Pub Date : 2025-03-20DOI: 10.1016/j.jtocrr.2025.100826
Jia Liao MD , Song Wu MD , Yi Min MD , Yiran Li MD , Yuanhang Nie MD , Quwen Chen MD , Zhiliang Mao MD , Qinglan Zong MS , Ning Gao MS , Ding Zhang PhD , Weiquan Liang MD
Introduction
MET exon 14 (METex14) skipping mutations are observed in approximately 0.9% to 4% of patients with NSCLC. This study aimed to compare the detection rates of METex14 skipping in Chinese patients with lung cancer using DNA-based next-generation sequencing (NGS) with capture-based library construction and synchronous DNA-based and RNA-based NGS with amplicon-based library construction.
Methods
A total of 11,330 tissue samples from 11,330 Chinese patients with lung cancer were included in the study to confirm the presence of METex14 skipping. Simultaneously, MET immunohistochemistry testing was performed on 30 patients.
Results
The highest detection rate of METex14 skipping was observed in the synchronous DNA and RNA-based NGS with amplicon-based library construction, reaching 2.20%. A total of 45 different variants leading to METex14 skipping were detected at the DNA level. These variants were widely distributed across a 197–base pair DNA sequence. In the overall population, the incidence of METex14 skipping was significantly higher in individuals aged 60 years and above (p < 0.0001) and needle biopsy samples (p < 0.0001) and reported no significant association with gender and tumor location. A positive correlation was observed between microsatellite instability–high and METex14 skipping (p < 0.0001).
Conclusions
The mutations causing METex14 skipping exhibit diversity in terms of variant types and are widely distributed across various genomic regions. Synchronous DNA-based and RNA-based NGS is considered the optimal method for detecting METex14 skipping. Furthermore, METex14 skipping is enriched in specific populations, including individuals aged 60 years and above, with advanced-stage disease and a microsatellite instability-high status.
{"title":"The Landscape of MET Exon 14 Skipping Mutations in Patients With Lung Cancer Identified by Next-Generation Sequencing","authors":"Jia Liao MD , Song Wu MD , Yi Min MD , Yiran Li MD , Yuanhang Nie MD , Quwen Chen MD , Zhiliang Mao MD , Qinglan Zong MS , Ning Gao MS , Ding Zhang PhD , Weiquan Liang MD","doi":"10.1016/j.jtocrr.2025.100826","DOIUrl":"10.1016/j.jtocrr.2025.100826","url":null,"abstract":"<div><h3>Introduction</h3><div><em>MET</em> exon 14 (<em>MET</em>ex14) skipping mutations are observed in approximately 0.9% to 4% of patients with NSCLC. This study aimed to compare the detection rates of <em>MET</em>ex14 skipping in Chinese patients with lung cancer using DNA-based next-generation sequencing (NGS) with capture-based library construction and synchronous DNA-based and RNA-based NGS with amplicon-based library construction.</div></div><div><h3>Methods</h3><div>A total of 11,330 tissue samples from 11,330 Chinese patients with lung cancer were included in the study to confirm the presence of <em>MET</em>ex14 skipping. Simultaneously, MET immunohistochemistry testing was performed on 30 patients.</div></div><div><h3>Results</h3><div>The highest detection rate of <em>MET</em>ex14 skipping was observed in the synchronous DNA and RNA-based NGS with amplicon-based library construction, reaching 2.20%. A total of 45 different variants leading to <em>MET</em>ex14 skipping were detected at the DNA level. These variants were widely distributed across a 197–base pair DNA sequence. In the overall population, the incidence of <em>MET</em>ex14 skipping was significantly higher in individuals aged 60 years and above (<em>p</em> < 0.0001) and needle biopsy samples (<em>p</em> < 0.0001) and reported no significant association with gender and tumor location. A positive correlation was observed between microsatellite instability–high and <em>MET</em>ex14 skipping (<em>p</em> < 0.0001).</div></div><div><h3>Conclusions</h3><div>The mutations causing <em>MET</em>ex14 skipping exhibit diversity in terms of variant types and are widely distributed across various genomic regions. Synchronous DNA-based and RNA-based NGS is considered the optimal method for detecting <em>MET</em>ex14 skipping. Furthermore, <em>MET</em>ex14 skipping is enriched in specific populations, including individuals aged 60 years and above, with advanced-stage disease and a microsatellite instability-high status.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 7","pages":"Article 100826"},"PeriodicalIF":3.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chemoradiotherapy (CRT) followed by durvalumab is the standard of care for unresectable locally advanced NSCLC. Limited prospective data have been reported on intensity-modulated radiotherapy (IMRT)–adapted CRT in the immunotherapy era.
Methods
In this multicenter prospective observational study, patients underwent IMRT-adapted CRT (platinum-doublet chemotherapy plus 60 Gy IMRT in 30 fractions under a prespecified radiation protocol), followed by consolidative durvalumab. The primary outcome was the durvalumab introduction rate within 42 days post-CRT.
Results
Thirty-two patients with unresectable locally advanced NSCLC were enrolled between November 2019 and February 2021. Among the 28 evaluable cases, durvalumab was introduced in 24 (85.7%, 90% confidence interval: 70.2%–95.0%) of 28 patients after CRT, achieving the primary end point. All 29 patients who received IMRT completed the scheduled 60 Gy radiotherapy dose. One year of durvalumab treatment was completed in 12 of 24 patients (50%). In the 24 patients who were durvalumab-introduced, the median progression-free survival and overall survival were 20.9 (95% confidence interval: 6.9–not evaluable) months and not reached, respectively. Two-year progression-free survival and overall survival rates were 44% and 73%, respectively. Among the 29 patients in the safety analysis set, there were no treatment-related deaths or grade 4 nonhematological adverse events. Pneumonitis grade 1 was observed in 13 patients (45%), grade 2 in seven (24%), and grade 3 in one (3%).
Conclusions
High durvalumab introduction rate was reported after the completion of IMRT-adapted CRT under a prespecified radiation protocol. Its efficacy has been suggested, with favorable safety profiles, including a low incidence of severe pneumonitis.
Trial Registration
University Hospital Medical Information Network database ID: UMIN000038366
{"title":"Intensity-Modulated Radiotherapy for Locally Advanced Lung Cancer in the Immunotherapy Era: A Prospective Study WJOG12019L","authors":"Hideyuki Harada MD, PhD , Akito Hata MD , Masahiro Konno PhD , Nobuaki Mamesaya MD, PhD , Kiyoshi Nakamatsu MD, PhD , Koji Haratani MD, PhD , Takaya Yamamoto MD, PhD , Ryota Saito MD, PhD , Hiroshi Mayahara MD, PhD , Masaki Kokubo MD, PhD , Yuki Sato MD , Nobuki Imano MD, PhD , Takeshi Masuda PD, PhD , Haruyuki Fukuda MD, PhD , Toshikatsu Sado MD, PhD , Kenichi Yoshimura PhD , Yasumasa Nishimura MD, PhD , Kazuhiko Nakagawa MD, PhD , Isamu Okamoto MD, PhD , Nobuyuki Yamamoto MD, PhD","doi":"10.1016/j.jtocrr.2025.100828","DOIUrl":"10.1016/j.jtocrr.2025.100828","url":null,"abstract":"<div><h3>Introduction</h3><div>Chemoradiotherapy (CRT) followed by durvalumab is the standard of care for unresectable locally advanced NSCLC. Limited prospective data have been reported on intensity-modulated radiotherapy (IMRT)–adapted CRT in the immunotherapy era.</div></div><div><h3>Methods</h3><div>In this multicenter prospective observational study, patients underwent IMRT-adapted CRT (platinum-doublet chemotherapy plus 60 Gy IMRT in 30 fractions under a prespecified radiation protocol), followed by consolidative durvalumab. The primary outcome was the durvalumab introduction rate within 42 days post-CRT.</div></div><div><h3>Results</h3><div>Thirty-two patients with unresectable locally advanced NSCLC were enrolled between November 2019 and February 2021. Among the 28 evaluable cases, durvalumab was introduced in 24 (85.7%, 90% confidence interval: 70.2%–95.0%) of 28 patients after CRT, achieving the primary end point. All 29 patients who received IMRT completed the scheduled 60 Gy radiotherapy dose. One year of durvalumab treatment was completed in 12 of 24 patients (50%). In the 24 patients who were durvalumab-introduced, the median progression-free survival and overall survival were 20.9 (95% confidence interval: 6.9–not evaluable) months and not reached, respectively. Two-year progression-free survival and overall survival rates were 44% and 73%, respectively. Among the 29 patients in the safety analysis set, there were no treatment-related deaths or grade 4 nonhematological adverse events. Pneumonitis grade 1 was observed in 13 patients (45%), grade 2 in seven (24%), and grade 3 in one (3%).</div></div><div><h3>Conclusions</h3><div>High durvalumab introduction rate was reported after the completion of IMRT-adapted CRT under a prespecified radiation protocol. Its efficacy has been suggested, with favorable safety profiles, including a low incidence of severe pneumonitis.</div></div><div><h3>Trial Registration</h3><div>University Hospital Medical Information Network database ID: UMIN000038366</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 6","pages":"Article 100828"},"PeriodicalIF":3.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-20DOI: 10.1016/j.jtocrr.2025.100827
Micah Tratt BA , Anshu Bandhlish MD , Keith D. Eaton MD, PhD , Ted Gooley PhD , Nicholas Giustini MD , Lei Deng MD
Introduction
Lung adenocarcinoma (LUAD) with intestinal differentiation (LAID) comprises a rare and heterogeneous NSCLC of invasive mucinous, enteric, and colloid characteristics. In the era of chemotherapy, LAID was associated with a poorer prognosis compared with other LUADs. Leveraging the National Cancer Database, we assessed survival outcomes of LAID in the era of immunotherapy.
Methods
The National Cancer Database was queried for stage IV adenocarcinoma cases diagnosed from 2016 to 2019. LAID was defined as invasive mucinous adenocarcinoma, colloid adenocarcinoma, or enteric adenocarcinoma. An unadjusted comparison of survival distributions was performed using a log-rank test and adjusted by Cox multivariable regression.
Results
A total of 40,516 patients were identified, of whom 855 had LAID and 39,661 had other LUAD. Among the cases of LAID, 593 were classified as colloid, 253 as mucinous, and nine as enteric. Patients with LAID had a higher risk of death compared with other LUAD subtypes, with a hazard ratio (HR) of 1.31 (95% confidence interval: 1.21–1.43) and a median survival of 9.19 months and 11.81 months, respectively. This was relatively consistent across all treatment subgroups (HR = 1.40: immunotherapy alone, HR = 1.29: chemoimmunotherapy; HR = 1.25: chemotherapy alone). Patients with LAID treated with chemoimmunotherapy had a median overall survival of 11.16 months, 9.19 months when treated with immunotherapy alone, and 7.09 months when treated with chemotherapy alone.
Conclusions
Compared with other LUADs, LAID remains associated with poorer survival in the era of immunotherapy. Nevertheless, exposure to immunotherapy may be associated with improved survival compared with chemotherapy alone in this rare subgroup.
{"title":"Survival Outcomes of Lung Adenocarcinoma With Intestinal Differentiation in the Era of Immunotherapy","authors":"Micah Tratt BA , Anshu Bandhlish MD , Keith D. Eaton MD, PhD , Ted Gooley PhD , Nicholas Giustini MD , Lei Deng MD","doi":"10.1016/j.jtocrr.2025.100827","DOIUrl":"10.1016/j.jtocrr.2025.100827","url":null,"abstract":"<div><h3>Introduction</h3><div>Lung adenocarcinoma (LUAD) with intestinal differentiation (LAID) comprises a rare and heterogeneous NSCLC of invasive mucinous, enteric, and colloid characteristics. In the era of chemotherapy, LAID was associated with a poorer prognosis compared with other LUADs. Leveraging the National Cancer Database, we assessed survival outcomes of LAID in the era of immunotherapy.</div></div><div><h3>Methods</h3><div>The National Cancer Database was queried for stage IV adenocarcinoma cases diagnosed from 2016 to 2019. LAID was defined as invasive mucinous adenocarcinoma, colloid adenocarcinoma, or enteric adenocarcinoma. An unadjusted comparison of survival distributions was performed using a log-rank test and adjusted by Cox multivariable regression.</div></div><div><h3>Results</h3><div>A total of 40,516 patients were identified, of whom 855 had LAID and 39,661 had other LUAD. Among the cases of LAID, 593 were classified as colloid, 253 as mucinous, and nine as enteric. Patients with LAID had a higher risk of death compared with other LUAD subtypes, with a hazard ratio (HR) of 1.31 (95% confidence interval: 1.21–1.43) and a median survival of 9.19 months and 11.81 months, respectively. This was relatively consistent across all treatment subgroups (HR = 1.40: immunotherapy alone, HR = 1.29: chemoimmunotherapy; HR = 1.25: chemotherapy alone). Patients with LAID treated with chemoimmunotherapy had a median overall survival of 11.16 months, 9.19 months when treated with immunotherapy alone, and 7.09 months when treated with chemotherapy alone.</div></div><div><h3>Conclusions</h3><div>Compared with other LUADs, LAID remains associated with poorer survival in the era of immunotherapy. Nevertheless, exposure to immunotherapy may be associated with improved survival compared with chemotherapy alone in this rare subgroup.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 7","pages":"Article 100827"},"PeriodicalIF":3.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-19DOI: 10.1016/j.jtocrr.2025.100829
Anne C. Chiang MD, PhD , Russell W. Madison MS , Zoe June Assaf PhD , Alexander Fine PhD , Yi Cao PhD , Ole Gjoerup PhD , Yanmei Huang PhD , Dexter X. Jin PhD , Jason Hughes PhD , Vladan Antic MD, PhD , Amanda Young PhD , David Fabrizio MS , David Shames PhD , Sophia Maund PhD , Alexia Exarchos MPH , Shailendra Lakhanpal MD , Richard Zuniga MD , Lincoln W. Pasquina PhD , Katja Schulze PhD
Introduction
Circulating tumor DNA (ctDNA) monitoring is emerging as a minimally invasive complement to tumor imaging. We evaluated the validity of tissue-agnostic ctDNA quantification across four treatment modalities in NSCLC and SCLC.
Methods
Data from consenting patients were collected from electronic health records as part of the Prospective Clinico-Genomic study (NCT04180176). ctDNA tumor fraction (TF) was retrospectively calculated for plasma collected six to 15 weeks after therapy initiation. TF dynamics were compared among an exploratory cohort, NSCLC and SCLC validity cohorts, and by therapy class.
Results
In on-treatment plasma, undetectable TF was associated with longer real-world progression-free survival and real-world overall survival in exploratory (21.8 versus 8.8 mo; hazard ratio [HR] = 0.35, 95% confidence interval [CI]: 0.24–0.50), validity NSCLC (23.5 versus 9.5 mo; HR = 0.34, 95% CI: 0.22–0.53), and validity SCLC (15.9 versus 8.3 mo; HR = 0.19, 95% CI: 0.08–0.42) cohorts. Equal to or greater than 90% and equal to or greater than 50% TF reduction from baseline was also associated with significantly improved outcomes. ctDNA dynamics differed by treatment class: TF reported greater discriminatory power for selecting tumor responses to immunotherapy and targeted therapy (≥50% decrease in 91% of responders versus 24% of nonresponders) than chemotherapy and chemo-immunotherapy (86% versus 60%). TF dynamics correlated with outcomes, but models of real-world progression-free survival and real-world overall survival were improved when tumor response was included.
Conclusions
Tissue-agnostic monitoring of molecular response on the basis of ctDNA TF dynamics has utility in the real-world setting across four different treatment regimens. These results suggest that ctDNA dynamics may be complementary to tumor imaging in both NSCLC and SCLC to better inform patient care.
{"title":"Real-World Validity of Tissue-Agnostic Circulating Tumor DNA Response Monitoring in Lung Cancers Treated With Chemotherapy, Immunotherapy, or Targeted Agents","authors":"Anne C. Chiang MD, PhD , Russell W. Madison MS , Zoe June Assaf PhD , Alexander Fine PhD , Yi Cao PhD , Ole Gjoerup PhD , Yanmei Huang PhD , Dexter X. Jin PhD , Jason Hughes PhD , Vladan Antic MD, PhD , Amanda Young PhD , David Fabrizio MS , David Shames PhD , Sophia Maund PhD , Alexia Exarchos MPH , Shailendra Lakhanpal MD , Richard Zuniga MD , Lincoln W. Pasquina PhD , Katja Schulze PhD","doi":"10.1016/j.jtocrr.2025.100829","DOIUrl":"10.1016/j.jtocrr.2025.100829","url":null,"abstract":"<div><h3>Introduction</h3><div>Circulating tumor DNA (ctDNA) monitoring is emerging as a minimally invasive complement to tumor imaging. We evaluated the validity of tissue-agnostic ctDNA quantification across four treatment modalities in NSCLC and SCLC.</div></div><div><h3>Methods</h3><div>Data from consenting patients were collected from electronic health records as part of the Prospective Clinico-Genomic study (NCT04180176). ctDNA tumor fraction (TF) was retrospectively calculated for plasma collected six to 15 weeks after therapy initiation. TF dynamics were compared among an exploratory cohort, NSCLC and SCLC validity cohorts, and by therapy class.</div></div><div><h3>Results</h3><div>In on-treatment plasma, undetectable TF was associated with longer real-world progression-free survival and real-world overall survival in exploratory (21.8 versus 8.8 mo; hazard ratio [HR] = 0.35, 95% confidence interval [CI]: 0.24–0.50), validity NSCLC (23.5 versus 9.5 mo; HR = 0.34, 95% CI: 0.22–0.53), and validity SCLC (15.9 versus 8.3 mo; HR = 0.19, 95% CI: 0.08–0.42) cohorts. Equal to or greater than 90% and equal to or greater than 50% TF reduction from baseline was also associated with significantly improved outcomes. ctDNA dynamics differed by treatment class: TF reported greater discriminatory power for selecting tumor responses to immunotherapy and targeted therapy (≥50% decrease in 91% of responders versus 24% of nonresponders) than chemotherapy and chemo-immunotherapy (86% versus 60%). TF dynamics correlated with outcomes, but models of real-world progression-free survival and real-world overall survival were improved when tumor response was included.</div></div><div><h3>Conclusions</h3><div>Tissue-agnostic monitoring of molecular response on the basis of ctDNA TF dynamics has utility in the real-world setting across four different treatment regimens. These results suggest that ctDNA dynamics may be complementary to tumor imaging in both NSCLC and SCLC to better inform patient care.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 9","pages":"Article 100829"},"PeriodicalIF":3.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-13DOI: 10.1016/j.jtocrr.2025.100824
Cheol-Kyu Park MD, PhD , Maryam Khalil BSc , Nhu-An Pham PhD , Stephanie Wong BSc , Dalam Ly PhD , Adrian Sacher MD, FRCPC , Ming-Sound Tsao MD, FRCPC
{"title":"Corrigendum to ‘Humanized Mouse Models for Immuno-Oncology Research: A Review and Implications in Lung Cancer Research’ [JTO Clinical and Research Reports Volume 6 Issue 3 (2025) 100781]","authors":"Cheol-Kyu Park MD, PhD , Maryam Khalil BSc , Nhu-An Pham PhD , Stephanie Wong BSc , Dalam Ly PhD , Adrian Sacher MD, FRCPC , Ming-Sound Tsao MD, FRCPC","doi":"10.1016/j.jtocrr.2025.100824","DOIUrl":"10.1016/j.jtocrr.2025.100824","url":null,"abstract":"","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 5","pages":"Article 100824"},"PeriodicalIF":3.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705770","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}
Pub Date : 2025-03-10DOI: 10.1016/j.jtocrr.2025.100823
Margaret Stalker MD , Suzanne L. Walker PhD, CRNP, AOCN, BC , Emily Lebow MD , Emily Ling-Lin Pai MD, PhD , Alex Watts MS , Wei-Ting Hwang PhD , Amir Banihashemi MD , Evan Anderson MSN , Leonid Roshkovan MD , Sharyn I. Katz MD , Leslie Litzky MD , Andrew R. Haas MD, PhD , Sunil Singhal MD , Corey J. Langer MD , Keith Cengel MD, PhD , Melina E. Marmarelis MD, MSCE
Introduction
Immunotherapy (IO) has reported efficacy in pleural mesothelioma (PM). Brain metastases (BMs) in PM are rare; thus, surveillance brain imaging is not included in the guidelines. We evaluated the incidence of BM by treatment type.
Methods
In this retrospective analysis, patients with PM treated at the University of Pennsylvania between January 1, 2015, and August 31, 2023, were included. Demographic and clinical data were extracted from the medical records. The treatment categories included chemotherapy, single-agent IO, and dual-agent IO. A two-tailed Z score was used to determine a difference in the proportion of BM. Overall survival (OS) was analyzed using the Kaplan-Meier method. Of those with BM, available brain tissue was further analyzed.
Results
In total, 251 patients were included; the median age of the participants was 73 years (range: 35–92 y), 79% were male individuals, 91% were white, and 73% had epithelioid histology. In the study, 102 (40.6%) were treated with chemotherapy, 100 (39.8%) with single-agent IO, and 49 (19.5%) with dual-agent IO. The median OS (mOS) was 21.6 months (95% confidence interval: 17.7–25.5) and did not differ between treatment groups (p = 0.774). A higher proportion of patients treated with IO developed BM than those treated with chemotherapy (6/149 [4%] versus 0/102 [0%]; Z score p = 0.04). The mOS from BM diagnosis was 95 days (range: 16–1025 d). The histomorphology of three patients with available brain tissue were similar to the primary site and reported substantial edema and hemorrhage.
Conclusions
In this retrospective study, clinically significant BM was most prevalent in those exposed to IO and not seen in those receiving chemotherapy despite similar mOS between the groups. Brain imaging should be considered before starting IO in patients with PM.
{"title":"Incidence and Outcomes of Brain Metastasis in Pleural Mesothelioma in the Era of Immunotherapy","authors":"Margaret Stalker MD , Suzanne L. Walker PhD, CRNP, AOCN, BC , Emily Lebow MD , Emily Ling-Lin Pai MD, PhD , Alex Watts MS , Wei-Ting Hwang PhD , Amir Banihashemi MD , Evan Anderson MSN , Leonid Roshkovan MD , Sharyn I. Katz MD , Leslie Litzky MD , Andrew R. Haas MD, PhD , Sunil Singhal MD , Corey J. Langer MD , Keith Cengel MD, PhD , Melina E. Marmarelis MD, MSCE","doi":"10.1016/j.jtocrr.2025.100823","DOIUrl":"10.1016/j.jtocrr.2025.100823","url":null,"abstract":"<div><h3>Introduction</h3><div>Immunotherapy (IO) has reported efficacy in pleural mesothelioma (PM). Brain metastases (BMs) in PM are rare; thus, surveillance brain imaging is not included in the guidelines. We evaluated the incidence of BM by treatment type.</div></div><div><h3>Methods</h3><div>In this retrospective analysis, patients with PM treated at the University of Pennsylvania between January 1, 2015, and August 31, 2023, were included. Demographic and clinical data were extracted from the medical records. The treatment categories included chemotherapy, single-agent IO, and dual-agent IO. A two-tailed Z score was used to determine a difference in the proportion of BM. Overall survival (OS) was analyzed using the Kaplan-Meier method. Of those with BM, available brain tissue was further analyzed.</div></div><div><h3>Results</h3><div>In total, 251 patients were included; the median age of the participants was 73 years (range: 35–92 y), 79% were male individuals, 91% were white, and 73% had epithelioid histology. In the study, 102 (40.6%) were treated with chemotherapy, 100 (39.8%) with single-agent IO, and 49 (19.5%) with dual-agent IO. The median OS (mOS) was 21.6 months (95% confidence interval: 17.7–25.5) and did not differ between treatment groups (<em>p</em> = 0.774). A higher proportion of patients treated with IO developed BM than those treated with chemotherapy (6/149 [4%] versus 0/102 [0%]; Z score <em>p</em> = 0.04). The mOS from BM diagnosis was 95 days (range: 16–1025 d). The histomorphology of three patients with available brain tissue were similar to the primary site and reported substantial edema and hemorrhage.</div></div><div><h3>Conclusions</h3><div>In this retrospective study, clinically significant BM was most prevalent in those exposed to IO and not seen in those receiving chemotherapy despite similar mOS between the groups. Brain imaging should be considered before starting IO in patients with PM.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 5","pages":"Article 100823"},"PeriodicalIF":3.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791223","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}
Pub Date : 2025-03-08DOI: 10.1016/j.jtocrr.2025.100822
Marcello Moro Queiroz MD , Ricardo Dahmer Tiecher MD , João Felipe Lima Feldmann MD , Elisangela Monteiro Coser BSc , Mariana Vargas Cruz PhD , Livia Loureiro PhD , Gabriela Franco Katz MD , Marina Henkin Behar MD , João Victor Machado Alessi MD , Leonardo de Abreu Testagrossa PhD , Anamaria Aranha Camargo PhD , Paula Fontes Asprino PhD , Fabiana Bettoni PhD , Artur Katz MD
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by ectopic fibroblast growth factor-23 (FGF23) production. We report a unique case of a 78-year-old female patient with refractory hypophosphatemia, ultimately diagnosed as TIO, in the context of two metastatic primary lung cancers: adenocarcinoma and SCLC. Molecular analyses of tumor samples highlighted FGF23 amplification in one adenocarcinoma sample and FGF23 deletion in one SCLC sample, suggesting a potential link between tumor FGF23 molecular alterations and elevated serum FGF23 levels. This case underscores the complexity of diagnoses and management of TIO when associated with solid tumors and highlights the need for awareness of this condition to prevent diagnostic delays. Future research should explore the mechanisms linking FGF23 alterations and cancer progression and evaluate targeted therapies for TIO in the context of resistant metastatic cancers.
{"title":"Tumor-Induced Osteomalacia in a Patient With FGF23-Amplified Lung Adenocarcinoma and FGF23-Deleted SCLC: Case Report","authors":"Marcello Moro Queiroz MD , Ricardo Dahmer Tiecher MD , João Felipe Lima Feldmann MD , Elisangela Monteiro Coser BSc , Mariana Vargas Cruz PhD , Livia Loureiro PhD , Gabriela Franco Katz MD , Marina Henkin Behar MD , João Victor Machado Alessi MD , Leonardo de Abreu Testagrossa PhD , Anamaria Aranha Camargo PhD , Paula Fontes Asprino PhD , Fabiana Bettoni PhD , Artur Katz MD","doi":"10.1016/j.jtocrr.2025.100822","DOIUrl":"10.1016/j.jtocrr.2025.100822","url":null,"abstract":"<div><div>Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by ectopic fibroblast growth factor-23 (FGF23) production. We report a unique case of a 78-year-old female patient with refractory hypophosphatemia, ultimately diagnosed as TIO, in the context of two metastatic primary lung cancers: adenocarcinoma and SCLC. Molecular analyses of tumor samples highlighted <em>FGF23</em> amplification in one adenocarcinoma sample and <em>FGF23</em> deletion in one SCLC sample, suggesting a potential link between tumor <em>FGF23</em> molecular alterations and elevated serum FGF23 levels. This case underscores the complexity of diagnoses and management of TIO when associated with solid tumors and highlights the need for awareness of this condition to prevent diagnostic delays. Future research should explore the mechanisms linking <em>FGF23</em> alterations and cancer progression and evaluate targeted therapies for TIO in the context of resistant metastatic cancers.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 6","pages":"Article 100822"},"PeriodicalIF":3.0,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-05DOI: 10.1016/j.jtocrr.2025.100821
Ning Xu MD , Changlu Wang MD , Qin Zhang MD , Xiuxiu Hao MD , Teng Mao MD , Jianxin Shi MD , Zhitao Gu MD , Lanting Gao MD , Yan Shen MD , Lei Zhu MD , Xuefei Zhang MD , Yuan Liu MD , Wentao Fang MD
Introduction
Optimal management of locally advanced thymic tumors remains controversial. We conducted a clinical trial (ChiCTR-TNC-10001204) to investigate the safety and efficacy of neoadjuvant concurrent chemoradiotherapy in patients with locally advanced thymic tumors.
Methods
The trial was conducted at the Shanghai Chest Hospital in patients with potentially unresectable high-grade thymic tumors. Induction consisted of chemotherapy (docetaxel and cisplatin) and concurrent radiation (40 Gy). The primary end point was objective response rate (ORR).
Results
A total of 33 patients were accrued, including 11 with thymomas, 20 with thymic carcinomas, and two with neuroendocrine thymic tumors. ORR was 48.5%, with 16 patients having partial response. The other 17 had stable disease (SD). Thymomas had higher ORR (63.6%) than carcinomas (40.9%). A total of 13 patients (39.4%) experienced grades 3 to 4 toxicity. Surgical resection was feasible after induction in 23 patients (69.7%), among which 19 (82.6%) had complete resection. A higher rate of surgery (87.5% versus 52.9%, p = 0.057) and a significantly higher rate of R0 resection rate (81.3% versus 35.3%, p = 0.024) were observed in patients with partial response than in those with SD. Five-year overall survival and progression-free survival for the whole group were 63.5% and 44.9%, respectively. Patients with thymomas had significantly higher 5-year progression-free survival than the others (81.8% versus 25.6%, p = 0.012). Cumulative incidence of progression was significantly lower in patients with surgery than in those without (5-y CIP: 38.2% versus 80.0%, p = 0.045).
Conclusions
Neoadjuvant concurrent chemoradiotherapy is well tolerated and effective for patients with potentially unresectable high-grade thymic tumors, especially for patients with thymomas. Effective induction chemoradiation may help increase the chance of surgical resection and prolonged disease control. Future studies are in need to find more effective treatment approaches for patients with thymic carcinomas.
局部晚期胸腺肿瘤的最佳治疗仍有争议。我们进行了一项临床试验（ChiCTR-TNC-10001204），以研究局部晚期胸腺肿瘤患者新辅助同步放化疗的安全性和有效性。方法本试验在上海胸科医院进行，患者为可能无法切除的高级别胸腺肿瘤。诱导包括化疗（多西紫杉醇和顺铂）和同期放疗（40 Gy）。主要终点为客观缓解率（ORR）。结果共纳入33例患者，其中胸腺瘤11例，胸腺癌20例，胸腺神经内分泌肿瘤2例。ORR为48.5%，16例患者部分缓解。其余17例病情稳定（SD）。胸腺瘤的ORR（63.6%）高于癌（40.9%）。共有13例患者（39.4%）出现3至4级毒性。诱导后手术切除可行23例（69.7%），其中完全切除19例（82.6%）。部分缓解患者的手术率（87.5%比52.9%,p = 0.057）和R0切除率（81.3%比35.3%,p = 0.024）明显高于SD患者。整个组的5年总生存率和无进展生存率分别为63.5%和44.9%。胸腺瘤患者的5年无进展生存率明显高于其他患者（81.8%对25.6%,p = 0.012）。手术患者的累积进展发生率明显低于未手术患者（5-y CIP: 38.2% vs 80.0%, p = 0.045）。结论辅助同步放化疗对可能无法切除的高级别胸腺肿瘤患者，尤其是胸腺瘤患者具有良好的耐受性和疗效。有效的诱导放化疗可能有助于增加手术切除的机会和延长疾病控制。未来的研究需要为胸腺癌患者找到更有效的治疗方法。
{"title":"A Phase II Clinical Trial of Neoadjuvant Concurrent Chemoradiotherapy for Locally Advanced High-Grade Thymic Tumors","authors":"Ning Xu MD , Changlu Wang MD , Qin Zhang MD , Xiuxiu Hao MD , Teng Mao MD , Jianxin Shi MD , Zhitao Gu MD , Lanting Gao MD , Yan Shen MD , Lei Zhu MD , Xuefei Zhang MD , Yuan Liu MD , Wentao Fang MD","doi":"10.1016/j.jtocrr.2025.100821","DOIUrl":"10.1016/j.jtocrr.2025.100821","url":null,"abstract":"<div><h3>Introduction</h3><div>Optimal management of locally advanced thymic tumors remains controversial. We conducted a clinical trial (ChiCTR-TNC-10001204) to investigate the safety and efficacy of neoadjuvant concurrent chemoradiotherapy in patients with locally advanced thymic tumors.</div></div><div><h3>Methods</h3><div>The trial was conducted at the Shanghai Chest Hospital in patients with potentially unresectable high-grade thymic tumors. Induction consisted of chemotherapy (docetaxel and cisplatin) and concurrent radiation (40 Gy). The primary end point was objective response rate (ORR).</div></div><div><h3>Results</h3><div>A total of 33 patients were accrued, including 11 with thymomas, 20 with thymic carcinomas, and two with neuroendocrine thymic tumors. ORR was 48.5%, with 16 patients having partial response. The other 17 had stable disease (SD). Thymomas had higher ORR (63.6%) than carcinomas (40.9%). A total of 13 patients (39.4%) experienced grades 3 to 4 toxicity. Surgical resection was feasible after induction in 23 patients (69.7%), among which 19 (82.6%) had complete resection. A higher rate of surgery (87.5% versus 52.9%, <em>p</em> = 0.057) and a significantly higher rate of R0 resection rate (81.3% versus 35.3%, <em>p</em> = 0.024) were observed in patients with partial response than in those with SD. Five-year overall survival and progression-free survival for the whole group were 63.5% and 44.9%, respectively. Patients with thymomas had significantly higher 5-year progression-free survival than the others (81.8% versus 25.6%, <em>p</em> = 0.012). Cumulative incidence of progression was significantly lower in patients with surgery than in those without (5-y CIP: 38.2% versus 80.0%, <em>p</em> = 0.045).</div></div><div><h3>Conclusions</h3><div>Neoadjuvant concurrent chemoradiotherapy is well tolerated and effective for patients with potentially unresectable high-grade thymic tumors, especially for patients with thymomas. Effective induction chemoradiation may help increase the chance of surgical resection and prolonged disease control. Future studies are in need to find more effective treatment approaches for patients with thymic carcinomas.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 6","pages":"Article 100821"},"PeriodicalIF":3.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-28DOI: 10.1016/j.jtocrr.2025.100820
Olivia Wilkins DO , Adedamola Omogbehin MD , Peter J. Bergquist MD , Chul Kim MD, MPH , Stephen V. Liu MD , Joshua E. Reuss MD
Therapeutic advancement for malignant pleural mesothelioma (MPM) has been limited. Combination immunotherapy with nivolumab plus ipilimumab is a frontline treatment option for advanced MPM that is typically deployed for patients with sarcomatoid or biphasic MPM. Here, we present a case of biphasic MPM that exhibited a unique response pattern to first-line treatment with nivolumab plus ipilimumab, with brisk response in pleural and mediastinal sites of disease, but rapid progression in osseous/soft tissue sites of disease complicated by pathologic spinal cord compression. Pathologic findings from bony metastasis at progression found pure epithelioid histology without any evidence of sarcomatoid differentiation. Next-generation sequencing of this specimen revealed a BRAF V600E mutation, and the patient was subsequently treated with dabrafenib plus trametinib, achieving ongoing clinical and imaging response in all sites of the disease, including bones. This case supports the use of next-generation sequencing profiling in MPM, particularly in circumstances in which novel discordant response patterns are observed.
{"title":"Discordant Response to Nivolumab Plus Ipilimumab and Identification of BRAF V600E Mutation in Biphasic Malignant Pleural Mesothelioma: Case Report","authors":"Olivia Wilkins DO , Adedamola Omogbehin MD , Peter J. Bergquist MD , Chul Kim MD, MPH , Stephen V. Liu MD , Joshua E. Reuss MD","doi":"10.1016/j.jtocrr.2025.100820","DOIUrl":"10.1016/j.jtocrr.2025.100820","url":null,"abstract":"<div><div>Therapeutic advancement for malignant pleural mesothelioma (MPM) has been limited. Combination immunotherapy with nivolumab plus ipilimumab is a frontline treatment option for advanced MPM that is typically deployed for patients with sarcomatoid or biphasic MPM. Here, we present a case of biphasic MPM that exhibited a unique response pattern to first-line treatment with nivolumab plus ipilimumab, with brisk response in pleural and mediastinal sites of disease, but rapid progression in osseous/soft tissue sites of disease complicated by pathologic spinal cord compression. Pathologic findings from bony metastasis at progression found pure epithelioid histology without any evidence of sarcomatoid differentiation. Next-generation sequencing of this specimen revealed a <em>BRAF</em> V600E mutation, and the patient was subsequently treated with dabrafenib plus trametinib, achieving ongoing clinical and imaging response in all sites of the disease, including bones. This case supports the use of next-generation sequencing profiling in MPM, particularly in circumstances in which novel discordant response patterns are observed.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 5","pages":"Article 100820"},"PeriodicalIF":3.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697854","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}
Significant improvement in progression-free survival (PFS; primary end point) was reported in the phase 3 RELAY study with ramucirumab (RAM) plus erlotinib (ERL) versus placebo (PL) in untreated EGFR-mutated NSCLC (hazard ratio [HR] = 0.59, 95% confidence interval [CI]: 0.46–0.76, p < 0.0001), including in the Japanese subset. We report updated PFS and final overall survival (OS) for the Japanese subset.
Methods
Patients (no central nervous system metastases) were randomized 1:1 (stratification included EGFR leucine to arginine substitution [L858R]/exon 19 deletion [ex19del]) to ERL (150 mg/d) with RAM (10 mg/kg; n = 106) or PL (n = 105) intravenously every 2 weeks. The study was not powered for OS.
Results
At final OS data cutoff (median follow-up = 48.2 mo), PFS benefit was sustained with RAM plus ERL versus PL plus ERL (median [m] PFS: 19.4 versus 11.2 mo; HR = 0.69, 95% CI: 0.51–0.93); the mOS was 54.3 and 46.0 months (HR = 0.91, 95% CI: 0.65–1.26), respectively. In L858R (n = 110) and ex19del (n = 100) subgroups, the mOS was 54.3 versus 43.2 months (HR = 0.63, 95% CI: 0.40–0.99) and 53.9 versus 62.1 months (HR = 1.40, 95% CI: 0.86–2.28), respectively. T790M rates post-progression were 52.0% versus 51.1%, respectively. Osimertinib as subsequent therapy was received by 61.0% versus 55.2% patients (L858R: 58.2% versus 48.1%; ex19del: 65.3% versus 62.7%); the median (range) osimertinib treatment duration was 16.8 (0.7–58.3) versus 20.1 (2.1–77.2) months. Safety was consistent with known RAM and ERL profiles, with no increased toxicity over time.
Conclusions
The Japanese subset reported that RAM plus ERL improved PFS, and a mOS greater than 50 months was achieved. OS differed by EGFR mutation type, with an indication of benefit for patients with L858R.
{"title":"Final Survival Outcomes With Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib in Patients With Untreated EGFR-Mutated Metastatic NSCLC: RELAY Japanese Subset","authors":"Makoto Nishio MD, PhD , Takashi Seto MD, PhD , Martin Reck PhD , Edward B. Garon MD , Kazuto Nishio MD, PhD , Kazuo Kasahara MD, PhD , Kazumi Nishino MD, PhD , Miyako Satouchi MD, PhD , Kiyotaka Yoh MD , Hidetoshi Hayashi MD, PhD , Kazuko Sakai PhD , Sotaro Enatsu MD, PhD , Bente Frimodt-Møller MSc , Tomoko Matsui , Sunoj Chacko Varughese MSc , Michelle Carlsen MS , Carla Visseren-Grul MD , Kazuhiko Nakagawa MD, PhD","doi":"10.1016/j.jtocrr.2025.100819","DOIUrl":"10.1016/j.jtocrr.2025.100819","url":null,"abstract":"<div><h3>Introduction</h3><div>Significant improvement in progression-free survival (PFS; primary end point) was reported in the phase 3 RELAY study with ramucirumab (RAM) plus erlotinib (ERL) versus placebo (PL) in untreated <em>EGFR</em>-mutated NSCLC (hazard ratio [HR] = 0.59, 95% confidence interval [CI]: 0.46–0.76, <em>p</em> < 0.0001), including in the Japanese subset. We report updated PFS and final overall survival (OS) for the Japanese subset.</div></div><div><h3>Methods</h3><div>Patients (no central nervous system metastases) were randomized 1:1 (stratification included <em>EGFR</em> leucine to arginine substitution [L858R]/exon 19 deletion [ex19del]) to ERL (150 mg/d) with RAM (10 mg/kg; n = 106) or PL (n = 105) intravenously every 2 weeks. The study was not powered for OS.</div></div><div><h3>Results</h3><div>At final OS data cutoff (median follow-up = 48.2 mo), PFS benefit was sustained with RAM plus ERL versus PL plus ERL (median [m] PFS: 19.4 versus 11.2 mo; HR = 0.69, 95% CI: 0.51–0.93); the mOS was 54.3 and 46.0 months (HR = 0.91, 95% CI: 0.65–1.26), respectively. In L858R (n = 110) and ex19del (n = 100) subgroups, the mOS was 54.3 versus 43.2 months (HR = 0.63, 95% CI: 0.40–0.99) and 53.9 versus 62.1 months (HR = 1.40, 95% CI: 0.86–2.28), respectively. T790M rates post-progression were 52.0% versus 51.1%, respectively. Osimertinib as subsequent therapy was received by 61.0% versus 55.2% patients (L858R: 58.2% versus 48.1%; ex19del: 65.3% versus 62.7%); the median (range) osimertinib treatment duration was 16.8 (0.7–58.3) versus 20.1 (2.1–77.2) months. Safety was consistent with known RAM and ERL profiles, with no increased toxicity over time.</div></div><div><h3>Conclusions</h3><div>The Japanese subset reported that RAM plus ERL improved PFS, and a mOS greater than 50 months was achieved. OS differed by <em>EGFR</em> mutation type, with an indication of benefit for patients with L858R.</div></div><div><h3>Trial Registration</h3><div>NCT02411448</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 6","pages":"Article 100819"},"PeriodicalIF":3.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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