Pub Date : 2025-05-15DOI: 10.1016/j.jtocrr.2025.100849
Jun-Chieh J. Tsay MD, MS , Antonio Velez MD , Destiny Collazo BS , Isaac Laniado MD , Jamie Bessich MD , Vivek Murthy MD , Andrew DeMaio MD , Samaan Rafeq MD , Benjamin Kwok MD , Fares Darawshy MD , Ray Pillai MD , Kendrew Wong MD , Yonghua Li MD, PhD , Rosemary Schluger RN , Alena Lukovnikova BS , Sofia Roldan BS , Matt Blaisdell BS , Fernanda Paz , Kelsey Krolikowski BS , Katherine Gershner MD , Daniel H. Sterman MD
Introduction
Outcomes for NSCLC remain suboptimal. Recent data suggest that cryoablation can generate antitumor immune effects. In this first-in-human phase I clinical trial, we investigated the safety and feasibility of bronchoscopic cryoimmunotherapy (BCI) delivered during standard-of-care bronchoscopy and explored associated systemic immune responses.
Methods
Subjects with known or suspected advanced-stage NSCLC were recruited. BCI was delivered in dose-escalated freeze-thaw cycles to determine maximum dose tolerance. Feasibility assessment was determined with a pre-set goal of achieving successful BCI in more than or equal to 80% of subjects. Safety was assessed by review of BCI-related complications, including grades 2 to 3 bleeding, pneumothorax requiring intervention, and National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 to 5 adverse events. Pre- and post-BCI blood samples were collected to explore changes in the systemic immune profile.
Results
Subjects with predominantly clinical TNM stage 3 or 4 adenocarcinoma or squamous cell carcinoma were enrolled. We reached the maximum dose of 30 seconds with 100% feasibility and no BCI-related adverse events. In peripheral blood analysis, we observed a significant decrease in derived neutrophil-to-lymphocyte ratio in the high-dose BCI group in comparison to the low-dose BCI cohort. We also observed increases in inflammatory cytokines—GM-CSF, IFN-γ, IL-1β, IL-17A, and IL-2—and effector memory T cells post-BCI.
Conclusion
BCI is safe and feasible. In addition, we provide preliminary evidence that at higher dose levels there is a systemic immune response consistent with a cytotoxic profile. Further immune analyses will determine the potential of BCI as an adjunctive therapy in combination with immune checkpoint inhibition in NSCLC treatment.
{"title":"A Phase I Dose-Escalation Clinical Trial of Bronchoscopic Cryoimmunotherapy in Advanced-Stage NSCLC","authors":"Jun-Chieh J. Tsay MD, MS , Antonio Velez MD , Destiny Collazo BS , Isaac Laniado MD , Jamie Bessich MD , Vivek Murthy MD , Andrew DeMaio MD , Samaan Rafeq MD , Benjamin Kwok MD , Fares Darawshy MD , Ray Pillai MD , Kendrew Wong MD , Yonghua Li MD, PhD , Rosemary Schluger RN , Alena Lukovnikova BS , Sofia Roldan BS , Matt Blaisdell BS , Fernanda Paz , Kelsey Krolikowski BS , Katherine Gershner MD , Daniel H. Sterman MD","doi":"10.1016/j.jtocrr.2025.100849","DOIUrl":"10.1016/j.jtocrr.2025.100849","url":null,"abstract":"<div><h3>Introduction</h3><div>Outcomes for NSCLC remain suboptimal. Recent data suggest that cryoablation can generate antitumor immune effects. In this first-in-human phase I clinical trial, we investigated the safety and feasibility of bronchoscopic cryoimmunotherapy (BCI) delivered during standard-of-care bronchoscopy and explored associated systemic immune responses.</div></div><div><h3>Methods</h3><div>Subjects with known or suspected advanced-stage NSCLC were recruited. BCI was delivered in dose-escalated freeze-thaw cycles to determine maximum dose tolerance. Feasibility assessment was determined with a pre-set goal of achieving successful BCI in more than or equal to 80% of subjects. Safety was assessed by review of BCI-related complications, including grades 2 to 3 bleeding, pneumothorax requiring intervention, and National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 to 5 adverse events. Pre- and post-BCI blood samples were collected to explore changes in the systemic immune profile.</div></div><div><h3>Results</h3><div>Subjects with predominantly clinical TNM stage 3 or 4 adenocarcinoma or squamous cell carcinoma were enrolled. We reached the maximum dose of 30 seconds with 100% feasibility and no BCI-related adverse events. In peripheral blood analysis, we observed a significant decrease in derived neutrophil-to-lymphocyte ratio in the high-dose BCI group in comparison to the low-dose BCI cohort. We also observed increases in inflammatory cytokines—GM-CSF, IFN-γ, IL-1β, IL-17A, and IL-2—and effector memory T cells post-BCI.</div></div><div><h3>Conclusion</h3><div>BCI is safe and feasible. In addition, we provide preliminary evidence that at higher dose levels there is a systemic immune response consistent with a cytotoxic profile. Further immune analyses will determine the potential of BCI as an adjunctive therapy in combination with immune checkpoint inhibition in NSCLC treatment.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 8","pages":"Article 100849"},"PeriodicalIF":3.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144480623","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}
Predictive markers for chemotherapy and immunotherapy response in advanced NSCLC are limited, and no objective tool exists to assess immune function, which is critical for treatment outcomes. This study prospectively evaluated the interferon gamma (IFN-γ) release assay (IGRA) as a potential predictor of treatment response and a tool for assessing immune function.
Methods
We enrolled patients with stage IV NSCLC undergoing first-line chemotherapy, EGFR tyrosine kinase inhibitor (TKI) therapy, or any line of single-agent immunotherapy, alongside stage I controls. Peripheral blood samples were collected pre- and post-treatment for IGRA testing using the QuantiFERON-TB Gold In-Tube (QFT-GIT) kit. Phytohemagglutinin-stimulated IFN-γ (PSIG) responses were measured by both QFT-GIT and in-house enzyme-linked immunosorbent assay, with stage IV patients categorized into high- and low-PSIG response groups based on median pretreatment values.
Results
A total of 117 patients were analyzed (32 surgery, 30 EGFR TKI, 25 chemotherapy, 30 immunotherapy). The median PSIG response was significantly higher in stage I patients than stage IV (1420 pg/mL versus 960 pg/mL; p = 0.032). In stage IV, those with driver mutations had higher pretreatment PSIG responses (1278 pg/mL versus 288 pg/mL; p = 0.004). Kaplan–Meier analysis suggested a trend toward longer progression-free and overall survival in the EGFR TKI and immunotherapy groups with higher PSIG responses, though not statistically significant.
Conclusions
Patients with advanced-stage NSCLC exhibited reduced lymphocyte function, and patients with driver mutations correlated to less exhausted lymphocyte. IGRA demonstrates potential as a clinical tool for assessing immune function in these patients.
晚期非小细胞肺癌化疗和免疫治疗反应的预测标志物有限，没有客观的工具来评估免疫功能，而免疫功能对治疗结果至关重要。本研究前瞻性地评估了干扰素γ (IFN-γ)释放试验（IGRA）作为治疗反应的潜在预测因子和评估免疫功能的工具。方法：我们招募了正在接受一线化疗、EGFR酪氨酸激酶抑制剂（TKI）治疗或任何单药免疫治疗的IV期NSCLC患者，以及I期对照。采用QuantiFERON-TB金管（QFT-GIT）试剂盒采集外周血样本进行IGRA检测。采用QFT-GIT和内部酶联免疫吸附法测量植物血凝素刺激的IFN-γ (PSIG)反应，根据中位预处理值将IV期患者分为高PSIG反应组和低PSIG反应组。结果共分析117例患者，其中手术32例，EGFR TKI 30例，化疗25例，免疫治疗30例。I期患者的PSIG应答中位数显著高于IV期(1420 pg/mL vs 960 pg/mL；P = 0.032)。在IV期，驱动突变患者有更高的预处理PSIG反应(1278 pg/mL vs 288 pg/mL；P = 0.004)。Kaplan-Meier分析显示，EGFR TKI组和免疫治疗组的无进展生存期和总生存期较长，PSIG反应较高，但无统计学意义。结论晚期非小细胞肺癌患者淋巴细胞功能降低，驱动突变患者淋巴细胞耗竭程度较低。IGRA显示了作为评估这些患者免疫功能的临床工具的潜力。
{"title":"A Prospective Exploratory Study of Functional Immunity Assessed by Pretreatment Interferon Gamma Release Assay in Relation to Different Systemic Therapies in Patients With Advanced-Stage NSCLC","authors":"Hsu-Ching Huang MD , Han-Jhih Chang MS , Chi-Lu Chiang MD , Hsin-Yi Huang MS , Yung-Hung Luo MD , Yuh-Min Chen MD , Tsu-Hui Shiao MD , Chao-Hua Chiu MD","doi":"10.1016/j.jtocrr.2025.100845","DOIUrl":"10.1016/j.jtocrr.2025.100845","url":null,"abstract":"<div><h3>Introduction</h3><div>Predictive markers for chemotherapy and immunotherapy response in advanced NSCLC are limited, and no objective tool exists to assess immune function, which is critical for treatment outcomes. This study prospectively evaluated the interferon gamma (IFN-γ) release assay (IGRA) as a potential predictor of treatment response and a tool for assessing immune function.</div></div><div><h3>Methods</h3><div>We enrolled patients with stage IV NSCLC undergoing first-line chemotherapy, EGFR tyrosine kinase inhibitor (TKI) therapy, or any line of single-agent immunotherapy, alongside stage I controls. Peripheral blood samples were collected pre- and post-treatment for IGRA testing using the QuantiFERON-TB Gold In-Tube (QFT-GIT) kit. Phytohemagglutinin-stimulated IFN-γ (PSIG) responses were measured by both QFT-GIT and in-house enzyme-linked immunosorbent assay, with stage IV patients categorized into high- and low-PSIG response groups based on median pretreatment values.</div></div><div><h3>Results</h3><div>A total of 117 patients were analyzed (32 surgery, 30 EGFR TKI, 25 chemotherapy, 30 immunotherapy). The median PSIG response was significantly higher in stage I patients than stage IV (1420 pg/mL versus 960 pg/mL; <em>p</em> = 0.032). In stage IV, those with driver mutations had higher pretreatment PSIG responses (1278 pg/mL versus 288 pg/mL; <em>p =</em> 0.004). Kaplan–Meier analysis suggested a trend toward longer progression-free and overall survival in the EGFR TKI and immunotherapy groups with higher PSIG responses, though not statistically significant.</div></div><div><h3>Conclusions</h3><div>Patients with advanced-stage NSCLC exhibited reduced lymphocyte function, and patients with driver mutations correlated to less exhausted lymphocyte. IGRA demonstrates potential as a clinical tool for assessing immune function in these patients.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 8","pages":"Article 100845"},"PeriodicalIF":3.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330142","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}
The safety of discontinuing immune checkpoint inhibitors (ICIs) because of a durable response in patients with advanced NSCLC remains uncertain, and post-discontinuation survival outcomes based on the reason for cessation are not well defined.
Methods
A pooled analysis was conducted using data from four prospective cohort studies involving 835 patients with advanced NSCLC who discontinued ICIs. Patients were categorized based on discontinuation reasons: durable response; immune-related adverse events (irAEs) (subcategorized by tumor response at discontinuation); non-irAE adverse events; disease progression; and other causes.
Results
Disease progression was the most common reason for ICI discontinuation (N = 528 [63.2%]), followed by irAEs (N = 187 [22.4%]) and tumor response (N = 23 [2.8%]). Regarding response status at ICI discontinuation due to irAEs, complete/partial response (CR/PR) was the most frequent (N = 85), followed by stable disease/not evaluable (SD/NE, N = 69) and disease progression (N = 33). After a median post-discontinuation follow-up of 15.8 months (interquartile range, 6.9–23.2), patients who discontinued because of a response had excellent outcomes, with no deaths and only three progression-free survival events. While post-discontinuation overall survival was comparable between the irAE-CR/PR and irAE-SD/NE groups, ICI therapy ≥12 months was associated with improved post-ICI discontinuation survival in the irAE-CR/PR group.
Conclusions
Discontinuation of ICIs because of a durable tumor response is rare in real-world settings but represents a feasible strategy for patients with advanced NSCLC. Patients in the irAE-CR/PR group had favorable post-ICI discontinuation survival if they received ICI therapy lasting ≥12 months.
{"title":"Post-discontinuation Survival in Patients With Advanced NSCLC Receiving Immune Checkpoint Inhibitors: A Pooled Analysis of Prospective Cohort Studies","authors":"Yusuke Inoue MD, PhD , Yoshihiro Kitahara MD , Masato Karayama MD, PhD , Kazuhiro Asada MD, PhD , Koji Nishimoto MD, PhD , Shun Matsuura MD, PhD , Dai Hashimoto MD, PhD , Masato Fujii MD, PhD , Takashi Matsui MD, PhD , Nao Inami MD , Mikio Toyoshima MD, PhD , Hiroyuki Matsuda MD, PhD , Masaki Ikeda MD, PhD , Mitsuru Niwa MD, PhD , Yusuke Kaida MD, PhD , Masaki Sato MD, PhD , Yasuhiro Ito MD , Hideki Yasui MD, PhD , Yuzo Suzuki MD, PhD , Hironao Hozumi MD, PhD , Takafumi Suda MD, PhD","doi":"10.1016/j.jtocrr.2025.100847","DOIUrl":"10.1016/j.jtocrr.2025.100847","url":null,"abstract":"<div><h3>Introduction</h3><div>The safety of discontinuing immune checkpoint inhibitors (ICIs) because of a durable response in patients with advanced NSCLC remains uncertain, and post-discontinuation survival outcomes based on the reason for cessation are not well defined.</div></div><div><h3>Methods</h3><div>A pooled analysis was conducted using data from four prospective cohort studies involving 835 patients with advanced NSCLC who discontinued ICIs. Patients were categorized based on discontinuation reasons: durable response; immune-related adverse events (irAEs) (subcategorized by tumor response at discontinuation); non-irAE adverse events; disease progression; and other causes.</div></div><div><h3>Results</h3><div>Disease progression was the most common reason for ICI discontinuation (<em>N</em> = 528 [63.2%]), followed by irAEs (<em>N</em> = 187 [22.4%]) and tumor response (<em>N</em> = 23 [2.8%]). Regarding response status at ICI discontinuation due to irAEs, complete/partial response (CR/PR) was the most frequent (<em>N</em> = 85), followed by stable disease/not evaluable (SD/NE, <em>N</em> = 69) and disease progression (<em>N</em> = 33). After a median post-discontinuation follow-up of 15.8 months (interquartile range, 6.9–23.2), patients who discontinued because of a response had excellent outcomes, with no deaths and only three progression-free survival events. While post-discontinuation overall survival was comparable between the irAE-CR/PR and irAE-SD/NE groups, ICI therapy ≥12 months was associated with improved post-ICI discontinuation survival in the irAE-CR/PR group.</div></div><div><h3>Conclusions</h3><div>Discontinuation of ICIs because of a durable tumor response is rare in real-world settings but represents a feasible strategy for patients with advanced NSCLC. Patients in the irAE-CR/PR group had favorable post-ICI discontinuation survival if they received ICI therapy lasting ≥12 months.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 8","pages":"Article 100847"},"PeriodicalIF":3.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330153","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}
{"title":"Erratum to ‘Primary Results from IMscin002: A Study to Evaluate Patient Preferences and Perceptions of Health Care Professionals for Atezolizumab Subcutaneous Versus Intravenous for the Treatment of NSCLC’ [JTO Clinical and Research Reports Volume 6 Issue 5 (2025) 100815]","authors":"Federico Cappuzzo MD , Zanete Zvirbule MD , Ernesto Korbenfeld MD , Jaroslaw Kolb-Sielecki MD , Dolores Isla MD, PhD , Aleksandra Szczesna MD, PhD , Amparo Yovanna Castro Sanchez PhD , Alberto Bustillos MD , Xiaoyan Liu PhD , Fiona Young MbChB , Nadia Tosti PhD , Marta Freitas Monteiro MSc, PhD , Margarita Majem MD, PhD","doi":"10.1016/j.jtocrr.2025.100842","DOIUrl":"10.1016/j.jtocrr.2025.100842","url":null,"abstract":"","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 7","pages":"Article 100842"},"PeriodicalIF":3.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203728","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 : 2025-05-09DOI: 10.1016/j.jtocrr.2025.100840
Mariona Riudavets MD, PhD , David Planchard MD, PhD
{"title":"Erratum to ‘Targeting DLL3: A New Weapon in Lung Neuroendocrine Tumors?’ [JTO Clinical and Research Reports Volume 6 Issue 5 (2025) 100796]","authors":"Mariona Riudavets MD, PhD , David Planchard MD, PhD","doi":"10.1016/j.jtocrr.2025.100840","DOIUrl":"10.1016/j.jtocrr.2025.100840","url":null,"abstract":"","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 7","pages":"Article 100840"},"PeriodicalIF":3.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203729","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 : 2025-04-22DOI: 10.1016/j.jtocrr.2025.100837
Kassandra R. Bisson MHSc , Andrea Beharry MLT , Normand Blais MD , Michael D. Carter MD, PhD , Parneet K. Cheema MD , Patrice Desmeules MD , John G. Garratt RT , Barbara Melosky MD , Bryan Lo PhD , Stephanie Snow MD , Basile Tessier-Cloutier MD , Edwin Tio MD , Stephen Yip MD, PhD , Jennifer R. Won PhD , Brandon S. Sheffield MD
Introduction
Timely access to quality biomarker testing in NSCLC is critical to patient outcomes. The Canadian Pathology Quality Assurance provides external quality assurance (EQA) to laboratories in Canada. The Canadian Pathology Quality Assurance has recently developed a novel approach to molecular biomarker EQA testing, assessing accuracy, turnaround time, and interpretation of reports. This study reports the results of the first end-to-end biomarker EQA challenge in NSCLC.
Methods
Three challenge specimens were made using NSCLC tissue and paired with clinical vignettes mimicking referred-in cases. Participants were to provide all required molecular testing (immunohistochemistry and gene sequencing) and submit final reports for each case, while being timed. Reports were assessed by molecular pathologists and medical oncologists who recommended a systemic treatment based on vignettes and reports.
Results
A total of 13 Canadian laboratories participated. The turnaround time of molecular reporting ranged from five to 57 (median 22.5) calendar days. Two laboratories (15%) reported their results within 2 weeks. Four laboratories (31%) reported the results of their biomarkers after more than 30 days.
Only three laboratories received optimal status (23%). One laboratory (8%) failed due to a critical genotyping error, three (23%) received a suboptimal status due to inappropriately long turnaround times, and the remaining six (69%) received an adequate status.
Conclusions
This report demonstrates the utility of this proficiency testing style compared with standard laboratory self-reporting. The approach has elucidated substantial differences in the quality of NSCLC biomarker results produced by Canadian laboratories. Ongoing efforts to improve turnaround times and clarity of reporting, including regular external measurement, are tools that can improve patient outcomes in NSCLC.
{"title":"Novel Approach to Proficiency Testing Reveals Significant Variations in Biomarker Practice Leading to Critical Differences in Lung Cancer Management","authors":"Kassandra R. Bisson MHSc , Andrea Beharry MLT , Normand Blais MD , Michael D. Carter MD, PhD , Parneet K. Cheema MD , Patrice Desmeules MD , John G. Garratt RT , Barbara Melosky MD , Bryan Lo PhD , Stephanie Snow MD , Basile Tessier-Cloutier MD , Edwin Tio MD , Stephen Yip MD, PhD , Jennifer R. Won PhD , Brandon S. Sheffield MD","doi":"10.1016/j.jtocrr.2025.100837","DOIUrl":"10.1016/j.jtocrr.2025.100837","url":null,"abstract":"<div><h3>Introduction</h3><div>Timely access to quality biomarker testing in NSCLC is critical to patient outcomes. The Canadian Pathology Quality Assurance provides external quality assurance (EQA) to laboratories in Canada. The Canadian Pathology Quality Assurance has recently developed a novel approach to molecular biomarker EQA testing, assessing accuracy, turnaround time, and interpretation of reports. This study reports the results of the first end-to-end biomarker EQA challenge in NSCLC.</div></div><div><h3>Methods</h3><div>Three challenge specimens were made using NSCLC tissue and paired with clinical vignettes mimicking referred-in cases. Participants were to provide all required molecular testing (immunohistochemistry and gene sequencing) and submit final reports for each case, while being timed. Reports were assessed by molecular pathologists and medical oncologists who recommended a systemic treatment based on vignettes and reports.</div></div><div><h3>Results</h3><div>A total of 13 Canadian laboratories participated. The turnaround time of molecular reporting ranged from five to 57 (median 22.5) calendar days. Two laboratories (15%) reported their results within 2 weeks. Four laboratories (31%) reported the results of their biomarkers after more than 30 days.</div><div>Only three laboratories received optimal status (23%). One laboratory (8%) failed due to a critical genotyping error, three (23%) received a suboptimal status due to inappropriately long turnaround times, and the remaining six (69%) received an adequate status.</div></div><div><h3>Conclusions</h3><div>This report demonstrates the utility of this proficiency testing style compared with standard laboratory self-reporting. The approach has elucidated substantial differences in the quality of NSCLC biomarker results produced by Canadian laboratories. Ongoing efforts to improve turnaround times and clarity of reporting, including regular external measurement, are tools that can improve patient outcomes in NSCLC.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 7","pages":"Article 100837"},"PeriodicalIF":3.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263817","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}
The combination of immune checkpoint inhibitors with chemotherapy is the standard treatment for extensive-stage (ES) SCLC. However, its safety for elderly patients is not fully validated. We evaluated the safety and efficacy of durvalumab plus carboplatin and etoposide in elderly patients with ES-SCLC.
Methods
In this prospective, single-arm, multicenter, phase 2 clinical trial, patients with ES-SCLC aged above or equal to 75 years received chemotherapy with up to four cycles of durvalumab 1500 mg on day 1, carboplatin at a dose equivalent to an area under the curve of 5 on day 1, and etoposide 80 mg/m2 on days 1 to 3 every 3 weeks as induction therapy. Maintenance therapy with durvalumab 1500 mg was administered every 4 weeks until disease progression or unacceptable toxicity. The primary end point was safety, and key secondary end points were objective response rate, progression-free survival, overall survival, quality of life, and Geriatric Assessment.
Results
Between August 2021 and February 2023, 40 patients were enrolled at 17 institutions and 38 were assessable for safety and efficacy. Grade 3 or higher adverse events occurred in 36 patients (94.6%). The most common adverse events were hematologic, including grade 3 or higher neutropenia (76.3%) and febrile neutropenia (15.8%). The objective response rate, median progression-free survival, and median overall survival were 89.5%, 5.4 months, and 16.1 months, respectively. No decrease in quality of life or functional assessment scores was observed after treatment.
Conclusion
Durvalumab plus carboplatin and etoposide was tolerable and expected to be effective in elderly patients with ES-SCLC.
{"title":"Turtle Study: A Phase 2 Study of Durvalumab Plus Carboplatin and Etoposide in Elderly Patients With Extensive-Stage SCLC (LOGiK 2003)","authors":"Hidenobu Ishii MD, PhD , Koichi Azuma MD, PhD , Yuta Yamanaka MD , Hiroshige Yoshioka MD, PhD , Yukihiro Toi MD , Naoki Shingu MD , Katsuhiko Naoki MD, PhD , Masaki Okamoto MD, PhD , Yuko Tsuchiya-Kawano MD, PhD , Taishi Harada MD , Hiroyuki Inoue MD, PhD , Hiroshi Ishii MD, PhD , Kazunori Tobino MD, PhD , Chiho Nakashima MD, PhD , Yoshifusa Koreeda MD , Yasushi Hisamatsu MD , Shinsuke Tsumura MD , Takashi Inagaki MD , Keiko Mizuno MD, PhD , Takayuki Shimose MMath , Isamu Okamoto MD, PhD","doi":"10.1016/j.jtocrr.2025.100836","DOIUrl":"10.1016/j.jtocrr.2025.100836","url":null,"abstract":"<div><h3>Introduction</h3><div>The combination of immune checkpoint inhibitors with chemotherapy is the standard treatment for extensive-stage (ES) SCLC. However, its safety for elderly patients is not fully validated. We evaluated the safety and efficacy of durvalumab plus carboplatin and etoposide in elderly patients with ES-SCLC.</div></div><div><h3>Methods</h3><div>In this prospective, single-arm, multicenter, phase 2 clinical trial, patients with ES-SCLC aged above or equal to 75 years received chemotherapy with up to four cycles of durvalumab 1500 mg on day 1, carboplatin at a dose equivalent to an area under the curve of 5 on day 1, and etoposide 80 mg/m<sup>2</sup> on days 1 to 3 every 3 weeks as induction therapy. Maintenance therapy with durvalumab 1500 mg was administered every 4 weeks until disease progression or unacceptable toxicity. The primary end point was safety, and key secondary end points were objective response rate, progression-free survival, overall survival, quality of life, and Geriatric Assessment.</div></div><div><h3>Results</h3><div>Between August 2021 and February 2023, 40 patients were enrolled at 17 institutions and 38 were assessable for safety and efficacy. Grade 3 or higher adverse events occurred in 36 patients (94.6%). The most common adverse events were hematologic, including grade 3 or higher neutropenia (76.3%) and febrile neutropenia (15.8%). The objective response rate, median progression-free survival, and median overall survival were 89.5%, 5.4 months, and 16.1 months, respectively. No decrease in quality of life or functional assessment scores was observed after treatment.</div></div><div><h3>Conclusion</h3><div>Durvalumab plus carboplatin and etoposide was tolerable and expected to be effective in elderly patients with ES-SCLC.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 7","pages":"Article 100836"},"PeriodicalIF":3.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230340","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 : 2025-04-21DOI: 10.1016/j.jtocrr.2025.100835
Illaa Smesseim MD , Paul Baas MD, PhD , Jacobus A. Burgers MD, PhD
The CheckMate 743 trial established nivolumab and ipilimumab as the standard first-line treatment for unresectable pleural mesothelioma. However, optimal management following disease progression after a durable response to dual immunotherapy remains unclear. We report two cases of patients with pleural mesothelioma (epithelioid subtype) initially treated with nivolumab-ipilimumab, achieving prolonged disease control. Both patients experienced disease progression several years after treatment discontinuation and were subsequently retreated with nivolumab-ipilimumab on regulatory approval. In both cases, retreatment resulted in stable disease for at least 12 months. However, immune-related toxicities occurred, with one patient developing recurrent colitis and the other experiencing nephrotic syndrome, ultimately leading to treatment discontinuation. These cases suggest that retreatment with dual immunotherapy may be a viable strategy for selected patients with previous durable responses, although the risk of immune-related toxicity remains significant. Given the lack of prospective data, further research is needed to determine whether rechallenge with nivolumab-ipilimumab offers superior outcomes compared with chemotherapy or best supportive care in this setting. Rechallenging patients with pleural mesothelioma with nivolumab-ipilimumab after a durable response is feasible but associated with immune-related toxicity.
{"title":"Retreatment With Nivolumab and Ipilimumab in Pleural Mesothelioma Following Disease Progression After a Durable Response: Case Series","authors":"Illaa Smesseim MD , Paul Baas MD, PhD , Jacobus A. Burgers MD, PhD","doi":"10.1016/j.jtocrr.2025.100835","DOIUrl":"10.1016/j.jtocrr.2025.100835","url":null,"abstract":"<div><div>The CheckMate 743 trial established nivolumab and ipilimumab as the standard first-line treatment for unresectable pleural mesothelioma. However, optimal management following disease progression after a durable response to dual immunotherapy remains unclear. We report two cases of patients with pleural mesothelioma (epithelioid subtype) initially treated with nivolumab-ipilimumab, achieving prolonged disease control. Both patients experienced disease progression several years after treatment discontinuation and were subsequently retreated with nivolumab-ipilimumab on regulatory approval. In both cases, retreatment resulted in stable disease for at least 12 months. However, immune-related toxicities occurred, with one patient developing recurrent colitis and the other experiencing nephrotic syndrome, ultimately leading to treatment discontinuation. These cases suggest that retreatment with dual immunotherapy may be a viable strategy for selected patients with previous durable responses, although the risk of immune-related toxicity remains significant. Given the lack of prospective data, further research is needed to determine whether rechallenge with nivolumab-ipilimumab offers superior outcomes compared with chemotherapy or best supportive care in this setting. Rechallenging patients with pleural mesothelioma with nivolumab-ipilimumab after a durable response is feasible but associated with immune-related toxicity.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 7","pages":"Article 100835"},"PeriodicalIF":3.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144240390","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}
Dysregulated MET signaling, such as MET overexpression or MET amplification (METamp), is a important mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant lung adenocarcinoma (LUAD). Combination therapy with EGFR TKIs and MET TKIs has revealed efficacy in these patients. This study aimed to analyze the real-world experience of TKI combination in patients with EGFR-mutant MET-overexpressed LUAD.
Methods
This retrospective cohort study included patients with advanced EGFR-mutant LUAD who progressed after EGFR TKIs and were treated with combination therapy of EGFR TKIs and MET TKIs (capmatinib or tepotinib). Immunohistochemistry was used to detect MET overexpression.
Results
This study included 27 patients, with a median age of 69 years; 40.7% of the patients were male individuals, and 88.9% never smoked. Overall, the treatment response of the TKI combination reported 29.6% (eight of 27) partial response, 55.6% (15 of 27) stable disease, a median progression-free survival of 7.3 months, and an overall survival of 26.9 months. The adverse events were mostly grade 1 to 2, with only one patient experiencing a grade 3 or greater event, which was peripheral edema. The most common adverse events were hypoalbuminemia (44.4%), increased creatinine (44.4%), and peripheral edema (44.4%). Eight patients underwent next-generation sequencing analysis, and two (25.0%) of them had METamp. Three patients (37.5%) had TP53 mutations, which were the most common concurrent alterations. Those with positive METamp had significantly longer median progression-free survival than those without (25.3 versus 5.8 mo; p = 0.034).
Conclusions
The TKI combination reported clinical activities in patients with advanced EGFR-mutant LUAD resistant to EGFR TKIs and mild toxicity in those with MET overexpression.
{"title":"Combination Therapy With MET Tyrosine Kinase Inhibitor and EGFR Tyrosine Kinase Inhibitor in Patients With MET-Overexpressed EGFR-Mutant Lung Adenocarcinoma","authors":"Jia-Jun Wu MD , Zhe-Rong Zheng MD , Tse-Hsien Lo MD , Cheng-Hsiang Chu MD , Kun-Chieh Chen MD, PhD , Gee-Chen Chang MD, PhD","doi":"10.1016/j.jtocrr.2025.100832","DOIUrl":"10.1016/j.jtocrr.2025.100832","url":null,"abstract":"<div><h3>Introduction</h3><div>Dysregulated <em>MET</em> signaling, such as MET overexpression or <em>MET</em> amplification (<em>MET</em>amp), is a important mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) in patients with <em>EGFR</em>-mutant lung adenocarcinoma (LUAD). Combination therapy with EGFR TKIs and MET TKIs has revealed efficacy in these patients. This study aimed to analyze the real-world experience of TKI combination in patients with <em>EGFR</em>-mutant MET-overexpressed LUAD.</div></div><div><h3>Methods</h3><div>This retrospective cohort study included patients with advanced <em>EGFR</em>-mutant LUAD who progressed after EGFR TKIs and were treated with combination therapy of EGFR TKIs and MET TKIs (capmatinib or tepotinib). Immunohistochemistry was used to detect MET overexpression.</div></div><div><h3>Results</h3><div>This study included 27 patients, with a median age of 69 years; 40.7% of the patients were male individuals, and 88.9% never smoked. Overall, the treatment response of the TKI combination reported 29.6% (eight of 27) partial response, 55.6% (15 of 27) stable disease, a median progression-free survival of 7.3 months, and an overall survival of 26.9 months. The adverse events were mostly grade 1 to 2, with only one patient experiencing a grade 3 or greater event, which was peripheral edema. The most common adverse events were hypoalbuminemia (44.4%), increased creatinine (44.4%), and peripheral edema (44.4%). Eight patients underwent next-generation sequencing analysis, and two (25.0%) of them had <em>MET</em>amp. Three patients (37.5%) had <em>TP53</em> mutations, which were the most common concurrent alterations. Those with positive <em>MET</em>amp had significantly longer median progression-free survival than those without (25.3 versus 5.8 mo; <em>p</em> = 0.034).</div></div><div><h3>Conclusions</h3><div>The TKI combination reported clinical activities in patients with advanced <em>EGFR</em>-mutant LUAD resistant to EGFR TKIs and mild toxicity in those with MET overexpression.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 6","pages":"Article 100832"},"PeriodicalIF":3.0,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912809","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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