Multiple programmed death-ligand 1 (PD-L1) immunohistochemistry assays performed using different antibodies including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1—predictive markers for response to various immune checkpoint inhibitors in NSCLC—have been approved in several countries. The differences in multiple PD-L1 immunohistochemistry assay results in predicting the therapeutic response to combined chemoimmunotherapy in patients with NSCLC remain unclear.
Methods
In this multicenter prospective observational study, we monitored 70 patients with advanced NSCLC treated with combined chemoimmunotherapy at 10 institutions in Japan. The expression of PD-L1 in pretreatment tumors was evaluated using the 22C3, 28-8, and SP142 assays in all patients.
Results
The PD-L1 level in tumor cells determined using the 22C3 assay was the highest among the three assays performed with different antibodies. According to the 22C3 assay results, the PD-L1 tumor proportion score greater than or equal to 50% group had a significantly longer progression-free survival period than the PD-L1 tumor proportion score less than 50% group. Nevertheless, the other assays did not reveal remarkable differences in the objective response rate or progression-free survival.
Conclusions
In our study, PD-L1 expression determined using the 22C3 assay was more correlated with the therapeutic response of patients with NSCLC treated with combined chemoimmunotherapy than that determined using the 28-8 and SP142 assays. Therefore, the 22C3 assay may be useful for clinical decision-making for patients with NSCLC treated with combined chemoimmunotherapy. Trial registration number: UMIN 000043958.
{"title":"Comparing Three Different Anti–Programmed Death-Ligand 1 Antibodies in Immunohistochemical Evaluation of Combined Chemoimmunotherapy Response in Patients With NSCLC: A Prospective Study","authors":"Yuki Katayama MD, PhD , Tadaaki Yamada MD, PhD , Kenji Morimoto MD, PhD , Hiroyuki Fujii MD , Satomi Morita MD, PhD , Keiko Tanimura MD, PhD , Takayuki Takeda MD, PhD , Asuka Okada MD, PhD , Shinsuke Shiotsu MD, PhD , Yusuke Chihara MD, PhD , Osamu Hiranuma MD , Takahiro Yamada MD, PhD , Takahiro Ota MD, PhD , Taishi Harada MD , Isao Hasegawa MD, PhD , Masahiro Iwasaku MD, PhD , Shinsaku Tokuda MD, PhD , Noriyuki Tanaka MD, PhD , Aya Miyagawa-Hayashino MD, PhD , Koichi Takayama MD, PhD","doi":"10.1016/j.jtocrr.2024.100644","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100644","url":null,"abstract":"<div><h3>Introduction</h3><p>Multiple programmed death-ligand 1 (PD-L1) immunohistochemistry assays performed using different antibodies including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1—predictive markers for response to various immune checkpoint inhibitors in NSCLC—have been approved in several countries. The differences in multiple PD-L1 immunohistochemistry assay results in predicting the therapeutic response to combined chemoimmunotherapy in patients with NSCLC remain unclear.</p></div><div><h3>Methods</h3><p>In this multicenter prospective observational study, we monitored 70 patients with advanced NSCLC treated with combined chemoimmunotherapy at 10 institutions in Japan. The expression of PD-L1 in pretreatment tumors was evaluated using the 22C3, 28-8, and SP142 assays in all patients.</p></div><div><h3>Results</h3><p>The PD-L1 level in tumor cells determined using the 22C3 assay was the highest among the three assays performed with different antibodies. According to the 22C3 assay results, the PD-L1 tumor proportion score greater than or equal to 50% group had a significantly longer progression-free survival period than the PD-L1 tumor proportion score less than 50% group. Nevertheless, the other assays did not reveal remarkable differences in the objective response rate or progression-free survival.</p></div><div><h3>Conclusions</h3><p>In our study, PD-L1 expression determined using the 22C3 assay was more correlated with the therapeutic response of patients with NSCLC treated with combined chemoimmunotherapy than that determined using the 28-8 and SP142 assays. Therefore, the 22C3 assay may be useful for clinical decision-making for patients with NSCLC treated with combined chemoimmunotherapy. Trial registration number: UMIN 000043958.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000146/pdfft?md5=6b465a7124f91c9ea13f64ca0b06a8ae&pid=1-s2.0-S2666364324000146-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140015276","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 : 2024-03-01DOI: 10.1016/j.jtocrr.2024.100643
Debora S. Bruno MD, MS , Xiaohong Li MPH , Lisa M. Hess PhD
Introduction
Biomarker testing in oncology is fundamental for targeted therapy use and clinical trial participation. Factors contributing to previously identified racial disparities in biomarker testing remain unclear. This study investigated biomarker testing, clinical trial participation, and targeted therapy by race among patients with metastatic lung cancer with Medicaid coverage in the United States.
Methods
The Merative MarketScan Medicaid claims database was used for this study to identify patients diagnosed with having metastatic lung cancer between 2017 and 2019 with at least 121 days of follow-up. Racial differences in biomarker testing, clinical trial enrollment, and targeted therapy use were analyzed using chi-square/t tests followed by logistic regression for confounding covariates.
Results
A total of 3845 patients were eligible. A total of 970 (25.2%) patients included in this study were Black. Biomarker testing was observed among 57.0%, targeted therapy among 4.6%, and 2.6% of the study cohort had evidence of clinical trial participation. No significant disparities between Black and White races were identified. Younger age and metastatic disease at initial diagnosis were the strongest independent factors associated with increased biomarker testing. Biomarker testing was positively associated with targeted therapy use (OR = 1.69, p = 0.005).
Conclusions
Patients with metastatic lung cancer with Medicaid coverage were found to have exceedingly low biomarker testing rates; only 57% had evidence of any biomarker testing. Although no consistent differences between Black and White races were identified, this study calls attention to care experienced by socioeconomically disadvantaged patients with metastatic lung cancer in the United States.
{"title":"Biomarker Testing, Targeted Therapy and Clinical Trial Participation by Race Among Patients With Lung Cancer: A Real-World Medicaid Database Study","authors":"Debora S. Bruno MD, MS , Xiaohong Li MPH , Lisa M. Hess PhD","doi":"10.1016/j.jtocrr.2024.100643","DOIUrl":"10.1016/j.jtocrr.2024.100643","url":null,"abstract":"<div><h3>Introduction</h3><p>Biomarker testing in oncology is fundamental for targeted therapy use and clinical trial participation. Factors contributing to previously identified racial disparities in biomarker testing remain unclear. This study investigated biomarker testing, clinical trial participation, and targeted therapy by race among patients with metastatic lung cancer with Medicaid coverage in the United States.</p></div><div><h3>Methods</h3><p>The Merative MarketScan Medicaid claims database was used for this study to identify patients diagnosed with having metastatic lung cancer between 2017 and 2019 with at least 121 days of follow-up. Racial differences in biomarker testing, clinical trial enrollment, and targeted therapy use were analyzed using chi-square/<em>t</em> tests followed by logistic regression for confounding covariates.</p></div><div><h3>Results</h3><p>A total of 3845 patients were eligible. A total of 970 (25.2%) patients included in this study were Black. Biomarker testing was observed among 57.0%, targeted therapy among 4.6%, and 2.6% of the study cohort had evidence of clinical trial participation. No significant disparities between Black and White races were identified. Younger age and metastatic disease at initial diagnosis were the strongest independent factors associated with increased biomarker testing. Biomarker testing was positively associated with targeted therapy use (OR = 1.69, <em>p</em> = 0.005).</p></div><div><h3>Conclusions</h3><p>Patients with metastatic lung cancer with Medicaid coverage were found to have exceedingly low biomarker testing rates; only 57% had evidence of any biomarker testing. Although no consistent differences between Black and White races were identified, this study calls attention to care experienced by socioeconomically disadvantaged patients with metastatic lung cancer in the United States.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000134/pdfft?md5=77600ead9f365e8eab58b497409a8a1c&pid=1-s2.0-S2666364324000134-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139826805","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 : 2024-03-01DOI: 10.1016/j.jtocrr.2024.100635
Minal S. Kale MD, MPH , Keith Sigel MD, PhD , Arushi Arora MPH , Bart S. Ferket MD, PhD , Juan Wisnivesky MD, DrPh , Chung Yin Kong PhD
Introduction
Individuals with a history of smoking and a high risk of lung cancer often have a high prevalence of smoking-related comorbidities. The presence of these comorbidities might alter the benefit-to-harm ratio of lung cancer screening by influencing the risk of complications, quality of life, and competing risks of death. Nevertheless, individuals with chronic diseases are underrepresented in screening clinical trials. In this study, we use microsimulation modeling to determine the impact of chronic diseases on lung cancer benefits and harms.
Methods
We extended a validated lung cancer screening microsimulation model that comprehensively recapitulates an individual’s lung cancer development, progression, detection, follow-up, treatment, and survival. We parameterized the model to reflect the impact of chronic diseases on complications from invasive testing, quality of life, and mortality in individuals in five-year age categories between the ages of 50 and 80 years. Outcomes included life-years (LY) gained per 100,000 in patients with chronic obstructive pulmonary disease, diabetes mellitus, heart disease, and history of stroke compared with screening-eligible individuals without comorbidities.
Results
Among individuals between the ages of 50 and 54 years, we found that the presence of a comorbidity altered the LY gained from screening per 100,000 individuals depending on the comorbidity: 4296 LY with no comorbidities; 3462 LY, 3260 LY, 3031 LY, and 3257 LY with chronic obstructive pulmonary disease, heart disease, diabetes mellitus, and stroke, respectively. We observed greater reductions in LY gained in individuals with two comorbidities; we observed similar patterns for individuals between the ages of 55 and 59 years, 60 and 64 years, 65 and 69 years, 70 and 74 years, and 75 and 80 years.
Conclusions
Comorbidities reduce LY gained from screening per 100,000 compared with no comorbidities, and our results can be used by clinicians when discussing the benefits and harms of screening in their patients with comorbidities.
{"title":"The Benefits and Harms of Lung Cancer Screening in Individuals With Comorbidities","authors":"Minal S. Kale MD, MPH , Keith Sigel MD, PhD , Arushi Arora MPH , Bart S. Ferket MD, PhD , Juan Wisnivesky MD, DrPh , Chung Yin Kong PhD","doi":"10.1016/j.jtocrr.2024.100635","DOIUrl":"10.1016/j.jtocrr.2024.100635","url":null,"abstract":"<div><h3>Introduction</h3><p>Individuals with a history of smoking and a high risk of lung cancer often have a high prevalence of smoking-related comorbidities. The presence of these comorbidities might alter the benefit-to-harm ratio of lung cancer screening by influencing the risk of complications, quality of life, and competing risks of death. Nevertheless, individuals with chronic diseases are underrepresented in screening clinical trials. In this study, we use microsimulation modeling to determine the impact of chronic diseases on lung cancer benefits and harms.</p></div><div><h3>Methods</h3><p>We extended a validated lung cancer screening microsimulation model that comprehensively recapitulates an individual’s lung cancer development, progression, detection, follow-up, treatment, and survival. We parameterized the model to reflect the impact of chronic diseases on complications from invasive testing, quality of life, and mortality in individuals in five-year age categories between the ages of 50 and 80 years. Outcomes included life-years (LY) gained per 100,000 in patients with chronic obstructive pulmonary disease, diabetes mellitus, heart disease, and history of stroke compared with screening-eligible individuals without comorbidities.</p></div><div><h3>Results</h3><p>Among individuals between the ages of 50 and 54 years, we found that the presence of a comorbidity altered the LY gained from screening per 100,000 individuals depending on the comorbidity: 4296 LY with no comorbidities; 3462 LY, 3260 LY, 3031 LY, and 3257 LY with chronic obstructive pulmonary disease, heart disease, diabetes mellitus, and stroke, respectively. We observed greater reductions in LY gained in individuals with two comorbidities; we observed similar patterns for individuals between the ages of 55 and 59 years, 60 and 64 years, 65 and 69 years, 70 and 74 years, and 75 and 80 years.</p></div><div><h3>Conclusions</h3><p>Comorbidities reduce LY gained from screening per 100,000 compared with no comorbidities, and our results can be used by clinicians when discussing the benefits and harms of screening in their patients with comorbidities.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000055/pdfft?md5=0b627dc63eb51da85b2b89dffb3e06a2&pid=1-s2.0-S2666364324000055-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139539906","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}
Lenvatinib, a multitarget tyrosine kinase inhibitor for c-Kit and other kinases, has exhibited promising efficacy in treating advanced or metastatic thymic carcinoma (TC). Here, we present the case of a patient with metastatic TC harboring a KIT exon 11 deletion and amplification. The patient exhibited a remarkable response to lenvatinib but experienced rapid disease progression after discontinuation of lenvatinib, referred to as a “disease flare.” This case report indicates that KIT mutations and amplification can predict lenvatinib response in patients with TC. However, in such cases, there might be a risk of disease flares after lenvatinib discontinuation.
{"title":"Rapid Response to Lenvatinib and Disease Flare After Discontinuation in a Patient With Thymic Carcinoma Harboring KIT Exon 11 Mutation: A Case Report","authors":"Masahiro Torasawa MD , Tatsuya Yoshida MD, PhD , Kouya Shiraishi PhD , Naoko Goto BS , Toshihide Ueno PhD , Hitoshi Ichikawa MD, PhD , Shigehiro Yagishita MD, PhD , Shinji Kohsaka MD, PhD , Yasushi Goto MD, PhD , Yasushi Yatabe MD, PhD , Akinobu Hamada PhD , Hiroyuki Mano MD, PhD , Yuichiro Ohe MD, PhD","doi":"10.1016/j.jtocrr.2024.100657","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100657","url":null,"abstract":"<div><p>Lenvatinib, a multitarget tyrosine kinase inhibitor for c-Kit and other kinases, has exhibited promising efficacy in treating advanced or metastatic thymic carcinoma (TC). Here, we present the case of a patient with metastatic TC harboring a <em>KIT</em> exon 11 deletion and amplification. The patient exhibited a remarkable response to lenvatinib but experienced rapid disease progression after discontinuation of lenvatinib, referred to as a “disease flare.” This case report indicates that <em>KIT</em> mutations and amplification can predict lenvatinib response in patients with TC. However, in such cases, there might be a risk of disease flares after lenvatinib discontinuation.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000274/pdfft?md5=b9ec22f6643d5497789d13c673ed5b47&pid=1-s2.0-S2666364324000274-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140163115","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}
RET inhibitors with impressive overall response rates are now available for patients with NSCLC, yet the identification of RET fusions remains a difficult challenge. Most guidelines encourage the upfront use of next-generation sequencing (NGS), or alternatively, fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) when NGS is not possible or available. Taken together, the suboptimal performance of single-analyte assays to detect RET fusions, although consistent with the notion of encouraging universal NGS, is currently widening some of the clinical practice gaps in the implementation of predictive biomarkers in patients with advanced NSCLC.
Methods
This situation prompted us to evaluate several RET assays in a large multicenter cohort of RET fusion–positive NSCLC (n = 38) to obtain real-world data. In addition to RNA-based NGS (the criterion standard method), all positive specimens underwent break-apart RET FISH with two different assays and were also tested by an RT-PCR assay.
Results
The most common RET partners were KIF5B (78.9%), followed by CCDC6 (15.8%). The two RET NGS-positive but FISH-negative samples contained a KIF5B(15)-RET(12) fusion. The three RET fusions not identified with RT-PCR were AKAP13(35)-RET(12), KIF5B(24)-RET(9) and KIF5B(24)-RET(11). All three false-negative RT-PCR cases were FISH-positive, exhibited a typical break-apart pattern, and contained a very high number of positive tumor cells with both FISH assays. Signet ring cells, psammoma bodies, and pleomorphic features were frequently observed (in 34.2%, 39.5%, and 39.5% of tumors, respectively).
Conclusions
In-depth knowledge of the advantages and disadvantages of the different RET testing methodologies could help clinical and molecular tumor boards implement and maintain sensible algorithms for the rapid and effective detection of RET fusions in patients with NSCLC. The likelihood of RET false-negative results with both FISH and RT-PCR reinforces the need for upfront NGS in patients with NSCLC.
目前,可用于 NSCLC 患者的导入 RET 抑制剂的总体反应率令人印象深刻,但 RET 融合的鉴定仍是一项艰巨的挑战。大多数指南都鼓励在前期使用新一代测序(NGS),或者在无法使用 NGS 时使用荧光原位杂交(FISH)或反转录聚合酶链反应(RT-PCR)。这种情况促使我们在 RET 融合阳性 NSCLC(n = 38)的大型多中心队列中评估了几种 RET 检测方法,以获得真实世界的数据。除了基于 RNA 的 NGS(标准方法)外,所有阳性标本都接受了两种不同检测方法的 RET FISH 检测,还接受了 RT-PCR 检测。结果最常见的 RET 伴侣是 KIF5B(78.9%),其次是 CCDC6(15.8%)。两个 RET NGS 阳性但 FISH 阴性的样本含有 KIF5B(15)-RET(12) 融合。RT-PCR 未鉴定出的三例 RET 融合为 AKAP13(35)-RET(12)、KIF5B(24)-RET(9) 和 KIF5B(24)-RET(11)。三例 RT-PCR 假阴性病例均为 FISH 阳性,表现出典型的断裂模式,且两种 FISH 检测方法均含有大量阳性肿瘤细胞。结论深入了解不同 RET 检测方法的优缺点有助于临床和分子肿瘤委员会实施和维护合理的算法,快速有效地检测 NSCLC 患者的 RET 融合。FISH和RT-PCR都有可能出现RET假阴性结果,这加强了对NSCLC患者进行前期NGS检测的必要性。
{"title":"RET Fusion Testing in Patients With NSCLC: The RETING Study","authors":"Esther Conde MD, PhD , Susana Hernandez PhD , Jose Luis Rodriguez Carrillo MD , Rebeca Martinez APT , Marta Alonso APT , Daniel Curto MD , Beatriz Jimenez MD , Alejandra Caminoa MD, PhD , Amparo Benito MD , Pilar Garrido MD, PhD , Sergi Clave PhD , Edurne Arriola MD, PhD , Isabel Esteban-Rodriguez MD, PhD , Javier De Castro MD, PhD , Irene Sansano MD , Enriqueta Felip MD, PhD , Federico Rojo MD, PhD , Manuel Dómine MD, PhD , Ihab Abdulkader MD, PhD , Jorge Garcia-Gonzalez MD , Fernando Lopez-Rios MD, PhD","doi":"10.1016/j.jtocrr.2024.100653","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100653","url":null,"abstract":"<div><h3>Introduction</h3><p><em>RET</em> inhibitors with impressive overall response rates are now available for patients with NSCLC, yet the identification of <em>RET</em> fusions remains a difficult challenge. Most guidelines encourage the upfront use of next-generation sequencing (NGS), or alternatively, fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) when NGS is not possible or available. Taken together, the suboptimal performance of single-analyte assays to detect <em>RET</em> fusions, although consistent with the notion of encouraging universal NGS, is currently widening some of the clinical practice gaps in the implementation of predictive biomarkers in patients with advanced NSCLC.</p></div><div><h3>Methods</h3><p>This situation prompted us to evaluate several <em>RET</em> assays in a large multicenter cohort of <em>RET</em> fusion–positive NSCLC (n = 38) to obtain real-world data. In addition to RNA-based NGS (the criterion standard method), all positive specimens underwent break-apart <em>RET</em> FISH with two different assays and were also tested by an RT-PCR assay.</p></div><div><h3>Results</h3><p>The most common <em>RET</em> partners were <em>KIF5B</em> (78.9%), followed by <em>CCDC6</em> (15.8%). The two <em>RET</em> NGS-positive but FISH-negative samples contained a <em>KIF5B(15)-RET(12)</em> fusion. The three <em>RET</em> fusions not identified with RT-PCR were <em>AKAP13(35)-RET(12)</em>, <em>KIF5B(24)-RET(9)</em> and <em>KIF5B(24)-RET(11)</em>. All three false-negative RT-PCR cases were FISH-positive, exhibited a typical break-apart pattern, and contained a very high number of positive tumor cells with both FISH assays. Signet ring cells, psammoma bodies, and pleomorphic features were frequently observed (in 34.2%, 39.5%, and 39.5% of tumors, respectively).</p></div><div><h3>Conclusions</h3><p>In-depth knowledge of the advantages and disadvantages of the different <em>RET</em> testing methodologies could help clinical and molecular tumor boards implement and maintain sensible algorithms for the rapid and effective detection of <em>RET</em> fusions in patients with NSCLC. The likelihood of <em>RET</em> false-negative results with both FISH and RT-PCR reinforces the need for upfront NGS in patients with NSCLC.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000237/pdfft?md5=1d0484197557d1fce0d0732e03259f18&pid=1-s2.0-S2666364324000237-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140141940","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 : 2024-02-20DOI: 10.1016/j.jtocrr.2024.100656
Judith L. Gulikers MSc , G.D. Marijn Veerman MD, PhD , Merel Jebbink MD, PhD , Paul D. Kruithof PharmD , Christi M.J. Steendam MD, PhD , René J. Boosman PhD , Ron H.J. Mathijssen MD, PhD , Vivianne C.G. Tjan-Heijnen MD, PhD , Johanna H.M. Driessen PhD , Safiye Dursun MD , Egbert F. Smit MD, PhD , Anne-Marie C. Dingemans MD, PhD , Robin M.J.M. van Geel PharmD, PhD , Sander Croes PharmD, PhD , Lizza E.L. Hendriks MD, PhD
Introduction
Brain metastases (BM) are common in patients with advanced EGFR-mutated (EGFRm+) NSCLC. Despite good BM-related outcomes of osimertinib, several patients still experience intracranial progression. A possible explanation is pharmacologic failure due to low plasma trough levels (Cmin,SS) and consequently limited intracranial osimertinib exposure. We investigated the relation between osimertinib Cmin,SS and BM development or progression.
Methods
A prospective multicenter cohort study, including patients receiving osimertinib for advanced EGFRm+ NSCLC. At osimertinib start, patients were allocated to the BM or no or unknown BM cohort and were further divided into subgroups based on osimertinib Cmin,SS (low, middle, and high exposure). Cumulative incidence of BM progression or development and overall survival were determined for each group.
Results
A total of 173 patients were included, with 49 (28.3%) had baseline BM. Of these patients, 36.7% experienced BM progression, of which 16.7% in the low (<159.3 ng/mL), 40.0% in the middle, and 47.1% in the high (>270.7 ng/mL) Cmin,SS subgroups. After 12 months, the cumulative incidence of BM progression for the BM cohort was 20% (95% confidence interval [CI] 2.6–49.0), 31% (95% CI:10.6–53.9), and 31% (95% CI:10.8–54.5) per Cmin,SS subgroup, respectively. After 20 months, this was 20% (95% CI:2.6–49.0), 52% (95% CI:23.8–74.2), and 57% (95% CI:24.9–79.7), respectively. For the no or unknown BM cohort, 4.0% developed BM without differences within Cmin,SS subgroups.
Conclusions
No relation was found between osimertinib Cmin,SS and BM development or progression in patients with advanced EGFRm+ NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development or progression.
{"title":"Osimertinib Plasma Trough Concentration in Relation to Brain Metastases Development in Patients With Advanced EGFR-Mutated NSCLC","authors":"Judith L. Gulikers MSc , G.D. Marijn Veerman MD, PhD , Merel Jebbink MD, PhD , Paul D. Kruithof PharmD , Christi M.J. Steendam MD, PhD , René J. Boosman PhD , Ron H.J. Mathijssen MD, PhD , Vivianne C.G. Tjan-Heijnen MD, PhD , Johanna H.M. Driessen PhD , Safiye Dursun MD , Egbert F. Smit MD, PhD , Anne-Marie C. Dingemans MD, PhD , Robin M.J.M. van Geel PharmD, PhD , Sander Croes PharmD, PhD , Lizza E.L. Hendriks MD, PhD","doi":"10.1016/j.jtocrr.2024.100656","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100656","url":null,"abstract":"<div><h3>Introduction</h3><p>Brain metastases (BM) are common in patients with advanced <em>EGFR</em>-mutated (<em>EGFR</em>m+) NSCLC. Despite good BM-related outcomes of osimertinib, several patients still experience intracranial progression. A possible explanation is pharmacologic failure due to low plasma trough levels (C<sub>min,SS</sub>) and consequently limited intracranial osimertinib exposure. We investigated the relation between osimertinib C<sub>min,SS</sub> and BM development or progression.</p></div><div><h3>Methods</h3><p>A prospective multicenter cohort study, including patients receiving osimertinib for advanced <em>EGFR</em>m<em>+</em> NSCLC. At osimertinib start, patients were allocated to the BM or no or unknown BM cohort and were further divided into subgroups based on osimertinib C<sub>min,SS</sub> (low, middle, and high exposure). Cumulative incidence of BM progression or development and overall survival were determined for each group.</p></div><div><h3>Results</h3><p>A total of 173 patients were included, with 49 (28.3%) had baseline BM. Of these patients, 36.7% experienced BM progression, of which 16.7% in the low (<159.3 ng/mL), 40.0% in the middle, and 47.1% in the high (>270.7 ng/mL) C<sub>min,SS</sub> subgroups. After 12 months, the cumulative incidence of BM progression for the BM cohort was 20% (95% confidence interval [CI] 2.6–49.0), 31% (95% CI:10.6–53.9), and 31% (95% CI:10.8–54.5) per C<sub>min,SS</sub> subgroup, respectively. After 20 months, this was 20% (95% CI:2.6–49.0), 52% (95% CI:23.8–74.2), and 57% (95% CI:24.9–79.7), respectively. For the no or unknown BM cohort, 4.0% developed BM without differences within C<sub>min,SS</sub> subgroups.</p></div><div><h3>Conclusions</h3><p>No relation was found between osimertinib C<sub>min,SS</sub> and BM development or progression in patients with advanced <em>EGFR</em>m<em>+</em> NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development or progression.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000262/pdfft?md5=a80aff0e7fabe98c2bffb809b20caea9&pid=1-s2.0-S2666364324000262-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140180174","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}
Immune checkpoint inhibitor (ICI)–based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo).
Methods
This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores.
Results
Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29–0.72], OW-adjusted HR = 0.52 [95% CI: 0.35–0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70–1.48], OW-adjusted HR = 0.93 [95% CI: 0.65–1.33]).
Conclusions
Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.
{"title":"Immunotherapy With Radiotherapy for Brain Metastases in Patients With NSCLC: NEJ060","authors":"Takehiro Tozuka MD , Yuji Minegishi MD, PhD , Ou Yamaguchi MD, PhD , Kana Watanabe MD , Yukihiro Toi MD , Ryota Saito MD, PhD , Yoshiaki Nagai MD, PhD , Yosuke Tamura MD, PhD , Tetsuaki Shoji MD, PhD , Haruka Odagiri MD , Noriyuki Ebi MD , Kosuke Sakai MD, PhD , Nobuhiro Kanaji MD, PhD , Makoto Izumi MD , Sayo Soda MD, PhD , Satoshi Watanabe MD, PhD , Satoshi Morita PhD , Kunihiko Kobayashi MD, PhD , Masahiro Seike MD, PhD","doi":"10.1016/j.jtocrr.2024.100655","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100655","url":null,"abstract":"<div><h3>Introduction</h3><p>Immune checkpoint inhibitor (ICI)–based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo).</p></div><div><h3>Methods</h3><p>This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores.</p></div><div><h3>Results</h3><p>Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29–0.72], OW-adjusted HR = 0.52 [95% CI: 0.35–0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70–1.48], OW-adjusted HR = 0.93 [95% CI: 0.65–1.33]).</p></div><div><h3>Conclusions</h3><p>Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000250/pdfft?md5=347b3200c1c497c4800c5752fb07e40f&pid=1-s2.0-S2666364324000250-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140163116","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 : 2024-02-19DOI: 10.1016/j.jtocrr.2024.100652
Sunny Y. Lai MD, Noah H. Richardson MD, Mya Tran PharmD, Nasser H. Hanna MD, Misty D. Shields MD, PhD
EGFR mutations are among the most common driver mutations in lung adenocarcinoma. Rare alterations, such as the EGFR-RAD51 fusion, respond to treatment with EGFR tyrosine kinase inhibitors but can be missed by limited genomic sequencing panels. Here, we report a case of metastatic lung adenocarcinoma in a never-smoker patient who initially did not have a targetable alteration identified on two different sequencing panels. The initial response to combination chemoimmunotherapy was short-lived. A rare EGFR-RAD51 fusion was then identified using a more in-depth sequencing panel. The patient experienced a dramatic and durable response to osimertinib. This case highlights the rarity of EGFR-RAD51 fusions, the efficacy of EGFR tyrosine kinase inhibitors, and the importance of a thorough search for targetable alterations in never-smokers with lung adenocarcinoma.
{"title":"Adenocarcinoma Harboring EGFR-RAD51 Fusion Treated With Osimertinib: A Case Report","authors":"Sunny Y. Lai MD, Noah H. Richardson MD, Mya Tran PharmD, Nasser H. Hanna MD, Misty D. Shields MD, PhD","doi":"10.1016/j.jtocrr.2024.100652","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100652","url":null,"abstract":"<div><p><em>EGFR</em> mutations are among the most common driver mutations in lung adenocarcinoma. Rare alterations, such as the <em>EGFR-RAD51</em> fusion, respond to treatment with EGFR tyrosine kinase inhibitors but can be missed by limited genomic sequencing panels. Here, we report a case of metastatic lung adenocarcinoma in a never-smoker patient who initially did not have a targetable alteration identified on two different sequencing panels. The initial response to combination chemoimmunotherapy was short-lived. A rare <em>EGFR-RAD51</em> fusion was then identified using a more in-depth sequencing panel. The patient experienced a dramatic and durable response to osimertinib. This case highlights the rarity of <em>EGFR-RAD51</em> fusions, the efficacy of EGFR tyrosine kinase inhibitors, and the importance of a thorough search for targetable alterations in never-smokers with lung adenocarcinoma.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000225/pdfft?md5=6fe60be7fd389bf5543280384dcab5de&pid=1-s2.0-S2666364324000225-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140141824","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 : 2024-02-07DOI: 10.1016/j.jtocrr.2024.100647
Carlos Torrado MD , Jamie Feng MD, FRCPC , Elizabeth Faour MD, FRCPC , Natasha B. Leighl MD, MMSc, FRCPC, FASCO
MET exon 14 skipping mutation has emerged as a new oncogenic driver in NSCLC with available targeted therapies, including Food and Drug Administration–approved inhibitors capmatinib and tepotinib. Potential resistance mechanisms are beginning to be described and include several on-target and off-target mutations. Here, we report an emergent secondary RET fusion in a patient with a primary MET exon 14 skipping mutation that progressed on capmatinib after the initial response. Subsequently, this patient received both a RET inhibitor (selpercatinib) followed by another MET-targeted treatment (tepotinib) without clinical benefit. Thereafter, cabozantinib, a multikinase inhibitor with activity against RET and MET was started with a rapid clinical and radiologic benefit.
MET第14外显子跳越突变已成为NSCLC新的致癌驱动因素,现有的靶向疗法包括美国食品药品管理局批准的抑制剂卡马替尼和泰泊替尼。目前已开始描述潜在的耐药机制,包括几种靶上和靶下突变。在此,我们报告了一名原发性 MET 14 号外显子跳越突变患者出现的继发性 RET 融合,该患者在服用卡马替尼后出现了初步应答,但病情有所进展。随后,该患者同时接受了一种 RET 抑制剂(赛铂替尼)和另一种 MET 靶向治疗(替泊替尼),但均未获得临床获益。此后,该患者开始接受卡博替尼(一种对RET和MET具有活性的多激酶抑制剂)治疗,并迅速获得了临床和放射学疗效。
{"title":"Cabozantinib Response in a Patient With NSCLC Harboring Both MET Exon 14 Skipping Mutation and Secondary RET Fusion: A Case Report","authors":"Carlos Torrado MD , Jamie Feng MD, FRCPC , Elizabeth Faour MD, FRCPC , Natasha B. Leighl MD, MMSc, FRCPC, FASCO","doi":"10.1016/j.jtocrr.2024.100647","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100647","url":null,"abstract":"<div><p>MET exon 14 skipping mutation has emerged as a new oncogenic driver in NSCLC with available targeted therapies, including Food and Drug Administration–approved inhibitors capmatinib and tepotinib. Potential resistance mechanisms are beginning to be described and include several on-target and off-target mutations. Here, we report an emergent secondary RET fusion in a patient with a primary MET exon 14 skipping mutation that progressed on capmatinib after the initial response. Subsequently, this patient received both a RET inhibitor (selpercatinib) followed by another MET-targeted treatment (tepotinib) without clinical benefit. Thereafter, cabozantinib, a multikinase inhibitor with activity against RET and MET was started with a rapid clinical and radiologic benefit.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000171/pdfft?md5=873c3988b4ea93bcebc85f563c2e0064&pid=1-s2.0-S2666364324000171-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140195513","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 : 2024-02-03DOI: 10.1016/j.jtocrr.2024.100646
Vladmir C. Cordeiro de Lima MD, PhD , Ana Gelatti MD, MSc , José F.P. Moura MD, PhD , Aline F. Fares MD, MSc , Gilberto de Castro Jr. MD, PhD , Clarissa Mathias MD, PhD , Ricardo M. Terra MD, PhD , Gustavo Werutsky MD, PhD , Marcelo Corassa MD , Luiz Henrique L. Araújo MD, PhD , Eduardo Cronenberger MD, MSc , Fernanda K. Fujiki MD , Sandro Reichow MD , Antônio Vinícius T. da Silva MD , Tércia V. Reis MD , Mônica Luciana A. Padoan MD , Patrícia Pacheco MD , Rosely Yamamura MD , Caroline Kawamura MD , Eldsamira Mascarenhas MD, MSc , Clarissa Baldotto MD, PhD
Introduction
Stage III NSCLC is a heterogeneous disease, representing approximately one-third of newly diagnosed lung cancers. Brazil lacks detailed information regarding stage distribution, treatment patterns, survival, and prognostic variables in locally advanced NSCLC.
Methods
RELANCE/LACOG 0118 is an observational, retrospective cohort study assessing sociodemographic and clinical data of patients diagnosed with having stage III NSCLC from January 2015 to June 2019, regardless of treatment received. The study was conducted across 13 cancer centers in Brazil. Disease status and survival data were collected up to June 2021. Descriptive statistics, survival analyses, and a multivariable Cox regression model were performed. p values less than 0.05 were considered significant.
Results
We recruited 403 patients with stage III NSCLC. Most were male (64.0%), White (31.5%), and smokers or former smokers (86.1%). Most patients had public health insurance (67.5%), had stage IIIA disease (63.2%), and were treated with concurrent chemoradiation (53.1%). The median follow-up time was 33.83 months (95% confidence interval [CI]: 30.43–37.50). Median overall survival (OS) was 27.97 months (95% CI: 21.57–31.73), and median progression-free survival was 11.23 months (95% CI: 10.70–12.77). The type of treatment was independently associated with OS and progression-free survival, whereas the types of health insurance and histology were independent predictors of OS only.
Conclusions
Brazilian patients with stage III NSCLC with public health insurance are diagnosed later and have poorer OS. Nevertheless, patients with access to adequate treatment have outcomes similar to those reported in the pivotal trials. Health policy should be improved to make lung cancer diagnosis faster and guarantee prompt access to adequate treatment in Brazil.
{"title":"Health Services Access Inequalities in Brazil Result in Poorer Outcomes for Stage III NSCLC—RELANCE/LACOG 0118","authors":"Vladmir C. Cordeiro de Lima MD, PhD , Ana Gelatti MD, MSc , José F.P. Moura MD, PhD , Aline F. Fares MD, MSc , Gilberto de Castro Jr. MD, PhD , Clarissa Mathias MD, PhD , Ricardo M. Terra MD, PhD , Gustavo Werutsky MD, PhD , Marcelo Corassa MD , Luiz Henrique L. Araújo MD, PhD , Eduardo Cronenberger MD, MSc , Fernanda K. Fujiki MD , Sandro Reichow MD , Antônio Vinícius T. da Silva MD , Tércia V. Reis MD , Mônica Luciana A. Padoan MD , Patrícia Pacheco MD , Rosely Yamamura MD , Caroline Kawamura MD , Eldsamira Mascarenhas MD, MSc , Clarissa Baldotto MD, PhD","doi":"10.1016/j.jtocrr.2024.100646","DOIUrl":"10.1016/j.jtocrr.2024.100646","url":null,"abstract":"<div><h3>Introduction</h3><p>Stage III NSCLC is a heterogeneous disease, representing approximately one-third of newly diagnosed lung cancers. Brazil lacks detailed information regarding stage distribution, treatment patterns, survival, and prognostic variables in locally advanced NSCLC.</p></div><div><h3>Methods</h3><p>RELANCE/LACOG 0118 is an observational, retrospective cohort study assessing sociodemographic and clinical data of patients diagnosed with having stage III NSCLC from January 2015 to June 2019, regardless of treatment received. The study was conducted across 13 cancer centers in Brazil. Disease status and survival data were collected up to June 2021. Descriptive statistics, survival analyses, and a multivariable Cox regression model were performed. <em>p</em> values less than 0.05 were considered significant.</p></div><div><h3>Results</h3><p>We recruited 403 patients with stage III NSCLC. Most were male (64.0%), White (31.5%), and smokers or former smokers (86.1%). Most patients had public health insurance (67.5%), had stage IIIA disease (63.2%), and were treated with concurrent chemoradiation (53.1%). The median follow-up time was 33.83 months (95% confidence interval [CI]: 30.43–37.50). Median overall survival (OS) was 27.97 months (95% CI: 21.57–31.73), and median progression-free survival was 11.23 months (95% CI: 10.70–12.77). The type of treatment was independently associated with OS and progression-free survival, whereas the types of health insurance and histology were independent predictors of OS only.</p></div><div><h3>Conclusions</h3><p>Brazilian patients with stage III NSCLC with public health insurance are diagnosed later and have poorer OS. Nevertheless, patients with access to adequate treatment have outcomes similar to those reported in the pivotal trials. Health policy should be improved to make lung cancer diagnosis faster and guarantee prompt access to adequate treatment in Brazil.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S266636432400016X/pdfft?md5=57c47047bb2b8edb7d9c4b08d8eae3c3&pid=1-s2.0-S266636432400016X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139686193","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}