Pub Date : 2025-09-01Epub Date: 2025-06-19DOI: 10.1016/j.jtocrr.2025.100866
Jay M. Lee MD , Alessandro Brunelli MD , Amy L. Cummings MD , Enriqueta Felip MD, PhD , Catherine A. Shu MD , Benjamin J. Solomon M.B.B.S., PhD , Masahiro Tsuboi MD , Heather Wakelee MD , Anjali Saqi MD , Yi-Long Wu MD , Pao-Chen Li PhD , Barbara J. Gitlitz MD
Phase 3 trials of neoadjuvant, perioperative, and adjuvant immune checkpoint inhibitors combined with chemotherapy (ICI-CT) in resectable early-stage NSCLC (eNSCLC) have reported that all three approaches confer an event-free or disease-free survival benefit over CT alone, with acceptable safety profiles. All three strategies are approved standards of care for eNSCLC. This review provides a detailed analysis of these phase 3 ICI-CT trials and addresses the considerations regarding the selection of each approach, including protocol schema and baseline patient and tumor differences, preoperative staging, surgical outcomes, efficacy end points, safety, treatment disposition, and the programmed death-ligand 1 (PD-L1) efficacy biomarker. The differences between regimens and study populations among these ICI-CT trials hamper cross-trial comparisons and highlight the need for head-to-head trials. Patients achieving pathologic complete response with neoadjuvant ICI-CT have better survival outcomes irrespective of subsequent treatment, but the optimal number of preoperative ICI-CT cycles needed to achieve pathologic complete response has not been defined. The choice between a neoadjuvant or perioperative versus adjuvant treatment approach involves a risk-benefit assessment of the potential for preoperative attrition to surgery, postoperative attrition to ICI-CT, and the anticipated toxicity profile. Current limitations of invasive lymph node staging mean that adjuvant ICI remains an important treatment strategy, but preoperative node staging is imperative. Future studies that identify the safety and toxicity contributions of each treatment phase in perioperative trials will confirm whether a pre- or postoperative ICI approach is superior, whether there is added benefit to adjuvant after neoadjuvant ICI-CT, and which patients will benefit the most from each approach.
{"title":"Phase 3 Trials of Neoadjuvant, Perioperative, and Adjuvant Chemoimmunotherapy for Resectable, Early-Stage NSCLC: Comprehensive Review and Detailed Analysis","authors":"Jay M. Lee MD , Alessandro Brunelli MD , Amy L. Cummings MD , Enriqueta Felip MD, PhD , Catherine A. Shu MD , Benjamin J. Solomon M.B.B.S., PhD , Masahiro Tsuboi MD , Heather Wakelee MD , Anjali Saqi MD , Yi-Long Wu MD , Pao-Chen Li PhD , Barbara J. Gitlitz MD","doi":"10.1016/j.jtocrr.2025.100866","DOIUrl":"10.1016/j.jtocrr.2025.100866","url":null,"abstract":"<div><div>Phase 3 trials of neoadjuvant, perioperative, and adjuvant immune checkpoint inhibitors combined with chemotherapy (ICI-CT) in resectable early-stage NSCLC (eNSCLC) have reported that all three approaches confer an event-free or disease-free survival benefit over CT alone, with acceptable safety profiles. All three strategies are approved standards of care for eNSCLC. This review provides a detailed analysis of these phase 3 ICI-CT trials and addresses the considerations regarding the selection of each approach, including protocol schema and baseline patient and tumor differences, preoperative staging, surgical outcomes, efficacy end points, safety, treatment disposition, and the programmed death-ligand 1 (PD-L1) efficacy biomarker. The differences between regimens and study populations among these ICI-CT trials hamper cross-trial comparisons and highlight the need for head-to-head trials. Patients achieving pathologic complete response with neoadjuvant ICI-CT have better survival outcomes irrespective of subsequent treatment, but the optimal number of preoperative ICI-CT cycles needed to achieve pathologic complete response has not been defined. The choice between a neoadjuvant or perioperative versus adjuvant treatment approach involves a risk-benefit assessment of the potential for preoperative attrition to surgery, postoperative attrition to ICI-CT, and the anticipated toxicity profile. Current limitations of invasive lymph node staging mean that adjuvant ICI remains an important treatment strategy, but preoperative node staging is imperative. Future studies that identify the safety and toxicity contributions of each treatment phase in perioperative trials will confirm whether a pre- or postoperative ICI approach is superior, whether there is added benefit to adjuvant after neoadjuvant ICI-CT, and which patients will benefit the most from each approach.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 9","pages":"Article 100866"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725044","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 : 2025-09-01Epub 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":"2025-09-01","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 : 2025-09-01Epub Date: 2025-06-30DOI: 10.1016/j.jtocrr.2025.100870
Alexander S. Watson MD, DPhil , Alyse W. Staley MS , Benjamin Yoder PharmD, BCOP , Sean J. Iwamoto MD , Vida Alami BA , Erin L. Schenk MD, PhD , Tejas Patil MD , D. Ross Camidge MD, PhD , John M. Taormina MD
Introduction
Therapy-associated weight gain affects the quality of life and health of patients with ALK-positive NSCLC treated with tyrosine kinase inhibitors (TKIs). The severity and timing of real-world weight gain on ALK TKIs and associated risk factors are poorly understood, impairing timely interventions.
Methods
A retrospective chart review of patients with ALK-positive NSCLC receiving TKIs at our institution from January 1, 2020 to December 31, 2023 was conducted. Demographics, metabolic comorbidities, treatment details, and clinic-measured weights were collected. The grade of weight gain, maximum weight gain (% of baseline), and early weight gain (within 6 mo of TKI start) were calculated. Univariable and multivariable linear mixed effects analyses for predictors of weight gain were performed.
Results
A total of 91 patients received 156 treatment lines of TKI. Patients receiving lorlatinib experienced significantly higher maximum weight gain (mean 13.5% [95% confidence interval 10.8–16.2]) than those receiving other TKIs (p <0.001). Any-grade and grade 3 weight gain rates exceeded those from clinical trials. In multivariate modeling, early weight gain of at least 5% within 6 months (p <0.001), lorlatinib use (p = 0.007), and age 50 years or younger (p = 0.046) were associated with maximum weight gain. Among patients receiving lorlatinib, early weight gain (p = 0.001) remained significantly associated with higher maximum weight gain.
Conclusions
In this real-world cohort, rates and severity of weight gain on ALK TKIs were higher than in registrational trials, and highest on lorlatinib. Patients with early weight gain of greater than or equal to 5% within 6 months developed higher maximum gain. Prospective investigation of early weight management interventions is encouraged.
{"title":"Early Weight Gain as a Risk Factor for Increased Maximum Weight Gain Among Patients With NSCLC on Lorlatinib and Other ALK Tyrosine Kinase Inhibitors","authors":"Alexander S. Watson MD, DPhil , Alyse W. Staley MS , Benjamin Yoder PharmD, BCOP , Sean J. Iwamoto MD , Vida Alami BA , Erin L. Schenk MD, PhD , Tejas Patil MD , D. Ross Camidge MD, PhD , John M. Taormina MD","doi":"10.1016/j.jtocrr.2025.100870","DOIUrl":"10.1016/j.jtocrr.2025.100870","url":null,"abstract":"<div><h3>Introduction</h3><div>Therapy-associated weight gain affects the quality of life and health of patients with ALK-positive NSCLC treated with tyrosine kinase inhibitors (TKIs). The severity and timing of real-world weight gain on ALK TKIs and associated risk factors are poorly understood, impairing timely interventions.</div></div><div><h3>Methods</h3><div>A retrospective chart review of patients with ALK-positive NSCLC receiving TKIs at our institution from January 1, 2020 to December 31, 2023 was conducted. Demographics, metabolic comorbidities, treatment details, and clinic-measured weights were collected. The grade of weight gain, maximum weight gain (% of baseline), and early weight gain (within 6 mo of TKI start) were calculated. Univariable and multivariable linear mixed effects analyses for predictors of weight gain were performed.</div></div><div><h3>Results</h3><div>A total of 91 patients received 156 treatment lines of TKI. Patients receiving lorlatinib experienced significantly higher maximum weight gain (mean 13.5% [95% confidence interval 10.8–16.2]) than those receiving other TKIs (<em>p</em> <0.001). Any-grade and grade 3 weight gain rates exceeded those from clinical trials. In multivariate modeling, early weight gain of at least 5% within 6 months (<em>p</em> <0.001), lorlatinib use (<em>p</em> = 0.007), and age 50 years or younger (<em>p</em> = 0.046) were associated with maximum weight gain. Among patients receiving lorlatinib, early weight gain (<em>p</em> = 0.001) remained significantly associated with higher maximum weight gain.</div></div><div><h3>Conclusions</h3><div>In this real-world cohort, rates and severity of weight gain on ALK TKIs were higher than in registrational trials, and highest on lorlatinib. Patients with early weight gain of greater than or equal to 5% within 6 months developed higher maximum gain. Prospective investigation of early weight management interventions is encouraged.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 9","pages":"Article 100870"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756736","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 : 2025-09-01Epub 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":"2025-09-01","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}
Pub Date : 2025-09-01Epub 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":"2025-09-01","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 : 2025-09-01Epub Date: 2025-07-10DOI: 10.1016/j.jtocrr.2025.100877
Iris van 't Erve PhD , Isabelle Blanchard BS , Judy Y. Pagtama MSN , Alison J. Holmes Tisch MSN , Ash A. Alizadeh MD, PhD , Kavitha Ramchandran MD , Heather A. Wakelee MD , Sukhmani K. Padda MD , Maximilian Diehn MD, PhD , Joel W. Neal MD, PhD
Immune checkpoint inhibitors provide clinical benefit to a subset of patients with metastatic NSCLC, yet the reliable prediction of long-term outcomes remains challenging. We conducted a prospective phase 2 clinical trial to evaluate circulating tumor DNA (ctDNA) as a surrogate biomarker for early clinical response to pembrolizumab monotherapy (NCT02955758). Tumor-informed targeted sequencing of pretreatment and early on-treatment plasma ctDNA in 25 patients with metastatic NSCLC was performed. On-treatment ctDNA response, defined as at least a threefold ctDNA variant allele frequency decrease after three cycles of pembrolizumab versus baseline, was able to predict with 100%, 66%, and 100% accuracy partial response, stable disease, and progressive disease radiologic response, respectively. Molecular response was also correlated with progression-free survival. This study confirms the potential clinical utility of early on-treatment ctDNA-based response evaluation in patients treated with immune checkpoint inhibitors, creating the opportunity for early treatment intervention in nonresponders.
{"title":"Brief Report: Prospective Trial of Pembrolizumab Monotherapy in Metastatic NSCLC Evaluating Circulating Tumor DNA as a Surrogate Biomarker of Response","authors":"Iris van 't Erve PhD , Isabelle Blanchard BS , Judy Y. Pagtama MSN , Alison J. Holmes Tisch MSN , Ash A. Alizadeh MD, PhD , Kavitha Ramchandran MD , Heather A. Wakelee MD , Sukhmani K. Padda MD , Maximilian Diehn MD, PhD , Joel W. Neal MD, PhD","doi":"10.1016/j.jtocrr.2025.100877","DOIUrl":"10.1016/j.jtocrr.2025.100877","url":null,"abstract":"<div><div>Immune checkpoint inhibitors provide clinical benefit to a subset of patients with metastatic NSCLC, yet the reliable prediction of long-term outcomes remains challenging. We conducted a prospective phase 2 clinical trial to evaluate circulating tumor DNA (ctDNA) as a surrogate biomarker for early clinical response to pembrolizumab monotherapy (NCT02955758). Tumor-informed targeted sequencing of pretreatment and early on-treatment plasma ctDNA in 25 patients with metastatic NSCLC was performed. On-treatment ctDNA response, defined as at least a threefold ctDNA variant allele frequency decrease after three cycles of pembrolizumab versus baseline, was able to predict with 100%, 66%, and 100% accuracy partial response, stable disease, and progressive disease radiologic response, respectively. Molecular response was also correlated with progression-free survival. This study confirms the potential clinical utility of early on-treatment ctDNA-based response evaluation in patients treated with immune checkpoint inhibitors, creating the opportunity for early treatment intervention in nonresponders.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 9","pages":"Article 100877"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879600","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 : 2025-09-01Epub 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":"2025-09-01","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}
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":"2025-09-01","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 : 2025-08-01Epub 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":"2025-08-01","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 : 2025-08-01Epub 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":"2025-08-01","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}
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