tissue PD-L1 and blood PD-L1 ≥ 50%, p = 0.024. The negative blood MSI correlated to low tissue TMB in 83% ( n = 60) whereas positive blood MSI correlated to high tissue TMB in 25% (n = 19), p = 0.023. Conclusions: Our results indicate a linear correlation between tissue PD-L1 and blood PD-L1. Similarly, a linear correlation was seen between blood MSI and tissue TMB. Further studies are needed to elucidate the efficacy of ICB therapy using blood MSI and blood PD-L1 as biomarkers for response to therapy.
Assessing the risk of serious adverse events (SAEs) and death in non-small cell lung cancer (NSCLC) trials.
Authors: Marvania Nirali , Chan Abigail Sy , Abraham Joseph , Miller Kenneth David
Published: May 2020

e21576

Background: Lung cancer is a leading cause of morbidity and mortality despite advances in targeted therapy and immunotherapy. Clinical trials play a critical role in improving treatment options however, pose significant known and unknown risks. The purpose of this study was to analyze the risk of SAEs (Grade 3 and 4 toxicity) and deaths in advanced NSCLC patients participating in phase I/II and III clinical trials. Methods: A literature search using Clinicaltrials.gov was conducted to identify published phase I/II and III clinical trials in advanced NSCLC patients. The data extracted included study name, total number of participants, SAEs, and deaths attributable to a study drug. A fixed-effects model was implemented to estimate summary proportions of SAEs among participants. The Freeman-Tukey double arcsine transformation was applied to stabilize the variances of SAEs and mortality proportions. Results: We evaluated 112 studies, of which 87% were phase I/II, and 13% were phase III clinical trials. Study sample sizes ranged from 7 to 659 patients for phase I/II studies and from 186 to 1391 for phase III studies. 107 studies had SAEs while 5 phase I/II studies had no SAEs reported. The overall estimated percentage of SAEs was 39.5% (95% Confidence Interval, CI: 38.8%, 40.2%). The estimated percentages of patients with SAE in phase I/II and phase III trials were 40.9% (95%CI: 39.8%, 42.0%) and 38.7% (95%CI: 37.8%, 39.6%), respectively (p = 0.001). The estimated percentages of deaths among patients were 1.1% (95%CI: 0.90%, 1.3%) overall, 1.1% (95%CI: 0.7%, 1.5%) in phase I/II trials and 1.7% (95%CI: 1.5%, 2.0%) in phase III trials. The difference in mortality between phase I/II and phase III trials was not statistically significant (p = 0.408). Conclusions: Patients with advanced stages (III/IV) of NSCLC have a high risk of morbidity and mortality from their primary disease and also from their treatment. Our study demonstrated SAEs and toxic deaths attributable to the treatment of approximately 40% and 1%, respectively. Phase I/II trials patients are at a slightly higher risk of SAEs compared to patients participating in phase III trials, although the differences might not be clinically significant.
Prevalence of ALK mutations in advanced NSCLC patients in the United States: Analysis with a real world oncology database.
Authors: Allen Timothy , Xiao Yan , Abraham Anup , Redpath Stella , Engstrom-Melnyk Julia , Croix Denise , Yang Baiyu , Shah Roma , Madala Jaya , Bernicker Eric
Published: May 2020

e21586

Background: ALK mutation rate is widely reported to be 3-7% of advanced non-small cell lung carcinoma (aNSCLC) patients. A cross-sectional study to assess the prevalence of ALK mutations in the real world was performed on the nationwide Flatiron Health electronic record-derived de-identified database. Methods: Patients with aNSCLC (stage IIIB-IV) diagnosed between 1 Jan 2015 – 31 May 2019, age ≥18 at the time of aNSCLC diagnosis, known ALK result and smoking status were included in the analysis. The included patient cohort had 19,895 eligible patients, with a mean age of 68.5 (Standard deviation = 10.0), most of them were ever-smokers (85.5%) and from community centers (92.2%). Results: The overall ALK mutation prevalence was 2.6%. Prevalence of ALK mutation was calculated by age, gender, race, ECOG status and cancer type. Non-smokers had the greatest mutation rate (9.3% non-squamous histology, 6.3% NSCLC histology not otherwise specified [NOS], 3.3% squamous) vs smokers (1.7% non-squamous, 1.4% NSCLC NOS, 0.7% squamous). Differences in ALK status varied by age and race with young patients (18-44 yrs) having a greater mutation rate (16.2%) vs older patients (age 45-64 = 4.5%, age ≥ 65 = 2.2%) and Asian patients having a mutation prevalence of 6.3%. Patients that were positive for other biomarkers (EGFR, ROS1, KRAS or BRAF) had a lower ALK positivity rate (0.5%) while patients reported to be positive for PD-L1 had an ALK mutation rate of 3.0%. Conclusions: While this data overwhelmingly represented testing in the community setting vs academic medical centers, it provides insight into the ALK mutation prevalence across the US. The prevalence of ALK mutations in smokers suggests that a smoking patient (with non-squamous, mixed histology or small biopsy) should not be excluded from testing. This also highlights the need to capture smoking histories as accurate pack-year histories
Use of pulse steroids to treat renal IRAE to maintain patients with metastatic non-small cell carcinoma cancer on pembrolizumab.
Authors: Abudayyeh Ala , Abdelrahim Maen , Fossella Frank V.
Published: May 2020

e21589

Background: Immune checkpoint inhibitor (ICI) has a major clinical success in many cancers including non-small cell lung cancer. Renal Immune related adverse events is one of the rare IRAE’s with a reported incidence of 3-5%. In this abstract we present two cases of patients with metastatic NSCL cancer with biopsy proven acute interstitial nephritis and maintained on pembrolizumab with co-treatment of steroids. Methods: We reviewed all patients diagnosed with NSCL cancer and treated with ICI who have been diagnosed with biopsy proven AIN. We selected only the patients who were re-challenged with ICI and co-treated with steroids. Results: Two patients were identified. First patient a 40 y.o. female who was diagnosed with metastatic NSCLC. Patient was started on carboplatin, alimta, and pembrolizumab. After cycle 4 she acute kidney injury where creatinine increased to 3.26mg/dl from baseline 0.69mg/dl she was initially pulsed with steroids due to suspected renal IRAE. A kidney biopsy that indicated acute tubular necrosis which is likely related to pemetrexed and/or carboplatin. In addition, she did have acute tubular interstitial nephritis related to pembrolizumab. Creatinine stabilized at 2.0mg/dl and was continue only on pembrolizumab for the last 5 months with prednisone 40mg daily tapered off over 4 days. She has maintained her creatinine at 2.0mg/dl with continued excellent disease control. Second patient diagnosed with poorly differentiated non-small cell carcinoma with metastatic disease and PD-L1 expression is 80-90%. She was initially started on carboplatin, alimta, and pembrolizumab with complete response after 4 cycles. Her creatinine peaked to 1.84mg/dl from baseline of 0.67mg/dl. A kidney biopsy revealed chronic active interstitial nephritis. She was treated with a prednisone taper and creatinine improved to 1.1mg/dl. Patient was continued on pembrolizumab and maintained for 14 months on prednisone (as above) and sustained complete tumor response. Conclusions: Steroids in patients with persistent AIN after re-challenge may provide an excellent option to continuation of treatment. As demonstrated above, use of steroids is controversial since concern of impact on tumor response; however, smaller doses for short duration maybe efficacious in treatment of renal IRAE without impact on tumor response. Further studies need to be initiated to evaluate this intervention and its long term effects.
Efficacy and safety of DCVAC/LuCa Treatment plus standard chemotherapy and TCM in patients with advanced non-small cell lung cancer: A single-arm phase II study.
Authors: Lou Yanni , Jia Liqun , Liu Qing , Li Liya , Cui Huijuan , Deng Chao , Liu Meng , Su Fei , Cheng Zhiqiang , Wan Donggui
Published: May 2020

e21590

Background: Lung cancer remains the leading cause of cancer-related death in China. DCVAC/LuCa is an active autologous cellular immunotherapy consisting of autologous DCs loaded with NSCLC antigens from NSCLC cell lines. SQFZ is a kind of TCM injection commonly uesed for NSCLC, made from Ginseng and Astragalus membranaceus. Intent of this study is to evaluate the efficacy and safety of DCVAC/LuCa plus chemotherapy and TCM in patients with advanced NSCLC and wild type driving gene(EGFR/ALK). Methods: This study consist of screening/leukapheresis/treatment/follow-up period. On the treatment period, chemotherapy started after leukapheresis. Four cycles are recommended with limitation to maximum 6 cycles. Up to 12 subcutaneous doses of DCVAC/LuCa treatment were administrated on the 15th day of chemotherapy cycle every 3 weeks for 4 doses, and continued alone after chemotherapy finishes/stops every 6 weeks for the remaining 8 doses. TCM therapies were administered on the -3 to 3 days of DCVAC/LuCa. After completion of the total 12 doses DCVAC/LuCa or discontinuation of study treatment, patients will be followed up until experienced OS event or till 1 year of survival time. The primary efficacy endpoint included ORR, PFS and survival. Results: 23 pts were included, 19 males and 4 females, median age 63(48-80). Pathological type:16 adenocarcinoma, 5 squamous cell carcinoma and 1 other. 7 Ⅲb and 16 Ⅳ stage. ORR was 17.39%(4/23), DCR was 60.87%(14/23). Median PFS was 10.9 months, median follow-up in surviving patients was 22.3 months, 1-year survival is currently 92.86%, 18-months survival is currently 79.59%. 1 case was diagnosed as acute myelogenous leukemia myelodysplastic syndrome after 9 doses of DCVAC/LuCa. There were no other adverse events related to DCVAC/LuCa treatment TCM therapies in this study. Conclusions: DCVAC/LuCa, combined with standard chemotherapy and TCM had exhibited the potential to improve the survival in patients with advanced NSCLC, and decrease the occurrence of adverse events. But the sample size of this study is small, a further clinical investigation is needed.
YES1 amplification as a primary driver of lung tumorigenesis and YES1/YAP1 amplifications as mediators of acquired resistance (AR) to ALK and EGFR tyrosine kinase inhibitors (TKIs).
Authors: Sato Hiroki , Kubota Daisuke , Paik Paul K. , Qiao Huan , Jungbluth Achim A , Rekhtman Natasha , Schoenfeld Adam Jacob , Yu Helena Alexandra , Riely Gregory J. , Lovly Christine Marie , Ladanyi Marc , Fan Pang-Dian
Published: May 2020

e21591

Background: Our previous work identified YES1 amplification as a mechanism of AR to EGFR TKIs. The current study investigates the potential role of YES1 amplification as a primary driver of tumorigenesis and of YES1/YAP1 amplifications as mediators of AR to ALK and EGFR TKIs. Methods: Models of ectopic expression were established and characterized for YES1 and YAP1 in human bronchial epithelial cells (HBECs) and ALK fusion-positive ( ALK+) and EGFR-mutant ( EGFRm) lung adenocarcinoma (LUAD) cell lines. MSK-IMPACT data for all LUAD cases and for ALK and EGFR TKI AR cases were surveyed for YES1 and YAP1 amplification. Results: YES1 was found to be amplified in 0.5% of all LUAD cases currently in the MSK-IMPACT database. To demonstrate its potential as a primary driver of tumorigenesis, YES1 was inducibly expressed in HBECs and shown to promote EGF-independent growth, focus formation, and increases in proliferation rate and sensitivity to Src family kinase (SFK) TKIs. Consistent with these findings, a partial response by RECIST criteria to third-line dasatinib was observed for a patient with stage IV LUAD in which MSK-IMPACT detected YES1 amplification and no established primary driver alteration. In models of AR, overexpression of either YES1 or YAP1 in multiple ALK+ and EGFRm cell lines conferred resistance to ALK and EGFR TKIs. Sensitivity to ALK or EGFR TKIs was partially recovered in YES1-overexpressing cells lines by siRNA-mediated gene knockdown of YAP1, and was restored in YAP1-overexpressing cells lines by knockdown of YES1 or mutation of the YES1-phosphorylation site on YAP1. ALK + or EGFR m cells overexpressing either YES1 or YAP1 were sensitive to dual inhibition of the primary driver and SFKs with single-agent repotrectinib or dasatinib, respectively. In contrast, treatment of YAP1-overexpressing ALK+ H3122 cells with alectinib induced changes in morphology and gene expression consistent with epithelial-to-mesenchymal transition (EMT) and rendered the cells insensitive to repotrectinib. Similar resistance to dual inhibition was seen in other YAP1-overexpressing cell lines after treatment with only ALK or EGFR blockade. To date, one LUAD case each of EGFR and ALK TKI AR has been found through MSK-IMPACT™ to be associated with YAP1 amplification. Conclusions: SFK inhibition can potentially be exploited to therapeutically target YES1 amplification as a primary driver in tumorigenesis and YES1/YAP1 amplifications as mediators of AR to ALK and EGFR TKIs.
Monitoring through flow cytometry as a biomarker of early response to checkpoint inhibitor.
Authors: Perez Ruiz Elisabeth , Onieva Zafra Juan Luis , Garcia-Aranda Marilina , Sojo Belen , Gallardo Constanza , Laborda-Illanes Aurora , Alvarez Martina , Villatoro Rosa , Bernal Jose Antonio , Jimenez Gallego Pedro , Berciano-Guerrero Miguel-Angel , Oliver Javier , Dols Manuel Cobo , Barragán Isabel
Published: May 2020

e21603

Background: Despite the efforts, there is still no biomarker that is able to predict the response and / or that can be used in the monitoring of patients treated with check-points inhibitors (ICI). Methods: Prospective study of a panel of blood biomarkers that help predict the response to ICI treatments. Since June 2019, a total of 60 patients with non-small cell lung cancer (NSCLC) or melanoma have been included. Prior to the start of treatment (T1 moment), after the first cycle of ICI (T2), and to progression (Tp) or 6 months after the start, blood sample has been drawn to the patients and the analysis has been carried out by flow cytometry of the percentage of lymphocytes CD8, CD3, Treg, Myeloids, NK and B lymphocytes. The one.way statistical test has been carried out that allows us to see the effect of the response on the variable at each time. Results: Of the 60 patients included, we have radiological assessment in 38. 80% are patients with NSCLC. In the evaluation at 8-10 weeks we found stable disease / partial response in 25 patients (66%), 8 progressions (21%) and 2 unknown reevaluations (13%). A significant increase in CD3, CD8, CD4, and B lymphocytes was observed in responders (p < 0.005); however, an increase in NK was observed in patients in progression (p < 0.02). No significant differences in Treg have been described and the result related to myeloid cells is pending analysis. Conclusions: Our results open a door to peripheral blood monitoring as a new tool for the management of ICI. However, our data are preliminary, having not yet reached the expected sample size and with aspects that we must clarify as the increase in NK in progressors. In addition, the final objective of this study is to generate a score combining several biomarkers of blood and tissue to be used as a predictor of response to ICI (data pending analysis).
Observation of clinical efficacy and survival of lung cancer patients with UMIPIC combined with low-dose chemotherapy.
Authors: Feng Jianbin , Jing Peng , Gao Feng , Liu Jian , Han Wei , Xu Xingyou , Zhang Xiaomin , Zhang Peicheng , Shang Wei , Teng Ye , Wu Yanfei , Yu Baofa
Published: May 2020

e21605

Background: To observe the clinical efficacy and survival of UMIPIC combined with low-dose chemotherapy in patients with lung cancer. Methods: 840 patients with lung cancer underwent UMIPIC treatment from January 2011 to December 2015 were selected as the study subjects, 341 cases combined with low-dose chemotherapy in group A and 499 cases not combined with chemotherapy in group B. All patients were diagnosed with lung cancer and signed a consent form for treatment. The patients were treated according to the UMIPIC treatment guidelines. This study was mainly to observe the adverse reactions, clinical efficacy, survival time and survival rate of lung cancer patients after receiving UMIPIC combined with or without low dose chemotherapy. Results: The common adverse reactions in group A were fever 38.12%, followed by pain 9.38%, hemoglobin 7.94%, white blood cells 5.01%, nausea 2.35%, liver function damage 1.19%, vomiting 1.17%, and kidney function damage 0.30%; Common adverse reactions in group B were fever 38.68%, followed by pain 13.23%, hemoglobin reduction 12.87%, white blood cell reduction 5.29%, nausea 2.00%, vomiting 2.00%, liver function damage 1.92%. The hemoglobin reduction in group A was significantly lower than that in group B (P < 0.05), and there was no difference in the other adverse reactions (P > 0.05). Clinical efficacy of the two groups revealed that the benefit rate of group A was 95.45% higher than that of group B 93.47% (P > 0.05). After follow-up, it was found that the average survival time and median survival time of patients in group A were 20.744 and 13.270 months, respectively, which were significantly higher than those of group B at 19.514 and 10.070 months (P < 0.05). The survival rates of the two groups of patients, The 1-year, 2-year, and 5-year survival rates of group A patients are 52.48%, 23.60%, and 16.95%, and the 1-year, 2-year, and 5-year survival rates of group B patients are 42.96% and 17.07 % And 10.26%, the one-year survival rate of group A was significantly higher than that of group B (P < 0.05). Conclusions: UMIPIC combined with low-dose chemotherapy has a good clinical effect in treating lung cancer without increasing the incidence of adverse reactions, and a significant effect on extending survival time and improving survival rate of lung cancer patients.
Prevalence of uncommon epidermal growth factor receptor (EGFR) alterations detected in circulating tumor DNA (ctDNA) of non-small cell lung cancer (NSCLC) patients from East Asia.
Authors: AHN Beung-Chul , Loong Herbert H. F. , Chan Oscar Siu-Hong , Lee Michelle Mei Lin , Olsen Steven R. , Cho Byoung Chul , Mok Tony S. K.
Published: May 2020

e21608

Background: EGFR is the most commonly altered biomarker in East Asian NSCLC patients. Common driver mutations (L858R or exon 19 deletions (del)) are the focus of conventional hotspot testing which may overlook less common activating alterations such as single nucleotide variants (SNVs) in the tyrosine kinase or extracellular domain as well as exon 20 insertions (ins). We investigated the prevalence of uncommon EGFR mutations in ctDNA from NSCLC patients in East Asia tested by a commercially available comprehensive next generation sequencing (NGS) assay (Guardant360). This assay identifies SNVs, ins and del, fusions, and amplifications (amp), with complete exon sequencing of EGFR. Methods: Guardant360 test results from Hong Kong, Korea, Japan, Taiwan, and Southeast Asia were reviewed (cut-off December 2019). We identified cases with a diagnosis of “lung cancer,” excluding pure squamous, small cell, neuroendocrine, carcinoid and sarcomatoid histology. Patients enrolled in certain prospective clinical trials were excluded at the investigators’ request. Clinically relevant biomarkers were mutations in EGFR, BRAF (V600E), ERBB2, or KRAS; MET amp or exon 14 skipping; and ALK, ROS1, or RET fusions. Uncommon EGFR mutations were defined as those other than L858R, exon 19 del, or resistance SNV in codons 790-797; synonymous mutations and amp were excluded. Results: Plasma from 820 non-squamous NSCLC patients was tested. Samples came from 436 women and 384 men, median age 61 years. ctDNA was identified in samples from 701 patients (85% detection rate). Alterations in at least one clinically relevant gene were detected in 75% of the ctDNA positive cases: EGFR (54%), KRAS (8%), ALK (5%), ERBB2 (5%), RET (2%), MET (2%), BRAF (1%), ROS1 ( < 1%). Uncommon EGFR alterations were found in 115 samples (16%), with 63 (9%) potentially actionable (exon 19 ins (1); exon 20 ins (22); activating SNV (40), some with multiple mutations, including L718Q (6), L718V (5), G719A (5), L861Q (5), S768I (4), and others) and 52 (7%) variants of unknown significance. Uncommon EGFR mutations were the only clinically relevant biomarker in 53 samples (8%). Conclusions: Uncommon, potentially actionable EGFR mutations were found in 9% of plasma samples from East Asian NSCLC patients. In this clinical practice dataset, uncommon EGFR mutations were more prevalent than actionable biomarkers in other genes. These data support the use of NGS testing methods to identify NSCLC patients for appropriate EGFR-targeted therapy.
Co-mutation features in treatment-naïve EGFR-mutant lung adenocarcinoma.
Authors: Zhao Jun , Fan Zaiwen , Chen Donghong , Zhuo Minglei , Liang Zhen , Li Lin , Gao Yun , Wang Xiaorong , Yu Zhuo , Cai Cunliang , Dong Dapeng , Zhao Jingquan , Gu Wenguang , Zhang Min , Chen Rongrong , Xia Xuefeng
Published: May 2020

e21616

Background: In Chinese patients with lung adenocarcinoma, the positive rate of EGFR mutation was 40% - 50%, EGFR-TKIs therapy for lung cancer was also aimed at this part of patients. However, different EGFR mutation types have different therapeutic effects, this study focuses on different EGFR mutation types to divide the population of lung adenocarcinoma. Methods: We retrospectively reviewed gene test results of two hundred and sixty-two treatment-naïve adenocarcinoma patients. Tumor tissues (199, 76%), plasma (46, 17.5%) and other samples (17, 6.5%) were subject to next-generation sequencing using a 59-gene panel, which enables simultaneously assess SNV, Indel, rearrangements and CNV variations. Results: There were 174 females. These patients were divided into four groups, which 139 were EGFR L858R, 99 were EGFR exon 19 deletion, 7 were EGFR 20 ins and 17 were uncommon EGFR mutations, the co-mutation proportions with EGFR were 84.9% (118/139), 76.8% (76/99), 71.4% (5/7) and 94.1% (16/17) respectively. The mean numbers of co-mutation genes in L858R and exon 19 deletion were 4.173 and 3.258 (p<0.05). TP53 mutation was detected in 14.3% (1/7) 20ins group, which had a significant difference to L858R (59.7%, 83/139) and uncommon mutation groups (70.6%, 12/17) (p<0.05). Meanwhile, EGFR amplification proportion in L858R (18%, 25/139) and exon 19 deletion (6.1%, 6/99) were significantly different (p<0.05). The actionable mutations associated with target therapy involved in multiple pathways, for example, the HRR pathway and cell cycle pathway, related genes had no significant difference among the four groups. In these lung adenocarcinoma patients, we also found 6 EGFR T790M (2.3%, 6/262). Three cases accompanied with exon 19 deletion, and another three were L858R, no distribution in 20ins and uncommon groups. Conclusions: The phenomenon of concurrent gene mutation in treatment-naïve EGFR-mutant lung adenocarcinoma is common. EGFR mutant subgroups have different co-mutation features, like gene number and mutated genes. It may be the factor leading to different therapeutic effects of EGFR-TKIs, and indicate the importance of multiplex molecular test and further researches of target therapies.
Utilization patterns of immune checkpoint inhibitors (ICI) for non-small cell lung cancer (NSCLC) within the veterans health administration (VHA).
Authors: Moghanaki Drew , Jiang Renjian , Gutman David , Burns Abigail , Sukhatme Vidula , Stokes William , Ramalingam Suresh S. , Sukhatme Vikas , Behera Madhusmita
Published: May 2020

e21630

Background: ICI are used routinely for treatment of lung cancer. We investigated the utilization of PD-1/PD-L1 inhibitors for NSCLC in the VHA. Methods: The VHA Corporate Data Warehouse was queried for data on ICI utilization in NSCLC [IRB #00113521]. The first date of any ICI dispensed was January 6, 2015 and therefore this investigation evaluated all patients diagnosed with NSCLC between 2015 –2019. Results: A total of 27,586 Veterans were diagnosed with NSCLC during the study period with demographics: 76.3% Caucasian, 16.3% black; 97.0% male; median age 71 years. Stage distribution was 27.9%, 7.9%, 15.8%, and 27.0% for stage I, II, III, or IV, respectively. A total of 3,990 patients were identified to have received any ICI, representing 20.1% of patients diagnosed with stage IV; 159 patients received more than one ICI. The median time from stage IV diagnosis to receipt of ICI was 5 months (IQR: 2-9 months). ICI was dispensed in 83.7% for duration of < 1 year, 13.3% for 1-2 years, and 3% for > = 2 years. The median duration of ICI receipt (with IQR in months): Nivolumab = 2.0 (0.5-5.5), Pembrolizumab = 2.1 (0.3-5.9), Durvalumab = 5.1 (1.8-9.2), and Atezolizumab = 0.3 (0.1-2.1). Multivariable analyses demonstrated female, not married, 0 comorbidity, and higher stage (II-IV) were independently associated with shorter time to receipt of ICI. Conclusions: The use of ICI for NSCLC is increasing within this integrated healthcare system and commonly prescribed within 5 months of stage IV diagnosis. Further investigations of this cohort using available clinical, pharmaceutical, and genomic data within the VHA present an opportunity to enhance our understanding of the efficacy of ICI for NSCLC. [Table: see text]
Efficacy of afatinib in the clinical practice: Final results of the GIDEON study in EGFR mutated non-small cell lung cancer (NSCLC) in Germany.
Authors: Brueckl Wolfgang M. , Reck Martin , Schäfer Harald , Kortsik Cornelius , Gaska Tobias , Rawluk Justyna , Krüger Stefan , Kokowski Konrad , Budweiser Stephan , Hoffmann Christopher , Schueler Andrea , Laack Eckardt
Published: May 2020

e21636

Background: Afatinib is an irreversible ErbB family blocker, which is approved for the treatment of advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. Here we report the final results of the prospective non-interventional study (NIS) GIDEON, which was initiated to investigate the efficacy and tolerability of afatinib in the daily clinical routine in Germany. Methods: EGFR-mutated NSCLC patients were treated with afatinib according to label until progression, death or discontinuation. Efficacy (progression-free survival (PFS) rate at 12 months, objective response rate, ORR; disease control rate, DCR; progression-free survival, PFS and overall survival, OS) was prospectively assessed by investigators. Data about tolerability were collected during routine treatment. Results: In total, 161 patients were enrolled at 41 sites in Germany, 152 patients received at least one dose of afatinib (treated set; TS) and 146 patients were treated according to the protocol (PPS). The majority of patients for the entire TS had exon 19 deletions (64.5%), followed by L858R point mut. (22.4%) and uncommon mut. (exon 18-21 point mut.; 13.1%). The primary objective was PFS-rate at 12 months, which was 50.2% in the PPS. Median PFS amounted to 12.2 months. ORR and DCR were 74.6% and 91.5% in the PPS, respectively. Median OS was 30.4 months with 1- and 2-year survival rates of 79.1% and 57.7%, respectively. Among pat. with uncommon EGFR-mut., the 12-months PFS rate was 40.2% with a mPFS of 10.7 months. ORR and DCR were 83.3% and 91.7%, respectively. The most frequent documented adverse drug reactions (ADRs) were diarrhea and rash/acne with 13.8% and 7.2% of grade 3 but no grade 4 or higher. Conclusions: Afatinib is a standard therapy for patients with activating EGFR mut. in Germany. The final results of this prospective NIS confirm the robust clinical data for afatinib in the clinical routine setting, including patients with uncommon exon 18-21 point mutations. Clinical trial information: NCT02047903.
Effect of uncommon and insensitive mutation on EGFR-TKI in treatment of non-small cell lung cancer.
Authors: Zhang Hui , Jiang Da , Wei Suju , Cui Yanzhi , Li Ying , Tian Caijuan , Dong Qian , Xu Zanmei
Published: May 2020

e21652

Background: EGFR-TKI application is directed by the situation of mutations of epidermal growth factor receptor, in addition, the mutations of ALK, ROS-1,C-met, BRAF, Her-2, RET,NTRK1, PI3K, MEKI have potential effects on guiding treatment. This study aimed to investigate the uncommon and insensitive mutations and their effect on prognosis in non-small cell lung cancer (NSCLC) patients treated with EGFR-TKI. Methods: 21 NSCLC patients treated with EGFR-TKIs were enrolled, 9 with Gefitinib, 5 with Osimertinib and 7 with Icotinib. All patients were detected with targeted NGS 1000 gene panel. Afterwards, the EGFR sensitive mutation, uncommon mutation and mutations accompanied EGFR T790M were analyzed. Furthermore, the correlations of gene mutation with metastasis, OS and PFS were analyzed. SPSS 21.0 was used for statistical analysis, t test for continuous variables and χ2 test for classified variables. Results: In all the patients, EGFR p.[T790M] and p.[L858R] mutations were detected in 4.76% and 23.81% of the patients, respectively. In the 5 patients treated with Osimertinib, one had EGFR p.[T790M] mutation and curative effects was stable disease (SD). The mutations accompanied EGFR T790M included SMARCA4 p.[K1390Q] (2.23%), DNMT3A p.[F755S] (2.17%), MTOR p.[Y1450*] (2.15%), TPMT p.[L182R] (1.84%), etc. For the other four patients treated with Osimertinib, two of them were partial response (PR) and two were SD, accompanied with mutations such as EGFR p.[L858R] (55.00%), ARID1A p.[P16del] (2.83%), TP53 p.[R248W] (21.73%) and AR p.[Q60L] (4.24%). In addition, among all the mutations, 18 uncommon mutations were detected, in which ATM (23.26%), AR (23.26%) and MTOR (37.21%) were markedly associated with OS. Besides, the mutation frequency of 67 genes, such as ABCG2, AURKA, EPHA3 and ATR were correlated with OS. The mutation frequency of FGFR1 was significantly different between the patients with and without metastasis. The mutations of 22 genes, for instance ABCG2 p.[P21L], FAT1 p.[L398F], GNAS p.[F226V] and KMT2C p.[N2842Ilefs], were correlated with PFS during the treatment. Conclusions: EGFR-TKI has similar curative effects in EGFR p.[T790M] negative patients. Gene mutations, including uncommon mutations and EGFR insensitive mutations, can significantly affect the prognosis in NSCLC patients treated with EGFR-TKIs.
ARC-4 study: Efficacy and safety of AB928 plus carboplatin, pemetrexed and a PD-1 antibody in participants with metastatic non-small cell lung cancer (mNSCLC).
Authors: Spira Alexander I. , Conkling Paul R. , Johnson Melissa Lynne , Gardner Olivia , Gilbert Houston N. , Scharville Michael , Yin Fangfang , Krishnan Kartik , Paoloni Melissa Constance , Chaudhry Arvind
Published: May 2020

e21659

Background: Adenosine, derived from ATP released by dying cancer cells in response to chemotherapy, binds to and activates the A2a and A2b receptors on immune cells, resulting in an ineffective anti-tumor immune response. Adenosine receptor blockade may therefore enhance the efficacy of chemotherapy when co-administered with a checkpoint inhibitor. AB928, the first clinical-stage small molecule dual A2aR/ A2bR antagonist, is highly potent and was well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Methods: ARC-4 (NCT03846310) is a Phase 1/1b, open-label study in participants (pts) with metastatic, locally advanced, or recurrent non-squamous NSCLC with no alternative or curative therapy option. Pts whose tumor has a genetic alteration for which targeted therapy exists must be chemo/immunotherapy naïve. Pts must have ECOG PS 0-1 and at least one measurable lesion. Two escalating doses of AB928 (75 or 150 mg) administered orally daily were given with standard doses of carboplatin, pemetrexed and pembrolizumab. Results: As of 27Dec19, 7 pts have received AB928 in Ph 1: 75 mg (n = 3), 150 mg (n = 4). Number of prior therapies range from 0 to 6 (median = 3). Most treatment emergent AEs (TEAEs) were Grade 1 or 2, with no Grade 5 events. The most common AEs were anemia, nausea and AST elevation. One pt experienced an SAE (Gr4 thrombocytopenia) that was at least possibly related to AB928. One pt discontinued before assessment due to adverse event (muscle weakness). Of the 6 patients with post-baseline disease assessments, all demonstrated decrease size of target lesion. Three patients (43%) achieved a confirmed partial response: one treatment naïve patient, one patient with EGFRmut disease that had previously progressed on treatment with erlotinib and osimertinib, and one patient who had progressed on therapy with ipilimumab and nivolumab. One additional pt had a > 30% decrease in target lesions and findings consistent with new lesions but opted to continue study treatment. Conclusions: Addition of AB928 to carboplatin, pemetrexed and pembrolizumab did not significantly add to the established safety profile of the standard agents. Combination treatment was associated with disease control in all evaluable pts, including responses in those with PD after TKI and immunotherapy. Expansion is on-going in pts with EGFRmut NSCLC that has failed treatment with TKI. Additional updates on the safety, clinical activity, and correlative biomarker results will be presented. Clinical trial information: 03846310.
Safety of nivolumab/pembrolizumab in hepatitis B surface antigen-positive non-small cell lung cancer (NSCLC) patients.
Authors: Xu Chongrui , Tu Hai-Yan , Sun Yue-Li , Li Yang-Si , Xu Bing-Fei , Wang Bin-Chao , Chen Hua-Jun , Wang Zhen , Zhou Qing , Yang Jin-Ji , Wu Yi-Long
Published: May 2020

e21670

Background: Chronic hepatitis B virus infection patients are noted about 7% in Chinese population who are excluded from the clinical trials of the nivolumab or pembrolizumab in non-small cell lung cancer (NSCLC). However, in clinical practice these patients received checkpoint inhibitors as well. Limited evidence exist on the safety of the checkpoint inhibitors in hepatitis B surface antigen positive NSCLC patients. Methods: From January 1, 2018 to September 30, 2019, clinical information of advanced non-small cell lung cancer patients who received nivolumab or pembrolizumab ± chemotherapy as routine clinical practice in Guangdong Lung Cancer Institute were collected according to a standardized procedure. Gender, histology, treatment regimens, experimental test, respose rate, and adverse events were recorded. Status of hepatitis B surface antigen (HBsAg) were tested for every patient before the treatment and data of the positive patients were accessed for this research. Adverse events were assessed according to Common Terminology Criteria for Adverse Events v5.0. Results: Among 232 eligible patients, HBsAg were found positive in 17 patients(7.3%). Clinical characteristics were list in the table. The median age was 55.2 years (range 39-72) and transaminase and bilirubin of all the patients were normal before treatment. The median treatment cycle was 7 (95%CI 4.6-10.3) and the median time to discontinuation was 4.4 months (95%CI 2.8-7.1). 8 patients received anti-virus therapy including entecavir and adefovir during the treatment. Grade 1 transaminase or bilirubin elevation were noted in 6 patients during the treatment. Grade 3 transaminase and grade 4 bilirubin elevation were found in 1 patient without evidence of viral reactivation. Conclusions: Nivolumab or pembrolizumab are safety treatment options for HBsAg positive NSCLC patients. [Table: see text]