Pub Date : 2025-10-03DOI: 10.1016/j.jtocrr.2025.100914
Surbhi Singhal MD , Caressa Hui MD , Joel W. Neal MD, PhD , Seema Nagpal MD , Mohana Roy MD , Millie Das MD , Kavitha Ramchandran MD , Erqi Pollom MD , Giovanni Selvaggi MD , Heather A. Wakelee MD , Nathaniel J. Myall MD
Introduction
Central nervous system (CNS) metastases are common in ALK-rearranged NSCLC. The optimal treatment strategy for patients who develop CNS progression during treatment with CNS-penetrable ALK tyrosine kinase inhibitors (TKIs) is unknown. Here, we characterized practice patterns and outcomes for patients who developed CNS progression during treatment with CNS-penetrable TKI.
Methods
This retrospective study included patients who developed CNS progression (time 0, [T0]) on alectinib, lorlatinib, brigatinib, or ensartinib. Patients were characterized according to TKI management (i.e., TKI unaltered, TKI-altered [switched TKI or increased TKI dose], TKI discontinued) at T0. Intracranial progression-free survival was evaluated using Kaplan-Meier and compared using the log-rank test.
Results
Among 98 patients treated with a CNS-penetrable TKI, 36 (37%) experienced CNS progression. Overall, 33 (92%) developed parenchymal and seven (19%) developed leptomeningeal progression, respectively. At T0, 16 (44%) had TKI unaltered, 14 (39%) had TKI altered (eight switched TKI, six increased TKI dose), and six (17%) discontinued TKI. Patients with TKI-altered tended to have more frequent leptomeningeal disease or concurrent systemic progression at T0. Intracranial radiation was given at T0 in 14 (88%) of TKI-unaltered and three (21%) of TKI-altered patients. The median intracranial progression-free survival from T0 was not significantly different between the TKI-altered versus unaltered groups (p = 0.21).
Conclusions
For patients with ALK-rearranged NSCLC with leptomeningeal progression or concurrent systemic progression, TKI change or dose increase was a feasible salvage strategy for CNS progression during treatment with CNS-penetrable TKI.
{"title":"Central Nervous System Progression in Patients Receiving ALK-Targeted Central Nervous System–Penetrable Tyrosine Kinase Inhibitors: Treatment Patterns and Outcomes","authors":"Surbhi Singhal MD , Caressa Hui MD , Joel W. Neal MD, PhD , Seema Nagpal MD , Mohana Roy MD , Millie Das MD , Kavitha Ramchandran MD , Erqi Pollom MD , Giovanni Selvaggi MD , Heather A. Wakelee MD , Nathaniel J. Myall MD","doi":"10.1016/j.jtocrr.2025.100914","DOIUrl":"10.1016/j.jtocrr.2025.100914","url":null,"abstract":"<div><h3>Introduction</h3><div>Central nervous system (CNS) metastases are common in <em>ALK</em>-rearranged NSCLC. The optimal treatment strategy for patients who develop CNS progression during treatment with CNS-penetrable <em>ALK</em> tyrosine kinase inhibitors (TKIs) is unknown. Here, we characterized practice patterns and outcomes for patients who developed CNS progression during treatment with CNS-penetrable TKI.</div></div><div><h3>Methods</h3><div>This retrospective study included patients who developed CNS progression (time 0, [T0]) on alectinib, lorlatinib, brigatinib, or ensartinib. Patients were characterized according to TKI management (i.e., TKI unaltered, TKI-altered [switched TKI or increased TKI dose], TKI discontinued) at T0. Intracranial progression-free survival was evaluated using Kaplan-Meier and compared using the log-rank test.</div></div><div><h3>Results</h3><div>Among 98 patients treated with a CNS-penetrable TKI, 36 (37%) experienced CNS progression. Overall, 33 (92%) developed parenchymal and seven (19%) developed leptomeningeal progression, respectively. At T0, 16 (44%) had TKI unaltered, 14 (39%) had TKI altered (eight switched TKI, six increased TKI dose), and six (17%) discontinued TKI. Patients with TKI-altered tended to have more frequent leptomeningeal disease or concurrent systemic progression at T0. Intracranial radiation was given at T0 in 14 (88%) of TKI-unaltered and three (21%) of TKI-altered patients. The median intracranial progression-free survival from T0 was not significantly different between the TKI-altered versus unaltered groups (<em>p</em> = 0.21).</div></div><div><h3>Conclusions</h3><div>For patients with <em>ALK-</em>rearranged NSCLC with leptomeningeal progression or concurrent systemic progression, TKI change or dose increase was a feasible salvage strategy for CNS progression during treatment with CNS-penetrable TKI.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 12","pages":"Article 100914"},"PeriodicalIF":3.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145420517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.jtocrr.2025.100894
Noa Amin PhD, MRCP , Thanika Ketpueak DM , Simon Jordan MBBCh, MD , Andrew G. Nicholson DM, FRCPath , Yu Zhi Zhang MBBS, PhD, FRCPath , Sanjay Popat PhD FRCP
Thymic mucoepidermoid carcinoma (MEC) is a rare thymic carcinoma subtype. Current metastatic thymic carcinoma guidelines recommend first-line platinum-based chemotherapy. However, evidence suggests that MECs, including those of the lung and salivary gland, are chemorefractory, highlighting a more nuanced approach to systemic therapy decision-making. Here, we report a case of durable partial response to second-line lenvatinib in a patient with metastatic high-grade thymic MEC, refractory to first-line platinum-based chemotherapy, suggesting a potentially preferred first-line role for lenvatinib for this subtype.
{"title":"Durable Response to Lenvatinib in Platinum-Refractory Metastatic High-Grade Thymic Mucoepidermoid Carcinoma: A Case Report","authors":"Noa Amin PhD, MRCP , Thanika Ketpueak DM , Simon Jordan MBBCh, MD , Andrew G. Nicholson DM, FRCPath , Yu Zhi Zhang MBBS, PhD, FRCPath , Sanjay Popat PhD FRCP","doi":"10.1016/j.jtocrr.2025.100894","DOIUrl":"10.1016/j.jtocrr.2025.100894","url":null,"abstract":"<div><div>Thymic mucoepidermoid carcinoma (MEC) is a rare thymic carcinoma subtype. Current metastatic thymic carcinoma guidelines recommend first-line platinum-based chemotherapy. However, evidence suggests that MECs, including those of the lung and salivary gland, are chemorefractory, highlighting a more nuanced approach to systemic therapy decision-making. Here, we report a case of durable partial response to second-line lenvatinib in a patient with metastatic high-grade thymic MEC, refractory to first-line platinum-based chemotherapy, suggesting a potentially preferred first-line role for lenvatinib for this subtype.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 10","pages":"Article 100894"},"PeriodicalIF":3.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-30DOI: 10.1016/j.jtocrr.2025.100913
Jacqueline V. Aredo MD, MS , Surbhi Singhal MD , Gerald J. Berry MD , Farshad Moradi MD, PhD , Heather A. Wakelee MD , Nathaniel J. Myall MD , Kavitha J. Ramchandran MD , Millie Das MD , Carlos J. Suarez MD, MS , Joel W. Neal MD, PhD , Jonathan W. Riess MD, MS
Introduction
Histologic transformation to high-grade neuroendocrine carcinoma occurs in resistance to EGFR targeted treatment in approximately 3% to 4% of patients with EGFR-mutant lung cancer and is associated with poor outcomes. The bispecific T-cell engager, tarlatamab, targets DLL3 and CD3 and has exhibited activity in classical SCLC. We evaluated DLL3 expression in patients with neuroendocrine-transformed EGFR-mutant lung cancer and present two cases who received tarlatamab.
Methods
Patients with high-grade neuroendocrine EGFR-mutant lung cancer de novo or after treatment with osimertinib were evaluated at two academic centers. DLL3 expression in neuroendocrine tissue was assessed by immunohistochemistry using the VENTANA SP347 assay (Roche Diagnostics International AG, Rotkreuz, Switzerland).
Results
Twelve patients were identified. Initial histologic diagnoses included adenocarcinoma (n = 10), adenosquamous (n = 1), and combined small cell carcinoma with an adenocarcinoma component (n = 1), with eight having EGFR exon 19 deletions and four with EGFR L858R. TP53 co-mutations and RB1 loss were detected in all patients tested (10 and 7, respectively). The median time from osimertinib initiation to neuroendocrine transformation was 27.8 months (range 3.6–52.9). DLL3 expression was positive in 11 patients with 15 samples (median 80%, range 1–100) and negative in one patient. Two patients with small cell transformation and 100% tumor DLL3 expression underwent treatment with tarlatamab with progression; osimertinib was subsequently added to tarlatamab in one patient with substantial improvement in all lesions.
Conclusions
In this study, neuroendocrine-transformed EGFR-mutant lung cancer exhibited variable DLL3 expression. Tarlatamab appeared effective when added to osimertinib. Further analysis of the combination of bispecific DLL3 T-cell engager and EGFR tyrosine kinase inhibitor is warranted to confirm these findings.
{"title":"DLL3 Immunohistochemical Expression in Neuroendocrine-Transformed EGFR-Mutant Lung Cancer and Two Cases of Tarlatamab Therapy","authors":"Jacqueline V. Aredo MD, MS , Surbhi Singhal MD , Gerald J. Berry MD , Farshad Moradi MD, PhD , Heather A. Wakelee MD , Nathaniel J. Myall MD , Kavitha J. Ramchandran MD , Millie Das MD , Carlos J. Suarez MD, MS , Joel W. Neal MD, PhD , Jonathan W. Riess MD, MS","doi":"10.1016/j.jtocrr.2025.100913","DOIUrl":"10.1016/j.jtocrr.2025.100913","url":null,"abstract":"<div><h3>Introduction</h3><div>Histologic transformation to high-grade neuroendocrine carcinoma occurs in resistance to EGFR targeted treatment in approximately 3% to 4% of patients with <em>EGFR</em>-mutant lung cancer and is associated with poor outcomes. The bispecific T-cell engager, tarlatamab, targets DLL3 and CD3 and has exhibited activity in classical SCLC. We evaluated DLL3 expression in patients with neuroendocrine-transformed <em>EGFR</em>-mutant lung cancer and present two cases who received tarlatamab.</div></div><div><h3>Methods</h3><div>Patients with high-grade neuroendocrine <em>EGFR</em>-mutant lung cancer <em>de novo</em> or after treatment with osimertinib were evaluated at two academic centers. DLL3 expression in neuroendocrine tissue was assessed by immunohistochemistry using the VENTANA SP347 assay (Roche Diagnostics International AG, Rotkreuz, Switzerland).</div></div><div><h3>Results</h3><div>Twelve patients were identified. Initial histologic diagnoses included adenocarcinoma (n = 10), adenosquamous (n = 1), and combined small cell carcinoma with an adenocarcinoma component (n = 1), with eight having <em>EGFR</em> exon 19 deletions and four with <em>EGFR</em> L858R. <em>TP53</em> co-mutations and <em>RB1</em> loss were detected in all patients tested (10 and 7, respectively). The median time from osimertinib initiation to neuroendocrine transformation was 27.8 months (range 3.6–52.9). DLL3 expression was positive in 11 patients with 15 samples (median 80%, range 1–100) and negative in one patient. Two patients with small cell transformation and 100% tumor DLL3 expression underwent treatment with tarlatamab with progression; osimertinib was subsequently added to tarlatamab in one patient with substantial improvement in all lesions.</div></div><div><h3>Conclusions</h3><div>In this study, neuroendocrine-transformed <em>EGFR</em>-mutant lung cancer exhibited variable DLL3 expression. Tarlatamab appeared effective when added to osimertinib. Further analysis of the combination of bispecific DLL3 T-cell engager and EGFR tyrosine kinase inhibitor is warranted to confirm these findings.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 12","pages":"Article 100913"},"PeriodicalIF":3.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145420518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ramucirumab (RAM) plus gefitinib (GEF) exhibited favorable efficacy and safety as first-line treatment in the primary analysis of the RELAY+ study of East Asian patients with metastatic EGFR-mutated NSCLC. We report the final overall survival (OS) and safety.
Methods
This open-label, two-period, single-arm exploratory study included patients with untreated NSCLC having EGFR ex19del or L858R mutations and no central nervous system metastasis or EGFR T790M mutation. Patients received RAM (10 mg/kg every 2 wk) plus GEF (250 mg once daily) until disease progression (period 1); patients with disease progression who acquired a T790M mutation received RAM plus osimertinib (80 mg once daily) (period 2).
Results
At final OS data cutoff (October 20, 2023; median follow-up: 42.5 mo), median (95% confidence interval [CI]) OS was 47.4 (35.9‒57.6) months, and the 3-year OS rate was 61.8%. In the L858R and ex19del subgroups, median OS was 51.9 and 38.4 months, and 3-year OS rates were 70.2% and 52.8%, respectively. Overall, 85.4% of patients received subsequent systemic therapy post study treatment discontinuation. Grade 3 or higher treatment-related adverse events (AEs) were reported by 51 (62.2%) patients. The most common grade 3 or higher treatment-emergent AE of special interest was hypertension (25.6%; grade 3 event only). Treatment-emergent T790M rate post progression was 81.3%.
Conclusions
RELAY+ revealed a favorable benefit-risk profile for RAM plus GEF in East Asian patients with untreated EGFR-mutated metastatic NSCLC, supporting RAM plus GEF as an alternative first-line treatment option, particularly in those with an L858R mutation.
{"title":"RELAY+: Final Overall Survival With Ramucirumab Plus Gefitinib in Patients With Untreated EGFR-Mutated Metastatic NSCLC","authors":"Makoto Nishio MD, PhD , Takashi Seto MD, PhD , Martin Reck PhD , Edward B. Garon MD , Kazuto Nishio MD, PhD , Kazuo Kasahara MD, PhD , Kazumi Nishino MD, PhD , Miyako Satouchi MD, PhD , Kiyotaka Yoh MD , Hidetoshi Hayashi MD, PhD , Kazuko Sakai PhD , Sotaro Enatsu MD, PhD , Tomoko Matsui BSc, RPh , Sunoj Chacko Varughese MSc , Michelle Carlsen MS , Carla Visseren-Grul MD , Kazuhiko Nakagawa MD, PhD","doi":"10.1016/j.jtocrr.2025.100912","DOIUrl":"10.1016/j.jtocrr.2025.100912","url":null,"abstract":"<div><h3>Introduction</h3><div>Ramucirumab (RAM) plus gefitinib (GEF) exhibited favorable efficacy and safety as first-line treatment in the primary analysis of the RELAY+ study of East Asian patients with metastatic <em>EGFR</em>-mutated NSCLC. We report the final overall survival (OS) and safety.</div></div><div><h3>Methods</h3><div>This open-label, two-period, single-arm exploratory study included patients with untreated NSCLC having <em>EGFR</em> ex19del or L858R mutations and no central nervous system metastasis or <em>EGFR</em> T790M mutation. Patients received RAM (10 mg/kg every 2 wk) plus GEF (250 mg once daily) until disease progression (period 1); patients with disease progression who acquired a T790M mutation received RAM plus osimertinib (80 mg once daily) (period 2).</div></div><div><h3>Results</h3><div>At final OS data cutoff (October 20, 2023; median follow-up: 42.5 mo), median (95% confidence interval [CI]) OS was 47.4 (35.9‒57.6) months, and the 3-year OS rate was 61.8%. In the L858R and ex19del subgroups, median OS was 51.9 and 38.4 months, and 3-year OS rates were 70.2% and 52.8%, respectively. Overall, 85.4% of patients received subsequent systemic therapy post study treatment discontinuation. Grade 3 or higher treatment-related adverse events (AEs) were reported by 51 (62.2%) patients. The most common grade 3 or higher treatment-emergent AE of special interest was hypertension (25.6%; grade 3 event only). Treatment-emergent T790M rate post progression was 81.3%.</div></div><div><h3>Conclusions</h3><div>RELAY+ revealed a favorable benefit-risk profile for RAM plus GEF in East Asian patients with untreated <em>EGFR</em>-mutated metastatic NSCLC, supporting RAM plus GEF as an alternative first-line treatment option, particularly in those with an L858R mutation.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 12","pages":"Article 100912"},"PeriodicalIF":3.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-19DOI: 10.1016/j.jtocrr.2025.100907
Min Yuan PhD † , Haolun Ding MS † , Weiwei Zhuang PhD , Yaning Yang PhD , Xu Steven Xu PhD
<div><h3>Introduction</h3><div>In the first-line (1L) NSCLC setting, overall survival (OS) as a trial end point is increasingly challenging due to longer survival and confounding from novel later-line therapies. This study aims to evaluate whether circulating tumor DNA (ctDNA) clearance (alone or with radiographic response) is a reliable early surrogate end point for progression-free survival (PFS) and OS in 1L NSCLC studies.</div></div><div><h3>Methods</h3><div>Data from a phase III trial (IMpower150) of patients with untreated metastatic nonsquamous NSCLC were used. ctDNA clearance, unconfirmed radiographic response, and confirmed radiographic response at approximately 6 months after treatment were evaluated as surrogates for PFS and OS. The meta-analytic approaches were used. The data were randomly split into four cohorts, treating each as an independent “trial” to simulate a multi-trial meta-analysis. This process was repeated 50 times for statistical robustness.</div></div><div><h3>Results</h3><div>ctDNA decline correlated with longer PFS and OS, with greater declines associated with better outcomes. Patients achieving ctDNA clearance (CL) by week 21 had the most significant PFS and OS improvements (<em>p</em> < 0.001). Radiographic response (Resp) within 6 months posttreatment was also associated with improved survival. Combined ctDNA_CL and Resp further enhanced prognostic discrimination. When comparing atezolizumab plus bevacizumab plus carboplatin plus paclitaxel versus bevacizumab plus carboplatin plus paclitaxel (BCP), the individual-level association between 6-month ctDNA CL plus Resp and survival yielded a global odds ratio of 2.06 (95% CI: 2.02–2.11) for PFS and 6.08 (95% CI: 5.92–6.23) for OS. Similar global odds ratios were observed for atezolizumab plus carboplatin plus paclitaxel versus BCP. For the atezolizumab plus bevacizumab plus carboplatin plus paclitaxel versus BCP comparison, cohort-level associations between 6-month ctDNA CL plus Resp and PFS were R<sup>2</sup><sub>WLS</sub> = 0.41 (95% CI: 0.33–0.50) and R<sup>2</sup><sub>copula</sub> = 0.38 (95% CI: 0.30–0.45), whereas associations with OS were R<sup>2</sup><sub>WLS</sub> = 0.48 (95% CI: 0.40–0.56) and R<sup>2</sup><sub>copula</sub> = 0.51 (95% CI: 0.43–0.60) at 6 months. Slightly lower cohort-level associations were observed for atezolizumab plus carboplatin plus paclitaxel versus BCP (R<sup>2</sup> = 0.34–0.41).</div></div><div><h3>Conclusion</h3><div>ctDNA decline is associated with improved survival outcomes in a clear dose–response manner. ctDNA clearance and radiologic response provide complementary prognostic information, and combining these end points (ctDNA_CL + Resp) can further improve prediction of PFS and OS. This combination also enhanced the correlation between treatment effects on the early end points and PFS/OS at the trial level. However, their overall ability to predict treatment effects at the trial level remained modest for both PFS and OS, lik
{"title":"Evaluating Circulating Tumor DNA Clearance as an Early Intermediate End Point Predicting Clinical Benefit in Metastatic Nonsquamous NSCLC After First-Line Chemoimmunotherapy","authors":"Min Yuan PhD † , Haolun Ding MS † , Weiwei Zhuang PhD , Yaning Yang PhD , Xu Steven Xu PhD","doi":"10.1016/j.jtocrr.2025.100907","DOIUrl":"10.1016/j.jtocrr.2025.100907","url":null,"abstract":"<div><h3>Introduction</h3><div>In the first-line (1L) NSCLC setting, overall survival (OS) as a trial end point is increasingly challenging due to longer survival and confounding from novel later-line therapies. This study aims to evaluate whether circulating tumor DNA (ctDNA) clearance (alone or with radiographic response) is a reliable early surrogate end point for progression-free survival (PFS) and OS in 1L NSCLC studies.</div></div><div><h3>Methods</h3><div>Data from a phase III trial (IMpower150) of patients with untreated metastatic nonsquamous NSCLC were used. ctDNA clearance, unconfirmed radiographic response, and confirmed radiographic response at approximately 6 months after treatment were evaluated as surrogates for PFS and OS. The meta-analytic approaches were used. The data were randomly split into four cohorts, treating each as an independent “trial” to simulate a multi-trial meta-analysis. This process was repeated 50 times for statistical robustness.</div></div><div><h3>Results</h3><div>ctDNA decline correlated with longer PFS and OS, with greater declines associated with better outcomes. Patients achieving ctDNA clearance (CL) by week 21 had the most significant PFS and OS improvements (<em>p</em> < 0.001). Radiographic response (Resp) within 6 months posttreatment was also associated with improved survival. Combined ctDNA_CL and Resp further enhanced prognostic discrimination. When comparing atezolizumab plus bevacizumab plus carboplatin plus paclitaxel versus bevacizumab plus carboplatin plus paclitaxel (BCP), the individual-level association between 6-month ctDNA CL plus Resp and survival yielded a global odds ratio of 2.06 (95% CI: 2.02–2.11) for PFS and 6.08 (95% CI: 5.92–6.23) for OS. Similar global odds ratios were observed for atezolizumab plus carboplatin plus paclitaxel versus BCP. For the atezolizumab plus bevacizumab plus carboplatin plus paclitaxel versus BCP comparison, cohort-level associations between 6-month ctDNA CL plus Resp and PFS were R<sup>2</sup><sub>WLS</sub> = 0.41 (95% CI: 0.33–0.50) and R<sup>2</sup><sub>copula</sub> = 0.38 (95% CI: 0.30–0.45), whereas associations with OS were R<sup>2</sup><sub>WLS</sub> = 0.48 (95% CI: 0.40–0.56) and R<sup>2</sup><sub>copula</sub> = 0.51 (95% CI: 0.43–0.60) at 6 months. Slightly lower cohort-level associations were observed for atezolizumab plus carboplatin plus paclitaxel versus BCP (R<sup>2</sup> = 0.34–0.41).</div></div><div><h3>Conclusion</h3><div>ctDNA decline is associated with improved survival outcomes in a clear dose–response manner. ctDNA clearance and radiologic response provide complementary prognostic information, and combining these end points (ctDNA_CL + Resp) can further improve prediction of PFS and OS. This combination also enhanced the correlation between treatment effects on the early end points and PFS/OS at the trial level. However, their overall ability to predict treatment effects at the trial level remained modest for both PFS and OS, lik","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 12","pages":"Article 100907"},"PeriodicalIF":3.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eastern Cooperative Oncology Group performance status 2 to 3 is associated with poor survival and chemotherapy-related adverse events (AEs). The impact of poor PS on the safety and efficacy of immune checkpoint inhibitors has not been elucidated. This study aimed to assess first-line durvalumab in patients with PS 2 to 3 with advanced NSCLC and high programmed cell death-ligand 1 (PD-L1) expression.
Methods
In this single-arm, prospective, multicenter, phase II trial, patients with PS 2 to 3 aged 18 to 75 years with metastatic NSCLC and PD-L1 tumor proportion score more than or equal to 25% received durvalumab until progression or toxicity. Primary end point was safety, that is incidence of grade more than or equal to 3 TRAEs during the first 8 weeks. Secondary end points included blinded independent central review overall response rate, progression-free survival, duration of response, overall survival (OS), and PS improvement at 8 weeks and health-related quality of life.
Results
A total of 50 patients were enrolled. Median follow-up was 26.2 (19.9–35.2) months. Prevalence of grade more than or equal to 3 TRAEs during the first 8 weeks was 10.0% (five of 50, 95% confidence interval [CI] 1.7–18.3), and no grade 5 occurred. Overall response rate at 8 weeks was 26% (95% CI 13.8–38.2). Median duration of response, progression-free survival, and OS were 11.8 months (95% CI, 7.2-not reached), 2.3 months (95% CI 1.7–5.6), and 7.1 months (95% CI 3.9–14.5), respectively. The 12-month OS rate was 40% (95% CI 26.5–53.1). Median OS in patients with PS 2 and PS 3 was 11.4 (95% CI 4.4–32.8) and 3.0 (95% CI 0.2–5.6) months, respectively. Of 27 patients, 12 (44.4%) still receiving durvalumab at 8 weeks had improved PS (p = 0.0096). Mean global QLQ-C30 score significantly increased at 8 weeks.
Conclusions
In patients with a PS of 2 to 3 with advanced NSCLC and high PD-L1 expression, first-line durvalumab was safe with 40% 1-year OS.
东部肿瘤合作组表现状态2 - 3与生存差和化疗相关不良事件（ae）相关。不良PS对免疫检查点抑制剂的安全性和有效性的影响尚未阐明。该研究旨在评估durvalumab在ps2 - 3伴晚期NSCLC和程序性细胞死亡配体1 （PD-L1）高表达患者中的一线治疗效果。在这项单组、前瞻性、多中心、II期试验中，年龄在18至75岁、转移性NSCLC和PD-L1肿瘤比例评分大于或等于25%的PS 2至3患者接受durvalumab治疗，直至进展或出现毒性。主要终点是安全性，即在前8周内超过或等于3个trae级别的发生率。次要终点包括盲法独立中心评价：总缓解率、无进展生存期、缓解持续时间、总生存期（OS）、8周时PS改善和健康相关生活质量。结果共纳入50例患者。中位随访时间为26.2（19.9-35.2）个月。前8周发生≥3级trae的发生率为10.0%(50例中的5例，95%可信区间[CI] 1.7-18.3)，未发生5级trae。8周总缓解率为26% （95% CI 13.8-38.2）。中位缓解持续时间、无进展生存期和OS分别为11.8个月（95% CI， 7.2-未达到）、2.3个月（95% CI 1.7-5.6）和7.1个月（95% CI 3.9-14.5）。12个月OS率为40% （95% CI 26.5-53.1）。ps2和ps3患者的中位生存期分别为11.4个月（95% CI 4.4-32.8）和3.0个月（95% CI 0.2-5.6）。在27例患者中，12例（44.4%）患者在8周时仍接受杜伐单抗治疗，PS得到改善（p = 0.0096）。总体QLQ-C30平均评分在8周时显著升高。结论在PS为2 ~ 3的晚期NSCLC和PD-L1高表达患者中，一线durvalumab是安全的，1年OS为40%。
{"title":"Durvalumab in Patients With Treatment-Naive Stage IV NSCLC With an ECOG Performance Status of 2 to 3 and High PD-L1 Tumor Expression (IFCT-1802 SAVIMMUNE): A Multicenter Phase 2 Trial","authors":"Valérie Gounant MD , Laurent Greillier MD, PhD , Céline Mascaux MD, PhD , François Pinquie MD , Delphine Carmier MD , Lionel Moreau MD , Benoît Roch MD , Didier Debieuvre MD , Xavier Dhalluin MD , Etienne Giroux-Leprieur MD, PhD , Elodie Berton MD , Audrey Rabeau MD , Judith Raimbourg MD , Adrien Dixmier MD , Charles Naltet MD , Antoine Khalil MD, PhD , Lynn Ezzeddine MD , Mostafa El Hajjam MD, PhD , Alexandra Langlais MSc , Franck Morin MSc , Michael Duruisseaux MD, PhD","doi":"10.1016/j.jtocrr.2025.100908","DOIUrl":"10.1016/j.jtocrr.2025.100908","url":null,"abstract":"<div><h3>Introduction</h3><div>Eastern Cooperative Oncology Group performance status 2 to 3 is associated with poor survival and chemotherapy-related adverse events (AEs). The impact of poor PS on the safety and efficacy of immune checkpoint inhibitors has not been elucidated. This study aimed to assess first-line durvalumab in patients with PS 2 to 3 with advanced NSCLC and high programmed cell death-ligand 1 (PD-L1) expression.</div></div><div><h3>Methods</h3><div>In this single-arm, prospective, multicenter, phase II trial, patients with PS 2 to 3 aged 18 to 75 years with metastatic NSCLC and PD-L1 tumor proportion score more than or equal to 25% received durvalumab until progression or toxicity. Primary end point was safety, that is incidence of grade more than or equal to 3 TRAEs during the first 8 weeks. Secondary end points included blinded independent central review overall response rate, progression-free survival, duration of response, overall survival (OS), and PS improvement at 8 weeks and health-related quality of life.</div></div><div><h3>Results</h3><div>A total of 50 patients were enrolled. Median follow-up was 26.2 (19.9–35.2) months. Prevalence of grade more than or equal to 3 TRAEs during the first 8 weeks was 10.0% (five of 50, 95% confidence interval [CI] 1.7–18.3), and no grade 5 occurred. Overall response rate at 8 weeks was 26% (95% CI 13.8–38.2). Median duration of response, progression-free survival, and OS were 11.8 months (95% CI, 7.2-not reached), 2.3 months (95% CI 1.7–5.6), and 7.1 months (95% CI 3.9–14.5), respectively. The 12-month OS rate was 40% (95% CI 26.5–53.1). Median OS in patients with PS 2 and PS 3 was 11.4 (95% CI 4.4–32.8) and 3.0 (95% CI 0.2–5.6) months, respectively. Of 27 patients, 12 (44.4%) still receiving durvalumab at 8 weeks had improved PS (<em>p</em> = 0.0096). Mean global QLQ-C30 score significantly increased at 8 weeks.</div></div><div><h3>Conclusions</h3><div>In patients with a PS of 2 to 3 with advanced NSCLC and high PD-L1 expression, first-line durvalumab was safe with 40% 1-year OS.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 12","pages":"Article 100908"},"PeriodicalIF":3.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-18DOI: 10.1016/j.jtocrr.2025.100906
Viviane Teixeira Loiola de Alencar MD, PhD candidate , Felipe Navarro Balbino Alves BSc, MSc , Guilherme de Souza Velozo BSc, MSc , Luiz Edmundo Lopes Mizutani BSc, MSc , Iusta Caminha MD, MSc, PhD candidate , Gabriel Barbosa Silva BSc in Biomedical Science , Vladmir Cláudio Cordeiro de Lima MD, PhD , Fábio Rocha Fernandes Távora MD, PhD
Introduction
Lung cancer is the leading cause of cancer-related deaths worldwide, with accurate histologic subtype classification critical for diagnosis and treatment planning. Diagnostic variability and resource disparities, particularly in underrepresented regions such as Latin America, pose substantial challenges. This study developed and evaluated novel artificial intelligence models trained on both global and Latin American pathology samples for subtype classification of hematoxylin and eosin (HE)–stained whole-slide images (WSIs).
Methods
Two DinoV2-based feature extractors, LungDino and OncoDino, trained on large data sets for task-specific and general pathology applications, were developed. The training data set consisted of 1308 HE-stained WSIs, including 412 adenocarcinomas, 323 squamous cell carcinomas, 41 small cell carcinomas, and 532 benign tissue samples, sourced from The Cancer Genome Atlas and an in-house Latin American data set. A ResNet model trained on ImageNet served as the baseline. Models were evaluated on 79 Latin American WSIs using receiver operating characteristic curves, and heatmaps were generated for tumor localization.
Results
The DinoV2-based models outperformed the ResNet baseline. LungDino achieved the highest overall performance, with area under the curves of 0.97 for adenocarcinoma and 0.96 for squamous cell carcinoma. OncoDino excelled in underrepresented categories, achieving an area under the curve of 0.99 for small cell carcinoma, demonstrating its generalizability. Both models generated interpretable heatmaps, with LungDino demonstrating precise tumor localization. In the subset of samples classified as poorly differentiated or undifferentiated in HE pathology reports, the DinoV2 models also maintained high classification performance.
Conclusion
These findings underscore the effectiveness of task-specific and general feature extractors in delivering accurate, explainable results and address a gap in artificial intelligence–driven histopathology advancements, paving the way for future clinical applications.
{"title":"Machine Learning Models Using General and Tissue-Specific Feature Extractors for Accurate Subtyping of Biopsy Samples: Advancing Lung Cancer Diagnosis in Latin America","authors":"Viviane Teixeira Loiola de Alencar MD, PhD candidate , Felipe Navarro Balbino Alves BSc, MSc , Guilherme de Souza Velozo BSc, MSc , Luiz Edmundo Lopes Mizutani BSc, MSc , Iusta Caminha MD, MSc, PhD candidate , Gabriel Barbosa Silva BSc in Biomedical Science , Vladmir Cláudio Cordeiro de Lima MD, PhD , Fábio Rocha Fernandes Távora MD, PhD","doi":"10.1016/j.jtocrr.2025.100906","DOIUrl":"10.1016/j.jtocrr.2025.100906","url":null,"abstract":"<div><h3>Introduction</h3><div>Lung cancer is the leading cause of cancer-related deaths worldwide, with accurate histologic subtype classification critical for diagnosis and treatment planning. Diagnostic variability and resource disparities, particularly in underrepresented regions such as Latin America, pose substantial challenges. This study developed and evaluated novel artificial intelligence models trained on both global and Latin American pathology samples for subtype classification of hematoxylin and eosin (HE)–stained whole-slide images (WSIs).</div></div><div><h3>Methods</h3><div>Two DinoV2-based feature extractors, LungDino and OncoDino, trained on large data sets for task-specific and general pathology applications, were developed. The training data set consisted of 1308 HE-stained WSIs, including 412 adenocarcinomas, 323 squamous cell carcinomas, 41 small cell carcinomas, and 532 benign tissue samples, sourced from The Cancer Genome Atlas and an in-house Latin American data set. A ResNet model trained on ImageNet served as the baseline. Models were evaluated on 79 Latin American WSIs using receiver operating characteristic curves, and heatmaps were generated for tumor localization.</div></div><div><h3>Results</h3><div>The DinoV2-based models outperformed the ResNet baseline. LungDino achieved the highest overall performance, with area under the curves of 0.97 for adenocarcinoma and 0.96 for squamous cell carcinoma. OncoDino excelled in underrepresented categories, achieving an area under the curve of 0.99 for small cell carcinoma, demonstrating its generalizability. Both models generated interpretable heatmaps, with LungDino demonstrating precise tumor localization. In the subset of samples classified as poorly differentiated or undifferentiated in HE pathology reports, the DinoV2 models also maintained high classification performance.</div></div><div><h3>Conclusion</h3><div>These findings underscore the effectiveness of task-specific and general feature extractors in delivering accurate, explainable results and address a gap in artificial intelligence–driven histopathology advancements, paving the way for future clinical applications.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 12","pages":"Article 100906"},"PeriodicalIF":3.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-18DOI: 10.1016/j.jtocrr.2025.100910
Sindhu Bhaarrati Naidu M.B.B.S. , Allegra Wisking BSc , Akul Karoshi BSc , Sarah Burdett MSc , Peter J. Godolphin PhD , Sanjay Popat PhD , OLIVE PPI Group, Sam M. Janes PhD , Neal Navani PhD
Objectives
Lung cancer is the leading cause of cancer mortality globally. Although often associated with smoking, up to 25% of cases worldwide and 50% in East Asia occur in “never-smokers.” There are currently no robust tools for predicting lung cancer in individuals who have never smoked (LCINS) for populations outside East Asia.
Together with a group of patient representatives, the authors of this study aimed to summarise risk factors for LCINS and quantify risk in different geographical regions.
Methods
This study was prospectively registered (PROSPERO-CRD42022379253). The systematic review and meta-analysis included studies published from 2017 and aimed to comprehensively investigate risk factors associated with LCINS incidence. Risk of bias was assessed using Newcastle-Ottawa Scale.
Results
A total of 6725 reports were identified and 54 studies were included, with multivariable analysis of 192 factors in 16 million never-smokers. No studies were assessed as having high risk of bias. Of the participants, 8,241,269 (51.0%) were from Western countries.
The meta-analysis found that female sex (adjusted hazard ratio [aHR] 1.28 [95% confidence interval or CI 1.12–1.47]), previous cancer (aHR 2.04 [1.95–2.13]), rheumatoid arthritis (aHR 1.41 [1.15–1.73]), passive smoking (aHR 1.30 [1.22–1.40]), PM10 (aHR 1.10 [1.09–1.11]), and PM2.5 (aHR 1.16 [1.03–1.30]) pollution were associated with LCINS. In planned subgroup analyses by region, LCINS was associated with family history of lung cancer in East Asian (aHR 1.56 [1.23–1.98]) but not Western countries (aHR 0.86 [0.35–2.11]).
Conclusion
We found key factors linked with LCINS, including female sex, rheumatoid arthritis, and pollution and, for the first time, quantified their association through meta-analyses of studies globally. This may be used to develop tools to detect LCINS earlier.
{"title":"Risk Factors Associated With Incidence of Lung Cancer in Never-Smokers: A Systematic Review and Meta-Analysis","authors":"Sindhu Bhaarrati Naidu M.B.B.S. , Allegra Wisking BSc , Akul Karoshi BSc , Sarah Burdett MSc , Peter J. Godolphin PhD , Sanjay Popat PhD , OLIVE PPI Group, Sam M. Janes PhD , Neal Navani PhD","doi":"10.1016/j.jtocrr.2025.100910","DOIUrl":"10.1016/j.jtocrr.2025.100910","url":null,"abstract":"<div><h3>Objectives</h3><div>Lung cancer is the leading cause of cancer mortality globally. Although often associated with smoking, up to 25% of cases worldwide and 50% in East Asia occur in “never-smokers.” There are currently no robust tools for predicting lung cancer in individuals who have never smoked (LCINS) for populations outside East Asia.</div><div>Together with a group of patient representatives, the authors of this study aimed to summarise risk factors for LCINS and quantify risk in different geographical regions.</div></div><div><h3>Methods</h3><div>This study was prospectively registered (PROSPERO-CRD42022379253). The systematic review and meta-analysis included studies published from 2017 and aimed to comprehensively investigate risk factors associated with LCINS incidence. Risk of bias was assessed using Newcastle-Ottawa Scale.</div></div><div><h3>Results</h3><div>A total of 6725 reports were identified and 54 studies were included, with multivariable analysis of 192 factors in 16 million never-smokers. No studies were assessed as having high risk of bias. Of the participants, 8,241,269 (51.0%) were from Western countries.</div><div>The meta-analysis found that female sex (adjusted hazard ratio [aHR] 1.28 [95% confidence interval or CI 1.12–1.47]), previous cancer (aHR 2.04 [1.95–2.13]), rheumatoid arthritis (aHR 1.41 [1.15–1.73]), passive smoking (aHR 1.30 [1.22–1.40]), PM10 (aHR 1.10 [1.09–1.11]), and PM2.5 (aHR 1.16 [1.03–1.30]) pollution were associated with LCINS. In planned subgroup analyses by region, LCINS was associated with family history of lung cancer in East Asian (aHR 1.56 [1.23–1.98]) but not Western countries (aHR 0.86 [0.35–2.11]).</div></div><div><h3>Conclusion</h3><div>We found key factors linked with LCINS, including female sex, rheumatoid arthritis, and pollution and, for the first time, quantified their association through meta-analyses of studies globally. This may be used to develop tools to detect LCINS earlier.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 12","pages":"Article 100910"},"PeriodicalIF":3.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-17DOI: 10.1016/j.jtocrr.2025.100909
Lorenza Landi MD , Rita Chiari MD , Marcello Tiseo MD, PhD , Giulio Metro MD , Filippo de Marinis MD , Angelo Delmonte MD , Silvia Novello MD , Diego Luigi Cortinovis MD , Domenico Galetta MD , Laura Bonanno MD , Cesare Gridelli MD , Alessandro Morabito MD , Francesco Grossi MD , Andrea Torchia MD , Diana Giannarelli PhD , Gloria Borra MD , Francesca Mazzoni MD , Sara Pilotto MD , Federico Cappuzzo MD
Introduction
Crizotinib, the first approved targeted therapy for ALK-positive advanced NSCLC, is also indicated for ROS1-rearranged NSCLC. This post hoc analysis of the phase II METROS trial explores long-term survival outcomes with crizotinib, focusing on the impact of baseline brain metastases (BM).
Methods
This post hoc analysis of the METROS study assessed survival outcomes in patients with ROS1-rearranged NSCLC, evaluating progression-free survival (PFS), overall survival (OS), and the incidence and severity of adverse events, both in the overall cohort and by baseline BM status.
Results
Among 64 patients with ROS1-positive NSCLC with a median follow-up of 54.4 months, median PFS and OS were 13.8 months (95% CI: 7.4–20.2) and 40.5 months (95% CI: 27.9–53.1), respectively. Patients with BM (N = 17) had significantly shorter PFS (6.8 versus 17.4 mo) and OS (16.4 versus 42.8 mo) than those without BM. The safety profile of crizotinib remained consistent with previous reports, with most adverse events being grade 1 or 2 and no new safety concerns identified.
Conclusion
This analysis supports the efficacy of crizotinib in patients with advanced NSCLC and ROS1 rearrangements, although its activity in patients with BM remains limited, highlighting the need for brain-penetrant tyrosine kinase inhibitors to improve outcomes in this patient group.
{"title":"Crizotinib in Patients With ROS1-Positive NSCLC With or Without Brain Metastases: Post Hoc Analysis of Phase II METROS Trial","authors":"Lorenza Landi MD , Rita Chiari MD , Marcello Tiseo MD, PhD , Giulio Metro MD , Filippo de Marinis MD , Angelo Delmonte MD , Silvia Novello MD , Diego Luigi Cortinovis MD , Domenico Galetta MD , Laura Bonanno MD , Cesare Gridelli MD , Alessandro Morabito MD , Francesco Grossi MD , Andrea Torchia MD , Diana Giannarelli PhD , Gloria Borra MD , Francesca Mazzoni MD , Sara Pilotto MD , Federico Cappuzzo MD","doi":"10.1016/j.jtocrr.2025.100909","DOIUrl":"10.1016/j.jtocrr.2025.100909","url":null,"abstract":"<div><h3>Introduction</h3><div>Crizotinib, the first approved targeted therapy for <em>ALK</em>-positive advanced NSCLC, is also indicated for <em>ROS1</em>-rearranged NSCLC. This post hoc analysis of the phase II METROS trial explores long-term survival outcomes with crizotinib, focusing on the impact of baseline brain metastases (BM).</div></div><div><h3>Methods</h3><div>This post hoc analysis of the METROS study assessed survival outcomes in patients with <em>ROS1</em>-rearranged NSCLC, evaluating progression-free survival (PFS), overall survival (OS), and the incidence and severity of adverse events, both in the overall cohort and by baseline BM status.</div></div><div><h3>Results</h3><div>Among 64 patients with <em>ROS1</em>-positive NSCLC with a median follow-up of 54.4 months, median PFS and OS were 13.8 months (95% CI: 7.4–20.2) and 40.5 months (95% CI: 27.9–53.1), respectively. Patients with BM (N = 17) had significantly shorter PFS (6.8 versus 17.4 mo) and OS (16.4 versus 42.8 mo) than those without BM. The safety profile of crizotinib remained consistent with previous reports, with most adverse events being grade 1 or 2 and no new safety concerns identified.</div></div><div><h3>Conclusion</h3><div>This analysis supports the efficacy of crizotinib in patients with advanced NSCLC and <em>ROS1</em> rearrangements, although its activity in patients with BM remains limited, highlighting the need for brain-penetrant tyrosine kinase inhibitors to improve outcomes in this patient group.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"6 12","pages":"Article 100909"},"PeriodicalIF":3.5,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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