Pub Date : 2025-06-13DOI: 10.1016/j.jtocrr.2025.100859
Jay M. Lee MD , Jean-Louis Pujol MD, PhD , Jun Zhang MD, PhD , Oleg Leonov MD, PhD , Masahiro Tsuboi MD, PhD , Edward S. Kim MD, MBA , Calvin Ng MD , Nicolas Moreno-Mata MD, PhD , Amy Cummings MD, PhD , Ilhan Hacibekiroglu MD , Abidin Sehitogullari MD , Nirmal Veeramachaneni MD , Cathy Spillane PhD , Jiawei Duan PhD , Claudia Bossen PhD , Alexander Savchenko MD, PhD , Chiara Lobetti-Bodoni MD, PhD , Tony Mok MD , Pilar Garrido MD
Introduction
Canakinumab is a human monoclonal anti–interleukin-1β antibody with the potential to enhance the activity of programmed death-ligand 1 inhibitors by inhibiting protumor inflammation.
Methods
CANOPY-N was a randomized, phase 2 study to evaluate safety and efficacy of neoadjuvant canakinumab (200 mg subcutaneous once every three weeks) and pembrolizumab (200 mg intravenous once every three weeks), either in combination or alone, in patients with early-stage (stage Ib–IIIa) NSCLC. The primary end point was major pathologic response (MPR) rates (≤10% of residual tumor cells) by central pathology review in the arms containing canakinumab. Secondary end points included overall response rates, safety, pharmacokinetics, surgical feasibility rates, and MPR rate in the pembrolizumab arm. The impact of treatment on surgical outcomes was assessed as an exploratory outcome.
Results
In total, 88 patients were enrolled: 35 to the canakinumab arm, 35 to the canakinumab + pembrolizumab arm, and 18 to the pembrolizumab arm. One patient (2.9%) in the canakinumab arm (95% confidence interval [CI]: 0.07–14.92), six patients (17.1%) in the canakinumab + pembrolizumab arm (95% CI: 6.56–33.65), and three patients (16.7%) in the pembrolizumab arm (95% CI: 3.58–41.42) achieved MPR. No unexpected safety signals were observed. Of the 84 patients (95.5%) who underwent operation, the prespecified 6-week window was achieved for 72 patients (85.7%).
Conclusions
Neoadjuvant treatment with canakinumab alone or combined with pembrolizumab did not improve MPR rates compared with pembrolizumab alone. No unexpected safety signals were observed and canakinumab did not adversely affect surgical outcomes. Intraoperative perihilar or perilobular fibrosis after neoadjuvant immunotherapy was rare.
{"title":"CANOPY-N: A Phase 2 Study of Canakinumab or Pembrolizumab, Alone or in Combination, as Neoadjuvant Therapy in Patients With Resectable, Stage IB–IIIA NSCLC","authors":"Jay M. Lee MD , Jean-Louis Pujol MD, PhD , Jun Zhang MD, PhD , Oleg Leonov MD, PhD , Masahiro Tsuboi MD, PhD , Edward S. Kim MD, MBA , Calvin Ng MD , Nicolas Moreno-Mata MD, PhD , Amy Cummings MD, PhD , Ilhan Hacibekiroglu MD , Abidin Sehitogullari MD , Nirmal Veeramachaneni MD , Cathy Spillane PhD , Jiawei Duan PhD , Claudia Bossen PhD , Alexander Savchenko MD, PhD , Chiara Lobetti-Bodoni MD, PhD , Tony Mok MD , Pilar Garrido MD","doi":"10.1016/j.jtocrr.2025.100859","DOIUrl":"10.1016/j.jtocrr.2025.100859","url":null,"abstract":"<div><h3>Introduction</h3><div>Canakinumab is a human monoclonal anti–interleukin-1β antibody with the potential to enhance the activity of programmed death-ligand 1 inhibitors by inhibiting protumor inflammation.</div></div><div><h3>Methods</h3><div>CANOPY-N was a randomized, phase 2 study to evaluate safety and efficacy of neoadjuvant canakinumab (200 mg subcutaneous once every three weeks) and pembrolizumab (200 mg intravenous once every three weeks), either in combination or alone, in patients with early-stage (stage Ib–IIIa) NSCLC. The primary end point was major pathologic response (MPR) rates (≤10% of residual tumor cells) by central pathology review in the arms containing canakinumab. Secondary end points included overall response rates, safety, pharmacokinetics, surgical feasibility rates, and MPR rate in the pembrolizumab arm. The impact of treatment on surgical outcomes was assessed as an exploratory outcome.</div></div><div><h3>Results</h3><div>In total, 88 patients were enrolled: 35 to the canakinumab arm, 35 to the canakinumab + pembrolizumab arm, and 18 to the pembrolizumab arm. One patient (2.9%) in the canakinumab arm (95% confidence interval [CI]: 0.07–14.92), six patients (17.1%) in the canakinumab + pembrolizumab arm (95% CI: 6.56–33.65), and three patients (16.7%) in the pembrolizumab arm (95% CI: 3.58–41.42) achieved MPR. No unexpected safety signals were observed. Of the 84 patients (95.5%) who underwent operation, the prespecified 6-week window was achieved for 72 patients (85.7%).</div></div><div><h3>Conclusions</h3><div>Neoadjuvant treatment with canakinumab alone or combined with pembrolizumab did not improve MPR rates compared with pembrolizumab alone. No unexpected safety signals were observed and canakinumab did not adversely affect surgical outcomes. Intraoperative perihilar or perilobular fibrosis after neoadjuvant immunotherapy was rare.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 8","pages":"Article 100859"},"PeriodicalIF":3.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144579962","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 : 2025-06-13DOI: 10.1016/j.jtocrr.2025.100861
Yota Suzuki MD , Rajeev Dhupar MD , Inderpal S. Sarkaria MD, MBA , Ian G. Christie MD , Summer N. Mazur BS , Arjun Pennathur MD , James D. Luketich MD , Ryan M. Levy MD , Rodney J. Landreneau MD , Matthew J. Schuchert MD
Objective
Besides the discussion on parenchymal margin, data on the extent of lymph node (LN) dissection are scarce, especially in segmentectomy. This study aimed to investigate the extent of LN dissection and detection of occult disease in segmentectomy compared with lobar resection.
Methods
We performed a single-institution, retrospective analysis for patients who underwent segmentectomy or lobectomy for clinical T1N0M0 (≤3 cm) NSCLC from 2012 to 2022. The extent of LN dissection and the rate of detection of occult LN disease were compared. N1 nodes were further classified as collected as a specimen during the operation (N1 dissection) and the nodes retrieved from lung specimens by pathologists (N1 lung specimen).
Results
During the study period, 957 lobectomies and 402 segmentectomies were performed for clinical T1N0M0 NSCLC. The median number of sampled LNs was significantly higher in the lobectomy group (18 versus 12; p < 0.001). This tendency was similar across all node groups, including N2 nodes (7 versus 5), N1 dissection nodes (6 versus 4), and most significantly N1 lung specimen nodes (4 versus 0; all p < 0.001) There was a significant difference in N1 occult nodes (13.3% versus 3.7%; p < 0.001), whereas the difference was not significant in N2 occult nodes (5.5% versus 3.2%; p = 0.074).
Conclusions
Segmentectomy was associated with less LN sampling, which translated into lower detection of occult nodal metastasis in N1 LNs. Although standardized pathologic dissection could potentially improve detection, there is likely an inevitable inferiority in LN sampling with segmentectomy.
{"title":"Occult Node Detection With Lobectomy Versus Segmentectomy for Stage IA NSCLC","authors":"Yota Suzuki MD , Rajeev Dhupar MD , Inderpal S. Sarkaria MD, MBA , Ian G. Christie MD , Summer N. Mazur BS , Arjun Pennathur MD , James D. Luketich MD , Ryan M. Levy MD , Rodney J. Landreneau MD , Matthew J. Schuchert MD","doi":"10.1016/j.jtocrr.2025.100861","DOIUrl":"10.1016/j.jtocrr.2025.100861","url":null,"abstract":"<div><h3>Objective</h3><div>Besides the discussion on parenchymal margin, data on the extent of lymph node (LN) dissection are scarce, especially in segmentectomy. This study aimed to investigate the extent of LN dissection and detection of occult disease in segmentectomy compared with lobar resection.</div></div><div><h3>Methods</h3><div>We performed a single-institution, retrospective analysis for patients who underwent segmentectomy or lobectomy for clinical T1N0M0 (≤3 cm) NSCLC from 2012 to 2022. The extent of LN dissection and the rate of detection of occult LN disease were compared. N1 nodes were further classified as collected as a specimen during the operation (N1 dissection) and the nodes retrieved from lung specimens by pathologists (N1 lung specimen).</div></div><div><h3>Results</h3><div>During the study period, 957 lobectomies and 402 segmentectomies were performed for clinical T1N0M0 NSCLC. The median number of sampled LNs was significantly higher in the lobectomy group (18 versus 12; <em>p</em> < 0.001). This tendency was similar across all node groups, including N2 nodes (7 versus 5), N1 dissection nodes (6 versus 4), and most significantly N1 lung specimen nodes (4 versus 0; all <em>p</em> < 0.001) There was a significant difference in N1 occult nodes (13.3% versus 3.7%; <em>p</em> < 0.001), whereas the difference was not significant in N2 occult nodes (5.5% versus 3.2%; <em>p</em> = 0.074).</div></div><div><h3>Conclusions</h3><div>Segmentectomy was associated with less LN sampling, which translated into lower detection of occult nodal metastasis in N1 LNs. Although standardized pathologic dissection could potentially improve detection, there is likely an inevitable inferiority in LN sampling with segmentectomy.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 8","pages":"Article 100861"},"PeriodicalIF":3.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588218","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 : 2025-06-13eCollection Date: 2025-09-01DOI: 10.1016/j.jtocrr.2025.100863
Heather Law, Huamao M Lin, Eileen Curran, Annette Szumski, Jacinta Wiens, Jennifer Blender, Emily S Venanzi, Erin L Schenk, Jessica J Lin, Jennifer C King
Introduction: This study investigated quality of life (QoL) and its role in treatment decision making among patients with anaplastic lymphoma kinase (ALK)+ NSCLC.
Methods: Adult patients with self-reported ALK+ NSCLC residing in the United States from the Lung Cancer Registry from GO2 for Lung Cancer were included. Measures included a core patient survey derived from Quality of Life Questionnaire - Core 30 items (QLQ-C30) and QLQ - lung cancer module 29 items domains and an ALK+ NSCLC module (ALK module). Associations were assessed between key domains and module questions using polyserial or Spearman's correlations and Cochran-Mantel-Haenszel tests.
Results: Seventy-one patients with ALK+ NSCLC completed the ALK module. Most patients (85%) felt their current therapy helped stop cancer growth, helped them live longer, and was worth taking despite side effects; however, 80% reported some cancer scan-related anxiety and only 32% reported having received "quite a bit" or "very much" mental health support information from their care team. Most patients (75%) reported QoL as a top concern in treatment decisions, regardless of responses to other ALK module questions (all associations p ≥ 0.50). Although most patients (87%) perceived their physicians as interested in their QoL, only 51% reported their physicians discussed QoL as a top concern in treatment decisions. QLQ-C30 composite global health status-QoL score had significant moderate to strong correlations with all other QLQ-C30 and lung cancer module 29 items domains (p ≤ 0.004) and some components of communication with care teams, treatment confidence, and impact on daily life.
Conclusions: QoL is important in treatment decision making for patients with ALK+ NSCLC. These findings highlight areas for improvement in mental health support and patient-provider communication.
{"title":"Role of Quality of Life in Daily Functioning, Communication with Care Teams, and Treatment Decisions in Patients with <i>ALK</i>+ NSCLC.","authors":"Heather Law, Huamao M Lin, Eileen Curran, Annette Szumski, Jacinta Wiens, Jennifer Blender, Emily S Venanzi, Erin L Schenk, Jessica J Lin, Jennifer C King","doi":"10.1016/j.jtocrr.2025.100863","DOIUrl":"10.1016/j.jtocrr.2025.100863","url":null,"abstract":"<p><strong>Introduction: </strong>This study investigated quality of life (QoL) and its role in treatment decision making among patients with anaplastic lymphoma kinase (<i>ALK</i>)+ NSCLC.</p><p><strong>Methods: </strong>Adult patients with self-reported <i>ALK</i>+ NSCLC residing in the United States from the Lung Cancer Registry from GO2 for Lung Cancer were included. Measures included a core patient survey derived from Quality of Life Questionnaire - Core 30 items (QLQ-C30) and QLQ - lung cancer module 29 items domains and an <i>ALK+</i> NSCLC module (ALK module). Associations were assessed between key domains and module questions using polyserial or Spearman's correlations and Cochran-Mantel-Haenszel tests.</p><p><strong>Results: </strong>Seventy-one patients with <i>ALK</i>+ NSCLC completed the ALK module. Most patients (85%) felt their current therapy helped stop cancer growth, helped them live longer, and was worth taking despite side effects; however, 80% reported some cancer scan-related anxiety and only 32% reported having received \"quite a bit\" or \"very much\" mental health support information from their care team. Most patients (75%) reported QoL as a top concern in treatment decisions, regardless of responses to other ALK module questions (all associations <i>p</i> ≥ 0.50). Although most patients (87%) perceived their physicians as interested in their QoL, only 51% reported their physicians discussed QoL as a top concern in treatment decisions. QLQ-C30 composite global health status-QoL score had significant moderate to strong correlations with all other QLQ-C30 and lung cancer module 29 items domains (<i>p</i> ≤ 0.004) and some components of communication with care teams, treatment confidence, and impact on daily life.</p><p><strong>Conclusions: </strong>QoL is important in treatment decision making for patients with <i>ALK+</i> NSCLC. These findings highlight areas for improvement in mental health support and patient-provider communication.</p>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 9","pages":"100863"},"PeriodicalIF":3.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873869","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 : 2025-06-13DOI: 10.1016/j.jtocrr.2025.100858
Xiao Yang PhD, Shuo Sun BSc, Xunjie Kuang BSc, Xianfeng Lu MM, He Xiao MM, Yi Duan BSc, Yanli Xiong MM, Di Zhang BSc, Yu Xu PhD, Jianwu Zhu PhD, Mengxia Li PhD
Background
Early recurrence limits the long-term survival of postoperative patients with stage IA lung adenocarcinoma (LUAD). This study aims to risk-stratify postoperative stage IA LUAD by means of the expression of Midkine (MDK).
Materials and Methods
We collected surgical samples from 62 patients with stage IA LUAD, of which 30 patients had early recurrence and others without. Intratumoral and peritumoral MDK expression were measured by immunohistochemistry staining. We also analyzed the MDK expression of stage IA LUAD from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus repository.
Results
The intratumoral MDK was significantly overexpressed in patients with early recurrence (p < 0.001). Kaplan-Meier survival analysis revealed that patients with higher intratumoral MDK expression had poor recurrence-free survival (p < 0.001) and overall survival (p = 0.004). Univariate Cox regression analysis indicated that intratumoral MDK expression significantly increased the risk of recurrence (hazard ratio [HR] 1.408 (1.076–1.842), p = 0.013) and death (HR 1.888 [1.127–3.162], p = 0.016). Stepwise Cox regression analysis revealed that smoking (HR 2.944 [1.419–6.107], p = 0.004), intratumoral MDK expression (HR 1.316 [1.037–1.669], p = 0.024), and EGFR mutation (HR 2.407 [1.110–5.221], p = 0.026) were independent prognostic factors for early recurrence. In TCGA data set, the MDK expression significantly increased the risk of recurrence (HR 1.559 [1.035–2.349], p = 0.034), and patients with higher MDK expression had worse disease-free survival (p = 0.024). In GSE31210, the MDK expression significantly increased the risk of recurrence (HR 2.617 [1.791–3.824], p < 0.001) and death (HR 2.495 [1.429–4.356], p = 0.001), whereas patients with higher MDK expression also had worse recurrence-free survival (p = 0.006) and overall survival (p < 0.001).
Conclusion
MDK was considered a putative candidate for predicting early recurrence in patients with stage IA LUAD.
背景：严重复发限制了IA期肺腺癌（LUAD）术后患者的长期生存。本研究旨在通过Midkine （MDK）的表达对术后IA期LUAD进行风险分层。材料与方法我们收集了62例IA期LUAD患者的手术标本，其中30例早期复发，其余无复发。免疫组织化学染色检测肿瘤内和肿瘤周围MDK的表达。我们还分析了来自癌症基因组图谱（TCGA）和基因表达综合库的IA期LUAD的MDK表达。结果肿瘤内MDK在早期复发患者中显著过表达(p <；0.001)。Kaplan-Meier生存分析显示，肿瘤内MDK表达较高的患者无复发生存期较差(p <；0.001)和总生存率（p = 0.004）。单因素Cox回归分析显示，瘤内MDK表达显著增加复发风险（危险比[HR] 1.408 (1.076 ~ 1.842), p = 0.013）和死亡风险（危险比[HR] 1.888 [1.127 ~ 3.162], p = 0.016）。逐步Cox回归分析显示，吸烟（HR 2.944 [1.419-6.107], p = 0.004）、瘤内MDK表达（HR 1.316 [1.037-1.669], p = 0.024）、EGFR突变（HR 2.407 [1.110-5.221], p = 0.026）是早期复发的独立预后因素。在TCGA数据集中，MDK表达显著增加复发风险（HR 1.559 [1.035-2.349], p = 0.034）， MDK表达较高的患者无病生存期较差（p = 0.024）。在GSE31210中，MDK表达显著增加复发风险(HR 2.617 [1.791-3.824], p <；0.001)和死亡（HR 2.495 [1.429-4.356], p = 0.001），而MDK表达较高的患者无复发生存期（p = 0.006）和总生存期(p <；0.001)。结论mdk可作为预测IA期LUAD患者早期复发的候选指标。
{"title":"Midkine Expression as a Candidate Biomarker to Predict the Recurrence of Stage IA Lung Adenocarcinoma","authors":"Xiao Yang PhD, Shuo Sun BSc, Xunjie Kuang BSc, Xianfeng Lu MM, He Xiao MM, Yi Duan BSc, Yanli Xiong MM, Di Zhang BSc, Yu Xu PhD, Jianwu Zhu PhD, Mengxia Li PhD","doi":"10.1016/j.jtocrr.2025.100858","DOIUrl":"10.1016/j.jtocrr.2025.100858","url":null,"abstract":"<div><h3>Background</h3><div>Early recurrence limits the long-term survival of postoperative patients with stage IA lung adenocarcinoma (LUAD). This study aims to risk-stratify postoperative stage IA LUAD by means of the expression of Midkine (MDK).</div></div><div><h3>Materials and Methods</h3><div>We collected surgical samples from 62 patients with stage IA LUAD, of which 30 patients had early recurrence and others without. Intratumoral and peritumoral MDK expression were measured by immunohistochemistry staining. We also analyzed the MDK expression of stage IA LUAD from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus repository.</div></div><div><h3>Results</h3><div>The intratumoral MDK was significantly overexpressed in patients with early recurrence (<em>p</em> < 0.001). Kaplan-Meier survival analysis revealed that patients with higher intratumoral MDK expression had poor recurrence-free survival (<em>p</em> < 0.001) and overall survival (<em>p</em> = 0.004). Univariate Cox regression analysis indicated that intratumoral MDK expression significantly increased the risk of recurrence (hazard ratio [HR] 1.408 (1.076–1.842), <em>p</em> = 0.013) and death (HR 1.888 [1.127–3.162], <em>p</em> = 0.016). Stepwise Cox regression analysis revealed that smoking (HR 2.944 [1.419–6.107], <em>p</em> = 0.004), intratumoral MDK expression (HR 1.316 [1.037–1.669], <em>p</em> = 0.024), and <em>EGFR</em> mutation (HR 2.407 [1.110–5.221], <em>p</em> = 0.026) were independent prognostic factors for early recurrence. In TCGA data set, the MDK expression significantly increased the risk of recurrence (HR 1.559 [1.035–2.349], <em>p</em> = 0.034), and patients with higher MDK expression had worse disease-free survival (<em>p</em> = 0.024). In GSE31210, the MDK expression significantly increased the risk of recurrence (HR 2.617 [1.791–3.824], <em>p</em> < 0.001) and death (HR 2.495 [1.429–4.356], <em>p</em> = 0.001), whereas patients with higher MDK expression also had worse recurrence-free survival (<em>p</em> = 0.006) and overall survival (<em>p</em> < 0.001).</div></div><div><h3>Conclusion</h3><div>MDK was considered a putative candidate for predicting early recurrence in patients with stage IA LUAD.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 9","pages":"Article 100858"},"PeriodicalIF":3.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695429","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}
Histologic transformation from adenocarcinoma to SCLC is a recognized mechanism of resistance in lung cancer. However, the transformation into squamous cell carcinoma is less common, and the associated genomic alterations remain unclear. Here, we present a case of lung adenocarcinoma harboring an EGFR (EGFR) mutation that transformed into squamous cell carcinoma. Although EGFR L858R mutation was detected throughout the transformation, genomic analyses were performed during the disease course, revealing the amplification of FGFR1 and NSD3, which have recently been proposed as potential driver oncogenes in lung squamous cell carcinoma. This case report highlights the genomic alterations observed in repeatedly biopsied specimens, along with a review of the relevant literature.
{"title":"Acquisition of FGFR1 and NSD3 Amplifications During the Transformation of EGFR-Mutated Lung Adenocarcinoma into Squamous Cell Carcinoma: A Case Report","authors":"Naoki Fukunaga MD , Hideki Terai MD, PhD , Rui Nomura MD , Yutaka Kurebayashi MD, PhD , Kohei Nakamura MD, PhD , Ryutaro Kawano MD , Kohei Shigeta MD, PhD , Koji Okabayashi MD , Katsuhito Kinoshita MD , Akihiko Ogata MD , Lisa Shigematsu MD , Fumimaro Ito MD , Hatsuyo Takaoka MD , Takahiro Fukushima MD , Shigenari Nukaga MD, PhD , Keiko Ohgino MD, PhD , Hiroyuki Yasuda MD, PhD , Hiroshi Nishihara MD, PhD , Yuko Kitagawa MD, PhD , Koichi Fukunaga MD, PhD","doi":"10.1016/j.jtocrr.2025.100862","DOIUrl":"10.1016/j.jtocrr.2025.100862","url":null,"abstract":"<div><div>Histologic transformation from adenocarcinoma to SCLC is a recognized mechanism of resistance in lung cancer. However, the transformation into squamous cell carcinoma is less common, and the associated genomic alterations remain unclear. Here, we present a case of lung adenocarcinoma harboring an EGFR (<em>EGFR</em>) mutation that transformed into squamous cell carcinoma. Although <em>EGFR</em> L858R mutation was detected throughout the transformation, genomic analyses were performed during the disease course, revealing the amplification of <em>FGFR1</em> and <em>NSD3</em>, which have recently been proposed as potential driver oncogenes in lung squamous cell carcinoma. This case report highlights the genomic alterations observed in repeatedly biopsied specimens, along with a review of the relevant literature.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 9","pages":"Article 100862"},"PeriodicalIF":3.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739622","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 : 2025-06-05DOI: 10.1016/j.jtocrr.2025.100857
Guilherme Harada MD , Fernando C. Santini MD , Clare J. Wilhelm PhD , Rebecca W. Repetti NP , Jason C. Chang MD , Soo-Ryum Yang MD , Yun-Te Lin MSc , Khadeja A. Moses BA , Christina Falcon MPH, PMP , Michelle Goldstein MSW , Alex Makhnin MA , Michelle S. Ginsberg MD , Andrew J. Plodkowski MD , Mark G. Kris MD , Alexander Drilon MD
Introduction
Only type I MET tyrosine kinase inhibitors (TKIs) are approved for treating MET-altered NSCLCs. Preclinically, type II TKIs, such as cabozantinib, can rescue progression on type I TKIs. This phase 2 trial (NCT01639508) evaluated the activity of cabozantinib in patients with MET-dependent lung cancers, including TKI-pretreated cancers.
Methods
This phase 2 trial with a Simon two-stage minimax design treated patients with metastatic, MET-altered lung cancers with cabozantinib (60 mg daily) until progression or intolerable toxicity. The primary end point was objective response rate (ORR). We prespecified that cabozantinib would be considered a useful agent if at least a 20% ORR was observed. Secondary end points included progression-free survival, overall survival, and safety.
Results
We enrolled 28 patients, 23 patients (82%) with only a MET exon 14 alteration, two patients (7%) with MET amplification, and three patients (11%) with concurrent MET exon 14 alteration and amplification. There were 24 patients (86%) previously treated with a type I MET TKI. The ORR was 20% (5/25 assessable patients; 95% confidence interval [CI]: 8.9%–39.1%), with five partial responses (duration ranged from 4 to 39 mo). Four of five responders were type I MET TKI pretreated. The median progression-free survival and overall survival were 4.5 (95% CI: 3.3–5.7) months and 7.2 (95% CI: 2.9–11.5) months, respectively. Dose modification and discontinuation occurred in 64% (18/28) and 7% (2/28) of patients, respectively.
Conclusion
This trial met its primary end point. Importantly, we demonstrated that cabozantinib, a type II MET TKI, could benefit patients with MET-altered lung cancers previously treated with type I MET TKIs.
{"title":"A Phase II Study of Cabozantinib in Patients With MET-Altered Lung Cancers","authors":"Guilherme Harada MD , Fernando C. Santini MD , Clare J. Wilhelm PhD , Rebecca W. Repetti NP , Jason C. Chang MD , Soo-Ryum Yang MD , Yun-Te Lin MSc , Khadeja A. Moses BA , Christina Falcon MPH, PMP , Michelle Goldstein MSW , Alex Makhnin MA , Michelle S. Ginsberg MD , Andrew J. Plodkowski MD , Mark G. Kris MD , Alexander Drilon MD","doi":"10.1016/j.jtocrr.2025.100857","DOIUrl":"10.1016/j.jtocrr.2025.100857","url":null,"abstract":"<div><h3>Introduction</h3><div>Only type I MET tyrosine kinase inhibitors (TKIs) are approved for treating <em>MET</em>-altered NSCLCs. Preclinically, type II TKIs, such as cabozantinib, can rescue progression on type I TKIs. This phase 2 trial (NCT01639508) evaluated the activity of cabozantinib in patients with MET-dependent lung cancers, including TKI-pretreated cancers.</div></div><div><h3>Methods</h3><div>This phase 2 trial with a Simon two-stage minimax design treated patients with metastatic, <em>MET</em>-altered lung cancers with cabozantinib (60 mg daily) until progression or intolerable toxicity. The primary end point was objective response rate (ORR). We prespecified that cabozantinib would be considered a useful agent if at least a 20% ORR was observed. Secondary end points included progression-free survival, overall survival, and safety.</div></div><div><h3>Results</h3><div>We enrolled 28 patients, 23 patients (82%) with only a <em>MET</em> exon 14 alteration, two patients (7%) with <em>MET</em> amplification, and three patients (11%) with concurrent <em>MET</em> exon 14 alteration and amplification. There were 24 patients (86%) previously treated with a type I MET TKI. The ORR was 20% (5/25 assessable patients; 95% confidence interval [CI]: 8.9%–39.1%), with five partial responses (duration ranged from 4 to 39 mo). Four of five responders were type I MET TKI pretreated. The median progression-free survival and overall survival were 4.5 (95% CI: 3.3–5.7) months and 7.2 (95% CI: 2.9–11.5) months, respectively. Dose modification and discontinuation occurred in 64% (18/28) and 7% (2/28) of patients, respectively.</div></div><div><h3>Conclusion</h3><div>This trial met its primary end point. Importantly, we demonstrated that cabozantinib, a type II MET TKI, could benefit patients with MET-altered lung cancers previously treated with type I MET TKIs.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 8","pages":"Article 100857"},"PeriodicalIF":3.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549819","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 : 2025-06-03DOI: 10.1016/j.jtocrr.2025.100850
Oluwaseun F. Ayoade MD, MSHA , Maureen E. Canavan PhD, MPH , Emily J. Zolfaghari MD, MS , Giorgio Caturegli MD , So Yeon Kim MD , Daniel J. Boffa MD, MBA
{"title":"Erratum to ‘Recent Survival Gains in Stage IV NSCLC by Sociodemographic Strata’ [JTO Clinical and Research Reports Volume 6 Issue 4 (2025) 100798]","authors":"Oluwaseun F. Ayoade MD, MSHA , Maureen E. Canavan PhD, MPH , Emily J. Zolfaghari MD, MS , Giorgio Caturegli MD , So Yeon Kim MD , Daniel J. Boffa MD, MBA","doi":"10.1016/j.jtocrr.2025.100850","DOIUrl":"10.1016/j.jtocrr.2025.100850","url":null,"abstract":"","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 12","pages":"Article 100850"},"PeriodicalIF":3.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468352","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 : 2025-05-27DOI: 10.1016/j.jtocrr.2025.100854
Justin A. Olivera MD, Sara Sakowitz MD, MPH, Mara B. Antonoff MD, FACS
{"title":"An Uneven Playing Field: Survival Gains in Stage IV NSCLC Across Sociodemographic Strata","authors":"Justin A. Olivera MD, Sara Sakowitz MD, MPH, Mara B. Antonoff MD, FACS","doi":"10.1016/j.jtocrr.2025.100854","DOIUrl":"10.1016/j.jtocrr.2025.100854","url":null,"abstract":"","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 8","pages":"Article 100854"},"PeriodicalIF":3.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330224","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 : 2025-05-26DOI: 10.1016/j.jtocrr.2025.100851
Omar Elghawy MD, Adam Barsouk MD, Jonathan H. Sussman BS, Benjamin A. Bleiberg MD, Lauren Reed-Guy MD, Christopher D’Avella MD, Aditi Singh MD, Christine Ciunci MD, MSCE, Kyle Robinson MD, John Kosteva MD, Corey Langer MD, Roger B. Cohen MD, Charu Aggarwal MD, MPH, Melina Marmarelis MD, MSCE, Lova Sun MD, MSCE
Background
Limited data are available on late immune-related adverse events (IRAEs) in patients with metastatic NSCLC receiving immunotherapy (ICI) beyond 2 years.
Methods
A single-institution retrospective analysis including patients who received longer than 2 years of ICI therapy for metastatic NSCLC between 2012 and 2023 was performed. Late IRAEs were defined as those occurring longer than 2 years after initiation of ICI therapy. The association of late IRAE with OS and PFS was assessed using an extended Cox regression with late IRAE modeled as a time-varying covariate.
Results
In a cohort of 76 patients who received longer than 2 years of ICI, the median duration of treatment was 41.9 months, and 44 out of 76 (58%) experienced an early IRAE before 2 years. After 2 years on ICI, 38 out of 76 (50%) of patients experienced a late IRAE, many of whom (39%) had no previous early IRAE. Higher rates of late IRAEs were seen in females (p = 0.032), White patients (p = 0.041), and patients with previous grade 2 or higher IRAE (p = 0.020). Late IRAE occurrence was not associated with median progression-free survival or median overall survival.
Conclusions
In patients receiving extended-duration ICI beyond 2 years, late IRAEs were common and often occurred in patients without previous history of IRAE. These findings support consideration of ICI discontinuation at 2 years.
{"title":"Late Immune-Related Adverse Events After At Least Two Years of Immune Checkpoint Inhibitor Therapy: Incidence and Association With Survival in Patients With Advanced NSCLC","authors":"Omar Elghawy MD, Adam Barsouk MD, Jonathan H. Sussman BS, Benjamin A. Bleiberg MD, Lauren Reed-Guy MD, Christopher D’Avella MD, Aditi Singh MD, Christine Ciunci MD, MSCE, Kyle Robinson MD, John Kosteva MD, Corey Langer MD, Roger B. Cohen MD, Charu Aggarwal MD, MPH, Melina Marmarelis MD, MSCE, Lova Sun MD, MSCE","doi":"10.1016/j.jtocrr.2025.100851","DOIUrl":"10.1016/j.jtocrr.2025.100851","url":null,"abstract":"<div><h3>Background</h3><div>Limited data are available on late immune-related adverse events (IRAEs) in patients with metastatic NSCLC receiving immunotherapy (ICI) beyond 2 years.</div></div><div><h3>Methods</h3><div>A single-institution retrospective analysis including patients who received longer than 2 years of ICI therapy for metastatic NSCLC between 2012 and 2023 was performed. Late IRAEs were defined as those occurring longer than 2 years after initiation of ICI therapy. The association of late IRAE with OS and PFS was assessed using an extended Cox regression with late IRAE modeled as a time-varying covariate.</div></div><div><h3>Results</h3><div>In a cohort of 76 patients who received longer than 2 years of ICI, the median duration of treatment was 41.9 months, and 44 out of 76 (58%) experienced an early IRAE before 2 years. After 2 years on ICI, 38 out of 76 (50%) of patients experienced a late IRAE, many of whom (39%) had no previous early IRAE. Higher rates of late IRAEs were seen in females (<em>p</em> = 0.032), White patients (<em>p</em> = 0.041), and patients with previous grade 2 or higher IRAE (<em>p</em> = 0.020). Late IRAE occurrence was not associated with median progression-free survival or median overall survival.</div></div><div><h3>Conclusions</h3><div>In patients receiving extended-duration ICI beyond 2 years, late IRAEs were common and often occurred in patients without previous history of IRAE. These findings support consideration of ICI discontinuation at 2 years.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 9","pages":"Article 100851"},"PeriodicalIF":3.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725043","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 : 2025-05-26DOI: 10.1016/j.jtocrr.2025.100853
J.W. Tijmen van der Wel MD , Merel Jebbink MD , Vincent van der Noort PhD , Ferry Lalezari MD, PhD , Daan van den Broek PhD , Gerrina Ruiter MD, PhD , Jacobus A. Burgers MD, PhD , Paul Baas MD, PhD , Anne S.R. van Lindert MD , Eva E. van der Wall MD , Lisanne E.A. Kastelijn MD, PhD , Marrit Vermeulen BSc , Linda J.W. Bosch PhD , Kim Monkhorst MD, PhD , Mirjam C. Boelens PhD , Egbert F. Smit MD, PhD , Adrianus J. de Langen MD, PhD
Introduction
In osimertinib-treated EGFR mutation (EGFRm)–positive NSCLC, resistance inevitably occurs. Early resistance mechanism (RM) detection by circulating tumor DNA (ctDNA) in plasma and consecutive targeted treatment may delay progressive disease (PD). In this multicenter prospective study, we evaluated the detection rate and time interval of RM emergence in plasma ctDNA before radiologic PD.
Methods
Patients with EGFRm–positive NSCLC, treated with second- or third-line osimertinib, underwent computed tomography of the thorax and ctDNA analysis (Roche AVENIO expanded panel, research use only [Roche Sequencing Solutions, Roche, Basel, Switzerland]) at baseline and every 8 weeks for response evaluation and EGFRm and RM detection. If MET amplification preceded PD, crizotinib was to be added to osimertinib. Other RMs were monitored but not acted on. After PD, patients underwent a tumor biopsy.
Results
Of the 21 evaluable patients, 18 had detectable ctDNA at baseline. In patients with undetectable ctDNA at baseline, ctDNA remained undetectable during treatment. In the 17 out of 18 (94%) patients with detectable ctDNA, PD occurred. In seven out of 21 patients (33%), the EGFRm variant allele frequency increase preceded radiologic PD with a median interval of 9 weeks (range 7–34). In seven out of 21 patients (33%), at least one RM was detected before PD, and the median interval was 14 weeks (range 7–34). Three had one or more RM in ctDNA at baseline. No MET amplification was observed, and treatment with crizotinib was not initiated in any patient. After PD, 16 biopsies were obtained. Five confirmed the RM detected in plasma, five biopsies revealed additional RMs, and six harbored no RM.
Conclusions
In 33% of patients treated with second- or third-line osimertinib, RMs in plasma preceded PD by a median of 14 weeks, suggesting an opportunity for early treatment adjustment, potentially extending tyrosine kinase inhibitor treatment duration.
{"title":"Longitudinal Circulating Tumor DNA–Guided Resistance Analysis During Second-Line Osimertinib Treatment","authors":"J.W. Tijmen van der Wel MD , Merel Jebbink MD , Vincent van der Noort PhD , Ferry Lalezari MD, PhD , Daan van den Broek PhD , Gerrina Ruiter MD, PhD , Jacobus A. Burgers MD, PhD , Paul Baas MD, PhD , Anne S.R. van Lindert MD , Eva E. van der Wall MD , Lisanne E.A. Kastelijn MD, PhD , Marrit Vermeulen BSc , Linda J.W. Bosch PhD , Kim Monkhorst MD, PhD , Mirjam C. Boelens PhD , Egbert F. Smit MD, PhD , Adrianus J. de Langen MD, PhD","doi":"10.1016/j.jtocrr.2025.100853","DOIUrl":"10.1016/j.jtocrr.2025.100853","url":null,"abstract":"<div><h3>Introduction</h3><div>In osimertinib-treated EGFR mutation (EGFRm)–positive NSCLC, resistance inevitably occurs. Early resistance mechanism (RM) detection by circulating tumor DNA (ctDNA) in plasma and consecutive targeted treatment may delay progressive disease (PD). In this multicenter prospective study, we evaluated the detection rate and time interval of RM emergence in plasma ctDNA before radiologic PD.</div></div><div><h3>Methods</h3><div>Patients with EGFRm–positive NSCLC, treated with second- or third-line osimertinib, underwent computed tomography of the thorax and ctDNA analysis (Roche AVENIO expanded panel, research use only [Roche Sequencing Solutions, Roche, Basel, Switzerland]) at baseline and every 8 weeks for response evaluation and EGFRm and RM detection. If MET amplification preceded PD, crizotinib was to be added to osimertinib. Other RMs were monitored but not acted on. After PD, patients underwent a tumor biopsy.</div></div><div><h3>Results</h3><div>Of the 21 evaluable patients, 18 had detectable ctDNA at baseline. In patients with undetectable ctDNA at baseline, ctDNA remained undetectable during treatment. In the 17 out of 18 (94%) patients with detectable ctDNA, PD occurred. In seven out of 21 patients (33%), the EGFRm variant allele frequency increase preceded radiologic PD with a median interval of 9 weeks (range 7–34). In seven out of 21 patients (33%), at least one RM was detected before PD, and the median interval was 14 weeks (range 7–34). Three had one or more RM in ctDNA at baseline. No MET amplification was observed, and treatment with crizotinib was not initiated in any patient. After PD, 16 biopsies were obtained. Five confirmed the RM detected in plasma, five biopsies revealed additional RMs, and six harbored no RM.</div></div><div><h3>Conclusions</h3><div>In 33% of patients treated with second- or third-line osimertinib, RMs in plasma preceded PD by a median of 14 weeks, suggesting an opportunity for early treatment adjustment, potentially extending tyrosine kinase inhibitor treatment duration.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 9","pages":"Article 100853"},"PeriodicalIF":3.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739621","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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