bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of different color unmixing methods for cMET-PDL1-EGFR multiplex assay.
Authors: MUKHERJEE SATARUPA , Sobh Nahil , Martin Jim , Nie Yao , Walker Erika , Landowski Terry 
Published: June 2023

e21080 Background: Multiplex brightfield imaging offers the advantage of simultaneously analyzing multiple biomarkers on a single slide, as opposed to single biomarker labeling on multiple consecutive slides. To accurately analyze multiple biomarkers localized to the same cellular compartment, a set of common lung panel markers were selected as a model, cMET-PDL1-EGFR. One of the most crucial preliminary stages for analyzing this assay is identifying the unique chromogens on individual cells. This is a challenging problem due to the co-localization of membranes from all the three biomarkers. It requires advanced color unmixing for creating equivalent singleplex images (referred as synthetic singleplexes) from each triplex image for each biomarker. Methods: We explored different unsupervised methods for unmixing cMET-PDL1-EGFR images. Initially we explored an unsupervised method based on Lee et al. [1], which formulated the color unmixing problem as a non-negative matrix factorization (NMF) method and proposed a system capable of performing the color decomposition in a fully automated manner, where no reference stain color selection is required. Next, we developed cycle-Generative Adversarial (cycle-GAN) [2] models, for each of the three stains – TAMRA (purple), QM-Dabsyl (yellow) and Green. The models were trained on 6 cases of lung having different intensities of the stains. Results: The NMF and cycle-GAN method was validated on 5400 lung images. On analysis of the results and on review with pathologists, we observed that NMF was able to produce reasonable results on synthetic PDL1 and EGFR, but the synthetic Green images did not replicate the adjacent Green images properly. On the other hand, cycle-GAN was able to generate similar synthetic images for all three stains as demonstrated by the similarity metrics in Table 1. Pathologist review of the cycle-GAN results determined that the difference in percentage scores between pairs of adjacent and synthetic singleplex images would be within the range 2%-5% only. Conclusions: In this project, we performed detailed analysis of two unsupervised methods for color unmixing on triplex images. On comparison of the methods based on image similarity measures and pathologist review, we conclude that the cycle-GAN method is competent in generating synthetic images. References: [1] Lee, Daniel, and H. Sebastian Seung, "Algorithms for non-negative matrix factorization." Advances in neural information processing systems 13 (2000). [2] Jun-Yan Zhu, Taesung Park, Phillip Isola, and Alexei A Efros. 2017. Unpaired image-to-image translation using cycle-consistent adversarial networks. In ICCV. 2223–2232.[Table: see text]
Prevention of amivantamab infusion related reactions with extended pre-infusion day oral steroid therapy.
Authors: Chan Daniel Boon Yeow 
Published: June 2023

e21083 Background: Initial results with amivantamab (ami) in CHRYSALIS-1, and ami and lazertinib (laz) regimen in CHRYSALIS-2 showed encouraging efficacy in patients whose disease progressed after standard-of-care chemotherapy, and osimertinib (osi) and platinum-based chemotherapy respectively. Infusion related reactions however were frequent; 65% all grades in both studies and 2%/7% respectively had >Grade 3 infusion related reactions. An on-going trial (NCT05663866) utilising dexamethasone (dex), montelukast and methotrexate to minimise ami infusion related reactions might be unacceptable to many patients; a simpler method would be more ideal. Ami has been available in Singapore since the third quarter of 2021. Laz is not commercially available in South Asia as at Jan 2023. Methods: A single medical oncologist in private practice in Singapore managing advanced lung cancer patients collated this cohort of 7 consecutive patients treated from August 2021 to Jan 2023 with ami. Infusion day pre-medication and infusion protocol were according to the ami product insert. All patients were EGFR mutation positive and treatment-refractory with KPS <2. All who were on EGFR Tyrosine Kinase Inhibitors (TKI) concomitant with ami had tolerated these agents before and upon rechallenge of the TKI. Oral dex 8mg BD for three days (starting two days before ami) was implemented for patients 5-7 after observing patients 3-4 with >Grade 3 infusion related reactions. Fisher exact test evaluated the statistical significance of the difference in the incidence rate of infusion related reactions between the patients who did and did not receive pre-infusion day steroids. Results: 0/5 and 2/2 patients with and without pre-infusion day steroids respectively had infusion related reactions (p = 0.0476). Both reactions were > Grade 3. Patient 4 did not have any infusion related reactions from Doses 2 to 6 once pre-infusion day dex was given. Conclusions: Premedicating with oral dex 8mg BD for 3 days starting 2 days prior to ami was able to prevent all-grades infusion related reactions. This approach should be confirmed in a larger study given the ease of such an intervention to make ami infusion safer. [Table: see text]
Preliminary dose escalation results from a first-in-human, phase I/II study of GB263T, a novel EGFR/cMET/cMET trispecific antibody, in patients with advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC).
Authors: Yang Jin-Ji , Pavlakis Nick , Xie Fan , Wu Yi-Long 
Published: June 2023

e21085 Background: GB263T, a novel trispecific antibody directed against EGFR and cMET, adopts the design of two humanized VHH antibodies that recognize two different cMET epitopes, in which a conformational change induced by the first VHH binding exposes the second epitope for the second VHH to bind. Sequential binding of the two VHH antibodies to cMET increases tumor specificity, which results in widening of the safety window. In vitro studies show that GB263T induces better antigen-antibody molecular endocytosis, more completely blocks the signal transduction pathway, and has better ADCC activity compared to a benchmark. In addition, GB263T has demonstrated promising pre-clinical activity in models with various EGFR/cMET alterations. Here, we report the preliminary dose escalation results of the first-in-human phase I/II study of GB263T in patients (pts) with advanced EGFRm NSCLC (NCT05332574). Methods: This multicenter (China and Australia), phase I/II study was conducted using an accelerated titration method followed by a traditional 3+3 design for dose escalation. Pts with EGFRm NSCLC with prior EGFR TKI and platinum-based chemotherapy were enrolled. GB263T was given at 140-1680 mg (5 dose cohorts) IV weekly for the first two 28-day cycles and biweekly thereafter. Objectives were to evaluate the safety and tolerability, determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D), and assess the pharmacokinetics, immunogenicity, and preliminary efficacy of GB263T. Results: As of Feb 7, 2023, 6 pts were treated: 140mg (n = 1), 420mg (n = 1), 840mg (n = 3), 1260mg (n = 1). The enrolment of the 1260mg cohort is ongoing. All pts had received previous third-generation EGFR-TKI and platinum-based chemotherapy. Medium treatment duration was 49.5 days (range 2-113). No DLTs were observed. Five (83.3%) pts experienced treatment-related AEs (TRAEs), and all TRAEs were mild (grade 1/2): infusion related reaction (n = 3, 50%), rash (n = 2, 33%), mouth ulcer (n = 1, 17%), fatigue (n = 1, 17%), GGT increased (n = 1, 17%), ALP increased (n = 1, 17%) and direct bilirubin increased (n = 1, 17%). There were no treatment-related discontinuations. Among five response-evaluable pts, three (60%) achieved stable disease (SD). Tumor shrinkage was observed in all three SD pts, with a maximum reduction of 17% in the target lesion. All three SD pts remained on treatment at data cutoff. Conclusions: Results to date demonstrate a favorable safety profile with early signal of clinical activity. Continued dose escalation and clinical investigation of GB263T is ongoing. Updated data will be presented. Clinical trial information: NCT05332574 .
Analysis on real-world chemotherapy outcomes in patients (pts) with tyrosine kinase inhibitor (TKI) resistant advanced EGFR-mutant non–small-cell lung cancer (NSCLC) in the United States.
Authors: Oksen Dina , Boutmy Emmanuelle , Ellers-Lenz Barbara , Karachaliou Niki , Le Xiuning 
Published: June 2023

e21088 Background: Chemotherapy is the current standard of care for pts with EGFR-mutant NSCLC whose tumor develops EGFR TKI resistance. We are conducting a real-world study to understand resistance mechanisms to EGFR TKI and outcomes with subsequent therapies (targeted and non-targeted). Here we report outcome results for standard of care given after resistance to a first-line (1L) EGFR TKI. Methods: This is a non-interventional descriptive cohort study using electronic medical record data and biomarker data from the United States TEMPUS database, which will continue until end of 2024 with new pts entering the study cohort over time. The study period for this reported analysis on real-world chemotherapy outcomes was any time until June 2022. Drug resistance was defined as disease progression on an EGFR TKI. Pts entering the study cohort were adult, with stage IIIB–IV NSCLC, had received an EGFR TKI either as a monotherapy or in combination with other systemic therapies, and had disease progression after EGFR TKI initiation. Pts were followed after tumor progression and from the initiation of a chemotherapy regimen, to describe treatment patterns and treatment outcomes (real-world progression-free survival [rw-PFS] and overall survival [OS]). Results: Of 21,425 pts with NSCLC, 1,087 patients were eligible for inclusion into the study cohort, with their stage IIIB–IV NSCLC diagnosis spanning from 1999 to 2021. A total of 588 pts (54.1%) received a 1L EGFR TKI and a subsequent second-line (2L) systemic therapy after disease progression. Of these, 100 pts received 2L chemotherapy regimens (platinum-based chemotherapy, n = 48; taxane monotherapy, n = 12; taxane + other chemotherapy, n = 3; pemetrexed, n = 28; other chemotherapy-only regimens, n = 9). Overall, these chemotherapy-treated pts had a median rw-PFS of 4.3 months (95% CI: 3.3, 5.1), and a median OS of 14.2 months (95% CI: 11.8, 22.2). Conclusions: Here, we show that after disease progression on a 1L EGFR TKI, patients had poor disease outcomes on 2L chemotherapy, indicating an unmet medical need as these pts likely developed EGFR TKI resistance. Treatment adaptation based on identified mechanism of resistance such as MET amplification, may improve outcomes for these patients.
Plasma cell-free RNA PD-L1 expression and survival with immune checkpoint inhibitor-based treatment in advanced non-small-cell lung cancer.
Authors: Walker Paul R. , Jayananda Sriraksha , Pasli Melisa , Muzaffar Mahvish 
Published: June 2023

e21090 Background: Tissue PD-L1 protein expression is predictive of immune checkpoint inhibitor (ICI)-based treatment outcomes in advanced non-small-cell lung cancer (aNSCLC). However, tissue PD-L1 can be fraught with tissue acquisition difficulties and tumor heterogeneity. Plasma cell-free RNA (cfRNA) PD-L1 expression assessed with a liquid biopsy potentially overcomes these tissue limitations and could identify additional patients likely to benefit from ICI therapy. Outcome studies validating this novel approach have not been previously reported. Methods: An observational cohort of patients with aNSCLC treated in an academic medical center with 1st-line ICI-based therapies were retrospectively evaluated for a pre-planned endpoint of overall survival (OS) based upon plasma cfRNA PD-L1 expression by a proprietary exosome-free real-time qPCR assay and/or tissue PD-L1 protein expression (Dako 22C3) performed in commercial CLIA/CAP accredited laboratories. Results: Of 75 consecutive aNSCLC patients, 16 (21.3%) were plasma cfRNA PD-L1 positive expression with 6 of these 16 (37%) tissue PD-L1 negative or quantity not sufficient. 35 patients were both tissue and plasma PD-L1 negative and 24 patients tissue PD-L1 positive but plasma PD-L1 negative. Median follow-up 34 months. The plasma PD-L1 or tissue PD-L1 positive patients demonstrated no difference in OS outcomes (median OS 16 months; 3-year landmark OS 30%; hazard ratio (HR) 0.97; 95% CI, 0.44-2.10). The plasma PD-L1 positive patients demonstrated superior OS outcomes compared to tissue and plasma PD-L1 negative patients (median OS 16 months versus 8 months; landmark 3-year OS 30% versus 20%; HR 0.59; 95% CI, 0.31-1.11). The plasma PD-L1 positive patients demonstrated no differing OS outcomes whether tissue PD-L1 positive or negative (median OS 13-16 months; 3-year landmark OS 30%; HR 1.15; 95% CI, 0.32-4.05). Conclusions: In this single-institution aNSCLC patients receiving 1st-line ICI therapy OS outcomes were the same for plasma PD-L1 positive patients vs. tissue PD-L1 positive patients. OS outcomes were superior for patients with positive plasma PD-L1 expression vs. similarly treated patients negative for tissue PD-L1 or plasma PD-L1 expression. In patients with plasma cfRNA PD-L1 expression, there was no OS differences whether tissue PD-L1 protein was positive or negative, suggesting that liquid biopsy might identify additional patients who could benefit from ICI therapy.
Real-world evidence of first-line pembrolizumab plus chemotherapy in metastatic non-squamous NSCLC: A single-centre experience.
Authors: Bose Subhadeep , Syed Khaja Mujtaba , Siva Asha , Wilson Paula , Grist Helen , Murukesh Nishanth 
Published: June 2023

e21091 Background: Pembrolizumab plus chemotherapy is now the standard of care in previously untreated patients with metastatic non-squamous NSCLC post the results of KEYNOTE 189 trial. This study is to evaluate the real world outcomes and toxicity data in similar subset of patients treated with this protocol in a non-trial setting. Methods: We analysed 38 patients who were treated with Pembrolizumab plus Platinum-Pemetrexed from June 2019 to October 2021. We stratified the patients based on age, performance status, smoking habits, PDL1 results, presence of brain metastases. Our primary endpoint was to collect survival outcome (OS and PFS) and toxicity profile. Baseline patient and disease characteristics were compared using the chi-square test. PFS and OS were calculated by Kaplan-Meier method. Data was analyzed using R version 4.1.1. Results: At a median follow-up of 15.6 (10.35 – 27.33) months, the median PFS was 11.1 months (95% CI 8.31-18.4) and median OS was 15.6 months (95% CI 11-27.3). Median OS at 12 months was 60.3 %(95% CI41.9 – 74.5).63% patients had completed all 4 induction cycles and the median of 7 (1-19) maintenance cycles were given. 63% patients had an objective response to induction chemo (56% PR,7% SD).The main toxicity profiles were fatigue (35%), renal impairment (13%), hepatitis (28%), myelosuppression (13%), rash (18.9%), thyroid problems (24%).Grade 3 diarrhea was seen in 8% and pneumonitis in 2.7%.12 patients stopped treatment due to toxicity. Conclusions: In comparison with the seminal Keynote 189 trial, our median PFS was better (11.1 months vs 9 months), however our 12-month OS rates were worse (60.3 vs 69.2%), however this needs a longer follow-up in relation to maintenance treatment to accurately assess this outcome. In general the tolerance has been at par with the reported trials as is evident from the results.[Table: see text]
Real world prognostic utility of body mass index and platelet lymphocyte ratio in first-line immunotherapy response in stage IV non-small cell lung cancer.
Authors: MacDonald Madeline , Hsu Robert , Poei Darin , Leyba Alexis , Chennapan Krithika , Leon Christopher , Diep Raymond , Gaur Kush , Xia Bing , Nieva Jorge J. 
Published: June 2023

e21092 Background: Meta-analyses show that increasing body mass index (BMI) may be associated with improved overall survival (OS) and progression free survival (PFS) compared to those with lower BMIs in patients receiving immunotherapy (IO). Pretreatment elevated platelet lymphocyte ratio (PLR) has been attributed to inferior PFS and OS in patients receiving IO. Our study evaluated real world data of Stage IV Non-Small Cell Lung Cancer (NSCLC) patients receiving first line (1L) treatment regimens involving immunotherapy while evaluating prognostic utility of BMI and PLR. Methods: Of the patients treated at USC Norris Comprehensive Cancer Center and LAC+USC Medical Center from 2015-2022, we looked at 75 Stage IV patients without EGFR, ALK, ROS1 mutations who received 1L IO therapy. Primary outcomes included PFS and OS from time of IO with a particular interest for patients with pre-treatment BMI < 22 and PLR > 180. Patients with previous IO exposure were excluded. Kaplan-Meier analysis using log-rank test was performed to evaluate for OS. Multivariate Cox proportion hazards regression was used for multivariate analysis of OS. Results: The median age at start of IO was 67.5 years with 49 (65.3%) males. 24 (32.0%) had BMI < 22. 40/70 (57.7%) had PLR > 180 at the start of 1L IO. Adenocarcinoma was the most common histology 50 (66.7%). 22 (29.3%) had PD-L1 > TPS 50% and 20 (26.7%) had PD-L1 TPS 1-49%. Pembrolizumab was the most common IO used 60/75 (80%) and 43/75 (57.3%) received chemotherapy with IO. Patients with a BMI < 22 had an inferior OS (BMI < 22: 13.1 vs. BMI > 28: 37.4 months (mos), p-value = 0.0420) with a trend towards worse PFS (BMI < 22: 6.2 mos vs. BMI > 28: 16 mos, p = 0.1702). Patients with PLR > 180 had an inferior PFS (4.4 vs. 11.1 mos, p-value = 0.025) and OS (8.3 vs. 23.0 mos, p-value = 0.0277). A composite of BMI < 22 and PLR > 180 had the worst OS (p-value = 0.0385) with a trend towards worse PFS (p-value = 0.1702). (Table 1) Multivariate analysis for OS controlling for age, smoking, gender, PD-L1 TPS, and histology showed that BMI (HR: 0.8739, 95% CI: 0.7966-0.9492) and PLR > 180 (HR: 2.286, 95% CI: 1.102-4.916) were significant for higher mortality risk. Conclusions: Patients with a composite profile of BMI < 22 and PLR > 180 had a significantly worse OS. This highlights the importance for pre-treatment screening for low BMI and high PLR to help provide additional supportive care in these patients prior to IO therapy. [Table: see text]
Patterns of weight change and overall survival (OS) during first-line pembrolizumab treatment in patients with non-small cell lung cancer (NSCLC).
Authors: Li Mingjia , Zhao Songzhu , Chian Kenneth , Kwon Hyunwoo , Jones Nicholas , Khorasanchi Adam , Gauntner Timothy , Coss Christopher C. , Phelps Mitch A. , Spakowicz Daniel , Wei Lai , Alahmadi Asrar , Memmott Regan Michelle , Kaufman Jacob , He Kai , Shields Peter G. , Carbone David Paul , Otterson Gregory Alan , Presley Carolyn J , Owen Dwight Hall 
Published: June 2023

e21094 Background: Cancer-associated cachexia and weight change from treatment-related side effects profoundly influence treatment outcomes for patients with NSCLC. Limited data are available to compare the association between weight change and OS for patients with NSCLC treated with pembrolizumab alone or combined with chemotherapy. Therefore, we evaluated the change in weight after the first cycle of pembrolizumab-based treatments and its association with OS in patients with metastatic NSCLC. Methods: This retrospective study included 306 patients with NSCLC treated with a first line pembrolizumab-based regimen at Ohio State University from 2018-2021. Baseline characteristics were collected within seven days before cycle one treatment. Percent of weight change (PWC) was calculated as (cycle two weight – baseline weight)/baseline weight x 100%. Severe weight loss was defined as ≥75th percentile (PWC ≤-3.5%). Kruskal Wallis test was used to compare the significance of median PWC between treatment groups. Cox proportional-hazards models were used to test associations with survival. Results: The median age was 64.0 (IQR 56.7-72.6) years. The median baseline BMI was 26.1 (IQR 22.4-30.7). There was no difference between the median PWCs of patients treated with pembrolizumab monotherapy (-1.2%, IQR -3.7-0.8%) vs. pembrolizumab with chemotherapy (-1.0%, IQR -3.4-0.6%), p = 0.587. The patients whose weight remained stable (PWC -1% to 1%, n = 87 (28.4%)) had the highest median OS at 45.6 months (95% CI 27.6 – not reached); while those with severe weight loss (PWC ≤-3.5%, n = 78 (25.5%)) and weight gain (PWC ≥1%, n = 65 (21.2%)) had significantly decreased survival with median OS 15.6 (95% CI 9.3-20.9) and 16.3 (95% CI 10.1-25.6) months respectively, overall model p-value < 0.001. The PWC remained significantly associated with OS after adjusting for performance status, PD-L1, and treatment with p < 0.001 (Table 1). Conclusions: For patients with metastatic NSCLC treated with first line pembrolizumab-based regimen, similar PWCs were seen between patients treated with pembrolizumab alone or combined with chemotherapy. Regardless of treatment, weight gain and severe weight loss after the first cycle of treatment were associated with reduced OS. Further in-depth analysis is warranted to investigate the potential causes of weight changes, especially for patients with positive PWC. [Table: see text]
Genomic profiling of cerebrospinal fluid ctDNA to characterize molecular features and monitor intracranial responses of patients with osimertinib-resistant non-small cell lung cancer with leptomeningeal metastases.
Authors: Hua Yichun , Xin Ying , Ding Xiaosheng , An Juan , Zheng Xixi , Zhou Lili , Shi Hui , Xu Weiran , Wei Fang , Wu Qichao , Li Yubin , Zhao Feilong , Huang Depei , Li Xiaoyan 
Published: June 2023

e21095 Background: Leptomeningeal metastasis (LM) indicates an unfavorable prognosis in non-small cell lung cancer (NSCLC). Due to the blood-brain barrier, plasma is not an ideal medium to evaluate osimertinib resistance mechanisms in patients with LM. This study aimed to use cerebrospinal fluid (CSF) as a source of ctDNA for characterizing molecular features and monitoring intracranial responses from patients with leptomeningeal metastases who progressed on osimertinib. Methods: From Jan 2020 to Nov 2022, 65 patients with advanced NSCLC, including 32 osimertinib-treated patients, 6 other TKI-treated patients, and 27 treatment-naïve patients, in Beijing Tiantan Hospital were enrolled in this study. CSF obtained via lumbar puncture was used for targeted sequencing and cytologic analysis. In parallel, paired plasma from 35 patients was also subjected to targeted sequencing. Results: Among 65 patients, the overall positive rate of CSF ctDNA was 77% (50/65), 94% (34/36) in patients with LM, and 55% (16/29) in patients with brain parenchymal metastases (p = 0.0002). CSF ctDNA analysis had a higher consistency with the cytologic diagnosis of LM than imaging. Among the patients cytologic diagnosed with LM, 94% (32/34) of the patients had positive CSF ctDNA analysis at the same time, while the positive diagnostic rate of imaging was only 39% (13/33). EGFR alteration was found in 97% (29/30) CSF of patients with LM who progressed on Osimertinib, including L858R (67%), exon19 deletion (17%), T790M (10%), L861Q (7%), G719X (7%) and L747X (7%). Other recurrent genes discovered in the CSF were TP53 (73%), PIK3CA (43%), ERBB2 (33%), POLE (33%), ALK (27%), BRCA2 (27%), BRAF (23%), BRCA1 (23%), RB1 (20%) and PALB (20%). In the 35 paired CSF-plasma pairs, more alterations were uniquely found in CSF than in plasma (71% vs 17%), and only 12% of alterations were shared. Serial surveillance of CSF ctDNA in 7 cases of LM patients treated with osimertinib found that the VAF of CSF ctDNA showed a highly consistent trend with the tumor cell fraction of cytology. Conclusions: For NSCLC patients with LM, liquid biopsy of CSF is more sensitive than plasma to characterize osimertinib-resistant mechanisms and guide follow-up treatment. Serial surveillance of CSF ctDNA dynamics may reflect the intracranial tumor responses, which still needs to be validated in a large sample size.