JTO Clinical and Research Reports最新文献

{"title":"Humanized Mouse Models for Immuno-Oncology Research: A Review and Implications in Lung Cancer Research","authors":"Cheol-Kyu Park MD, PhD ,&nbsp;Maryam Khalil BSc ,&nbsp;Nhu-An Pham PhD ,&nbsp;Stephanie Wong BSc ,&nbsp;Dalam Ly PhD ,&nbsp;Adrian Sacher MD, FRCPC ,&nbsp;Ming-Sound Tsao MD, FRCPC","doi":"10.1016/j.jtocrr.2024.100781","DOIUrl":"10.1016/j.jtocrr.2024.100781","url":null,"abstract":"<div><div>Cancer immunotherapy has brought significant clinical benefits to patients with cancer, including those with lung cancer. Patient-derived tumor xenograft mouse models have become the preferred animal model for translational cancer research and preclinical studies. Given the unmet need for improved predictive models in immuno-oncology, humanized mouse models which are co-engrafted with both human tumors and immune system components have been used to investigate novel immunotherapeutics. These models have similarly been used to predict immune-related adverse events and to develop predictive biomarkers. This review summarizes key concepts related to humanized mouse models. We highlight the various approaches to generate them, factors that are critical to successfully establishing such models, their respective limitations, and considerations in model selection for preclinical lung cancer immuno-oncology research and therapeutic studies.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 3","pages":"Article 100781"},"PeriodicalIF":3.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143174198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Solid Predominant Histology and High Podoplanin Expression in Cancer-Associated Fibroblast Predict Primary Resistance to Osimertinib in EGFR-Mutated Lung Adenocarcinoma","authors":"Yuji Uehara MD ,&nbsp;Hiroki Izumi MD, PhD ,&nbsp;Tetsuro Taki MD, PhD ,&nbsp;Tetsuya Sakai MD, PhD ,&nbsp;Hibiki Udagawa MD, PhD ,&nbsp;Eri Sugiyama MD, PhD ,&nbsp;Shigeki Umemura MD, PhD ,&nbsp;Yoshitaka Zenke MD, PhD ,&nbsp;Shingo Matsumoto MD, PhD ,&nbsp;Kiyotaka Yoh MD, PhD ,&nbsp;Shoko Kubota MD, PhD ,&nbsp;Keiju Aokage MD, PhD ,&nbsp;Naoya Sakamoto MD, PhD ,&nbsp;Shingo Sakashita MD, PhD ,&nbsp;Motohiro Kojima MD, PhD ,&nbsp;Michiko Nagamine MD, PhD ,&nbsp;Yukio Hosomi MD, PhD ,&nbsp;Masahiro Tsuboi MD, PhD ,&nbsp;Koichi Goto MD, PhD ,&nbsp;Genichiro Ishii MD, PhD","doi":"10.1016/j.jtocrr.2024.100779","DOIUrl":"10.1016/j.jtocrr.2024.100779","url":null,"abstract":"<div><h3>Introduction</h3><div>Resistance to EGFR tyrosine kinase inhibitors is influenced by tumor-intrinsic and -extrinsic factors. We investigated the impact of tumor cell histology and tumor microenvironment on the efficacy of osimertinib.</div></div><div><h3>Methods</h3><div>We evaluated surgically resected adenocarcinoma from patients treated with first-line osimertinib at the National Cancer Center Hospital East (2016–2023), evaluating clinicopathologic characteristics, tumor cell histology, podoplanin expression in cancer-associated fibroblasts (CAFs) identified by immunohistochemistry, and outcomes. We also investigated HGF mRNA expression levels, using The Cancer Genome Atlas Program and Singapore Oncology Data Portal cohorts.</div></div><div><h3>Results</h3><div>The study included 93 patients. Solid (n = 19) versus non-solid predominant (n = 74) histology was not associated with worse disease-free survival after surgery (<em>p</em> = 0.12), but was significantly associated with worse progression-free survival (PFS) and overall survival following osimertinib treatment (<em>p</em> = 0.026, <em>p</em> = 0.004). Similarly, high-podoplanin (n = 31) versus low-podoplanin (n = 62) expression in CAFs was not associated with worse disease-free survival after surgery (<em>p</em> = 0.65), but was significantly associated with worse PFS and showed a trend towards worse overall survival following osimertinib treatment (<em>p</em> &lt; 0.001, <em>p</em> = 0.11). In the multivariable analysis, solid predominant histology and high-podoplanin expression in CAFs were independently associated with worse PFS. In the cohorts of The Cancer Genome Atlas Program and Singapore Oncology Data Portal, <em>EGFR</em>-mutated lung adenocarcinoma with solid predominant histology or high-podoplanin expression exhibited significantly higher HGF expression.</div></div><div><h3>Conclusions</h3><div>Solid predominant histology and high-podoplanin expression in CAFs predicted osimertinib resistance, potentially guiding the selection of patients for more intensive treatments beyond osimertinib monotherapy.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 3","pages":"Article 100779"},"PeriodicalIF":3.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143348095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Access to Diagnostics and Treatment for People With Metastatic EGFR-Positive NSCLC: Lessons From Project PRIORITY","authors":"Jill Feldman MA ,&nbsp;Ivy Elkins MBA ,&nbsp;Zofia Piotrowska MD ,&nbsp;Bellinda L. King-Kallimanis PhD ,&nbsp;Tendai Chihuri MD ,&nbsp;Carly Johnson BS ,&nbsp;Alecia Clary PhD ,&nbsp;Teri Kennedy MA ,&nbsp;Upal Basu Roy PhD, MPH","doi":"10.1016/j.jtocrr.2024.100782","DOIUrl":"10.1016/j.jtocrr.2024.100782","url":null,"abstract":"<div><h3>Introduction</h3><div>The treatment landscape for people diagnosed with EGFR-mutated (EGFR-m) NSCLC has rapidly evolved, yet there remains limited self-reported information about the lived experience. In this paper, we describe the clinical characteristics and treatment experiences of people living with EGFR-m lung cancer from Project PRIORITY, a patient-driven study.</div></div><div><h3>Methods</h3><div>An online survey was distributed among the EGFR Resisters community between April 2019 and January 2020. The survey captured participants’ demographics and lung cancer risk factors, diagnostic and treatment pathways, and prevalence of side effects. Descriptive statistics were used and included subgroups based on residency and cancer stage.</div></div><div><h3>Results</h3><div>Of the 425 participants, most were female (67%), under 60 years old (53%), and resided in the United States (74%). The most frequently reported symptom at diagnosis was cough (54%), though 18% reported no symptoms. In addition, 89% reported receiving at least one tyrosine kinase inhibitor (TKI); osimertinib was the most prescribed first-line TKI for stage IV participants diagnosed after 2017. Participants residing in the United States were more likely to have access to advanced diagnostic (next-generating sequencing) and newer treatments such as osimertinib. Just under half of the sample (47%) had experienced progressive disease and were no longer on first-line treatment.</div></div><div><h3>Conclusion</h3><div>The TKI era has been practice changing; however, little is understood from the perspective of people living with EGFR-m NSCLC. This paper is the first to explore this and found it is possible to have people self-report complex health information about their lung cancer. In addition, although most participants were diagnosed after osimertinib became guideline-recommended treatment, disparities in treatment were identified.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 3","pages":"Article 100782"},"PeriodicalIF":3.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143348096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"J-TAIL-2: A Prospective, Observational Study of Atezolizumab Combined With Carboplatin and Etoposide in Patients With Extensive-Stage SCLC in Japan","authors":"Eisaku Miyauchi MD, PhD ,&nbsp;Makoto Nishio MD, PhD ,&nbsp;Kadoaki Ohashi MD, PhD ,&nbsp;Atsushi Osoegawa MD, PhD ,&nbsp;Eiki Kikuchi MD, PhD ,&nbsp;Hideharu Kimura MD, PhD ,&nbsp;Yasushi Goto MD, PhD ,&nbsp;Junichi Shimizu MD, PhD ,&nbsp;Hiroshige Yoshioka MD, PhD ,&nbsp;Ichiro Yoshino MD, PhD ,&nbsp;Toshihiro Misumi PhD ,&nbsp;Nobuyuki Katakami MD, PhD ,&nbsp;Masahide Oki MD, PhD ,&nbsp;Takashi Kijima MD, PhD ,&nbsp;Kenichi Chikamori MD, PhD ,&nbsp;Kazumi Nishino MD, PhD ,&nbsp;Yuki Kobayashi MS ,&nbsp;Asako Miwa BA ,&nbsp;Misa Tanaka MS ,&nbsp;Akihiko Gemma PhD","doi":"10.1016/j.jtocrr.2024.100783","DOIUrl":"10.1016/j.jtocrr.2024.100783","url":null,"abstract":"<div><h3>Introduction</h3><div>On the basis of the IMpower133 trial, atezolizumab plus carboplatin and etoposide (CE) is approved as first-line treatment for extensive-stage (ES)-SCLC. The J-TAIL-2 study evaluated atezolizumab plus CE in routine clinical practice settings.</div></div><div><h3>Methods</h3><div>J-TAIL-2 was a prospective, multicenter observational study in Japan. Patients with ES-SCLC received atezolizumab plus CE in clinical practice. The primary end point was 12-month OS rate. Secondary end points included overall survival (OS), progression-free survival (PFS), and safety in select subgroups, including the IMpower133-unlike (i.e., Eastern Cooperative Oncology Group performance status 2 or more, interstitial lung disease, autoimmune disease) versus IMpower133-like groups.</div></div><div><h3>Results</h3><div>Overall, 403 patients were included; the median age was 71 years, 16.6% (n = 67) had an Eastern Cooperative Oncology Group performance status 2 or more, 26.8% (n = 108) had brain metastasis, 6.9% (n = 28) had interstitial lung disease, 4.0% (n = 16) had autoimmune disease, and 72.7% (n = 293) were IMpower133-unlike. In the efficacy population (n = 399), the 12-month OS rate was 63.7%, median OS was 16.5 months, and median PFS was 5.1 months. In IMpower133-unlike versus IMpower133-like subgroups, the 12-month OS rate was 58.5% versus 77.5%, median OS was 15.5 versus 19.1 months (hazard ratio, 1.32; 95% confidence interval: 0.98–1.77), and median PFS was 4.8 versus 5.4 months (hazard ratio, 1.14; 95% confidence interval: 0.90–1.45). No new safety signals were observed (safety population, n = 400); safety outcomes in the IMpower133-unlike and IMpower133-like subgroups were similar.</div></div><div><h3>Conclusions</h3><div>In J-TAIL-2, atezolizumab plus CE had efficacy in patients with ES-SCLC in clinical practice that was consistent with that in IMpower133. Taken together with the acceptable safety profile, these data support the use of atezolizumab plus CE in patients with ES-SCLC in Japan, including those who would have been ineligible for IMpower133.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 3","pages":"Article 100783"},"PeriodicalIF":3.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143173721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Utility of Combined Tissue and Plasma Next-Generation Sequencing in Patients With Advanced, Treatment-Naïve NSCLC","authors":"Helena Bote-de Cabo MD ,&nbsp;Marco Siringo MD ,&nbsp;Esther Conde MD, PhD ,&nbsp;Susana Hernández PhD ,&nbsp;Fernando López-Ríos MD, PhD ,&nbsp;Alicia Castelo-Loureiro MD ,&nbsp;Esther García-Lorenzo MD ,&nbsp;Javier Baena MD-PhD ,&nbsp;Mercedes Herrera MD ,&nbsp;Ana Belén Enguita MD ,&nbsp;Yolanda Ruano PhD ,&nbsp;Jon Zugazagoitia MD, PhD ,&nbsp;Luis Paz-Ares MD, PhD","doi":"10.1016/j.jtocrr.2024.100778","DOIUrl":"10.1016/j.jtocrr.2024.100778","url":null,"abstract":"<div><h3>Introduction</h3><div>Tissue and plasma-based next-generation sequencing (NGS) have complementary roles in patients with advanced NSCLC. Nevertheless, whether there is any added clinical value in combining both methods in the treatment of naïve patients remains unclear.</div></div><div><h3>Methods</h3><div>We retrospectively collected clinical and genomic data from 275 patients with treatment-naïve advanced NSCLC who had undergone plasma-based NGS at diagnosis in our institution. We analyzed patient data in two separate cohorts, each assessed with a different plasma-based NGS method: cohort 1 (n = 127, Guardant360), and cohort 2 (n = 148, FoundationACT/FoundationOne Liquid CDx). Ninety-five patients (75%) in cohort 1 and 108 patients (73%) in cohort 2 underwent concurrent amplicon-based tissue NGS testing locally.</div></div><div><h3>Results</h3><div>Forty-three patients in cohort 1 (34%) and 49 patients in cohort 2 (33%) harbored European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) I or II targetable driver alterations. The addition of orthogonal biopsy (tissue to liquid, or liquid to tissue) offered no relevant clinical value in cases with ESCAT I or II targetable drivers already detected by one method. In contrast, adding orthogonal biopsy incremented the detection of ESCAT I or II targetable drivers not only in cases with uninformative testing (undetectable circulating tumor DNA, unavailable/inadequate tissue) but also in about 5% of the patients with seemingly informative but driver undetected molecular results. The prevalence of ESCAT I or II targetable drivers in plasma was significantly higher in patients with adenocarcinoma, 20 pack-year or less smoking history, and abdominal metastases.</div></div><div><h3>Conclusions</h3><div>Our study suggests that the addition of sequential orthogonal biopsy should be considered whenever an ESCAT I or II targetable driver has not been detected by the initial method, including cases with seemingly informative molecular analysis.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 3","pages":"Article 100778"},"PeriodicalIF":3.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143348094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individualized Cell-Free DNA Monitoring With Chromosomal Junctions for Mesothelioma","authors":"Kaushal Parikh MD ,&nbsp;Faye R. Harris MS ,&nbsp;Giannoula Karagouga MS ,&nbsp;Amy Schrandt CRA ,&nbsp;Jay Mandrekar PhD ,&nbsp;Sarah Johnson MS ,&nbsp;Alexa McCune BS ,&nbsp;Dorsay Sadeghian MD ,&nbsp;Debarshi Roy PhD ,&nbsp;Katarzyna Polonis PhD ,&nbsp;Athanasios Gaitatzes MS ,&nbsp;Aaron O. Bungum BS ,&nbsp;Eric S. Edell MD ,&nbsp;Mitesh J. Borad MD ,&nbsp;Tobias Peikert MD ,&nbsp;Farhad Kosari PhD ,&nbsp;John Cheville MD ,&nbsp;George Vasmatzis PhD ,&nbsp;Aaron S. Mansfield MD","doi":"10.1016/j.jtocrr.2024.100692","DOIUrl":"10.1016/j.jtocrr.2024.100692","url":null,"abstract":"<div><h3>Introduction</h3><div>The spatially complex nature of mesothelioma and interventions like pleurodesis, surgery, and radiation often complicate imaging-based assessment. Further, cell-free DNA (cfDNA) based monitoring strategies are inadequate for mesothelioma, given the presence of a few recurring nonsynonymous somatic variants. However, patient-specific chromosomal rearrangements are commonly found in mesothelioma. Our study objective was to develop an individualized cfDNA assay to enable blood-based monitoring using circulating tumor DNA (ctDNA) in mesothelioma. We hypothesized that the unique chromosomal rearrangement junctions found in mesothelioma could be employed for individualized ctDNA detection and disease monitoring.</div></div><div><h3>Methods</h3><div>DNA was extracted from tumor specimens for whole genome sequencing. Chromosomal junctions, prioritized by highest allele frequency and low homology to the rest of the genome, were selected for detection. Primers and Taqman probes were designed to span the junctions, forming personalized junction panels. Patient plasma obtained before therapy and at response assessment was tested for the presence of personalized junctions via quantitative polymerase chain reaction.</div></div><div><h3>Results</h3><div>Our study included nine patients, four with peritoneal and five with pleural mesothelioma. 763 chromosomal junctions were identified in the tumors of all cases. We selected three to five junctions per sample for quantitative polymerase chain reaction. We detected 25/30 (83%) of selected junctions in the plasma of seven out of nine patients (78%). Cell-free junction detection at follow-up was concordant with disease status: cfDNA junctions were detected in three patients with persistent disease, and not detected in a patient with no evidence of disease after surgery.</div></div><div><h3>Conclusions</h3><div>With further validation, individualized ctDNA junction assays could supplement imaging for disease monitoring in mesothelioma.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"5 12","pages":"Article 100692"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141131670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Should Radiation Dose Be Personalized in Patients With Localized NSCLC and Actionable Genetic Alterations? Insight From a Multicenter Real-World Study","authors":"Salman Ashraf MB BCh BAO ,&nbsp;Madeha Khan FRCR ,&nbsp;Nada Naguib FRCR ,&nbsp;Robert Rulach FRCR, PhD ,&nbsp;Katharine Welsh FRCR ,&nbsp;Rebecca Carozzi MRCP ,&nbsp;Ashley Horne FRCR ,&nbsp;Amelia Payne MRCP, MRes ,&nbsp;Sarah Bowen Jones FRCR ,&nbsp;Mary Denholm FRCR ,&nbsp;Georgia Stewart MB MSc ,&nbsp;Ahmed Bedair FRCR ,&nbsp;Colin R. Lindsay MRCP, PhD ,&nbsp;Stephen Harrow FRCR, PhD ,&nbsp;Corinne Faivre-Finn FRCR, PhD ,&nbsp;Jonathan McAleese FRCR ,&nbsp;Gerard G. Hanna FRCR, PhD ,&nbsp;Allan Hackshaw PhD ,&nbsp;Fiona McDonald FRCR, MD ,&nbsp;Gerard M. Walls FRCR, PhD","doi":"10.1016/j.jtocrr.2024.100774","DOIUrl":"10.1016/j.jtocrr.2024.100774","url":null,"abstract":"<div><h3>Objectives</h3><div>Radiation therapy (RT) is central to the management of unresectable stage I to III NSCLC. However, the impact of actionable genetic driver alterations (AGAs) on locoregional control (LRC) from RT remains uncertain. A retrospective, multicenter real-world study was undertaken to determine if common AGAs impact LRC after RT.</div></div><div><h3>Methods</h3><div>Patients who received curative-intent RT for NSCLC between 2018 and 2020 at four centers in the United Kingdom and had available molecular testing were included. Locoregional control was compared in a 1:2 ratio between a group of patients with an AGA and a control group without AGAs. Locoregional control was assessed with competing risks analysis and overall survival was analyzed by Cox regression, adjusting for established prognostic clinical factors.</div></div><div><h3>Results</h3><div>Data was collected for 185 eligible patients: 50 with an AGA and 135 without. Baseline characteristics, including patient demographics, tumor features, and treatment details were evenly distributed between the two groups. LRC was similar in the AGA and non-AGA groups (39% versus 34%, hazard ratio = 1.13, 95% confidence interval: 0.61–1.984, <em>p</em> = 0.84). Actionable genetic driver alterations were not associated with LRC according to multivariable regression analysis. Median overall survival was significantly higher in the AGA group (45 mo versus 26 mo, hazard ratio = 0.64, 95% confidence interval: 0.43–0.96, <em>p</em> = 0.044), and all these patients received targeted therapies on relapse.</div></div><div><h3>Conclusion</h3><div>LRC was comparable in the AGA and non-AGA groups suggesting that there is no role for personalization of RT dose solely due to the detection of an AGA. Nevertheless, survival rates were notably higher among patients with AGAs, likely owing to the availability of efficacious targeted therapies on relapse.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 4","pages":"Article 100774"},"PeriodicalIF":3.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myasthenia Gravis in Patients Treated With Immune Checkpoint Inhibitors","authors":"Abdulrahman Alghabban MD ,&nbsp;Lucy Corke MD ,&nbsp;Hans Katzberg MD ,&nbsp;Vera Bril MD ,&nbsp;Carolina Barnett-Tapia MD ,&nbsp;Warren Mason MD ,&nbsp;Raed Alothman MD ,&nbsp;Abdul Razak Albiruni Ryan MD ,&nbsp;David Hogg MD ,&nbsp;Srikala Sridhar MD ,&nbsp;Neesha Dhani MD ,&nbsp;Anna Spreafico MD ,&nbsp;Lawson Eng MD ,&nbsp;Adrian Sacher MD ,&nbsp;Penelope Bradbury MD ,&nbsp;Geoffrey Liu MD ,&nbsp;Natasha Leighl MD ,&nbsp;Frances A. Shepherd MD","doi":"10.1016/j.jtocrr.2024.100772","DOIUrl":"10.1016/j.jtocrr.2024.100772","url":null,"abstract":"<div><h3>Background</h3><div>Immune checkpoint inhibitors (ICIs) have improved outcomes significantly for patients across multiple tumor types, and now are being used in combination with other therapies and in earlier settings where treatment intent is curative. Immune-related adverse events occur commonly and there are clear guidelines regarding management. Neurological toxicities such as myasthenia gravis (MG) with or without myositis are rare but are associated with high morbidity and mortality.</div></div><div><h3>Methods</h3><div>This single-centre study presents a series of patients treated with ICIs who subsequently developed immune-related MG. Presenting symptoms, treatments and outcomes were abstracted from retrospective chart review.</div></div><div><h3>Results</h3><div>We identified 16 patients (9 thoracic malignancies, 7 other tumor sites) who were diagnosed with MG after one or more cycles of ICI. Eleven had overlapping myositis. The median time from the first ICI treatment to the onset of symptoms was 49 days (range 17–361). All patients received steroids (prednisone 1–2 mg/kg); six required other immunosuppressive agents, and five underwent plasma exchange. Only two patients had complete resolution, eight improved with residual symptoms, two experienced initial improvement followed by deterioration, and four worsened despite treatment. Six patients died as a result of myasthenia-related complications (38%), three from progressive cancer (19%) and seven remain alive at the time of review (44%).</div></div><div><h3>Conclusion</h3><div>ICI-related MG is a rare and potentially fatal adverse event. Diagnosis and management remain a challenge, especially with negative serological markers and in the presence of overlapping syndromes with high mortality rates. Prompt recognition and multimodality treatment are key. Clinicians should have a low threshold for diagnosis and early management.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 5","pages":"Article 100772"},"PeriodicalIF":3.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Durvalumab Combined With Pemetrexed-Based Chemotherapy in Trial-Ineligible Patients With Mesothelioma: A Brief Report","authors":"Ibiayi Dagogo-Jack MD ,&nbsp;Aubrey Lasko PharmD ,&nbsp;Elizabeth A. Krueger NP ,&nbsp;Kitman Tsang NP ,&nbsp;Revati Rao MD ,&nbsp;Grace Hambelton BA ,&nbsp;Subba R. Digumarthy MD","doi":"10.1016/j.jtocrr.2024.100775","DOIUrl":"10.1016/j.jtocrr.2024.100775","url":null,"abstract":"<div><h3>Introduction</h3><div>Chemoimmunotherapy is associated with promising activity in mesothelioma in phase II to III trials. Studies exploring this approach in patients ineligible for clinical trials are lacking. We assembled a cohort of patients receiving pemetrexed-based chemotherapy with durvalumab outside of clinical trials.</div></div><div><h3>Methods</h3><div>Patients with pleural mesothelioma received pemetrexed plus durvalumab or carboplatin plus pemetrexed plus durvalumab via off-label authorization at Massachusetts General Hospital. Response to chemoimmunotherapy was assessed per modified Response Evaluation Criteria in Solid Tumors version 1.1. A retrospective chart review was conducted to assess safety per Common Terminology Criteria for Adverse Events version 5.0.</div></div><div><h3>Results</h3><div>Twelve patients were included in the series. Nine patients were treated with triplet chemoimmunotherapy. Three patients received doublet chemoimmunotherapy because of platinum ineligibility. Concurrent active malignancies and symptomatic cardiac disease were present in three patients (25%) and two patients (17%), respectively. Ten patients had measurable disease at baseline. With the triplet regimen, partial responses were observed in four of the seven (57%) patients with measurable disease. All three patients receiving pemetrexed plus durvalumab had measurable disease and experienced a partial response. Primary progression was not observed with either regimen. Overall, eight patients (75%) remained on treatment for more than 6 months without progression. Five patients developed immune-related adverse events (n = 1 each pyrexia, arthritis, neutropenia, Raynaud’s disease, stomatitis). Three patients discontinued treatment because of toxicity or symptomatic comorbid conditions (n = 1 grade 3 heart failure, n = 1 grade 2 fever + progressive kidney cancer, n = 1 grade 2 fatigue).</div></div><div><h3>Conclusions</h3><div>Antitumor activity of chemoimmunotherapy reported in phase II to III clinical trials is generalizable to the broader patient population with mesothelioma. However, the tolerability of chemoimmunotherapy is impacted by comorbid conditions in real-world patients.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 5","pages":"Article 100775"},"PeriodicalIF":3.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143761081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Personalized Therapy in a Patient With EGFR-Mutated NSCLC Developing Sequential CCDC6-RET Fusion and BRAF V600E Mutation as Bypass Resistance Mechanisms","authors":"Arianna Marinello MD ,&nbsp;Claudia Parisi MD ,&nbsp;Damien Vasseur PhD ,&nbsp;David Combarel PharmD ,&nbsp;Juliette Bihoreau NP ,&nbsp;Pernelle Lavaud MD ,&nbsp;Rémy Ezzedine MD ,&nbsp;Lodovica Zullo MD ,&nbsp;Luc Friboulet PhD ,&nbsp;Gerard Zalcman MD, PhD ,&nbsp;Antoine Italiano MD, PhD ,&nbsp;Benjamin Besse MD, PhD ,&nbsp;Mihaela Aldea MD, PhD","doi":"10.1016/j.jtocrr.2024.100773","DOIUrl":"10.1016/j.jtocrr.2024.100773","url":null,"abstract":"<div><div>In this case report, we describe a case of sequential acquired <em>CCDC6</em><em>-RET</em> fusion and <em>BRAF</em> V600E mutation observed in a patient with <em>EGFR</em>-mutated NSCLC treated with osimertinib and with combined selpercatinib and osimertinib. The discovery of genomic resistance mechanisms was facilitated by serial liquid and tissue biopsies and molecular tumor board discussion. After the identification of <em>CCDC6-RET</em> fusion, the patient received a combination of selpercatinib and osimertinib with prolonged benefit and manageable toxicity. When a novel <em>BRAF</em> V600E mutation was detected at progression, the molecular tumor board suggested the administration of triple therapy, adding trametinib (anti-MEK). Nevertheless, treatment was discontinued for toxicity, highlighting the challenges of using multiple drug combinations to address complex resistance.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 3","pages":"Article 100773"},"PeriodicalIF":3.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143173713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}