bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective correlation between the patient microbiome with response to and development of immune-mediated adverse effects to immunotherapy in lung cancer.
Authors: Chau Justin , Yadav Meeta , Liu Ben , Furqan Muhammad , Dai Qun , Shahi Shailesh , Gupta Arnav , Nace Mercer Keri , Eastman Evan , Abu Hejleh Taher , Chan Carlos Hou Fai , Weiner George J. , Cherwin Catherine , Lee Sonny T.M. , Zhong Cuncong , Mangalam Ashutosh , Zhang Jun
Published: June 2021

e21024

Background: Though the gut microbiome has been associated with immunotherapy (ICI) efficacy in certain cancers, similar correlations between microbiomes at other body sites with treatment response and immune related adverse events (irAEs) in lung cancer (LC) patients receiving ICIs have not been made. We designed a prospective cohort study conducted from 2018-2020 at a single-center academic institution to assess for correlations between the microbiome in various body sites with treatment response and development of irAEs in LC patients treated with ICIs. Methods: Patients with histopathologically confirmed, unresectable/advanced/metastatic LC planned to undergo ICI-based therapy were enrolled between September 2018 and June 2019. Patients must have had measurable disease, ECOG 0-2, and good organ function to be included. Data was collected for analysis from January 2019 to October 2020. Nasal, buccal and gut microbiome samples were obtained prior to ICI initiation, at development of irAEs, improvement of irAEs to grade 1 or less, and at disease progression. 16S rRNA sequenced data was mapped to the SILVA 13.2 database; operational taxonomic unit clusters were analyzed using MicrobiomeAnalyst and METAGENassist. Results: 37 patients were enrolled, and 34 patients were evaluable for this report. 32 healthy controls (HC) from the same geographic region were included to compare baseline gut microbiota. Compared to HC, LC gut microbiota exhibited significantly lower α-diversity. The gut microbiome of patients who did not suffer irAEs were found to have relative enrichment of Bifidobacterium ( p = 0.001) and Desulfovibrio ( p = 0.0002). Responders to combined chemoimmunotherapy exhibited increased Clostridiales ( p = 0.018) but reduced Rikenellaceae ( p = 0.016). In responders to chemoimmunotherapy we also observed enrichment of Finegoldia in nasal microbiome, and increased Megasphaera but reduced Actinobacillus in buccal samples. Longitudinal samples exhibited a trend of α-diversity and certain microbial changes during the development and resolution of irAEs. Conclusions: This pilot study identified significant differences in the gut microbiome between HC and LC patients, and correlates specific bacterial genera to ICI response and irAEs in LC. In addition, it suggests potential predictive utility in nasal and buccal microbiomes, warranting further validation with a larger cohort and mechanistic dissection using preclinical models. Clinical trial information: NCT03688347.
Clinical predictive markers of response to immune checkpoint inhibitor therapy in advanced non-small cell lung cancer.
Authors: Rhone Raena , Dumais Katerine , Powery Herman W. , Gentile Frank , Raez Luis E.
Published: June 2021

e21044

Background: Overweight and obesity have been associated with improved overall survival (OS) and progression-free survival (PFS) in patients treated with immune checkpoint inhibitors (ICI). EPSILoN score (EPSILoN), comprised of five clinical variables (smoking, Eastern Cooperative Oncology Group performance status, liver metastases, lactate dehydrogenase (LDH), and neutrophil-lymphocyte ratio), is a known predictive marker of response to ICI. This study aims to validate body mass index (BMI) and EPSILoN as predictive markers of response in frontline treatment of advanced non-small cell lung cancer (NSCLC) with ICI with or without concomitant chemotherapy. Methods: Patients with advanced NSCLC who received frontline ICI were identified using the electronic medical record. PFS and OS were retrospectively evaluated and stratified based on baseline BMI and EPSILoN. Due to lack of routine LDH testing, a modified EPSILoN (mEPSILoN) was used. For statistical analysis, log-rank tests were used to compare PFS and OS between groups, and Kaplan-Meier survival curves were used to report PFS and OS. Results: Thirty-six normal weight (NW) and 25 overweight and obese (OWO) patients were studied. Median PFS (mPFS) for OWO vs NW patients was 8.90 months vs 5.53 months (HR 0.54; 95% CI, 0.30-0.96; p = 0.04). mPFS at 12 months was 45% for OWO patients vs 23% for NW patients. Of the patients with PD-L1 ≥ 50%, 14 patients were NW and 11 patients were OWO. Among patients with PD-L1 ≥ 50%, mPFS for OWO was not reached (NR) vs 6.73 months in NW patients (HR 0.23; 95% CI, 0.09-0.60; p = 0.003), and the percent of patients that were PF at 12 months was 71% vs 15%. Of 56 patients with a calculable mEPSILoN, 29 patients had baseline mEPSILoN 1 and 27 patients had mEPSILoN 2-3. Median OS for patients with mEPSILoN 1 vs 2-3 was NR vs 11.13 months (HR 0.32; 95% CI, 0.14-0.76; p = 0.01) and 78% vs 49% survived at 12 months. Conclusions: OWO and lower mEPSILoN were associated with longer PFS and OS, respectively, in patients with advanced NSCLC who were treated with frontline ICI with or without concomitant chemotherapy, regardless of PD-L1 expression. These findings are consistent with recent studies that have reported these parameters as predictive markers of response in patients with NSCLC. However, this is the first study to our knowledge to evaluate these markers in frontline ICI treatment with or without chemotherapy.[Table: see text]
Financial impact of tepotinib for the treatment of adult patients with metastatic non-small cell lung cancer bearing METex14 skipping in the United States.
Authors: Stargardter Matthew , Yang Mo , Tosh Jon , Ambavane Apoorva , Mittal Madhav , Vioix Helene , Liu Frank Xiaoqing , McBride Ali
Published: June 2021

e21108

Background: MET exon 14 ( METex14) skipping is found in approximately 3% of the non-small cell lung cancer (NSCLC) population and is associated with poor prognoses. We estimated the financial impact to US Medicare and commercial plans of reimbursing the receptor tyrosine kinase inhibitor (TKI) tepotinib for adult patients with metastatic NSCLC bearing METex14 skipping. Methods: We developed an Excel-based economic model to project plan financial outlays with or without tepotinib from 2021-2023. The number of patients eligible for treatment with MET TKIs was estimated from epidemiological data, real-world evidence, and forecasted biomarker testing rates. It was assumed this population has access to other TKIs (capmatinib and crizotinib) and non-targeted standards of care, including immune checkpoint inhibitors, anti–vascular endothelial growth factor (VEGF) medications, and chemotherapy. It was also assumed most patients receiving tepotinib would otherwise be treated with another TKI. Efficacy and safety inputs were obtained from the Phase II VISION study (July 2020 data cut-off), published literature and prescribing information. Resource utilization and costs (2020 US dollars) were informed by online pricing databases, CMS fee schedules, Healthcare Cost and Utilization Project (HCUP) and trial data, expert opinion, and publicly available sources. Results: In hypothetical Medicare and commercial plans with one million members each, an estimated 160 and 32 adult patients with metastatic NSCLC would test positive for METex14 skipping between 2021-2023, respectively. Of these, 26 Medicare and 5 commercial plan members would receive tepotinib. Introducing tepotinib reduced cumulative financial outlays by $661,379 and $151,700 for Medicare and commercial payers respectively, or $0.0061 and $0.0014 per patient per month, primarily due to lower overall drug acquisition and disease management costs relative to a treatment mix without tepotinib. Results are most sensitive to the clinical efficacy of tepotinib and capmatinib. Conclusions: Using tepotinib in adult patients with metastatic NSCLC bearing METex14 skipping is expected to have minimal financial impact on Medicare and commercial payers in the US.[Table: see text]
Associations between interaction effects of mutational events and efficient immunotherapy in squamous NSCLC: Results from 373 patients.
Authors: Zhang Fan , Zhao Lei , Li Tao , Xu Yu , Wang Guoqiang , Li Chengcheng , Cai Shangli , Liu Hao , Hu Yi , Wang Jinliang
Published: June 2021

e21136

Background: Predictive biomarkers might not be similarly predictive in every single subpopulation, and they might be merely valid under certain circumstances, which is termed by “interaction effect”. Here, we proposed to investigate the interaction effect of mutational events on predicting efficacy of immune checkpoint inhibitors (ICIs), and to explore whether adding these interaction terms could optimize the prediction model based on genomic alterations. Methods: In total, 373 patients with squamous NSCLC were included. 191 patients with both PFS and OS data receiving monotherapy from the MSKCC, DFCI, SNCC, and POPLAR/OAK cohorts were included in the training set. 130 patients from the POPLAR/OAK cohort treated with docetaxel were included in the control set. Validation set-1 consists of 34 patients receiving monotherapy from the NCC and MSKCC cohorts, and validation set-2 comprises 18 patients treated with combination therapy from the MSKCC cohort. Risk models using single mutations (uni-model) and both single mutations and interactions (inter-model) were developed via multivariable Cox proportional hazards regression model. Results: Four single mutational events, including mutations of NOTCH1/2/3, LRP1B, RB1, and members in PI3K pathway, and two interactions ( TP53* NFE2L2 and TP53*HRR pathway) were identified as predictive biomarkers. The score of inter-model exhibited higher correlation with immunotherapeutic PFS in the training sets, compared to the uni-model ( Dxy: 0.196 vs. 0.175). Uni-score low was barely associated with the PFS (HR=0.32, 95% CI 0.07-1.50, P=0.15) and OS (HR=1.20, 95% CI 0.45-3.17, P=0.71) in the validation set-1, and the PFS in the validation set-2 (HR=0.96, 95% CI 0.31-2.95, P=0.94). Inter-score low showed better association with longer PFS (HR=0.17, 95% CI 0.03-0.84, P=0.029) and OS (HR=0.33, 95% CI 0.12-0.92, P=0.033) in the validation set-1, and longer PFS in the validation set-2 (HR=0.50, 95% CI 0.13-1.85, P=0.30). In addition, no association was observed between inter-score low and the PFS and OS in the control set, indicating that inter-score low might not be a prognostic biomarker, but a positive predictive biomarker to efficacious immunotherapy. Conclusions: Two interaction effects of mutational events on predicting efficacious immunotherapy in squamous NSCLC ( TP53* NFE2L2 and TP53*HRR pathway) were identified. Adding these interaction terms to the prediction model could optimize the predictive utility. Deeper understanding of these inter-relations might provide insights for basic research on anti-tumor immunity.
Machine learning based biomarkers to predict CD8 infiltration in non-small cell lung cancers using CT imaging.
Authors: Liu Yan , Francis Danny , Groza Vladimir , Voyton Charles , Baili-Laya Afef , Huet Benoit , Boujemaa Nozha
Published: June 2021

e21145

Background: Immune-checkpoint inhibitors (ICIs), specifically monoclonal antibodies targeting the programmed cell death protein-1 and programmed death-ligand 1 (PD-1 and PD-L1) have shown promise in the treatment of non-small cell lung cancer (NSCLC). Unfortunately, patients response to ICI is difficult to predict, with cancer stage, treatment line and regimen all affecting response rates. Identification of patients who will be “responsive” to ICI is of great importance to increase treatment efficacy. Current techniques used to identify responsive patients rely on PD-L1/PD-1 expression, microsatellite instability, tumor mutagenic burden and less commonly CD8+ infiltration, all of which are invasive and costly procedures. In this study we aim to develop a machine learning derived CT imaging biomarker that predicts CD8 status of tumors, allowing for non-invasive determination of ICI treatment efficacy. Methods: To study CD8 infiltration we extracted patients that included CT scans and CD8 transcript data from publicly available cohorts (TCGA-LUSC, TCGA-LUAD, NSCLC-Radiogenomics) to produce the Lung3 cohort (104 patients). Using this cohort, we trained (80 patients) and tested (24 patients) an AI model to predict tumor CD8 infiltration using patient CT scans as the sole input. CD8 expression (high and low) was characterized using transcriptomic quantification and served as surrogate for CD8+ infiltration, following previously described methods. Supervised and unsupervised models previously trained to identify lung features were trained to identify CD8 status using the CD8 expression data provided in the Lung3 dataset. Algorithm performance was tested on a randomly chosen subset of the cohort (24 patients) and compared against transcriptomic confirmed CD8 expression. AUC were calculated for supervised and unsupervised models. Results: AUC for the supervised and unsupervised models generated using the Lung3 cohort are shown below. Our results suggest that the derived supervised and unsupervised models could identify the CD8 infiltration status using only patient CT scans in the test dataset. Conclusions: The machine learning based models described here show encouraging results suggesting that CT imaging of NSCLC lung cancers contain sufficient information to predict the CD8 infiltration status of tumors. Although these results are just a proof of concept, the promise of a CT based non-invasive marker for tumor immune status is encouraging to help advance treatment efficacy in the ever-growing field of ICI therapy. References: (1)Wu, X. et al. (2019). (2) Schulze, A. B. et al. (2020). (3) Sun, R. et al. (2018).[Table: see text]
Impact of age and frailty markers on overall survival among hospitalized patients with lung cancer treated with immunotherapy.
Authors: Olson Eric , Russell Gregory , Lantz Jeffrey , Roberts Nathan , Dothard Andy Shipe , Lycan Thomas , Klepin Heidi D.
Published: June 2021

e21151

Background: Although predictive of chemotherapy toxicity, geriatric assessment measures are not systematically collected in clinical practice and may or may not be predictive for immune-related adverse events. Furthermore, hospitalization during immune checkpoint inhibitor (ICI) treatment for advanced lung cancer has variable prognostic significance. This study aimed to evaluate whether age and documented patient characteristics mapped to geriatric assessment domains (frailty markers, FM) predict survival in this setting. Methods: A single-center retrospective cohort of advanced stage lung cancer patients who received >1 dose of an ICI from 6/1/18 to 2/1/20, were later hospitalized, and received ≥ 1 dose of systemic corticosteroids (n=97) was analyzed. Chart review ascertained documentation of any of the following FMs prior to ICI initiation: inability to walk one block, unintentional weight loss, decreased social activities, recent falls, need for assistance with medications, visual or hearing impairments, living alone, and concern regarding social support. Patients were stratified according to age and three FM categories (0 FM [low risk], ≥1 FMs [at risk], and ≥2 FMs [high risk]). Overall survival (OS) analysis was calculated from first dose of ICI to date of death or last follow-up. Cox’s proportional hazards models were used to assess the relationship between FMs and age on OS; hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Results: Analysis of < 75 and ≥ 75 yo revealed a median OS of 15.1 and 5.4 months respectively (HR 2.76, CI 1.62-4.72). Controlled for performance status (PS), older age (≥75 yo) was associated with a higher risk of death (HR 2.39, CI 1.32-4.31). FMs were associated with higher mortality, adjusted for PS and age (at risk patients HR 1.81, CI 1.03-3.16; high risk patients HR 2.02, CI 1.07-3.78). PS prior to starting ICI was not associated with OS. Conclusions: Age ≥ 75 yo is associated with short survival among lung cancer patients hospitalized while receiving ICI. Pre-treatment FMs documented as part of usual care were associated with worse OS, even after controlling for PS and age. This study shows promise for use of machine learning algorithms to stratify risk in hospitalized patients undergoing treatment for lung cancer with ICIs. These data would allow providers to better target serious illness conversations and end-of-life resources.[Table: see text]
Patterns of lung cancer in people living with human immunodeficiency virus (HIV): A retrospective, single-center study in Washington, D.C.
Authors: Pruitt Margaret , Janapala Rajesh Naidu , Haroun Faysal
Published: June 2021

e21154

Background: Lung cancer is the leading cause of cancer death and the most common non-acquired immune deficiency syndrome defining malignancy in people living with HIV (PLWH). Disparities in outcomes have been observed despite lung cancer mortality reportedly decreasing in the general population over the last decade due to lower rates of smoking and the advent of novel therapies. To better understand the current trend in lung cancer in PLWH, we explored demographic characteristics, comorbidities, and lung cancer pathology and molecular data in this population. Methods: A retrospective search of patient charts was conducted from 2004 to January 2021 using billing codes for HIV and primary lung cancer. Patients who had incorrect HIV or primary lung cancer diagnoses were excluded. Results: The search yielded 45 patients, of which 11 were excluded as described above: 66% were males, 82% African American, and 18% Caucasian. About two-thirds of patients were living in zip codes with predominantly low to medium household incomes. The median pack years of patients diagnosed with Stage I or II non-small cell lung cancer (NSCLC) was 40, Stage III or IV NSCLC was 20, early stage small cell lung cancer (SCLC) was 30, and late stage SCLC was 60. The median time between HIV and lung cancer diagnoses was 21.7 years for Stage I or II NSCLC, 17.1 years for Stage III or IV NSCLC, 15.2 for early stage SCLC, and 13.3 for late stage SCLC. Of 26 patients with viral load (VL) data, 21 (80.7%) had VL less than 500 when lung cancer was diagnosed. Of the 33 charts with available pathology data, there were 16 adenocarcinomas, 6 squamous carcinomas, 3 adenosquamous carcinomas, 1 large cell neuroendocrine cancer, 4 SCLCs, 1 mesothelioma, and 2 unspecified NSCLCs. Of 19 patients with a histologic grade, 11 had a high-grade tumor (57.9%). For the NSCLCs, 8 were Stage I (28.5%), 2 Stage II (7.1%), 8 Stage III (28.5%), 9 Stage IV (32.1%), and 1 with an unspecified stage. One SCLC was early stage and the remaining 3 were late stage. Five patients had brain metastasis. Molecular data or PDL-1 expression was available for 10 adenocarcinomas (62.5%), 1 adenosquamous (33%), 3 squamous carcinomas (50%), and the large cell neuroendocrine cancer. An EGFR mutation was detected in 2 cancers. ALK rearrangement was found in 1. Other mutations were detected. Two cancers were in each PDL1 expression category: < 1%, 1-50%, and > 50%. Conclusions: Our study suggests that PLWH with lung cancer continue to have high rates of smoking. Viral load was well controlled. A range in stages of lung cancer was observed including earlier stages. Although molecular data was limited, available EGFR and ALK gene alterations, and PD-L1 expression prevalence were on par with that of the general population. With advancements in lung cancer treatment, additional research is needed in the PLWH population to better understand and mitigate disparities.
An investigation on acquired mutations after TKI treatment in Chinese lung cancer patients.
Authors: Jiang Yong , Li Yingmei , Zha Jiandong , Liu Danni , Kong Feng-Ming Spring
Published: June 2021

e21162

Background: Targeted therapy has greatly extended the survival of certain molecular selected cancer patients. However, lots of them would eventually develop drug resistance and required alternative treatment. Research on the genomic changes before and after treatment allows us to understand the mechanism of drug resistance and to develop new treatment strategies. Methods: A total of 143 patients were enrolled and their specimens were sequenced with a panel of 680 cancer-related genes in this study. Briefly, tumor FFPE samples before treatment (T1) were collected and underwent deep sequencing (2000X), and blood samples after treatment (T2) were collected, cell-free DNA (cfDNA) was isolated and sequenced (20000X). Patients with positive EGFR mutations at T1 received TKIs afterwards. Results: A total of 160 mutations were identified in T1 and 206 mutations were found in T2 samples, while 90 of them were shared in both time points. EGFR mutations were found in 95 (66.4%) patients at T1 and 101 (70.6%) patients at T2. ERBB2 mutations were found in 9 (6.3%) patients at T1 and 19 (13.3%) patients at T2. Among them, one patient had ERBB2 amplification at T1, and new ERBB2 amplifications were found in 11 patients at T2. Conclusions: ERBB2 amplifications are associated with TKI treatment, and are likely to be involved with disease progression and TKI drug resistance.
Upfront thoracic radiotherapy to primary lession improve outcomes in patients with stage IV non-small cell lung cancer harboring EGFR mutations.
Authors: Kotek Sedef Ayse , Sümbül Ahmet Taner , Akkus Yildrim Berna , Topkan Erkan
Published: June 2021

e21167

Background: The role of thoracic radiotherapy in the treatment of metastatic EGFR mutant non-small cell lung cancer patients in literature datas are insufficient.The aim of this study was to examine the effectiveness of upfront thoracic radiotherapy in metastatic EGFR mutant NSCLC patients treated with chemotherapy or TKI. Methods: This study was designed as a hospital-based retrospective observational case-series study. A total of 141 patients with metastatic EGFR mutant non-small cell lung cancer who has followed in two different oncology centers at Turkey between 2014 and 2020. have been included to this study. Results: The median age of the patients was 63 (range 35-91) years. EGFR mutation results of exon 19 deletion, exon 21 mutation and exon 18 mutation were found in 82 (58.2%), 56 (39.7%) and 3 (2.1%) patients, respectively. The median follow-up time was 22 months and 94 (33.3%) patients died during follow-up. Median overall survival (OS) was 26 months and progression free survival (for first line treatment) (PFS) was 10 months for whole patients, respectively. Radiotherapy was given to the primary tumor site in 32 (22,6%) patients. Patients receiving radiotherapy to primary tumor site had better overall survival than those not (31 versus 23 months respectively and p = 0,02) The survival advantage was also seen for patients group taking TKI at upfront setting (33 versus 23 months respectively and p = 0.05). Conclusions: In this study, we have showed that upfront thoracic radiotherapy to primary lession as combination with EGFR-TKI treatment may improve the outcome in advanced stage IV NSCLC patients harboring EGFR mutations.
Effectiveness of osimertinib plus chemotherapy and avastin for untreated EGFR-mutated advanced non-small cell lung cancer.
Authors: Wang Fang , Liu Hui , Zeng Zhen , Wang Shasha , Qin Haifeng
Published: June 2021

e21178

Background: Osimertinib is recommended as a novel first-line standard treatment for advanced Non-Small-Cell Lung Cancer (NSCLC) patients with EGFR mutation. However, there are also patients with concurrent mutation or/and metastases have limited benefits. According to the current remission rate, regression depth and PFS data, the main mechanism of the benefit of combined anti-angiogenesis or chemotherapy is to reduce tumor load and heterogeneous reserve to a greater extent, so as to extend the remission time, that is, to delay the occurrence of drug resistance to extend PFS. This prospective study aims to investigate the efficacy and safety of Osimertinib plus chemotherapy and Avastin for Untreated EGFR-Mutated advanced NSCLC. Methods: The study enrolled 22 patients diagnosed with untreated advanced NSCLC and tested with EGFR mutation, who received osimertinib ( 80mg QD) plus pemetrexed (500mg/m2), cisplatin (75mg/m2) and bevacizumab (7.5mg/kg) for 6 cycles, then maintained with osimertinib/pemetrexed/bevacizumab. The primary endpoint was progression free survival (PFS). The secondary endpoint was objective response rate (ORR). Treatment was continued until disease progression and the tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. The toxicity was determined according to CTCAE 4.0. Results: From February, 2018 to July, 2020, 22 patients enrolled. All the patients were evaluated and showed partial response(PR) when make efficacy evaluation at the first time. The target lesions reduction were shown. The average reduction is 48%, ranged from 32% of Pt12 to 71% of Pt11. Up to January, 2021, all the patients are still under the treatment. Especially for Pt7 who has already benefited from the treatment protocol by 35months. The toxicities associated with this protocols were manageable. Only 1 patient was 3/4-grade Anemia, 1 patient was 3/4-grade Diarrhea and 3 patients was 3/4-grade Lymphopenia. Conclusions: Osimertinib in combination with chemotherapy and Bevacizumab. exhibits superior activity and generally manageable toxicities for the naive advanced NSCLC patients with EGFR mutant, especially for the patients with concurrent mutation or/and metastases. It may provide a new and effective therapy strategy for them, but large sample and additional clinical trials are also needed.
Molecular profiling by NGS upon progression disease in advanced stage NSCLC patients.
Authors: Serna Roberto , Sanchez Alfredo , De Julian Maria , García Girón Carlos , Domine Manuel , Blasco Ana , Sanchez Torres Jose Miguel , Oramas Juana , Bosch-Barrera Joaquim , Sala Maria Angeles , Sereno Maria , Ortega Ana Laura , Chara Velarde Luis Enrique , Hernandez Berta , Padilla Airam , Coves Juan , Jantus Lewintre Eloisa , Molina-Vila Miguel Angel , Romero Atocha , Provencio-Pulla Mariano
Published: June 2021

e21196

Background: Non-small cells lung cancer (NSCLC) patients treated with Tyrosine Kinase Inhibitors (TKI) at first-line ultimately develop disease progression after 10 to 14 months. Mechanisms underlying TKI-resistance are not complete understood. Tumor re-biopsy is often unfeasible for NSCLC patients and liquid biopsy is a suitable alternative in identify mechanism by which tumors progress. Methods: 113 plasma samples were collected from advanced stage EGFR positive NSCLC patients upon disease progression according to RECIST V1.1. cfDNA NGS profiling was carried out using the Oncomine™ Pan-Cancer Cell-Free Assay and sequenced on an Ion GeneStudio S5 Plus System. Variant calling and annotation were performed with Torrent Suite and Ion Reporter (v5.16) software, respectively. In addition, we developed a bioinformatic pipeline, using RStudio for variant filtering. Results: Overall, 344 somatic variants were detected with an average number of variants per patient of 2.32 and a median Mutant Allele Frequency (MAF) of 0.83%. Most mutated genes were EGFR (63.72%), TP53 (60.18%), APC (16.81%), MAP2K1 (11.50%), PIK3CA (10.62%), FGFR3 (7.08%), KRAS (7.08%) and BRAF (6.19%). As expected, SNPs were the most frequent mutation type (72.67%), following by INDELs (24.41%) and CNVs (2.91%). We found high co-occurrence between MYC-GNA11, MYC-CCND2, HRAS-AR and EGFR-TP53 genes using Jaccard’s score (0.5, 0.5, 0.5 and 0.46, respectively). Within EGFR-mutated patients, 40% had T790M resistance mutation. Finally, we found KRAS mutations and missense PIK3CA mutations were mutually exclusive. Conclusions: Molecular profiling of liquid biopsies collected upon disease progression using NGS help to identify molecular mechanisms underlying treatment failure.
Prognostic value of systemic inflammatory markers in first- and subsequent-line immunotherapy and durability of response in NSCLC.
Authors: Basher Fahmin , Saravia Diana , Lopes Gilberto
Published: June 2021

e21210

Background: Treatment of advanced non-small cell lung cancer with immune checkpoint inhibitors (ICI) has been shown to yield durable responses. High neutrophil-to-lymphocyte ratios (NLR), low lymphocyte-to-monocyte ratios (LMR) and high platelet-to-lymphocyte ratios (PLRs) have been used as surrogates for increased levels of inflammation in the tumor microenvironment that can predict cancer progression and response to therapy. However, the comparative prognostic role of these markers account for when immunotherapy is utilized has not been explicitly determined. Methods: We performed a retrospective review of 233 patients with advanced stage NSCLC at the University of Miami / Sylvester Comprehensive Cancer Center who received ICI either as first-line (1L) or second-line (2L) therapy and for whom laboratory data, in particular absolute neutrophil, lymphocyte, monocyte, and platelet counts, were available pre-treatment and 4 weeks after initiation of immunotherapy. Results: Using receiver operating characteristic (ROC) curves, we identified cutoff values with optimal prognostic value for NLR (4), LMR (2), and PLR (200). Median age, histology, and smoking history were equivalent across each group. Improved OS was observed in our cohort for patients in which pre-treatment NLR < 4 (54.4m vs. 35.9m, p = 0.0069), LMR > 2 (54.4m vs. 32.3m, p = 0.0016), and PLR < 200 (54.4m vs. 27.5m, p = 0.0007), while PFS was unaffected when looking strictly at these cutoffs. We then observed that PFS could be better predicted after stratifying NLR, LMR, or PLR when taking into account whether ICI was administered as 1L or 2L. We also determined that changes in (Δ) NLR or LMR (but not PLR) by at least 20% between baseline and 4 weeks after initiation of ICI could predict duration of response to ICI. Conclusions: In conclusion, the NLR, LMR, and PLR are powerful surrogates for the tumor microenvironment and can predict responses to ICI in advanced NSCLC when used in the context of previous lines of therapy and subsequent pro-inflammatory changes. Our study shows that ICI used in the first-line setting results in more durable responses, and can overcome an unfavorable tumor microenvironment. In addition, we demonstrate that in NSCLC, durability of responses can be predicted by changes in these systemic inflammatory response markers early after the initiation of ICI.[Table: see text]
The efficacy and safety analysis of PD-1 inhibitor combined with interferon-α1b: A real-world study in Chinese metastatic melanoma patients.
Authors: Zhu Guannan , Shi Qiong , Li Chunying , Gao Tianwen
Published: June 2021

e21507

Background: Clinical data on PD-1 inhibitor combined with interferon in metastatic melanoma treatment were still limited. The objective of this study was to assess the efficacy and safety of PD-1 inhibitor/interferon-α1b combination therapy for Chinese metastatic melanoma patients in the real world. Methods: We reviewed patients diagnosed as metastatic melanoma and had received PD-1 inhibitor (pembrolizumab, 2 mg/kg, every 3 weeks, intravenously or toripalimab 240mg every 2 weeks, intravenously) combined with interferon-α1b(10μg/kg, every other day, subcutaneously) in Xijing Hospital from Dec 2018 to Nov 2020. Efficacy and safety profiles were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 and Common Terminology Criteria for Adverse Events version 5.0, respectively. Results: In total 65 patients were reviewed in this study, including 13 cases with ECOG performance status ≥2. Acral and mucosal cases accounted for 47.7% and 23.1% respectively. In 27(41.5%) patients, the combination therapy was used as the first line treatment, whereas in the rest 38 patients as second or subsequent lines. The median follow-up period was 8 months (1.5-21 months). Median OS was 15 months (95CI%: 10.62-19.38 months). Median PFS was 6 months (95CI%: 2.54-9.46 months). 6-month and 1-year PFS rate were 48.1% and 35.3%. 6-month and 1-year OS rate were 80.9% and 59.8%. Objective response was seen in 18.46% cases, with 12.31% of patients exhibiting ongoing response. The best confirmed disease control rate was 73.85%. Multivariate analysis demonstrated that overall survival was significantly associated with ECOG performance status ≥2 (OR=3.32，95%CI=1.14-9.66 ), regardless of age(≥65), elevated LDH, PD-1 inhibitor type and the line of the combination therapy. Select treatment related AEs (TRAEs) of any grade were observed in 57(87.69%) patients. The leading 3 TRAEs were lymphopenia, fatigue and fever. Grade 3 to 4 TRAEs were recorded in 2 cases. Grade 4 hyponeutrophilia occurred in a patient with ECOG status 3 using interferon-α1b plus toripalimab and resulted in discontinuation of both PD-1 inhibitor and IFN-α1b. Grade 3 headache was reported by one patient using interferon-α1b plus pembrolizumab and was solved with celecoxib 200mg daily. No drug-related deaths were reported. Conclusions: PD-1 inhibitor combining interferon-α1b therapy shows promising efficacy and acceptable toxicity in this real-world cohort of Chinese metastatic melanoma patients.[Table: see text]
Is radiation necrosis in radiated melanoma brain metastasis increasing because immunotherapy is contributing to this or are patients just living longer?
Authors: Buchbinder Elizabeth Iannotti , Shi Diana D. , Pfaff Kathleen L. , Manos Michael P. , Ouyang Olivia , Liu David , Rodig Scott J. , Aizer Ayal
Published: June 2021

e21518

Background: The use of immune checkpoint inhibitors, particularly combination ipilimumab and nivolumab, has drastically changed the management of patients with melanoma brain metastasis. Select patients also benefit from brain-directed stereotactic radiation. Radiation necrosis is a risk associated with stereotactic radiation that oncologists have been observing more frequently in the era of immunotherapy. Methods: Patients were identified who had a history of metastatic melanoma treated with stereotactic brain radiation who subsequently developed radiation necrosis. Brain tissue from those patients with a subsequent resection of their radiation necrosis was obtained and examined for immune infiltrate and other factors. The tissue obtained was evaluated by blinded pathologists who graded % viable tissue, % necrosis, % tumor and % fibrosis. In addition, they graded inflammation on a scale of 1-3. Results: Seven patients were identified who had surgery for radiation necrosis following radiation to melanoma brain metastasis. Tissue was available for five patients. Two patients had received no prior immunotherapy, one patient had received ipilimumab and two patients received combination ipilimumab and nivolumab. The samples obtained consisted of almost entirely viable brain tissue or necrosis. There was minimal inflammation seen in all patients’ samples including those who had not received immunotherapy and those who had. Conclusions: Radiation necrosis in patients on immunotherapy who receive brain-directed stereotactic radiation is a rising problem. On pathologic evaluation increased immune infiltrate is not observed in patients on immunotherapy with radiation necrosis compared to those who never received immunotherapy. This suggests that the increased rates of radiation necrosis may be more likely associated with longer survival as opposed to a direct causative effect from the immunotherapy although with our limited sample size this will need further exploration.[Table: see text]
Robust prediction of response to immunotherapy in a mixed cohort of previously treated and immunotherapy-naive melanoma patients.
Authors: Abbott Charles , McDaniel Lee , Pyke Rachel , Levy Eric , Navarro Fabio , Zhang Simo V. , Wang Jing , McClory Rena , Snyder Michael , Jang Sekwon , Boyle Sean Michael , Chen Richard
Published: June 2021

e21548

Background: While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers. Methods: Pre-treatment samples from 51 unresectable, stage III/IV melanoma patients who underwent anti-PD-1 therapy were characterized to assess factors influencing response. RECIST criteria were used to evaluate tumor response to therapy, with a median follow-up of 24 months. For each patient, a single paired FFPE tumor and normal blood sample was collected and profiled using Personalis’ ImmunoID NeXT Platform; an augmented exome/transcriptome platform and analysis pipeline which produces comprehensive tumor mutation information, gene expression profiling, neoantigen characterization, HLA typing and LOH, TCR repertoire profiling, and tumor microenvironment profiling. These data were then integrated to form a composite neoantigen presentation score (NEOPS) for each patient. Results: We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB. Neoantigen burden score (NBS) was derived from SHERPA, our exome and transcriptome integrative neoantigen prediction model. We found that NBS more significantly stratified responders and non-responders (P = 0.016) than TMB alone (P = 0.049). A broader score, NEOPS, incorporated DASH, to capture HLA allele-specific loss of heterozygosity and additional antigen presenting machinery resistance mechanisms. NEOPS consequently demonstrated a stronger association with response (p = 0.002). We used area under the curve (AUC) to benchmark NEOPS performance against established mutational and transcriptomic predictive models, demonstrating the model was more predictive of response in both the treatment naive setting, as well as in a mixed cohort of treatment-naive and experienced patients. These findings were confirmed in an independent cohort of patients (n = 110), suggesting that NEOPS is a robust, novel biomarker of ICB response in melanoma. Conclusions: Given the complex nature of resistance to immunotherapy, as well as potential toxicities associated with treatment, there is a need for biomarkers that can more accurately predict response. Here we demonstrate that NEOPS can significantly improve stratification of patient response. We also demonstrate that data intensive biomarkers like NEOPS can be clinically practical, with comprehensive tumor profiling in our clinical cohort achieved using very limited tumor tissue.
Multiple primary melanoma in association with other personal and family history of cancers.
Authors: Yang Xi , Karapetyan Lilit , Bo Na , Wang Hong , Sander Cindy , Kirkwood John M.
Published: June 2021

e21559

Background: Patients (PTs) with cutaneous melanoma are at increased risk of developing second primary melanoma and non-melanoma skin cancers. The primary aim of this study was to define the association between MPM and personal history of non-melanoma skin cancers and other non-skin cancers. The secondary aim was to evaluate the association between MPM and the presence of other cancers among first-degree relatives (FDRs). Methods: We performed a retrospective case-control study including cases with MPM and controls with single primary melanoma (SPM) from the University of Pittsburgh Cancer Institute Melanoma Center Biological Sample and Nevus Bank. The proportions and percentages of non-melanoma skin cancer, other non-skin cancer, 1st degree family history of melanoma, and 1st degree family history of other non-melanoma cancers were calculated separately for MPM and SPM groups. Fisher’s exact tests were performed to test whether MPM was associated with these variables. For each significant variable, a multivariable logistic regression model was used to test its association with MPM after adjusting for age, gender, melanoma staging, and smoking status. Results: In total, 311 PTs (39.2% men; median age at initial diagnosis 51years) were enrolled, including 194 with SPM (38.6%; 51) and 117 with MPM (39.8%; 48). 28 (9%) of PTs had squamous cell carcinoma (SCC), and 63 (20%) had basal cell carcinoma (BCC). The most common non-skin cancers in the whole cohort were prostate (4.8%), breast (3.8%), hematological (1.9%), colorectal (1.3%), and cervical cancers (1.3%). FDR history of melanoma, non-melanoma skin cancer, and other cancers were positive in 15.4%, 7.1% and 46.3% PTs, respectively. The most common non-skin cancers in FDRs were breast, prostate, lung, colorectal and hematological malignancies. In comparison to PTs with SPM, PTs with MPM were more likely to have SCC (14.5% vs 5.7%, p=0.013) but not BCC and other non-skin cancers. FDRs of PTs with MPM had higher prevalence of melanoma (23.1% vs 10.8%, p=0.005), prostate cancer (31.9% vs 5.3%, p=0.0002) but not other non-melanoma skin and non-skin cancers. In multivariate analysis the association remained significant between MPM and SCC (OR 2.7, 95% CI 1.1-6.6, p=0.032), FDR history of melanoma (OR 2.0, 95% CI 1.03-4.1, p=0.042), and FDR history of prostate cancer (OR 5.6, 95% CI 1.6-20.3, p=0.008). Conclusions: MPM is associated with higher prevalence of SCC and FDR history of melanoma and prostate cancer, but not BCC and other non-melanoma cancers in comparison to SPM.
Short-course neoadjuvant intratumoral immunotherapy establishes immunologic memory in murine melanoma.
Authors: Aiken Taylor J. , Komjathy David , Rodriguez Mat , Feils Arika , Gillies Stephen D. , Erbe Amy K. , Rakhmilevich Alexander L. , Sondel Paul M.
Published: June 2021

e21561

Background: GD2 is disialoganglioside preferentially expressed in neuroblastoma and melanoma and anti-GD2 directed therapies are used clinically in neuroblastoma, with ongoing clinical trials in melanoma. We are currently developing an in situ vaccination approach using intratumoral (IT) delivery of an immunocytokine (IC) consisting of IL-2 linked to an anti-GD2 monoclonal antibody. While IT-IC monotherapy does not cure mice bearing established B78 melanoma tumors, it is effective when combined with local radiation therapy (RT). Here, we tested whether short course IT-IC monotherapy prior to surgical resection could result in a robust adaptive immune response preventing tumor recurrence following rechallenge after surgery. Methods: Mice bearing 50-100mm3 GD2-expressing melanoma (B78) tumors were treated with a 5-day course of 50μg IT-IC and complete surgical resection was performed 3 days following the final treatment. The immune infiltrate of resected tumors was assessed by flow cytometry. Rechallenge experiments consisted of either 2x106 B78 cells injected into the contralateral flank or 2x105 B16-GD2 cells injected via tail vein for pulmonary metastasis rechallenge. Results: IT-IC treated tumors had fewer viable tumor cells, increased CD8 T-cells, and an improved CD8:Treg ratio. Rejection of B78 contralateral flank rechallenge (implanted 40 days following surgical resection of the primary tumor) was observed in 78% (7/9) of mice treated with IT-IC compared to 50% (5/10) that received surgery alone and 0% (0/5) of naïve mice. Immunologic memory was potent in neoadjuvant-treated mice early after surgery, with all mice (5/5) rejecting contralateral B78 rechallenge that occurred on the day of surgery compared to 0% (0/5) in both surgery-alone and naïve mice. Neoadjuvant IT-IC also prevented the development of B16-GD2 lung metastasis compared to naïve mice or the surgery-alone group (when the IV injected experimental metastases were given 80 days following surgery). Conclusions: While ineffective in curing large B78 melanoma flank tumors as monotherapy, mice receiving neoadjuvant IT-IC developed robust immunologic memory preventing recurrence following surgery. The memory response was present as early as the day of surgery and was sufficient to prevent pulmonary metastasis. IT-IC should be further investigated as a neoadjuvant therapy for preventing recurrence in high-risk settings.
Artificial intelligence (AI) comparison of social media-based patient-reported outcomes of PD-1, BRAF, and CTLA-4 inhibitors for melanoma treatment.
Authors: Su Ashley , Jueng Jeremy , Dupuis Léonie , Brooks Ian , Sinha Ritika , Maner Brittany , Dellavalle Robert , Burton Vernon , Solomon James A.
Published: June 2021

e21572

Background: Due to side effects and adverse psychosocial factors, there can often be a disconnect between clinical impression and the patient perspective of treatment. Melanoma patients frequently use social media to discuss their disease sentiments and outcomes, providing a window into patient insight, otherwise not readily attainable. We analyzed publicly available full text posts on multiple social media platforms concerning melanoma treatments PD-1 inhibitors (pembrolizumab/Keytruda, nivolumab), BRAF inhibitors (dabrafenib, vemurafenib), and CTLA-4 inhibitor (ipilimumab/Yervoy) associated with Patient Global Impression of Change (PGIC) terms to compare and identify patient burden. Methods: Millions (12,599,313) of publicly available online social media text data were extracted and run through Brandwatch Artificial Intelligence-powered database and machine learning algorithm to categorize treatment-specific posts with PGIC terms associated with sentiment. Results: Out of 52,962 posts related to a select list of melanoma treatments, we identified Keytruda (6,080), nivolumab (1,614), dabrafenib (529), vemurafenib (329), and ipilimumab (1715) posts. The top ten types of posts by volume for each treatment were predominantly positive for PGIC terms (improving, well, progress) while being associated with negative emotions (fear and sadness). Patient-perceived better treatments were associated with decrease fear. PD-1 inhibitor Keytruda displayed markedly less fear (56.9%) with a very high positive PGIC (92.3%) in comparison with PD-1 inhibitor nivolumab with decreased positive PGIC (78.0%) and increased fear (81.6%). Likewise, this patten was discovered for the BRAF inhibitors and CTLA-4 inhibitor, albeit less distinct: dabrafenib (positive PGIC 86.4%, fear 71.9%), vemurafenib (positive PGIC 78.0%, 81.6%), ipilimumab (positive PGIC 75.0%, fear 79.3%). Conclusions: Our initial results indicate that despite patients reporting good outcomes from melanoma treatment, they remain fearful. Nonetheless, a trend is identified between patient-perceived better treatment and decreased patient fear. This analysis can help bridge the gap of understanding patient perspective and provides an indication for translation into more effective clinical and pharmaceutical response.