Effective predictors of response to atezolizumab plus carboplatin/etoposide (CE) therapy in extensive-stage SCLC (ES-SCLC) remain limited. This exploratory analysis from J-TAIL-2 aimed to identify markers of survival benefit with atezolizumab plus CE therapy in ES-SCLC.
Methods
J-TAIL-2 (ClinicalTrials.gov ID, NCT04501497) was a multicenter observational study that enrolled patients receiving atezolizumab plus CE (ES-SCLC cohort) in clinical practice in Japan per local label and treatment guidelines. In this exploratory analysis, the association of CD8+ tumor-infiltrating lymphocyte (TIL) density and SCLC subtypes (SCLC-A [ASCL1 dominant], SCLC-N [NEUROD1 dominant], SCLC-P [ASCL1/NEUROD1 double-negative with POU2F3 expression], and SCLC-O [ASCL1/NEUROD1 double-negative not otherwise specified]) with overall survival (OS) and progression-free survival (PFS) was evaluated. SCLC subtyping was performed by immunohistochemistry.
Results
SCLC samples (n = 100; data cutoff, February 3, 2023) were categorized as SCLC-A (73%), SCLC-N (16%), SCLC-P (8%), and SCLC-O (3%). Among 96 patients who received first-line atezolizumab plus CE, median age was 72 (range, 39–87) years and 81% were male. Furthermore, 56 patients were classified into the CD8+ TIL-high subgroup and 40 into the TIL-low subgroup. Median (m)PFS with atezolizumab plus CE was 6.1 months (95% confidence interval [CI]: 4.5–7.5) in the TIL-high versus 4.4 months (95% CI: 4.0–5.1) in the TIL-low subgroup (p = 0.01); mOS was 18.4 (95% CI: 11.8–not estimable) versus 10.8 months (95% CI: 7.7–16.2; p = 0.04). mOS and mPFS were not significantly different between SCLC subtypes but were numerically shorter in the SCLC-N group.
Conclusions
CD8+ TIL density is a potential biomarker of clinical benefit in ES-SCLC and may facilitate patient selection for atezolizumab combination therapy.
导语：atezolizumab联合卡铂/依托泊苷（CE）治疗大分期SCLC （ES-SCLC）的有效预测指标仍然有限。这项来自J-TAIL-2的探索性分析旨在确定atezolizumab加CE治疗ES-SCLC的生存获益标志物。J-TAIL-2 （ClinicalTrials.gov ID, NCT04501497）是一项多中心观察性研究，根据日本当地标签和治疗指南，在临床实践中招募了接受atezolizumab加CE （ES-SCLC队列）的患者。在这项探索性分析中，我们评估了CD8+肿瘤浸润淋巴细胞（TIL）密度和SCLC亚型（SCLC- a [ASCL1显性]、SCLC- n [NEUROD1显性]、SCLC- p [ASCL1/NEUROD1双阴性伴POU2F3表达]和SCLC- o [ASCL1/NEUROD1双阴性，另有说明]）与总生存期（OS）和无进展生存期（PFS）的关系。免疫组织化学进行SCLC分型。结果：SCLC样本（n = 100，数据截止日期为2023年2月3日）分为SCLC- a（73%）、SCLC- n（16%）、SCLC- p（8%）和SCLC- o（3%）。在96例接受一线atezolizumab + CE治疗的患者中，中位年龄为72岁（范围39-87），81%为男性。CD8+ til高亚组56例，til低亚组40例。在til -高亚组中，atezolizumab加CE的中位PFS (m)为6.1个月（95%可信区间[CI]: 4.5-7.5），而在til -低亚组中，PFS为4.4个月（95% CI: 4.0-5.1） （p = 0.01）；mOS为18.4个月（95% CI: 11.8-不可估计），而10.8个月（95% CI: 7.7-16.2; p = 0.04）。不同SCLC亚型间的mOS和mPFS无显著差异，但SCLC- n组的mOS和mPFS数值较短。结论：CD8+ TIL密度是ES-SCLC临床获益的潜在生物标志物，可能有助于患者选择atezolizumab联合治疗。
{"title":"Potential Immune Microenvironment Biomarkers in SCLC: J-TAIL-2 Observational Study","authors":"Masayuki Shirasawa MD, PhD , Makoto Nishio MD, PhD , Kadoaki Ohashi MD, PhD , Atsushi Osoegawa MD, PhD , Eiki Kikuchi MD, PhD , Hideharu Kimura MD, PhD , Yasushi Goto MD, PhD , Junichi Shimizu MD, PhD , Eisaku Miyauchi MD, PhD , Hiroshige Yoshioka MD, PhD , Ichiro Yoshino MD, PhD , Toshihiro Misumi PhD , Yasushi Yatabe MD, PhD , Tatsuya Yoshida MD, PhD , Jumpei Kashima MD, PhD , Masahide Oki MD, PhD , Hisao Ashimura MS , Yuki Kobayashi MS , Misa Tanaka MS , Akihiko Gemma MD, PhD","doi":"10.1016/j.jtocrr.2025.100926","DOIUrl":"10.1016/j.jtocrr.2025.100926","url":null,"abstract":"<div><h3>Introduction</h3><div>Effective predictors of response to atezolizumab plus carboplatin/etoposide (CE) therapy in extensive-stage SCLC (ES-SCLC) remain limited. This exploratory analysis from J-TAIL-2 aimed to identify markers of survival benefit with atezolizumab plus CE therapy in ES-SCLC.</div></div><div><h3>Methods</h3><div>J-TAIL-2 (<span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> ID, <span><span>NCT04501497</span><svg><path></path></svg></span>) was a multicenter observational study that enrolled patients receiving atezolizumab plus CE (ES-SCLC cohort) in clinical practice in Japan per local label and treatment guidelines. In this exploratory analysis, the association of CD8+ tumor-infiltrating lymphocyte (TIL) density and SCLC subtypes (SCLC-A [ASCL1 dominant], SCLC-N [NEUROD1 dominant], SCLC-P [ASCL1/NEUROD1 double-negative with POU2F3 expression], and SCLC-O [ASCL1/NEUROD1 double-negative not otherwise specified]) with overall survival (OS) and progression-free survival (PFS) was evaluated. SCLC subtyping was performed by immunohistochemistry.</div></div><div><h3>Results</h3><div>SCLC samples (n = 100; data cutoff, February 3, 2023) were categorized as SCLC-A (73%), SCLC-N (16%), SCLC-P (8%), and SCLC-O (3%). Among 96 patients who received first-line atezolizumab plus CE, median age was 72 (range, 39–87) years and 81% were male. Furthermore, 56 patients were classified into the CD8+ TIL-high subgroup and 40 into the TIL-low subgroup. Median (m)PFS with atezolizumab plus CE was 6.1 months (95% confidence interval [CI]: 4.5–7.5) in the TIL-high versus 4.4 months (95% CI: 4.0–5.1) in the TIL-low subgroup (<em>p</em> = 0.01); mOS was 18.4 (95% CI: 11.8–not estimable) versus 10.8 months (95% CI: 7.7–16.2; <em>p</em> = 0.04). mOS and mPFS were not significantly different between SCLC subtypes but were numerically shorter in the SCLC-N group.</div></div><div><h3>Conclusions</h3><div>CD8+ TIL density is a potential biomarker of clinical benefit in ES-SCLC and may facilitate patient selection for atezolizumab combination therapy.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"7 3","pages":"Article 100926"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147355479","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 : 2026-03-01Epub Date: 2025-12-23DOI: 10.1016/j.jtocrr.2025.100945
Myung-Ju Ahn MD, PhD , Daniel SW. Tan BSc, M.B.B.S., MRCP, PhD , Morgan Windsor FRACS , Boon-Hean Ong M.B.B.S., FRCSEd (CTh) , James Chung-Man Ho MD , Hong Kwan Kim MD, PhD , Victor Ho-Fun Lee MD , Feng-Ming Hsu MD, PhD , Jin Yuan Shih MD, PhD , Duc Nhat Minh Pham MD , Cam Phuong Pham MD, PhD , Sharon Chua PhD , See-Hwee Yeo PhD , Ivy de Dios MD
Introduction
The management of early stage NSCLC is evolving with new therapies. Given the lack of guidelines for Asia Pacific, understanding the different factors affecting treatment decisions is key to effective clinical practice. This cross-sectional study describes management patterns for early stage NSCLC in six territories across the region and identifies factors influencing treatment choices.
Methods
From June 2022 to July 2023, we recruited lung cancer specialists from public and private health care systems in Australia, Hong Kong, South Korea, Singapore, Taiwan, and Vietnam to complete a survey on treatment considerations in early stage NSCLC among three patient groups based on American Joint Committee on Cancer disease staging.
Results
Among 505 physicians screened, 212 were eligible for our study. They frequently screened high-risk individuals. Biomarker testing was common as part of diagnosis and at disease recurrence. Surgery followed by adjuvant chemotherapy, definitive concurrent chemoradiation, and definitive chemoradiation followed by immunotherapy were mostly recommended, depending on disease stage and presence of oncogenic alteration. Variations were observed among territories and specialties. Cisplatin was preferred over carboplatin for both neoadjuvant and adjuvant therapies. Physicians were more likely to prescribe neoadjuvant or adjuvant treatments for patients with lower Eastern Cooperative Oncology Group performance status and/or higher nodal stage.
Conclusions
This study revealed that management of early stage NSCLC across Asia Pacific largely follows international guidelines at the time of survey; however, variations exist. Our findings provide useful insights into real-world management patterns in the region and will be valuable in helping clinicians make informed management decisions.
{"title":"Treatment Patterns in Early Stage NSCLC in Asia: Findings From the ELEVATE Study","authors":"Myung-Ju Ahn MD, PhD , Daniel SW. Tan BSc, M.B.B.S., MRCP, PhD , Morgan Windsor FRACS , Boon-Hean Ong M.B.B.S., FRCSEd (CTh) , James Chung-Man Ho MD , Hong Kwan Kim MD, PhD , Victor Ho-Fun Lee MD , Feng-Ming Hsu MD, PhD , Jin Yuan Shih MD, PhD , Duc Nhat Minh Pham MD , Cam Phuong Pham MD, PhD , Sharon Chua PhD , See-Hwee Yeo PhD , Ivy de Dios MD","doi":"10.1016/j.jtocrr.2025.100945","DOIUrl":"10.1016/j.jtocrr.2025.100945","url":null,"abstract":"<div><h3>Introduction</h3><div>The management of early stage NSCLC is evolving with new therapies. Given the lack of guidelines for Asia Pacific, understanding the different factors affecting treatment decisions is key to effective clinical practice. This cross-sectional study describes management patterns for early stage NSCLC in six territories across the region and identifies factors influencing treatment choices.</div></div><div><h3>Methods</h3><div>From June 2022 to July 2023, we recruited lung cancer specialists from public and private health care systems in Australia, Hong Kong, South Korea, Singapore, Taiwan, and Vietnam to complete a survey on treatment considerations in early stage NSCLC among three patient groups based on American Joint Committee on Cancer disease staging.</div></div><div><h3>Results</h3><div>Among 505 physicians screened, 212 were eligible for our study. They frequently screened high-risk individuals. Biomarker testing was common as part of diagnosis and at disease recurrence. Surgery followed by adjuvant chemotherapy, definitive concurrent chemoradiation, and definitive chemoradiation followed by immunotherapy were mostly recommended, depending on disease stage and presence of oncogenic alteration. Variations were observed among territories and specialties. Cisplatin was preferred over carboplatin for both neoadjuvant and adjuvant therapies. Physicians were more likely to prescribe neoadjuvant or adjuvant treatments for patients with lower Eastern Cooperative Oncology Group performance status and/or higher nodal stage.</div></div><div><h3>Conclusions</h3><div>This study revealed that management of early stage NSCLC across Asia Pacific largely follows international guidelines at the time of survey; however, variations exist. Our findings provide useful insights into real-world management patterns in the region and will be valuable in helping clinicians make informed management decisions.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"7 3","pages":"Article 100945"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193057","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 : 2026-03-01Epub Date: 2025-10-27DOI: 10.1016/j.jtocrr.2025.100925
Richard Riedel MD , Lea Ruge MD , Malte Verheyen MD , Felix John MD , Heather Scharpenseel MD , Lucia Nogova MD, PhD , Sebastian Michels MD , Rieke N. Fischer MD , Anna Eisert MD , Carolin Jakob MD , Emanuel Niesen MD , Jana Fassunke MD , Janna Siemanowski-Hrach MD , Carina Heydt MD , Anne Bunck MD , Udo Siebolts MD, PhD , Sabine Merkelbach-Bruse MD, PhD , Reinhard Buettner MD, PhD , Jürgen Wolf MD, PhD , Matthias Scheffler MD, PhD
Introduction
KRAS G12C mutations define a molecularly distinct subset of NSCLC for which targeted therapy with sotorasib has exhibited clinical efficacy. However, acquired resistance is inevitable. MET amplification has been described as a putative off-target resistance mechanism, although its clinical relevance remains incompletely understood.
Methods
We conducted a retrospective case series of patients with KRAS G12C–mutant NSCLC treated with sotorasib at the University Hospital Cologne, Germany. Patients with available paired pre- and posttreatment biopsies were analyzed for resistance mechanisms using routine molecular diagnostics, including MET fluorescence in situ hybridization.
Results
Nine patients with paired pre and posttreatment biopsies were identified. High-level MET amplification was detected by fluorescence in situ hybridization in four cases and intermediate-level amplification in one case after progression on sotorasib. Notably, one patient with acquired MET amplification achieved a renewed partial response to the combination of sotorasib and tepotinib after progression on sotorasib monotherapy.
Conclusion
This study provides real-world evidence that MET amplification is an acquired and potentially targetable resistance mechanism to KRAS G12C inhibition in NSCLC. Our findings support rebiopsy at progression on sotorasib. Further prospective trials are warranted to validate MET amplification as a resistance mechanism and to define optimal therapeutic thresholds for combined KRAS and MET inhibition.
{"title":"MET-Driven Resistance to Sotorasib in KRAS G12C–Mutant NSCLC and Response to Combined KRAS and MET Inhibition","authors":"Richard Riedel MD , Lea Ruge MD , Malte Verheyen MD , Felix John MD , Heather Scharpenseel MD , Lucia Nogova MD, PhD , Sebastian Michels MD , Rieke N. Fischer MD , Anna Eisert MD , Carolin Jakob MD , Emanuel Niesen MD , Jana Fassunke MD , Janna Siemanowski-Hrach MD , Carina Heydt MD , Anne Bunck MD , Udo Siebolts MD, PhD , Sabine Merkelbach-Bruse MD, PhD , Reinhard Buettner MD, PhD , Jürgen Wolf MD, PhD , Matthias Scheffler MD, PhD","doi":"10.1016/j.jtocrr.2025.100925","DOIUrl":"10.1016/j.jtocrr.2025.100925","url":null,"abstract":"<div><h3>Introduction</h3><div><em>KRAS G12C</em> mutations define a molecularly distinct subset of NSCLC for which targeted therapy with sotorasib has exhibited clinical efficacy. However, acquired resistance is inevitable. <em>MET</em> amplification has been described as a putative off-target resistance mechanism, although its clinical relevance remains incompletely understood.</div></div><div><h3>Methods</h3><div>We conducted a retrospective case series of patients with <em>KRAS G12C</em>–mutant NSCLC treated with sotorasib at the University Hospital Cologne, Germany. Patients with available paired pre- and posttreatment biopsies were analyzed for resistance mechanisms using routine molecular diagnostics, including <em>MET</em> fluorescence in situ hybridization.</div></div><div><h3>Results</h3><div>Nine patients with paired pre and posttreatment biopsies were identified. High-level <em>MET</em> amplification was detected by fluorescence in situ hybridization in four cases and intermediate-level amplification in one case after progression on sotorasib. Notably, one patient with acquired <em>MET</em> amplification achieved a renewed partial response to the combination of sotorasib and tepotinib after progression on sotorasib monotherapy.</div></div><div><h3>Conclusion</h3><div>This study provides real-world evidence that <em>MET</em> amplification is an acquired and potentially targetable resistance mechanism to KRAS G12C inhibition in NSCLC. Our findings support rebiopsy at progression on sotorasib. Further prospective trials are warranted to validate <em>MET</em> amplification as a resistance mechanism and to define optimal therapeutic thresholds for combined KRAS and MET inhibition.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"7 3","pages":"Article 100925"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147402930","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 : 2026-03-01Epub Date: 2026-01-22DOI: 10.1016/j.jtocrr.2026.100960
David John McMahon MD , Alexius John MD , Foteini Kalofonou PhD , Nawa Amin PhD , Sarah Sarker , Joanna Vick , Nadia Yousaf MD , Nadza Tokaca MD , JanLukas Robertus PhD , Suzanne MacMahon PhD , Sanjay Popat FRCP, PhD
A number of drugs are in development for the treatment of ERBB2(HER2)-mutated NSCLC, including antibody-drug conjugates such as trastuzumab-deruxtecan and tyrosine kinase inhibitors such as zongertinib and sevabertinib. Herein, we report a case of relapsed advanced ERBB2-mutant NSCLC with acquired resistance to zongertinib potentially mediated through ERBB2 amplification and HER2 3+ immunohistochemistry overexpression with subsequent durable response to fifth-line trastuzumab-deruxtecan. We propose this as a mechanism for zongertinib resistance, one that may underpin a biological rationale for future ERBB2 tyrosine kinase inhibitor–antibody-drug conjugate combination therapy.
{"title":"Acquired ERBB2 Amplification and Overexpression as On-Target Resistance Mechanisms to Zongertinib With Subsequent Response to Trastuzumab-Deruxtecan: A Case Report","authors":"David John McMahon MD , Alexius John MD , Foteini Kalofonou PhD , Nawa Amin PhD , Sarah Sarker , Joanna Vick , Nadia Yousaf MD , Nadza Tokaca MD , JanLukas Robertus PhD , Suzanne MacMahon PhD , Sanjay Popat FRCP, PhD","doi":"10.1016/j.jtocrr.2026.100960","DOIUrl":"10.1016/j.jtocrr.2026.100960","url":null,"abstract":"<div><div>A number of drugs are in development for the treatment of <em>ERBB2</em>(<em>HER2</em>)-mutated NSCLC, including antibody-drug conjugates such as trastuzumab-deruxtecan and tyrosine kinase inhibitors such as zongertinib and sevabertinib. Herein, we report a case of relapsed advanced <em>ERBB2</em>-mutant NSCLC with acquired resistance to zongertinib potentially mediated through <em>ERBB2</em> amplification and <em>HER2</em> 3+ immunohistochemistry overexpression with subsequent durable response to fifth-line trastuzumab-deruxtecan. We propose this as a mechanism for zongertinib resistance, one that may underpin a biological rationale for future <em>ERBB2</em> tyrosine kinase inhibitor–antibody-drug conjugate combination therapy.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"7 3","pages":"Article 100960"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147377999","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 : 2026-03-01Epub Date: 2025-11-21DOI: 10.1016/j.jtocrr.2025.100934
Charles Hsu MD, Mohamed Yakoub MD, PhD, Michael Offin MD, Juliana Eng MD, Alexander Drilon MD, Soo-Ryum Yang MD
Background
ALK fusion-positive NSCLC is driven by a range of fusion partners, most often EML4::ALK. The clinical impact, oncogenicity, and resistance mechanisms of rare, noncanonical ALK fusions remain underexplored. We describe two previously unreported ALK fusion partners in NSCLC and explore the potential mechanisms of resistance in each case, including on-target and bypass mutations, as well as the use of next-generation sequencing (NGS) testing on cerebrospinal fluid (CSF) as a useful tool.
Case Presentation
We report two patients with metastatic NSCLC harboring novel ZFPM2::ALK and TRIM24::ALK fusions. Both patients achieved marked partial responses to first-line alectinib, confirming the oncogenic and actionable nature of the fusions. The patient with ZFPM2::ALK fusion developed leptomeningeal disease after 27 months; CSF NGS revealed persistent fusion and newly acquired CDKN2A/B deletion. The patient with TRIM24::ALK fusion, following durable responses to alectinib and lorlatinib, relapsed with detection of on-target ALK kinase domain mutations (F1174V, I1171N) and MYC amplification on progression.
Conclusions
These cases expand the landscape of noncanonical ALK fusions in NSCLC which are responsive to approved ALK TKIs and offer insights into oncogenic and resistance mechanisms. Comprehensive molecular workup, including RNA-based NGS, is essential for detecting rare but actionable ALK rearrangements and optimizing therapeutic strategy. NGS of CSF was a valuable tool for the detection of clinically suspected leptomeningeal disease and disease monitoring.
{"title":"ALK Inhibitor Response in Novel ZFPM2::ALK and TRIM24::ALK Fusion-Positive Lung Cancers: Case Report","authors":"Charles Hsu MD, Mohamed Yakoub MD, PhD, Michael Offin MD, Juliana Eng MD, Alexander Drilon MD, Soo-Ryum Yang MD","doi":"10.1016/j.jtocrr.2025.100934","DOIUrl":"10.1016/j.jtocrr.2025.100934","url":null,"abstract":"<div><h3>Background</h3><div><em>ALK</em> fusion-positive NSCLC is driven by a range of fusion partners, most often <em>EML4::ALK</em>. The clinical impact, oncogenicity, and resistance mechanisms of rare, noncanonical <em>ALK</em> fusions remain underexplored. We describe two previously unreported <em>ALK</em> fusion partners in NSCLC and explore the potential mechanisms of resistance in each case, including on-target and bypass mutations, as well as the use of next-generation sequencing (NGS) testing on cerebrospinal fluid (CSF) as a useful tool.</div></div><div><h3>Case Presentation</h3><div>We report two patients with metastatic NSCLC harboring novel <em>ZFPM2::ALK</em> and <em>TRIM24::ALK</em> fusions. Both patients achieved marked partial responses to first-line alectinib, confirming the oncogenic and actionable nature of the fusions. The patient with <em>ZFPM2::ALK</em> fusion developed leptomeningeal disease after 27 months; CSF NGS revealed persistent fusion and newly acquired <em>CDKN2A/B</em> deletion. The patient with <em>TRIM24::ALK</em> fusion, following durable responses to alectinib and lorlatinib, relapsed with detection of on-target <em>ALK</em> kinase domain mutations (F1174V, I1171N) and <em>MYC</em> amplification on progression.</div></div><div><h3>Conclusions</h3><div>These cases expand the landscape of noncanonical <em>ALK</em> fusions in NSCLC which are responsive to approved ALK TKIs and offer insights into oncogenic and resistance mechanisms. Comprehensive molecular workup, including RNA-based NGS, is essential for detecting rare but actionable ALK rearrangements and optimizing therapeutic strategy. NGS of CSF was a valuable tool for the detection of clinically suspected leptomeningeal disease and disease monitoring.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"7 3","pages":"Article 100934"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193069","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}
A 50-year-old woman with stage IVB lung adenocarcinoma tested negative for driver mutations using the Oncomine Dx Target Test Multi-CDx system (Thermo Fisher Scientific, Waltham, MA). After undergoing chemotherapy and immunotherapy, FoundationOne Liquid CDx (Foundation Medicine, Inc., Cambridge, MA) identified a rare EML4-ALK gene rearrangement. Treatment with alectinib led to rapid clinical improvement and sustained disease control for more than 7 months. This case highlights the value of next-generation sequencing-based profiling in detecting rare actionable alterations missed by standard tests. We also include a discussion on why the EML4-AKL fusion was not detected in the usual test.
{"title":"Detection of a Rare Intra-ALK Inversion and ALK Rearrangement in a Lung Adenocarcinoma Patient by FoundationOne Liquid CDx and Successful Treatment with Alectinib: Case Report","authors":"Chiaki Kanno MD, PhD, Satoshi Takahashi MD, PhD, Masaru Hagiwara MD, PhD, Hideyuki Furumoto MD, PhD, Yujin Kudo MD, PhD, Yoshihisa Shimada MD, PhD, Masatoshi Kakihana MD, PhD, Tatsuo Ohira MD, PhD, Norihiko Ikeda MD, PhD","doi":"10.1016/j.jtocrr.2026.100956","DOIUrl":"10.1016/j.jtocrr.2026.100956","url":null,"abstract":"<div><div>A 50-year-old woman with stage IVB lung adenocarcinoma tested negative for driver mutations using the Oncomine Dx Target Test Multi-CDx system (Thermo Fisher Scientific, Waltham, MA). After undergoing chemotherapy and immunotherapy, FoundationOne Liquid CDx (Foundation Medicine, Inc., Cambridge, MA) identified a rare <em>EML4</em>-<em>ALK</em> gene rearrangement. Treatment with alectinib led to rapid clinical improvement and sustained disease control for more than 7 months. This case highlights the value of next-generation sequencing-based profiling in detecting rare actionable alterations missed by standard tests. We also include a discussion on why the <em>EML4-AKL</em> fusion was not detected in the usual test.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"7 3","pages":"Article 100956"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193070","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 : 2026-03-01Epub Date: 2026-01-07DOI: 10.1016/j.jtocrr.2026.100957
Richard Pham MBBS , Surein Arulananda MBBS, PhD
{"title":"Immune Doublet Checkpoint Inhibition in EGFR-Mutated NSCLC: A Fire That Fails to Illuminate the Orchard","authors":"Richard Pham MBBS , Surein Arulananda MBBS, PhD","doi":"10.1016/j.jtocrr.2026.100957","DOIUrl":"10.1016/j.jtocrr.2026.100957","url":null,"abstract":"","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"7 3","pages":"Article 100957"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192422","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 : 2026-03-01Epub Date: 2025-09-10DOI: 10.1016/j.jtocrr.2025.100902
Emily Stone M.B.B.S., PhD, FRACP
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Pub Date : 2026-03-01Epub Date: 2025-05-15DOI: 10.1016/j.jtocrr.2025.100846
Gyerim Park MD , Youngkyu Moon MD, PhD , Meejeong Kim MD, PhD , Kyo Young Lee MD, PhD , Yeoun Eun Sung MD, PhD
Introduction
Early stage NSCLC presents a significant risk of recurrence despite surgical resection. The International Association for the Study of Lung Cancer–proposed histologic grading system identifies high-grade tumors (≥20% solid, micropapillary, or complex glandular patterns) as a potential prognostic tool. This study evaluates the prognostic significance of histologic grade 3 within stage IA non-mucinous adenocarcinoma and its comparability to stage IB.
Methods
We retrospectively analyzed 729 patients with stage I non-mucinous adenocarcinoma who underwent surgical resection (2010–2017). Tumors were graded per the International Association for the Study of Lung Cancer system. Kaplan-Meier survival curves and Cox proportional hazards models assessed overall survival (OS) and disease-free survival (DFS).
Results
Stage IA grade 3 tumors demonstrated significantly worse OS and DFS compared with grade 1 and 2 tumors (p < 0.001). Survival outcomes for stage IA grade 3 tumors were comparable to stage IB (p = 0.677 for OS, p = 0.248 for DFS). Stage IA grade 3 tumors also demonstrated a trend toward worse survival than stage IB grades 1 and 2. Grade 3 tumors exhibited sufficient risk stratification power, comparable to the already well-established risk factor of pleural invasion. Tumors with any high-grade patterns (>0%) had poorer survival than those without, but risks were less pronounced than the 20% cutoff.
Conclusions
Histologic grade 3 in stage IA identifies high-risk tumors comparable to stage IB, highlighting its potential for refining staging criteria and guiding adjuvant therapy. Validation studies are needed to confirm these findings.
尽管手术切除，早期非小细胞肺癌仍有明显的复发风险。国际肺癌研究协会提出的组织学分级系统将高级别肿瘤（≥20%的实性、微乳头状或复杂腺样）作为潜在的预后工具。本研究评估了组织学3级在IA期非粘液腺癌中的预后意义及其与ib期的可比性。方法：我们回顾性分析了2010-2017年729例手术切除的I期非粘液腺癌患者。肿瘤按照国际肺癌研究协会系统分级。Kaplan-Meier生存曲线和Cox比例风险模型评估总生存期（OS）和无病生存期（DFS）。结果：与1级和2级肿瘤相比，IA期3级肿瘤的OS和DFS明显更差（p < 0.001）。IA期3级肿瘤的生存结果与IB期相当（OS p = 0.677, DFS p = 0.248）。IA期3级肿瘤也表现出比IB期1级和2级更差的生存趋势。3级肿瘤表现出足够的危险分层能力，与已经确定的胸膜浸润危险因素相当。任何高级别肿瘤（> - 0%）的生存率都低于没有高级别肿瘤的生存率，但风险低于20%的临界值。结论：IA期的组织学分级为3级，可识别与IB期相当的高危肿瘤，强调其在细化分期标准和指导辅助治疗方面的潜力。需要进行验证性研究来证实这些发现。
{"title":"Histologic Grade 3 in Stage 1A Lung Adenocarcinoma: Survival Risks Comparable to Stage 1B","authors":"Gyerim Park MD , Youngkyu Moon MD, PhD , Meejeong Kim MD, PhD , Kyo Young Lee MD, PhD , Yeoun Eun Sung MD, PhD","doi":"10.1016/j.jtocrr.2025.100846","DOIUrl":"10.1016/j.jtocrr.2025.100846","url":null,"abstract":"<div><h3>Introduction</h3><div>Early stage NSCLC presents a significant risk of recurrence despite surgical resection. The International Association for the Study of Lung Cancer–proposed histologic grading system identifies high-grade tumors (≥20% solid, micropapillary, or complex glandular patterns) as a potential prognostic tool. This study evaluates the prognostic significance of histologic grade 3 within stage IA non-mucinous adenocarcinoma and its comparability to stage IB.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed 729 patients with stage I non-mucinous adenocarcinoma who underwent surgical resection (2010–2017). Tumors were graded per the International Association for the Study of Lung Cancer system. Kaplan-Meier survival curves and Cox proportional hazards models assessed overall survival (OS) and disease-free survival (DFS).</div></div><div><h3>Results</h3><div>Stage IA grade 3 tumors demonstrated significantly worse OS and DFS compared with grade 1 and 2 tumors (<em>p</em> < 0.001). Survival outcomes for stage IA grade 3 tumors were comparable to stage IB (<em>p</em> = 0.677 for OS, <em>p</em> = 0.248 for DFS). Stage IA grade 3 tumors also demonstrated a trend toward worse survival than stage IB grades 1 and 2. Grade 3 tumors exhibited sufficient risk stratification power, comparable to the already well-established risk factor of pleural invasion. Tumors with any high-grade patterns (>0%) had poorer survival than those without, but risks were less pronounced than the 20% cutoff.</div></div><div><h3>Conclusions</h3><div>Histologic grade 3 in stage IA identifies high-risk tumors comparable to stage IB, highlighting its potential for refining staging criteria and guiding adjuvant therapy. Validation studies are needed to confirm these findings.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"7 3","pages":"Article 100846"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147378170","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 : 2026-02-01Epub Date: 2025-11-20DOI: 10.1016/j.jtocrr.2025.100935
Erica Pietroluongo MD, PhD , Christine M. Bestvina MD , Rachel Brattin , Pietro De Placido MD, PhD , Anna Di Lello MD , Waqas Haque MD, MPH , Alessandra Esposito PhD , Roberto Bianco MD, PhD , Noura Choudhury MD , Marina Chiara Garassino MD
Introduction
Thymic neuroendocrine tumors (TNENs) are exceptionally rare and a clinically heterogeneous malignancy, often diagnosed at an advanced stage and lacking standardized treatment algorithms. Due to the scarcity of dedicated evidence, most therapeutic strategies are extrapolated from other neuroendocrine neoplasms.
Methods
This narrative review provides an updated overview of current and emerging treatment approaches for TNENs, focusing on histology-driven strategies and the evolving role of targeted and radionuclide therapies. A comprehensive literature search was conducted through PubMed/MEDLINE and Embase from January 1, 2000, up to May 31, 2025, integrating retrospective series, real-world data, and ongoing clinical trials.
Results
Surgical resection remains the cornerstone of treatment whenever feasible. The benefit of adjuvant therapy in well-differentiated tumors is unclear, whereas thymic neuroendocrine carcinomas often require multimodal approaches, including platinum–etoposide chemotherapy and radiotherapy. Retrospective evidence suggests that even well-differentiated, high-grade tumors may respond to cytotoxic agents. Somatostatin analogues are widely used in indolent or peptide receptor-positive tumors, whereas everolimus and, more recently, cabozantinib represent options for progressive disease. Peptide receptor radionuclide therapy has demonstrated encouraging results in somatostatin receptor–positive tumors and is currently under further investigation in prospective trials involving thymic primaries. However, the 5-year overall survival rate varies significantly (approximately 28%–80%), underlining an urgent need for prospective, subtype-specific studies.
Conclusions
The management of TNENs requires a multidisciplinary and individualized approach based on histologic subtype, somatostatin receptor status, and disease aggressiveness. Despite promising therapeutic options, robust prospective data remain limited. The integration of TNENs into basket trials, the molecular refinement of prognostic subgroups (e.g., NET G3), and the conduct of dedicated multicenter prospective studies are urgently needed to define optimal treatment algorithms and improve clinical outcomes in these rare entities.
{"title":"Thymic Neuroendocrine Tumors: Evolving Insights and Innovative Approaches","authors":"Erica Pietroluongo MD, PhD , Christine M. Bestvina MD , Rachel Brattin , Pietro De Placido MD, PhD , Anna Di Lello MD , Waqas Haque MD, MPH , Alessandra Esposito PhD , Roberto Bianco MD, PhD , Noura Choudhury MD , Marina Chiara Garassino MD","doi":"10.1016/j.jtocrr.2025.100935","DOIUrl":"10.1016/j.jtocrr.2025.100935","url":null,"abstract":"<div><h3>Introduction</h3><div>Thymic neuroendocrine tumors (TNENs) are exceptionally rare and a clinically heterogeneous malignancy, often diagnosed at an advanced stage and lacking standardized treatment algorithms. Due to the scarcity of dedicated evidence, most therapeutic strategies are extrapolated from other neuroendocrine neoplasms.</div></div><div><h3>Methods</h3><div>This narrative review provides an updated overview of current and emerging treatment approaches for TNENs, focusing on histology-driven strategies and the evolving role of targeted and radionuclide therapies. A comprehensive literature search was conducted through PubMed/MEDLINE and Embase from January 1, 2000, up to May 31, 2025, integrating retrospective series, real-world data, and ongoing clinical trials.</div></div><div><h3>Results</h3><div>Surgical resection remains the cornerstone of treatment whenever feasible. The benefit of adjuvant therapy in well-differentiated tumors is unclear, whereas thymic neuroendocrine carcinomas often require multimodal approaches, including platinum–etoposide chemotherapy and radiotherapy. Retrospective evidence suggests that even well-differentiated, high-grade tumors may respond to cytotoxic agents. Somatostatin analogues are widely used in indolent or peptide receptor-positive tumors, whereas everolimus and, more recently, cabozantinib represent options for progressive disease. Peptide receptor radionuclide therapy has demonstrated encouraging results in somatostatin receptor–positive tumors and is currently under further investigation in prospective trials involving thymic primaries. However, the 5-year overall survival rate varies significantly (approximately 28%–80%), underlining an urgent need for prospective, subtype-specific studies.</div></div><div><h3>Conclusions</h3><div>The management of TNENs requires a multidisciplinary and individualized approach based on histologic subtype, somatostatin receptor status, and disease aggressiveness. Despite promising therapeutic options, robust prospective data remain limited. The integration of TNENs into basket trials, the molecular refinement of prognostic subgroups (e.g., NET G3), and the conduct of dedicated multicenter prospective studies are urgently needed to define optimal treatment algorithms and improve clinical outcomes in these rare entities.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"7 2","pages":"Article 100935"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980963","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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