Pub Date : 2024-07-31DOI: 10.1016/j.jtocrr.2024.100712
A 20-year-old man with metastatic large cell neuroendocrine carcinoma of the lung was treated with the delta-like ligand 3–targeting bispecific T cell engager, tarlatamab. Treatment was complicated by transient cytokine release syndrome but resulted in a partial response. Bispecific T cell engagers may offer a novel treatment approach for large cell neuroendocrine carcinoma of the lung.
{"title":"Tarlatamab for Large Cell Neuroendocrine Carcinoma in a Young Adult: A Case Report","authors":"","doi":"10.1016/j.jtocrr.2024.100712","DOIUrl":"10.1016/j.jtocrr.2024.100712","url":null,"abstract":"<div><p>A 20-year-old man with metastatic large cell neuroendocrine carcinoma of the lung was treated with the delta-like ligand 3–targeting bispecific T cell engager, tarlatamab. Treatment was complicated by transient cytokine release syndrome but resulted in a partial response. Bispecific T cell engagers may offer a novel treatment approach for large cell neuroendocrine carcinoma of the lung.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000821/pdfft?md5=e7a77021a0e8cd2cd380bfac2c94fab0&pid=1-s2.0-S2666364324000821-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161829","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 : 2024-07-14DOI: 10.1016/j.jtocrr.2024.100706
Introduction
EGFR-mutated NSCLC is minimally responsive to programmed cell death protein 1 or programmed death-ligand 1 blockade. We evaluated the safety, tolerability, and immunomodulatory effects of the EGFR tyrosine kinase inhibitor (TKI) afatinib in combination with the programmed cell death protein 1 antibody pembrolizumab in patients with EGFR-mutant NSCLC.
Methods
Patients with advanced EGFR-mutant NSCLC with progression (PD) on previous EGFR TKI(s), aged above or equal to 18 years, Eastern Cooperative Oncology Group performance status less than or equal to 1, acceptable organ function, no significant autoimmune disease, measurable disease, and controlled brain metastases were eligible. Primary end point was determination of the maximum tolerated dose and recommended phase 2 dose. Serial specimens were collected to assess for alterations in cytokines and immune cell subsets by quantitative immunofluorescence in tissue and Luminex and flow cytometry in the blood.
Results
A total of 11 patients were enrolled, six in dose finding and five in dose expansion. No dose-limiting toxicities were observed. The maximum tolerated dose was determined to be afatinib 40 mg orally daily and pembrolizumab 200 mg intravenously every 21 days. Four (36%) patients had immune-related adverse events (irAEs). Ten patients were assessable for response: two partial response, seven stable disease, and one PD. Peripheral natural killer and natural killer T-cells (p = 0.027, p = 0.01) increased and exhausted CD8+ T-cells decreased on treatment (p = 0.0035). Peripheral CD4/CD8 T-cells (area under the curve = 0.96, p = 0.042) and central memory T-cells (CD4/CD8) (area under the curve = 1.0, p = 0.0006) increased in patients who had disease control more than 6 months or partial response to afatinib/pembrolizumab as did CD3+ T-cells in a patient with progression-free survival more than 6 months after afatinib/pembrolizumab treatment.
Conclusions
Afatinib and pembrolizumab were found to have modest activity associated with irAEs after PD on previous EGFR TKI setting. Proinflammatory changes in immune cell subsets in tissue and blood were detected and associated with antitumor activity and irAEs.
导言表皮生长因子受体(EGFR)突变的非小细胞肺癌对程序性细胞死亡蛋白1或程序性死亡配体1的阻断反应微弱。我们评估了EGFR酪氨酸激酶抑制剂(TKI)阿法替尼联合程序性细胞死亡蛋白1抗体pembrolizumab治疗EGFR突变NSCLC患者的安全性、耐受性和免疫调节作用。方法符合以下条件的晚期表皮生长因子受体突变型NSCLC患者:既往接受过表皮生长因子受体抑制剂(TKI)治疗,病情进展(PD);年龄大于或等于18岁;东部合作肿瘤学组(Eastern Cooperative Oncology Group)表现状态小于或等于1;器官功能可接受;无明显自身免疫性疾病;病情可测量;脑转移得到控制。主要终点是确定最大耐受剂量和第二阶段推荐剂量。通过组织中的定量免疫荧光和血液中的 Luminex 及流式细胞术,收集序列标本以评估细胞因子和免疫细胞亚群的变化。未观察到剂量限制性毒性。确定的最大耐受剂量为每日口服阿法替尼40毫克,每21天静脉注射pembrolizumab 200毫克。4名患者(36%)出现了免疫相关不良事件(irAEs)。10名患者可评估反应:2名部分反应,7名病情稳定,1名病情恶化。治疗期间,外周自然杀伤细胞和自然杀伤 T 细胞增加(p = 0.027,p = 0.01),CD8+ T 细胞减少(p = 0.0035)。外周 CD4/CD8 T 细胞(曲线下面积 = 0.96,p = 0.042)和中枢记忆 T 细胞(CD4/CD8)(曲线下面积 = 1.0,p = 0.结论阿法替尼和pembrolizumab在既往EGFR TKI治疗PD后具有与irAEs相关的适度活性。检测到组织和血液中免疫细胞亚群的促炎性变化与抗肿瘤活性和irAEs有关。
{"title":"Immune Cell Dynamics in EGFR-Mutated NSCLC Treated With Afatinib and Pembrolizumab: Results From a Phase IB Study","authors":"","doi":"10.1016/j.jtocrr.2024.100706","DOIUrl":"10.1016/j.jtocrr.2024.100706","url":null,"abstract":"<div><h3>Introduction</h3><p>EGFR-mutated NSCLC is minimally responsive to programmed cell death protein 1 or programmed death-ligand 1 blockade. We evaluated the safety, tolerability, and immunomodulatory effects of the EGFR tyrosine kinase inhibitor (TKI) afatinib in combination with the programmed cell death protein 1 antibody pembrolizumab in patients with EGFR-mutant NSCLC.</p></div><div><h3>Methods</h3><p>Patients with advanced EGFR-mutant NSCLC with progression (PD) on previous EGFR TKI(s), aged above or equal to 18 years, Eastern Cooperative Oncology Group performance status less than or equal to 1, acceptable organ function, no significant autoimmune disease, measurable disease, and controlled brain metastases were eligible. Primary end point was determination of the maximum tolerated dose and recommended phase 2 dose. Serial specimens were collected to assess for alterations in cytokines and immune cell subsets by quantitative immunofluorescence in tissue and Luminex and flow cytometry in the blood.</p></div><div><h3>Results</h3><p>A total of 11 patients were enrolled, six in dose finding and five in dose expansion. No dose-limiting toxicities were observed. The maximum tolerated dose was determined to be afatinib 40 mg orally daily and pembrolizumab 200 mg intravenously every 21 days. Four (36%) patients had immune-related adverse events (irAEs). Ten patients were assessable for response: two partial response, seven stable disease, and one PD. Peripheral natural killer and natural killer T-cells (<em>p</em> = 0.027, <em>p</em> = 0.01) increased and exhausted CD8+ T-cells decreased on treatment (<em>p</em> = 0.0035). Peripheral CD4/CD8 T-cells (area under the curve = 0.96, <em>p</em> = 0.042) and central memory T-cells (CD4/CD8) (area under the curve = 1.0, <em>p</em> = 0.0006) increased in patients who had disease control more than 6 months or partial response to afatinib/pembrolizumab as did CD3+ T-cells in a patient with progression-free survival more than 6 months after afatinib/pembrolizumab treatment.</p></div><div><h3>Conclusions</h3><p>Afatinib and pembrolizumab were found to have modest activity associated with irAEs after PD on previous EGFR TKI setting. Proinflammatory changes in immune cell subsets in tissue and blood were detected and associated with antitumor activity and irAEs.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000766/pdfft?md5=ce13645fd6b07f36ed9026d955d00ade&pid=1-s2.0-S2666364324000766-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141713891","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 : 2024-07-06DOI: 10.1016/j.jtocrr.2024.100704
Introduction
Transformation to SCLC is a resistance mechanism to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma (LUAD). Nevertheless, the clinical and molecular features of SCLC transformation in LUAD with leptomeningeal metastases (LM) are scarce.
Methods
We retrospectively collected 237 patients with NSCLC who underwent lumbar puncture owing to suggestion of LM. All SCLC transformation in cerebrospinal fluid (CSF) was confirmed by two experienced pathologists using cytologic evaluation. CSF circulating tumor DNA (ctDNA) was tested by next-generation sequencing.
Results
Tumor cells in CSF samples were found in 111 patients (111 of 237, 46.8%), and eight cases (eight of 111, 7.2%) were identified as having SCLC cells in CSF. Seven patients carried the EGFR mutation, including four patients with EGFR exon 19 deletion and three patients with EGFRexon21 L858R mutation. Another patient harbored ERBB2 insertion. Seven of these patients were resistant to targeted therapy. CSF ctDNA analysis reported that TP53 and RB1 mutations were common. The median time from the diagnosis of advanced NSCLC to SCLC transformation found in CSF was 9.7 months (95% confidence interval [CI]: 4.0–17.5 mo). The median overall survival since the initial diagnosis of metastatic NSCLC was 15.3 months (95% CI: 1.2–29.4 mo). The median overall survival after SCLC transformation detected in CSF was 5.0 months (95% CI: 4.0–5.9 mo).
Conclusions
SCLC transformation may be revealed in CSF by both cytologic evaluation and ctDNA, not just in tissue that underwent rebiopsy. SCLC transformation of CSF is informative for resistance mechanism in patients with LUAD with LM on tyrosine kinase inhibitor progression, which was associated with poor survival.
{"title":"Combination of Cytologic Findings and Circulating Tumor DNA From Cerebrospinal Fluid Revealed SCLC Transformation in Patients With Leptomeningeal Metastases of Lung Adenocarcinoma","authors":"","doi":"10.1016/j.jtocrr.2024.100704","DOIUrl":"10.1016/j.jtocrr.2024.100704","url":null,"abstract":"<div><h3>Introduction</h3><p>Transformation to SCLC is a resistance mechanism to tyrosine kinase inhibitor in <em>EGFR</em>-mutated lung adenocarcinoma (LUAD). Nevertheless, the clinical and molecular features of SCLC transformation in LUAD with leptomeningeal metastases (LM) are scarce.</p></div><div><h3>Methods</h3><p>We retrospectively collected 237 patients with NSCLC who underwent lumbar puncture owing to suggestion of LM. All SCLC transformation in cerebrospinal fluid (CSF) was confirmed by two experienced pathologists using cytologic evaluation. CSF circulating tumor DNA (ctDNA) was tested by next-generation sequencing.</p></div><div><h3>Results</h3><p>Tumor cells in CSF samples were found in 111 patients (111 of 237, 46.8%), and eight cases (eight of 111, 7.2%) were identified as having SCLC cells in CSF. Seven patients carried the <em>EGFR</em> mutation, including four patients with <em>EGFR exon 19 deletion</em> and three patients with <em>EGFR</em> <em>exon</em> <em>21 L858R</em> mutation. Another patient harbored <em>ERBB2</em> insertion. Seven of these patients were resistant to targeted therapy. CSF ctDNA analysis reported that <em>TP53</em> and <em>RB1</em> mutations were common. The median time from the diagnosis of advanced NSCLC to SCLC transformation found in CSF was 9.7 months (95% confidence interval [CI]: 4.0–17.5 mo). The median overall survival since the initial diagnosis of metastatic NSCLC was 15.3 months (95% CI: 1.2–29.4 mo). The median overall survival after SCLC transformation detected in CSF was 5.0 months (95% CI: 4.0–5.9 mo).</p></div><div><h3>Conclusions</h3><p>SCLC transformation may be revealed in CSF by both cytologic evaluation and ctDNA, not just in tissue that underwent rebiopsy. SCLC transformation of CSF is informative for resistance mechanism in patients with LUAD with LM on tyrosine kinase inhibitor progression, which was associated with poor survival.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000742/pdfft?md5=870ec4f4f2918aac97890cf20e833f5f&pid=1-s2.0-S2666364324000742-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141710322","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 : 2024-07-01DOI: 10.1016/j.jtocrr.2024.100682
Ellen Yang MD, FRCPC , Najd Alshamlan MD , Katrina Hueniken MSc , Jessica Weiss MSc , Michael Cabanero MD , Ming-Sound Tsao MD, FRCPC
Introduction
Lepidic growth is considered noninvasive in lung nonmucinous adenocarcinoma, whereas other patterns are invasive. Considerable interobserver variability in assessing “invasion” has been reported. We assessed the utility of cytokeratin 7 (CK7) stain and recently proposed International Association for the Study of Lung Cancer criteria to improve assessment of noninvasion in lung adenocarcinoma.
Methods
Four pathologists (two staff, two trainees) assessed 158 hematoxylin and eosin (HE)- and CK7-stained slides of 108 pT1N0-2 nonmucinous lung adenocarcinoma cases. Scoring took place in four rounds. First, sections were independently scored for percentage of noninvasive or probable noninvasive and invasive or probable invasive patterns. Second, after a consensus scoring algorithm for CK7 was formulated, the slides were rescored. Subsequent third-round scoring was conducted only on HE slides using the 2023 International Association for the Study of Lung Cancer proposed criteria, and fourth-round scoring on both HE and CK7 slides simultaneously. Intraclass correlation coefficient (ICC) was calculated for each round. Recurrence-free survival was assessed using Cox proportional hazards regression methods.
Results
In the first two rounds, interobserver concordance was consistently higher with CK7 (ICC range = 0.44–0.6) than HE (range = 0.24–0.49) scores. The IASLC proposed algorithm improved ICC of HE scores to 0.60 (95% confidence interval: 0.52–0.67), and round 4 HE and CK7 combined improved ICC to 0.75 (95% confidence interval: 0.70–0.80). Continuous measures of averaged noninvasive and probable noninvasive scores on HE were associated with improved recurrence-free survival (hazard ratio: 0.83–0.86).
Conclusions
CK7 staining consistently increased interobserver concordance in assessment of invasive versus noninvasive patterns than HE. Combining CK7 with the 2023 IASLC criteria for morphologic features of invasion may further improve the interobservers’ concordance for the recognition of lepidic growth in nonmucinous lung adenocarcinoma.
{"title":"Reproducibility of Assessment of Lepidic (Noninvasive) Patterns in Lung Adenocarcinoma With Cytokeratin Immunostain Compared With Hematoxylin and Eosin and the Proposed New International Association for the Study of Lung Cancer (IASLC) Algorithm","authors":"Ellen Yang MD, FRCPC , Najd Alshamlan MD , Katrina Hueniken MSc , Jessica Weiss MSc , Michael Cabanero MD , Ming-Sound Tsao MD, FRCPC","doi":"10.1016/j.jtocrr.2024.100682","DOIUrl":"10.1016/j.jtocrr.2024.100682","url":null,"abstract":"<div><h3>Introduction</h3><p>Lepidic growth is considered noninvasive in lung nonmucinous adenocarcinoma, whereas other patterns are invasive. Considerable interobserver variability in assessing “invasion” has been reported. We assessed the utility of cytokeratin 7 (CK7) stain and recently proposed International Association for the Study of Lung Cancer criteria to improve assessment of noninvasion in lung adenocarcinoma.</p></div><div><h3>Methods</h3><p>Four pathologists (two staff, two trainees) assessed 158 hematoxylin and eosin (HE)- and CK7-stained slides of 108 pT1N0-2 nonmucinous lung adenocarcinoma cases. Scoring took place in four rounds. First, sections were independently scored for percentage of noninvasive or probable noninvasive and invasive or probable invasive patterns. Second, after a consensus scoring algorithm for CK7 was formulated, the slides were rescored. Subsequent third-round scoring was conducted only on HE slides using the 2023 International Association for the Study of Lung Cancer proposed criteria, and fourth-round scoring on both HE and CK7 slides simultaneously. Intraclass correlation coefficient (ICC) was calculated for each round. Recurrence-free survival was assessed using Cox proportional hazards regression methods.</p></div><div><h3>Results</h3><p>In the first two rounds, interobserver concordance was consistently higher with CK7 (ICC range = 0.44–0.6) than HE (range = 0.24–0.49) scores. The IASLC proposed algorithm improved ICC of HE scores to 0.60 (95% confidence interval: 0.52–0.67), and round 4 HE and CK7 combined improved ICC to 0.75 (95% confidence interval: 0.70–0.80). Continuous measures of averaged noninvasive and probable noninvasive scores on HE were associated with improved recurrence-free survival (hazard ratio: 0.83–0.86).</p></div><div><h3>Conclusions</h3><p>CK7 staining consistently increased interobserver concordance in assessment of invasive versus noninvasive patterns than HE. Combining CK7 with the 2023 IASLC criteria for morphologic features of invasion may further improve the interobservers’ concordance for the recognition of lepidic growth in nonmucinous lung adenocarcinoma.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000523/pdfft?md5=505547fe19126cb010ec9fc15e678934&pid=1-s2.0-S2666364324000523-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141042571","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 : 2024-07-01DOI: 10.1016/j.jtocrr.2024.100689
Neurocognitive adverse events (NAEs) have been reported in up to 60% of patients on lorlatinib, a potent central nervous system–active ALK inhibitor. Manifestations may include psychotic, mood, speech, and cognitive symptoms. Current guidance recommends permanent discontinuation of lorlatinib in cases of grade IV NAEs. Here, we report a case of successful rechallenge of dose-reduced lorlatinib after recovery of grade IV psychosis in a patient with ALK-positive NSCLC.
{"title":"Successful Lorlatinib Rechallenge After Severe Drug-Induced Psychosis in ALK-Positive Metastatic NSCLC: A Case Report","authors":"","doi":"10.1016/j.jtocrr.2024.100689","DOIUrl":"10.1016/j.jtocrr.2024.100689","url":null,"abstract":"<div><p>Neurocognitive adverse events (NAEs) have been reported in up to 60% of patients on lorlatinib, a potent central nervous system–active ALK inhibitor. Manifestations may include psychotic, mood, speech, and cognitive symptoms. Current guidance recommends permanent discontinuation of lorlatinib in cases of grade IV NAEs. Here, we report a case of successful rechallenge of dose-reduced lorlatinib after recovery of grade IV psychosis in a patient with ALK-positive NSCLC.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000596/pdfft?md5=258aef7abde42af0bb09cd23862cb12a&pid=1-s2.0-S2666364324000596-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141033806","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}
Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma.
Methods
TROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University.
Results
RNA-seq data analysis from The Cancer Genome Atlas revealed that TACSTD2 (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted p = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%–100%) and 25.0 (range: 0–200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival.
Conclusions
TROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma.
{"title":"Trophoblast Cell Surface Antigen 2 Expression in Thymic Carcinoma: Brief Report","authors":"Kana Kurokawa MD, PhD , Tetsuhiko Asao MD, PhD , Takuo Hayashi MD, PhD , Satsuki Kishikawa MD, PhD , Koichiro Kanamori MD, PhD , Takehito Shukuya MD, PhD , Yosuke Miyashita MD , Ikuko Nakamura MD, PhD , Taichi Miyawaki MD, PhD , Ryota Kanemaru MD, PhD , Tomoyasu Mimori MD, PhD , Yoichiro Mitsuishi MD, PhD , Ken Tajima MD, PhD , Naoko Shimada MD, PhD , Fumiyuki Takahashi MD, PhD , Kazuya Takamochi MD, PhD , Kenji Suzuki MD, PhD , Kazuhisa Takahashi MD, PhD","doi":"10.1016/j.jtocrr.2024.100693","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100693","url":null,"abstract":"<div><h3>Introduction</h3><p>Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma.</p></div><div><h3>Methods</h3><p>TROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University.</p></div><div><h3>Results</h3><p>RNA-seq data analysis from The Cancer Genome Atlas revealed that <em>TACSTD2</em> (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted <em>p</em> = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%–100%) and 25.0 (range: 0–200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival.</p></div><div><h3>Conclusions</h3><p>TROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000638/pdfft?md5=1a7346fac754e5d1a82e44a3087f356b&pid=1-s2.0-S2666364324000638-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141480251","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 : 2024-07-01DOI: 10.1016/j.jtocrr.2024.100696
Introduction
The CASPIAN and IMpower133 trials revealed a significant survival benefit of chemotherapy plus immunotherapy in patients with extensive-stage SCLC. The current study characterizes the proportion of real-world patients who would have met eligibility for these trials and highlights factors influencing eligibility in the real-world setting.
Methods
A retrospective analysis of patient data was conducted for stage IV patients with SCLC treated at the Cancer Centre of Southeastern Ontario, Canada. Trial eligibility was based on criteria used in the IMpower133 and CASPIAN trials. Data were summarized using descriptive statistics. Overall survival was assessed using the Kaplan–Meier method.
Results
Of the 116 patients included, only 12.1% met the overall eligibility criteria for the IMpower133 trial, and 14.7% for the CASPIAN trial. The most common reasons for ineligibility included: Eastern Cooperative Oncology Group (ECOG) 2 or greater (77.5%), inadequate organ function (48%), and the presence of brain metastases at diagnosis (37.3%). Sixty-one patients (59.8%) met two or more major ineligibility criteria. If trial eligibility was expanded to include ECOG 2 patients, an additional 10.3% would have met eligibility. The median overall survival for all-comers was 6.5 months.
Conclusions
Only a small minority of real-world patients with extensive-stage SCLC would have met eligibility for the IMpower133 and CASPIAN trials, with ECOG greater than or equal to 2, inadequate organ function, and brain metastases comprising the most common reasons for trial ineligibility. Future clinical trials should expand the inclusion criteria to better represent real-world patient populations.
{"title":"Brief Report: Real-World Eligibility for Clinical Trials in Patients With Extensive-Stage SCLC at a Tertiary Care Center","authors":"","doi":"10.1016/j.jtocrr.2024.100696","DOIUrl":"10.1016/j.jtocrr.2024.100696","url":null,"abstract":"<div><h3>Introduction</h3><p>The CASPIAN and IMpower133 trials revealed a significant survival benefit of chemotherapy plus immunotherapy in patients with extensive-stage SCLC. The current study characterizes the proportion of real-world patients who would have met eligibility for these trials and highlights factors influencing eligibility in the real-world setting.</p></div><div><h3>Methods</h3><p>A retrospective analysis of patient data was conducted for stage IV patients with SCLC treated at the Cancer Centre of Southeastern Ontario, Canada. Trial eligibility was based on criteria used in the IMpower133 and CASPIAN trials. Data were summarized using descriptive statistics. Overall survival was assessed using the Kaplan–Meier method.</p></div><div><h3>Results</h3><p>Of the 116 patients included, only 12.1% met the overall eligibility criteria for the IMpower133 trial, and 14.7% for the CASPIAN trial. The most common reasons for ineligibility included: Eastern Cooperative Oncology Group (ECOG) 2 or greater (77.5%), inadequate organ function (48%), and the presence of brain metastases at diagnosis (37.3%). Sixty-one patients (59.8%) met two or more major ineligibility criteria. If trial eligibility was expanded to include ECOG 2 patients, an additional 10.3% would have met eligibility. The median overall survival for all-comers was 6.5 months.</p></div><div><h3>Conclusions</h3><p>Only a small minority of real-world patients with extensive-stage SCLC would have met eligibility for the IMpower133 and CASPIAN trials, with ECOG greater than or equal to 2, inadequate organ function, and brain metastases comprising the most common reasons for trial ineligibility. Future clinical trials should expand the inclusion criteria to better represent real-world patient populations.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000663/pdfft?md5=248c51a4b146492282fa8661f7951747&pid=1-s2.0-S2666364324000663-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141728899","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 : 2024-07-01DOI: 10.1016/j.jtocrr.2024.100685
Benjamin J. Solomon M.B.B.S., PhD , Ibiayi Dagogo-Jack MD , Se-Hoon Lee MD , Michael J. Boyer M.B.B.S., PhD , Suresh S. Ramalingam MD , Enric Carcereny MD , Enriqueta Felip MD, PhD , Ji-Youn Han MD, PhD , Toyoaki Hida PhD , Brett G.M. Hughes M.B.B.S. , Sang-We Kim MD, PhD , Makoto Nishio MD, PhD , Takashi Seto MD , Tatsuro Okamoto MD, PhD , Xiaoxi Zhang PhD , Jean-Francois Martini PhD , Erjian Wang MD, PhD , Steven De Beukelaer MD , Todd M. Bauer MD
Introduction
The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK-positive or ALK-negative advanced NSCLC, respectively.
Methods
Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1.
Results
In the avelumab plus lorlatinib group (ALK-positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group (ALK-negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%–70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%–57%) with avelumab plus crizotinib (all partial responses).
Conclusions
Avelumab plus lorlatinib treatment in ALK-positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK-negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group.
{"title":"Avelumab in Combination With Lorlatinib or Crizotinib in Patients With Previously Treated Advanced NSCLC: Phase 1b/2 Results From the JAVELIN Lung 101 Trial","authors":"Benjamin J. Solomon M.B.B.S., PhD , Ibiayi Dagogo-Jack MD , Se-Hoon Lee MD , Michael J. Boyer M.B.B.S., PhD , Suresh S. Ramalingam MD , Enric Carcereny MD , Enriqueta Felip MD, PhD , Ji-Youn Han MD, PhD , Toyoaki Hida PhD , Brett G.M. Hughes M.B.B.S. , Sang-We Kim MD, PhD , Makoto Nishio MD, PhD , Takashi Seto MD , Tatsuro Okamoto MD, PhD , Xiaoxi Zhang PhD , Jean-Francois Martini PhD , Erjian Wang MD, PhD , Steven De Beukelaer MD , Todd M. Bauer MD","doi":"10.1016/j.jtocrr.2024.100685","DOIUrl":"10.1016/j.jtocrr.2024.100685","url":null,"abstract":"<div><h3>Introduction</h3><p>The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in <em>ALK</em>-positive or <em>ALK</em>-negative advanced NSCLC, respectively.</p></div><div><h3>Methods</h3><p>Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1.</p></div><div><h3>Results</h3><p>In the avelumab plus lorlatinib group (<em>ALK</em>-positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group (<em>ALK</em>-negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%–70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%–57%) with avelumab plus crizotinib (all partial responses).</p></div><div><h3>Conclusions</h3><p>Avelumab plus lorlatinib treatment in <em>ALK</em>-positive NSCLC was feasible, but avelumab plus crizotinib treatment in <em>ALK</em>-negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group.</p></div><div><h3>ClinicalTrials.gov identifier</h3><p>NCT02584634</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000559/pdfft?md5=9922434c3e3787912adbec65662074b8&pid=1-s2.0-S2666364324000559-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141047129","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 : 2024-07-01DOI: 10.1016/j.jtocrr.2024.100683
Introduction
This study validated real-world pharmacokinetic (PK) data using an established population PK (PopPK) model for atezolizumab in Japanese patients with NSCLC and explored the relationship between PK parameters, effectiveness, and adverse events (AEs) for the 1200 mg once every three weeks regimen.
Methods
A subgroup of 262 of 1039 patients from J-TAIL consented to this exploratory research for PK evaluation of atezolizumab monotherapy for unresectable advanced/recurrent NSCLC (August 2018 to October 2019; 197 institutions). We evaluated plasma concentrations before the start of the third cycle of atezolizumab infusion classified into quartiles 1 to 4, their association with effectiveness, and the association between atezolizumab maximum plasma concentrations (Cmax) calculated using the existing PopPK model and AEs of special interest (AESIs).
Results
Overall, 175 of 262 patients were included; baseline characteristics were similar to those of patients enrolled in J-TAIL (Eastern Cooperative Oncology Group performance status ≥ 2, 12.0%; age ≥ 75 y, 28.9%; atezolizumab as more than or equal to third-line treatment, 57.5%). Atezolizumab plasma concentrations were similar to previously reported data among Japanese/non-Japanese patients. The overall survival was significantly shorter in patients with lower atezolizumab plasma concentrations in Q1 versus Q2 to Q4, although progression-free survival remained the same. The PK data adequately fit the PopPK model, with the frequency of AESIs increasing as the calculated Cmax at cycle 1 increased.
Conclusions
In real-world Japanese patients with unresectable advanced/recurrent NSCLC, PKs were similar to previous reports. Certain patient populations had shorter overall survival, and atezolizumab plasma concentrations in cycle 3 were lower in this population. Elevated Cmax at cycle 1 may be associated with an increased frequency of AESIs.
{"title":"Real-World Pharmacokinetics, Effectiveness, and Safety of Atezolizumab in Patients With Unresectable Advanced or Recurrent NSCLC: An Exploratory Study of J-TAIL","authors":"","doi":"10.1016/j.jtocrr.2024.100683","DOIUrl":"10.1016/j.jtocrr.2024.100683","url":null,"abstract":"<div><h3>Introduction</h3><p>This study validated real-world pharmacokinetic (PK) data using an established population PK (PopPK) model for atezolizumab in Japanese patients with NSCLC and explored the relationship between PK parameters, effectiveness, and adverse events (AEs) for the 1200 mg once every three weeks regimen.</p></div><div><h3>Methods</h3><p>A subgroup of 262 of 1039 patients from J-TAIL consented to this exploratory research for PK evaluation of atezolizumab monotherapy for unresectable advanced/recurrent NSCLC (August 2018 to October 2019; 197 institutions). We evaluated plasma concentrations before the start of the third cycle of atezolizumab infusion classified into quartiles 1 to 4, their association with effectiveness, and the association between atezolizumab maximum plasma concentrations (C<sub>max</sub>) calculated using the existing PopPK model and AEs of special interest (AESIs).</p></div><div><h3>Results</h3><p>Overall, 175 of 262 patients were included; baseline characteristics were similar to those of patients enrolled in J-TAIL (Eastern Cooperative Oncology Group performance status ≥ 2, 12.0%; age ≥ 75 y, 28.9%; atezolizumab as more than or equal to third-line treatment, 57.5%). Atezolizumab plasma concentrations were similar to previously reported data among Japanese/non-Japanese patients. The overall survival was significantly shorter in patients with lower atezolizumab plasma concentrations in Q1 versus Q2 to Q4, although progression-free survival remained the same. The PK data adequately fit the PopPK model, with the frequency of AESIs increasing as the calculated C<sub>max</sub> at cycle 1 increased.</p></div><div><h3>Conclusions</h3><p>In real-world Japanese patients with unresectable advanced/recurrent NSCLC, PKs were similar to previous reports. Certain patient populations had shorter overall survival, and atezolizumab plasma concentrations in cycle 3 were lower in this population. Elevated C<sub>max</sub> at cycle 1 may be associated with an increased frequency of AESIs.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000535/pdfft?md5=d2642a4e522e6dac6c7d912ac0573717&pid=1-s2.0-S2666364324000535-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141026180","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 : 2024-07-01DOI: 10.1016/j.jtocrr.2024.100690
John Nikitas MD , Jane Yanagawa MD , Sandra Sacks MD , Edward K. Hui MD , Alan Lee MD , Jie Deng MD, PhD , Fereidoun Abtin MD , Robert Suh MD , Jay M. Lee MD , Paul Toste MD , Bryan M. Burt MD , Sha’Shonda L. Revels MD , Robert B. Cameron MD , Drew Moghanaki MD, MPH
Chest wall pain syndromes can emerge following local therapies for lung cancer and can adversely affect patients’ quality-of-life. This can occur after lung surgery, radiation therapy, or percutaneous image-guided thermal ablation. This review describes the multifactorial pathophysiology of chest wall pain syndromes that develop following surgical and non-surgical local therapies for lung cancer and summarizes evidence-based management strategies for inflammatory, neuropathic, myofascial, and osseous pain. It discusses a step-wise approach to treating chest wall pain that begins with non-opioid oral analgesics and includes additional pharmacologic treatments as clinically indicated, such as anticonvulsants, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and various topical treatments. For myofascial pain, physical medicine techniques, such as acupuncture, trigger point injections, deep tissue massage, and intercostal myofascial release can also offer pain relief. For severe or refractory cases, opioid analgesics, intercostal nerve blocks, or intercostal nerve ablations may be indicated. Fortunately, palliation of treatment-related chest wall pain syndromes can be managed by most clinical providers, regardless of the type of local therapy utilized for a patient’s lung cancer treatment. In cases where a patient’s pain fails to respond to initial medical management, clinicians can consider referring to a pain specialist who can tailor a more specific pharmacologic approach or perform a procedural intervention to relieve pain.
{"title":"Pathophysiology and Management of Chest Wall Pain after Surgical and Non-Surgical Local Therapies for Lung Cancer","authors":"John Nikitas MD , Jane Yanagawa MD , Sandra Sacks MD , Edward K. Hui MD , Alan Lee MD , Jie Deng MD, PhD , Fereidoun Abtin MD , Robert Suh MD , Jay M. Lee MD , Paul Toste MD , Bryan M. Burt MD , Sha’Shonda L. Revels MD , Robert B. Cameron MD , Drew Moghanaki MD, MPH","doi":"10.1016/j.jtocrr.2024.100690","DOIUrl":"10.1016/j.jtocrr.2024.100690","url":null,"abstract":"<div><p>Chest wall pain syndromes can emerge following local therapies for lung cancer and can adversely affect patients’ quality-of-life. This can occur after lung surgery, radiation therapy, or percutaneous image-guided thermal ablation. This review describes the multifactorial pathophysiology of chest wall pain syndromes that develop following surgical and non-surgical local therapies for lung cancer and summarizes evidence-based management strategies for inflammatory, neuropathic, myofascial, and osseous pain. It discusses a step-wise approach to treating chest wall pain that begins with non-opioid oral analgesics and includes additional pharmacologic treatments as clinically indicated, such as anticonvulsants, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and various topical treatments. For myofascial pain, physical medicine techniques, such as acupuncture, trigger point injections, deep tissue massage, and intercostal myofascial release can also offer pain relief. For severe or refractory cases, opioid analgesics, intercostal nerve blocks, or intercostal nerve ablations may be indicated. Fortunately, palliation of treatment-related chest wall pain syndromes can be managed by most clinical providers, regardless of the type of local therapy utilized for a patient’s lung cancer treatment. In cases where a patient’s pain fails to respond to initial medical management, clinicians can consider referring to a pain specialist who can tailor a more specific pharmacologic approach or perform a procedural intervention to relieve pain.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000602/pdfft?md5=38240fb7ec1165f21f209d590ceb26a7&pid=1-s2.0-S2666364324000602-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141048998","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}