bluuebunny/crossref_metadata_2025 huggingface dataset:
Real world EGFR testing practices for non-small cell lung cancer by thoracic pathology laboratories across Europe.
Authors: Hofman Paul ,   on behalf of the Pulmonary Pathology Working Group of the European Society of Pathology
Published: June 2023

e21064

Background: Testing for EGFR mutations is an essential recommendation in both the ESMO and ASCO guidelines for metastatic non-squamous NSCLC, and is considered mandatory in European countries. However, in practice, considerable challenges are often faced when performing routine biomarker testing, including access to testing, inadequate tissue samples, and long turnaround times (TATs). Methods: In order to evaluate the real-world EGFR testing practices of thoracic pathology laboratories across Europe, an online survey was set up and validated by The Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories across Europe. The retrospective survey focused on the laboratory organisation and daily practice of pathologists and molecular biologists between 2018 and 2021, and covered the clinical circumstances in which EGFR testing was performed, sample types used, molecular biology techniques performed, average TATs for determining EGFR status, annual EGFR testing rates, laboratory accreditation, and external quality assessment. Results: TATs varied greatly depending on different parameters (notably relating to testing practices and methods used) both between and within countries. TATs were slightly (but non-significantly) faster for liquid biopsy samples (Mean: 7 days, IQR 4.5-12.5) when compared to tissue samples (mean 7 days, IQR 5-15) but were reported to take as long as 20 or 30 days, respectively. Discrepancies in TATs may be due in part to reflex testing practices, as 20% (11/54) of laboratories performed EGFR testing only at the request of the clinician. Many laboratories across Europe still favour targeted sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques, and 45.1% indicated they used targeted sequencing followed by NGS, depending on the case. Reported testing volumes were consistent over time with no significant decrease in the number of EGFR tests performed observed in 2020, despite the increased pressure and difficulties faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42% of molecular biology laboratories for targeted sequencing, and by 42.3% for NGS. 92% (49/53) of laboratories indicated they regularly participate in an EQA scheme. Conclusions: The results of the survey highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there remains large variability in testing capabilities, reflex testing practice and laboratory accreditation, which stresses the urgent need to harmonize budgets and reimbursement in Europe, in addition to harmonization of the technologies and decision-making algorithms.
Genomic profiling in advanced NSCLC in Italy: First results of NERoNE (NSCLC Emilia Romagna Next Generation Sequencing Evaluation) project.
Authors: Bertolini Federica , Alberti Giulia , Petracci Elisabetta , Bettelli Stefania , Ulivi Paola , Cravero Paola , Guaitoli Giorgia , Zanelli Francesca , Burgio Marco Angelo , Andrikou Kalliopi , Pagano Maria , Verlicchi Alberto , Calistri Daniele , Flospergher Michele , Mastrodomenico Luciana , Maur Michela , Di Emidio Katia , Dominici Massimo , Pinto Carmine , Delmonte Angelo
Published: June 2023

e21077

Background: The NERoNE Project evaluates the use of Next Generation Sequencing (NGS) in molecular profiling of advanced NSCLC (aNSCLC) patients (pts) in three Oncology Units (OU) of Emilia Romagna Region aiming to clarify the impact of such extensive tool in characterizing different NSCLC subpopulations. Methods: Since January 2020 to December 2022, 970 sequential aNSCLC pts from three OU (AUSL-IRCCS of Reggio Emilia, Modena University Hospital and IRST Meldola) were profiled by NGS. Samples from Modena and Reggio Emilia were analyzed at Modena University Hospital Molecular Pathology Lab using Myriapod IL- 56G, Cancer Panel DNA, Cancer Panel RNA, Oncomine DX Target Test Assay, Oncomine Focus Assay. Samples from IRST Meldola were processed at its Molecular Diagnostic Unit by Myriapod NGS cancer panel DNA e RNA, Oncomine Focus Assay and Oncomine Comprehensive Assay v3.We considered molecular alterations with available target therapies in Italy: EGFR mutations (mut) (exon 18,19,20,21), KRAS mut, BRAF V600E mut, ALK, ROS1, RET and NTRK rearrangements, MET exon 14 skipping mut, ErbB2 mut, FGFR 1-3 mut. PDL1 expression was assessed by standard immunohistochemistry on 486 pts. Results: Among 970 pts, 501 with at least one mut (52%) were considered for analysis: 266 were female (53%), mean age was 69 ± 11 years (min-max: 33-94) and 473 pts (94%) had adenocarcinoma. Molecular features are listed in table 1. Distribution of mut among ages, categorized as < 60, 60-70 and > 70 y, was similar, EGFR activating mut were most prevalent in females; KRAS mut (G12C and non G12C) were most prevalent in males; 41 pts had co-mutations (8.2%): the most frequent co-mut were EGFR mut (27%). PDL1 expression was < 1% 129 (27%), 1-49% 211 (43,4%) and ≥50% 146 pts (30%). The majority of pts with EGFR activating mut had PDL1 < 50%. Conclusions: NERoNE evaluates data from NGS profiling of three OU mapping key actionable molecular alterations in a large population of aNSCLC also accounting for PDL1 status. This preliminary analysis will be the starting point for further evaluations in order to improve the personalized approach to aNSCLC. [Table: see text]
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.
Multicenter pharmacokinetic study of pembrolizumab for non-small cell lung cancer in adults aged older than 75 years.
Authors: Yamanaka Yuta , Kurata Takayasu , Watanabe Kageaki , Hosomi Yukio , Horinouchi Hidehito , Ohe Yuichiro , Nakahara Yoshiro , Asao Tetsuhiko , Saeki Sho , Tsubata Yukari , Fujita Yu , Sakakibara-Konishi Jun , Mizugaki Hidenori , Ouchi Mayu , Yagishita Shigehiro , Hamada Akinobu
Published: June 2023

e21098

Background: Pembrolizumab (Pemb) is a key drug for the treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, there are limited data on Pemb use in older adults aged > 75 years with NSCLC, especially in terms of pharmacokinetics (PK). Methods: This open-label multicenter observational study aimed to evaluate real-world data on the safety, efficacy, and blood concentrations of Pemb (both monotherapy and combination therapies) in older adults with NSCLC. Blood samples for PK analysis were collected immediately before Pemb administration. Quantitative Pemb concentrations were measured by liquid chromatography-mass spectrometry. Results: We enrolled 100 patients from July 2019 to September 2020; one patient was excluded due to stage migration. Patient characteristics were as follows: median age, 78 (75–87) years; male/female ratio, 70/29; performance status (PS) 0–1/2–3, 85/14; adenocarcinoma/squamous cell carcinoma/others, 62/25/12; stage I–III/IV/postoperative recurrence (TNM 7th edition), 9/60/30; PD-L1 TPS < 1%/1%–49%/≥50%, 12/31/48; and monotherapy/combination therapy, 65/34. The best overall efficacy was CR/PR/SD/PD (7/40/32/20), and the response rate was 47.5%. The median progression-free survival (PFS) and overall survival (OS) were 8.0 and 19.0 months, respectively. The adverse event profile was generally similar to that reported in previous studies. In total, 77 blood samples were collected immediately before the second cycle (C1 trough). Although no clear association between Pemb concentrations and patient background was found, PFS and OS were significantly shortened in the population with low C1 trough, a population characterized by lower PS, high number of metastatic organs at the beginning of treatment, and low blood albumin level. Conclusions: In older adults aged > 75 years with NSCLC and low albumin levels and PS and a high number of metastatic organs, C1 trough of Pemb is reduced and not expected to prolong PFS and OS. Clinical trial information: UMIN000036606 .
First-line HDACi plus tislelizumab combined with chemotherapy in advanced NSCLC.
Authors: Wang Lijie , Gao Ming , Yang Wenyu , Wang Chunyu , Wang Ting , Jing Fangfang , Ma Junxun , Zhang Fan , Tao Haitao , Hu Yi
Published: June 2023

e21100

Background: Resistance to ICIs remains a challenge. HDAC inhibitors may synergize with PD-1 antibodies by inducing and activating NK cell and cytotoxic T cell (CTL) -mediated cellular immunity. Tislelizumab is an anti-PD-1 mAb approved for the treatment of NSCLC. Chidamide, a subtype-selective HDACi. This Phase 2 study assessed antitumor activity and tolerability of chidamide and tislelizumab combined with chemotherapy in advanced NSCLC. Methods: This was an open-label, prospective study. Patients with histologically or cytologically confirmed NSCLC (stage IIIB-IV) without prior systemic treatment was enrolled. EGFR/ALK mutation or fusion and symptomatic brain metastases were ineligible. Patients received chidamide 20 mg twice weekly orally, tislelizumab 200 mg Q3W intravenously, chemotherapy Q3W(≤4~6 cycles) until unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was ORR. Secondary endpoints include DCR、PFS、OS and safety. Tumor response was assessed using RECIST v1.1. Results: 20 patients were enrolled in the study. At the data cut-off February 10, 2023, the median age was 63.5 years (range: 49-75) and all patients were male 90% of who with smoking history. Most patients were stage IV(95%) .40% of the patients whose PD-L1 expression was positive (PD-L1 TPS≥1%) . The confirmed ORR was 75%(95%CI:56.0-94.0) and 1 patient was evaluated as CR. The DCR was 100%. The median follow-up was 13.1 months, median PFS was 11.7 months (95%CI:7.4m-16.0m) and 1-year PFS rate was 55.6% (95%CI:43.7%-67.5%). Median OS was not reached. 11 patients (55.0%) had ≥ Grade 3 TRAEs. The most common ≥Grade 3 TRAEs were leukopenia (25.0%), neutropenia (20.0%) and thrombocytopenia (15%). Conclusions: Adding HDACi(Chidamide) plus Tislelizumab combined with chemotherapy showed encouraging antitumor activity and a favorable safety profile as first-line therapy for advanced NSCLC. Clinical trial information: ChiCTR2000041542 . [Table: see text]
An individual patient-level meta-analysis of non–small-cell lung cancer leptomeningeal metastases treated with epidermal growth factor receptor inhibitors.
Authors: Bian David Jiahua , Lazaratos Anna-Maria , Maritan Sarah M. , Quaiattini Andrea , Zeng Zhimin , Zhu Zhengfei , Sener Ugur , Malani Rachna , Kim Yu Jung , Ichihara Eiki , Bouganim Nathaniel , Dankner Matthew
Published: June 2023

e21118

Background: Leptomeningeal metastasis (LM) is a debilitating condition associated with advanced non-small cell lung cancer (NSCLC). When driver mutations in the epidermal growth factor receptor (EGFR) are identified, targeted therapies (TT) represent an appealing therapeutic strategy. However, the efficacy of TT for LM is unknown as LM patients are routinely omitted from clinical trials. Methods: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of EGFR TT in EGFR-mutant NSCLC LM in accordance with PRISMA guidelines. EGFR-TTs evaluated were erlotinib, gefitinib, icotinib, afatinib, dacomitinib, osimertinib, zorifertinib, and furmonertinib. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS). To assess differences between groups, shared frailty Cox regression models were used to estimate the hazard ratio (HR), 95% confidence interval (CI) and p-value. Results: 7780 abstracts were screened, identifying 126 publications with 232 patients, corresponding to 272 lines of EGFR-TT for NSCLC LM which met inclusion criteria. The overall median PFS (mPFS) in patients receiving any EGFR-TT was 9.15 months and the median overall survival was 14.5 months. In univariable analyses, osimertinib was associated prolonged PFS compared to other EGFR-TT, (mPFS of 11 versus 8 months, HR = 0.64; 95% CI: 0.44-0.93; P = 0.02). Osimertinib was numerically associated with prolonged OS compared to other EGFR-TT (mOS 16.8 months versus 13.6 months, HR = 0.72; 95% CI 0.44-1.17, P = 0.188). In multivariable analyses, ECOG performance status > 2 was independently associated with shortened PFS (mPFS 10 versus 8 months, HR = 1.54, 95% CI: 1.26-3.04; P < 0.05) and OS (mOS 16.5 versus 10 months, HR = 3.33, 95% CI: 1.80-6.18; P < 0.05). Conclusions: In the largest cohort of NSCLC LM treated with EGFR TT compiled to date, osimertinib is associated with marginally improved outcomes compared to other EGFR TTs. ECOG performance status is an independent predictor of prognosis in these patients. These results highlight the need for prospective studies for this difficult to treat patient population.
Molecular characterization of nectin-4 in non-small cell lung cancer subtypes.
Authors: Hsu Robert , Gandhi Nishant , Kim Chul , Mamdani Hirva , Halmos Balazs , Vanderwalde Ari M. , Oberley Matthew James , Ma Patrick C. , Liu Stephen V. , Nieva Jorge J.
Published: June 2023

e21119

Background: Nectin-4 (Nectin cell adhesion molecule-4) is a tumor associated antigen overexpressed in multiple solid tumor types. Studies show that over 60% of NSCLC are nectin-4 overexpressed. As enfortumab vedotin, an antibody-drug conjugate directed against nectin-4, has been FDA approved for advanced urothelial carcinoma, this holds treatment implications. Here, we investigated nectin-4 expression in NSCLC subtypes. Methods: 27,607 NSCLC tumors were tested for whole transcriptome sequencing (WTS, NovaSeq) and NextGen DNA sequencing (592 gene panel or whole exome sequencing, WES) at Caris Life Sciences (Phoenix, AZ). Tumors were analyzed overall in quartiles by nectin-4 expression (Q4-greatest, Q1-least) and further analyzed in the adenocarcinoma (AD) and squamous carcinoma (SQ) cohorts. PD-L1 expression was tested by IHC (Dako 22C3). Immune cell populations were estimated by QuanTISeq. Statistical significance was determined using Chi-square/Fisher-Exact/Mann-Whitney U tests and adjusted for multiple comparisons (q < 0.05). Results: We saw significantly greater expression of nectin-4 in SQ (median TPM- 15.68) versus AD tumors (median TPM - 9.88) (p < 0.05). We saw a greater prevalence of NFE2L2, STK11, ERBB2 mutations and genomic loss of heterozygosity (LOH) but a lower percentage of PD-L1+ tumors in Q4 vs Q1 tumors (all q-value < 0.05, Table 1). mRNA expression of immune checkpoints PDL1, CTLA4, CD80, CD86, HAVCR2, and IDO1 was increased in Q4 tumors (1.1-1.3-fold, all q < 0.05). Q4 tumors had reduced estimates of M1 macrophages, regulatory T cells (Tregs), and CD8+ T cells and increased estimates of neutrophils and NK cells. The association of nectin-4 expression with the immune landscapes of AD and SQ was similar. Q4 tumors in AD and SQ displayed increased expression of the above-mentioned immune checkpoints (q < 0.05). In AD and SQ, estimates of M1 macrophages, Tregs, and CD8+ T cells were reduced, but neutrophils and NK cells were increased in Q4 tumors (q < 0.05). The pattern of molecular alterations was different in AD and SQ. While KEAP1, STK11 and ERBB2 mutations were significantly enriched in AD Q4 tumors, NFE2L2 mutations were significantly enriched in SQ Q4 tumors (Table 1). Prevalence of LOH was higher and PD-L1+ tumors was lower in Q4 tumors in both AD and SQ (Table 1). Conclusions: NFE2L2 alterations in SQ and STK11, KEAP1 mutations in AD, which are associated with poor immunotherapy (IO) response, were enriched in Q4 tumors. This suggests that the immune landscape associated with high nectin-4 expression in NSCLC may be driven by the dysregulated KEAP1-NFE2L2 pathway. Targeted therapy towards nectin-4 may benefit these NSCLC subtypes that do not respond well to IO. [Table: see text]
Yttrium-90 radioembolization for lung cancer metastases: Small institutional experience.
Authors: Kovalenko Iuliia , Ng Wern Lynn , Nasrollahi Elham , Sangha Lillian , Proskuriakova Ekaterina , Wert Yijin , Reninger Charles , Hoffman Todd
Published: June 2023

e21122

Background: Yttrium-90 radioembolization (Y-90) is a local cancer therapy which can provide quality of life improvement with minimal systemic toxicity. Yet, it remains underused in nonconventional cancers malignancies including lung cancer liver metastases. We present institutional experience in Central PA of treating metastatic liver disease in lung cancer patients. Methods: We performed retrospective analysis of patients with lung cancer liver metastasis who underwent Y90 in a 5-year period at the UPMC Harrisburg. Modified RESIST criteria were used to assess response rates. Common terminology criteria for adverse events v3.0 was used to grade adverse events (AEs). Descriptive statistics were reported including median and range. Results: A total of 7 patients were included in the study with median age of 67. Median time from diagnosis was 13.7 months (5-41), median number of metastases was 3 (1-4), and median number of previous systemic therapies was 1 (1-4). Five patients have received two Y-90 procedures while two patients have received one Y90 procedure. All patients achieved liver partial response with median sustained response of 9.4 months (2-36). A total of 3 patients (42%) developed Grade 1 AEs including rash, abdominal pain, and liver enzymes elevation. Only two patients (28%) developed Grade 3 AEs (liver enzymes elevation). Patient’s characteristics and treatment outcomes are listed in the Table 1. Conclusions: Our institutional experience supports growing body of literature demonstrating safety of Y-90 radioembolization for the treatment of metastatic lung cancer to the liver. Heterogeneity in the individual patient response is multifactorial with further investigation required to understand which patients and at what point in their treatment would benefit from treatment the most. [Table: see text]
Circulating tumour DNA (ctDNA) as a predictor of clinical outcome in non-small cell lung cancer undergoing targeted therapies: A systematic review and meta-analysis.
Authors: Zaman Farzana Yasmin , Subramaniam Ashwin , Afroz Afsana , Samoon Zarka , Zwieky Walid , Arulananda Surein , Alamgeer Muhammad
Published: June 2023

e21124

Background: Liquid biopsy (LB) analysis using circulating-tumour DNA (ctDNA)/cell-free DNA (cfDNA) is an emerging alternative to tissue profiling in non-small cell lung cancer (NSCLC). LB is used to guide treatment decisions, detect resistance mechanisms, and predicts responses, and therefore outcomes. This systematic review and meta-analysis evaluated the impact of LB quantification on clinical outcomes in molecularly altered advanced NSCLC undergoing targeted therapies. Methods: We searched Embase, MEDLINE, PubMed and Cochrane Database, between 01/01/2000 and 01/08/2022. The primary outcome was progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate (ORR), sensitivity and specificity of the test. Age stratification was performed based on the mean age of the individual study population. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS). Results: Twenty-seven studies reporting 2424 patients were included. Eleven studies (n = 1359) reported an association of baseline ctDNA levels, while 16 studies (n = 1649) reported an association of dynamic ctDNA changes to treatment, with clinical outcomes of PFS and/or OS. Baseline ctDNA-negative patients had higher PFS (pooled hazard ratio [pHR] = 2.97; (95%CI: 1.92-4.85; I2= 97.4%), and OS (pHR = 3.49; (95%CI: 1.73-6.95; I2= 84.2%), than ctDNA-positive patients. Egger’s test suggested publication bias (p < 0.001). Early reduction/clearance of ctDNA levels after treatment improved PFS (pHR = 3.78; 95%CI: 1.91-7.38; I2= 98.4%) and OS (pHR = 2.20; 95%CI: 1.49-3.28; I2= 90.6%), compared to those with no reduction/persistence of ctDNA levels. The PFS was comparable for patients stratified by age (age ≤60 years [pHR = 2.92; 95%CI: 1.43-5.93; I2= 98.3 %] vs. age > 60 years [pHR = 3.94; 95%CI: 1.54-10.07; I2= 83.6 %]). The sensitivity analysis based on study quality (NOS) demonstrated improved PFS only for good quality studies (pHR = 3.67; 95%CI: 1.79-7.54; I2= 91.6 %), but not for poor or fair quality studies. Conclusions: This large systematic review, despite heterogeneity, found that baseline negative ctDNA levels, and early reduction in ctDNA following treatment are strong prognostic markers for PFS and OS in patients undergoing targeted therapies for advanced NSCLC. Future randomised clinical trials should incorporate serial ctDNA monitoring to further establish the clinical utility in advanced NSCLC management. Systematic review registration: PROSPERO registration No. CRD42022347791 Keywords: non-small cell lung cancer; NSCLC; liquid biopsy; circulating tumour DNA; ctDNA; progression-free survival; targeted therapies.
Predictors of benefit to radiation for oligoprogressive disease in EGFR-mutant metastatic non-small cell lung cancer patients treated with osimertinib.
Authors: Chen Monica F , Ma Jennifer , Kris Mark G. , Gomez Daniel Richard , Yu Helena Alexandra
Published: June 2023

e21127

Background: While osimertinib has transformed the treatment paradigm of EGFR-mutant lung cancers (EGFR+ LC), all patients inevitably progress. Oligoprogression is a common pattern of progression for which radiation therapy (RT) can be utilized to prolong the time on osimertinib. However, data supporting the benefit of osimertinib in prolonging progression is limited. Furthermore, predictors of response to RT in the setting of oligoprogression are unknown. We aim to identify clinical and genomic factors associated with robust progression-free survival (PFS) after RT for oligoprogression in EGFR+ LC in patients treated with osimertinib. Methods: Patients with metastatic EGFR+ LC on osimertinib who underwent radiation from 2010 to 2022 for oligoprogression (i.e. progression in 5 or less lesions) were identified. Patients received RT to all active sites of intra- and extra- thoracic disease. Patients who progressed within 3 months of radiation therapy were classified as “rapid progressors,” and those that had longer PFS were “late progressors.” All cases underwent clinical and genomic annotation. Comparisons of categorical variables were performed by Fisher’s exact test. Results: 84 patients were identified who underwent RT for oligoprogression on osimertinib, of which 25% (n = 21) were rapid progressors. Median time from radiation to subsequent progression was 6 months (range 1-26mo) and upon progression most patients had growth of more than one lesion (71%). Median time to death or last follow-up was 13.5 months (range 1-48mo). There was no significant difference in gender, ethnicity, and baseline KPS between rapid and late progressors. Patients with baseline exon 19 deletion (63% vs 76%, p = 0.3) and atypical mutations (14% vs 3%, p = 0.1) were more likely to be rapid progressors while those with exon 21 L858R (10% vs 33%, p = 0.03) were more likely to be late progressors. Among the rapid progressors, 50% underwent radiation to the lung, 10% to the brain, 35% to the bone, and 5% to lymph nodes. Median size of the largest lesion and number of lesions was similar between the two groups (rapid 2.5 cm and 1.5 lesions vs late 2.7 cm and 1 lesion). In-field recurrence rate was 18% and did not differ between rapid and late progressors (14% vs 19%). Conclusions: Radiation therapy for oligoprogression results in clinically meaningful time on osimertinib beyond progression for many patients. However, 25% of patients rapidly progress after radiation therapy and should be directed to switch systemic therapy. Further study is needed to better elucidate benefit at the time of radiation, so that the systemic treatment approach for these patients can be optimized.