Pub Date : 2024-11-01DOI: 10.1016/j.esmoop.2024.103708
M. Kim , J.L. Lee , S.J. Shin , W.K. Bae , H.J. Lee , J.H. Byun , Y.J. Choi , J. Youk , C.Y. Ock , S. Kim , H. Song , K.H. Park , B. Keam
{"title":"Corrigendum to “Phase II study of a trastuzumab biosimilar in combination with paclitaxel for HER2-positive recurrent or metastatic urothelial carcinoma: KCSG GU18-18”","authors":"M. Kim , J.L. Lee , S.J. Shin , W.K. Bae , H.J. Lee , J.H. Byun , Y.J. Choi , J. Youk , C.Y. Ock , S. Kim , H. Song , K.H. Park , B. Keam","doi":"10.1016/j.esmoop.2024.103708","DOIUrl":"10.1016/j.esmoop.2024.103708","url":null,"abstract":"","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"9 11","pages":"Article 103708"},"PeriodicalIF":7.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.esmoop.2024.103729
H.-J. Lenz , G. Argilés , M.J.A. de Jonge , R. Yaeger , T. Doi , A. El-Khoueiry , F. Eskens , Y. Kuboki , J. Bertulis , S. Nazabadioko , L. Pronk , J. Tabernero
Background
Aberrant Wnt pathway signaling has been implicated in the development of many cancers. Targeting of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptors inhibits Wnt signaling and may be a novel therapy. BI 905677 is an LRP5/6 antagonist that has demonstrated preclinical antitumor activity.
Patients and methods
This (NCT03604445) was a phase I, dose-escalation study evaluating BI 905677 for patients with advanced solid tumors over two dosing schedules (A: i.v. infusion every 3 weeks, 3-week cycles; B: i.v. infusion every 2 weeks, 4-week cycles). Adult patients were eligible if they had exhausted treatment options and had an Eastern Cooperative Oncology Group performance status of 0-1. The primary endpoints were the maximum tolerated dose (MTD) and safety. Other endpoints were pharmacokinetics, pharmacodynamics, and efficacy.
Results
In total, 37 patients received BI 905677 over nine dose cohorts (0.05-3.6 mg/kg/every 3 weeks). Dose-limiting toxicities were only reported during cycle 1 in the 3.6 mg/kg cohort and the MTD was established at 2.8 mg/kg every 3 weeks. Enrollment for schedule B was not pursued. The most frequently reported adverse events were diarrhea (35.1%), vomiting (21.6%), and C-telopeptide increase (18.9%). All patients in the 3.6 mg/kg cohort experienced a dose-limiting toxicity, suggesting a narrow therapeutic index. Paired pre-treatment and on-treatment biopsies, where available, showed decreased Axin2 expression by reverse transcriptase polymerase chain reaction with treatment, suggesting target inhibition. Best response observed was stable disease in 14 (38%) patients.
Conclusion
The MTD of BI 905677 was set at 2.8 mg/kg every 3 weeks. BI 905677 was well tolerated but a narrow therapeutic range and minimal efficacy led to early termination of the trial.
{"title":"A phase I dose-escalation study of LRP5/6 antagonist BI 905677 in patients with advanced solid tumors","authors":"H.-J. Lenz , G. Argilés , M.J.A. de Jonge , R. Yaeger , T. Doi , A. El-Khoueiry , F. Eskens , Y. Kuboki , J. Bertulis , S. Nazabadioko , L. Pronk , J. Tabernero","doi":"10.1016/j.esmoop.2024.103729","DOIUrl":"10.1016/j.esmoop.2024.103729","url":null,"abstract":"<div><h3>Background</h3><div>Aberrant Wnt pathway signaling has been implicated in the development of many cancers. Targeting of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptors inhibits Wnt signaling and may be a novel therapy. BI 905677 is an LRP5/6 antagonist that has demonstrated preclinical antitumor activity.</div></div><div><h3>Patients and methods</h3><div>This (NCT03604445) was a phase I, dose-escalation study evaluating BI 905677 for patients with advanced solid tumors over two dosing schedules (A: i.v. infusion every 3 weeks, 3-week cycles; B: i.v. infusion every 2 weeks, 4-week cycles). Adult patients were eligible if they had exhausted treatment options and had an Eastern Cooperative Oncology Group performance status of 0-1. The primary endpoints were the maximum tolerated dose (MTD) and safety. Other endpoints were pharmacokinetics, pharmacodynamics, and efficacy.</div></div><div><h3>Results</h3><div>In total, 37 patients received BI 905677 over nine dose cohorts (0.05-3.6 mg/kg/every 3 weeks). Dose-limiting toxicities were only reported during cycle 1 in the 3.6 mg/kg cohort and the MTD was established at 2.8 mg/kg every 3 weeks. Enrollment for schedule B was not pursued. The most frequently reported adverse events were diarrhea (35.1%), vomiting (21.6%), and C-telopeptide increase (18.9%). All patients in the 3.6 mg/kg cohort experienced a dose-limiting toxicity, suggesting a narrow therapeutic index. Paired pre-treatment and on-treatment biopsies, where available, showed decreased Axin2 expression by reverse transcriptase polymerase chain reaction with treatment, suggesting target inhibition. Best response observed was stable disease in 14 (38%) patients.</div></div><div><h3>Conclusion</h3><div>The MTD of BI 905677 was set at 2.8 mg/kg every 3 weeks. BI 905677 was well tolerated but a narrow therapeutic range and minimal efficacy led to early termination of the trial.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"9 11","pages":"Article 103729"},"PeriodicalIF":7.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.esmoop.2024.103966
V.D. de Jager , P. Plomp , M.S. Paats , S. van Helvert , A.ter Elst , A. van den Berg , H.J. Dubbink , W.H. van Geffen , L. Zhang , L.E.L. Hendriks , T.J.N. Hiltermann , B.I. Hiddinga , L.B.M. Hijmering-Kappelle , M. Jalving , J. Kluiver , B. Koopman , M. van Kruchten , E.M.J. van der Logt , B. Piet , J. van Putten , A.J. van der Wekken
Purpose
Molecular tumor boards (MTBs) are considered beneficial for treatment decision making for patients with cancer with uncommon, rare, or complex mutational profiles. The lack of international MTB guidelines results in significant variation in practices and recommendations. Therefore, periodic follow-up is necessary to assess and govern MTB functioning. The objective of this study was to determine the effectiveness of MTB treatment recommendations for patients with rare and complex mutational profiles as implemented in the MTB of the University Medical Center Groningen (UMCG-MTB) in 2019-2020.
Patients and methods
A retrospective follow-up study was carried out to determine the clinical outcome of patients with uncommon or rare (combinations of) molecular aberrations for whom targeted therapy was recommended as the next line of treatment by the UMCG-MTB in 2019 and 2020.
Results
The UMCG-MTB recommended targeted therapy as the next line of treatment in 132 of 327 patients: 37 in clinical trials, 67 in the on-label setting, and 28 in the off-label setting. For on- and off-label treatment recommendations, congruence of recommended and received treatment was 85% in patients with available follow-up (67/79). Treatment with on-label therapy resulted in a response rate of 50% (21/42), a median progression-free survival (PFS) of 6.3 months [interquartile range (IQR) 2.9-14.9 months], and median overall survival (OS) of 15.8 months (IQR 6.4-34.2 months). Treatment with off-label therapy resulted in a response rate of 53% (8/15), a median PFS of 5.1 months (IQR 1.9-7.3 months), and a median OS of 17.7 months (IQR 5.1-23.7 months).
Conclusion
Treatment with MTB-recommended next-line targeted therapy for patients with often heavily pretreated cancer with rare and complex mutational profiles resulted in positive overall responses in over half of patients. Off-label use of targeted therapies, for which there is sufficient rationale as determined by an MTB, is an effective treatment strategy. This study underlines the relevance of discussing patients with rare and complex mutational profiles in an MTB.
{"title":"Molecular Tumor Board of the University Medical Center Groningen (UMCG-MTB): outcome of patients with rare or complex mutational profiles receiving MTB-advised targeted therapy","authors":"V.D. de Jager , P. Plomp , M.S. Paats , S. van Helvert , A.ter Elst , A. van den Berg , H.J. Dubbink , W.H. van Geffen , L. Zhang , L.E.L. Hendriks , T.J.N. Hiltermann , B.I. Hiddinga , L.B.M. Hijmering-Kappelle , M. Jalving , J. Kluiver , B. Koopman , M. van Kruchten , E.M.J. van der Logt , B. Piet , J. van Putten , A.J. van der Wekken","doi":"10.1016/j.esmoop.2024.103966","DOIUrl":"10.1016/j.esmoop.2024.103966","url":null,"abstract":"<div><h3>Purpose</h3><div>Molecular tumor boards (MTBs) are considered beneficial for treatment decision making for patients with cancer with uncommon, rare, or complex mutational profiles. The lack of international MTB guidelines results in significant variation in practices and recommendations. Therefore, periodic follow-up is necessary to assess and govern MTB functioning. The objective of this study was to determine the effectiveness of MTB treatment recommendations for patients with rare and complex mutational profiles as implemented in the MTB of the University Medical Center Groningen (UMCG-MTB) in 2019-2020.</div></div><div><h3>Patients and methods</h3><div>A retrospective follow-up study was carried out to determine the clinical outcome of patients with uncommon or rare (combinations of) molecular aberrations for whom targeted therapy was recommended as the next line of treatment by the UMCG-MTB in 2019 and 2020.</div></div><div><h3>Results</h3><div>The UMCG-MTB recommended targeted therapy as the next line of treatment in 132 of 327 patients: 37 in clinical trials, 67 in the on-label setting, and 28 in the off-label setting. For on- and off-label treatment recommendations, congruence of recommended and received treatment was 85% in patients with available follow-up (67/79). Treatment with on-label therapy resulted in a response rate of 50% (21/42), a median progression-free survival (PFS) of 6.3 months [interquartile range (IQR) 2.9-14.9 months], and median overall survival (OS) of 15.8 months (IQR 6.4-34.2 months). Treatment with off-label therapy resulted in a response rate of 53% (8/15), a median PFS of 5.1 months (IQR 1.9-7.3 months), and a median OS of 17.7 months (IQR 5.1-23.7 months).</div></div><div><h3>Conclusion</h3><div>Treatment with MTB-recommended next-line targeted therapy for patients with often heavily pretreated cancer with rare and complex mutational profiles resulted in positive overall responses in over half of patients. Off-label use of targeted therapies, for which there is sufficient rationale as determined by an MTB, is an effective treatment strategy. This study underlines the relevance of discussing patients with rare and complex mutational profiles in an MTB.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"9 11","pages":"Article 103966"},"PeriodicalIF":7.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142578094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.esmoop.2024.103704
M. Nannini , A. Repaci , M.C. Nigro , A. Colapinto , V. Vicennati , T. Maloberti , E. Gruppioni , A. Altimari , E. Solaroli , E. Lodi Rizzini , F. Monari , A. De Leo , S. Damiani , U. Pagotto , M.A. Pantaleo , D. de Biase , G. Tallini
{"title":"Corrigendum to “Clinical relevance of gene mutations and rearrangements in advanced differentiated thyroid cancer”","authors":"M. Nannini , A. Repaci , M.C. Nigro , A. Colapinto , V. Vicennati , T. Maloberti , E. Gruppioni , A. Altimari , E. Solaroli , E. Lodi Rizzini , F. Monari , A. De Leo , S. Damiani , U. Pagotto , M.A. Pantaleo , D. de Biase , G. Tallini","doi":"10.1016/j.esmoop.2024.103704","DOIUrl":"10.1016/j.esmoop.2024.103704","url":null,"abstract":"","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"9 11","pages":"Article 103704"},"PeriodicalIF":7.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.esmoop.2024.103967
V. Formica , C. Morelli , L. Fornaro , S. Riondino , M. Rofei , E. Fontana , E.C. Smyth , M. Roselli , H.-T. Arkenau
Background
High expression of programmed death-ligand 1 (PD-L1) has been recognized as a marker of improved efficacy of immunotherapy in gastroesophageal adenocarcinoma (GEA); however, the optimal PD-L1 cut-off is still debated. The aim of the present review was to analyze available phase III trials and to identify the appropriate PD-L1 expression cut-off for GEA.
Methods
Phase III trials investigating the efficacy of anti-programmed cell death protein 1 (PD-1) therapies in addition to standard chemotherapy versus standard chemotherapy in the first-line setting were selected. Progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were the analyzed outcome measures. Pooled treatment effects were assessed in the unselected population and in subpopulations with different levels of PD-L1 expression.
Results
PD-1 blockade efficacy was found to consistently increase in a linear manner with higher combined positive score (CPS) of PD-L1 expression: pooled hazard ratio (HR) for OS and PFS and pooled odds ratio (OR) for ORR of 0.80, 0.75 and 1.51, respectively, in the unselected population versus 0.67, 0.63 and 1.90, respectively, in the CPS ≥10 population (all P values < 0.0001). In the PD-L1-negative population (CPS <1) a significant benefit of anti-PD-1 agents could not be demonstrated in terms of OS and PFS (P = 0.28 and 0.12, respectively), but it was seen in terms of ORR (P = 0.03). PD-1 blockade was effective in the CPS <10 population (P value for pooled OS HR, PFS HR and response OR are all 0.01), while in the CPS <5 population the effect was of borderline significance for OS (P = 0.07) and significant for PFS and ORR (P = 0.02 and 0.03, respectively).
Conclusion
The present meta-analysis confirmed that the benefit of PD-1 blockade in GEA patients is related to PD-L1 CPS, with increased benefit observed for higher CPS cut-offs and no OS benefit in the CPS <1 subset. Overall, data indicate that PD-L1 CPS ≥5 could represent an acceptable cut-off to optimize the risk/benefit ratio of such agents. Our data suggest a potential clinical benefit of immunotherapy in selected patients within the CPS 1-4 population which needs further investigation.
{"title":"PD-L1 thresholds predict efficacy of immune checkpoint inhibition in first-line treatment of advanced gastroesophageal adenocarcinoma. A systematic review and meta-analysis of seven phase III randomized trials","authors":"V. Formica , C. Morelli , L. Fornaro , S. Riondino , M. Rofei , E. Fontana , E.C. Smyth , M. Roselli , H.-T. Arkenau","doi":"10.1016/j.esmoop.2024.103967","DOIUrl":"10.1016/j.esmoop.2024.103967","url":null,"abstract":"<div><h3>Background</h3><div>High expression of programmed death-ligand 1 (PD-L1) has been recognized as a marker of improved efficacy of immunotherapy in gastroesophageal adenocarcinoma (GEA); however, the optimal PD-L1 cut-off is still debated. The aim of the present review was to analyze available phase III trials and to identify the appropriate PD-L1 expression cut-off for GEA.</div></div><div><h3>Methods</h3><div>Phase III trials investigating the efficacy of anti-programmed cell death protein 1 (PD-1) therapies in addition to standard chemotherapy versus standard chemotherapy in the first-line setting were selected. Progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were the analyzed outcome measures. Pooled treatment effects were assessed in the unselected population and in subpopulations with different levels of PD-L1 expression.</div></div><div><h3>Results</h3><div>PD-1 blockade efficacy was found to consistently increase in a linear manner with higher combined positive score (CPS) of PD-L1 expression: pooled hazard ratio (HR) for OS and PFS and pooled odds ratio (OR) for ORR of 0.80, 0.75 and 1.51, respectively, in the unselected population versus 0.67, 0.63 and 1.90, respectively, in the CPS ≥10 population (all <em>P</em> values < 0.0001). In the PD-L1-negative population (CPS <1) a significant benefit of anti-PD-1 agents could not be demonstrated in terms of OS and PFS (<em>P</em> = 0.28 and 0.12, respectively), but it was seen in terms of ORR (<em>P</em> = 0.03). PD-1 blockade was effective in the CPS <10 population (<em>P</em> value for pooled OS HR, PFS HR and response OR are all 0.01), while in the CPS <5 population the effect was of borderline significance for OS (<em>P</em> = 0.07) and significant for PFS and ORR (<em>P</em> = 0.02 and 0.03, respectively).</div></div><div><h3>Conclusion</h3><div>The present meta-analysis confirmed that the benefit of PD-1 blockade in GEA patients is related to PD-L1 CPS, with increased benefit observed for higher CPS cut-offs and no OS benefit in the CPS <1 subset. Overall, data indicate that PD-L1 CPS ≥5 could represent an acceptable cut-off to optimize the risk/benefit ratio of such agents. Our data suggest a potential clinical benefit of immunotherapy in selected patients within the CPS 1-4 population which needs further investigation.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"9 11","pages":"Article 103967"},"PeriodicalIF":7.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.esmoop.2024.103964
A.A. Myers , A.M. Fang , M.J. Moussa , H. Hwang , N.R. Wilson , M.T. Campbell , P. Msaouel , B.H. Lee , C.C. Guo , M. Zhang , J. Zhao , A.O. Siefker-Radtke , A.M. Kamat , O. Alhalabi
Background
The purpose of this study was to analyze survival outcomes and pathologic response of patients with cT1N0 small-cell neuroendocrine carcinoma (SCNEC) of the bladder treated with neoadjuvant chemotherapy (neoCTX).
Materials and methods
All cases of bladder SCNEC treated at our institution from January 1996 to July 2023 were identified. cT1N0 was defined as transurethral resection pathology showing lamina propria invasion with present and uninvolved muscularis propria. Pathologic downstaging and recurrences were evaluated. Disease-free survival (DFS) and overall survival (OS) were analyzed using the Cox regression and Kaplan–Meier method.
Results
A total of 30 patients with cT1N0 bladder SCNEC were included. Median follow-up was 88 months [95% confidence interval (CI) 44-131 months]. NeoCTX was given to 21 (70%) patients with a median of 4 cycles (range 1-6 cycles). A total of 27 (90%) patients received definitive local therapy. In cT1 bladder SCNEC, neoCTX was associated with decreased odds of pathologic upstaging [odds ratio = 0.07 (95% CI 0.01-0.45), P = 0.004], decreased odds of relapse [odds ratio = 0.12 (95% CI 0.02-0.65), P = 0.01], improved DFS [hazard ratio (HR) 0.30, 95% CI 0.09-0.96, P = 0.04], and improved OS (HR 0.32, 95% CI 0.10-1.02, P = 0.05). Compared with cT2N0 treated with neoCTX, cT1N0 treated with neoCTX had improved median DFS (HR 0.44, 95% CI 0.19-1.03, P = 0.05) and improved median OS (HR 0.52, 95% CI 0.22-1.24, P = 0.14).
Conclusions
NeoCTX had suggestive benefit in patients with cT1 bladder SCNEC with decreased odds of pathologic upstaging, metastatic relapse, and improved survival.
研究背景本研究旨在分析接受新辅助化疗（neoCTX）的cT1N0膀胱小细胞神经内分泌癌（SCNEC）患者的生存结果和病理反应：cT1N0 的定义是经尿道切除病理显示膀胱固有层受侵，且存在未受累的固有肌。对病理降期和复发进行了评估。采用 Cox 回归法和 Kaplan-Meier 法分析无病生存期（DFS）和总生存期（OS）：结果：共纳入30例cT1N0膀胱SCNEC患者。中位随访时间为88个月[95%置信区间（CI）44-131个月]。21例（70%）患者接受了NeoCTX治疗，中位数为4个周期（1-6个周期不等）。共有 27 例（90%）患者接受了明确的局部治疗。在 cT1 膀胱 SCNEC 中，neoCTX 与病理分期上升几率降低 [几率比 = 0.07 (95% CI 0.01-0.45), P = 0.004]、复发几率降低 [几率比 = 0.12 (95% CI 0.02-0.65), P = 0.01]，改善 DFS [危险比 (HR) 0.30, 95% CI 0.09-0.96, P = 0.04]，改善 OS (HR 0.32, 95% CI 0.10-1.02, P = 0.05)。与接受新CTX治疗的cT2N0相比，接受新CTX治疗的cT1N0的中位DFS有所改善（HR 0.44，95% CI 0.19-1.03，P = 0.05），中位OS有所改善（HR 0.52，95% CI 0.22-1.24，P = 0.14）：结论：NeoCTX对cT1膀胱SCNEC患者有提示性益处，可降低病理分期和转移复发的几率，并提高生存率。
{"title":"Impact of systemic therapy on clinical T1 small-cell neuroendocrine carcinoma of the bladder","authors":"A.A. Myers , A.M. Fang , M.J. Moussa , H. Hwang , N.R. Wilson , M.T. Campbell , P. Msaouel , B.H. Lee , C.C. Guo , M. Zhang , J. Zhao , A.O. Siefker-Radtke , A.M. Kamat , O. Alhalabi","doi":"10.1016/j.esmoop.2024.103964","DOIUrl":"10.1016/j.esmoop.2024.103964","url":null,"abstract":"<div><h3>Background</h3><div>The purpose of this study was to analyze survival outcomes and pathologic response of patients with cT1N0 small-cell neuroendocrine carcinoma (SCNEC) of the bladder treated with neoadjuvant chemotherapy (neoCTX).</div></div><div><h3>Materials and methods</h3><div>All cases of bladder SCNEC treated at our institution from January 1996 to July 2023 were identified. cT1N0 was defined as transurethral resection pathology showing lamina propria invasion with present and uninvolved muscularis propria. Pathologic downstaging and recurrences were evaluated. Disease-free survival (DFS) and overall survival (OS) were analyzed using the Cox regression and Kaplan–Meier method.</div></div><div><h3>Results</h3><div>A total of 30 patients with cT1N0 bladder SCNEC were included. Median follow-up was 88 months [95% confidence interval (CI) 44-131 months]. NeoCTX was given to 21 (70%) patients with a median of 4 cycles (range 1-6 cycles). A total of 27 (90%) patients received definitive local therapy. In cT1 bladder SCNEC, neoCTX was associated with decreased odds of pathologic upstaging [odds ratio = 0.07 (95% CI 0.01-0.45), <em>P</em> = 0.004], decreased odds of relapse [odds ratio = 0.12 (95% CI 0.02-0.65), <em>P</em> = 0.01], improved DFS [hazard ratio (HR) 0.30, 95% CI 0.09-0.96, <em>P</em> = 0.04], and improved OS (HR 0.32, 95% CI 0.10-1.02, <em>P</em> = 0.05). Compared with cT2N0 treated with neoCTX, cT1N0 treated with neoCTX had improved median DFS (HR 0.44, 95% CI 0.19-1.03, <em>P</em> = 0.05) and improved median OS (HR 0.52, 95% CI 0.22-1.24, <em>P</em> = 0.14).</div></div><div><h3>Conclusions</h3><div>NeoCTX had suggestive benefit in patients with cT1 bladder SCNEC with decreased odds of pathologic upstaging, metastatic relapse, and improved survival.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"9 11","pages":"Article 103964"},"PeriodicalIF":7.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.esmoop.2024.103934
J.A. Ajani , L. Leung , S. Kanters , P. Singh , M. Kurt , I. Kim , M.-M. Pourrahmat , H.S. Friedman , P. Navaratnam , G. Reardon
Background
Establishing surrogate endpoints for overall survival (OS) may expedite assessment of new therapies in esophageal cancer (EC) and gastroesophageal junction cancer (GEJC). This study aimed to evaluate disease-free survival (DFS) as a surrogate endpoint for OS.
Methods
Patients from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database aged ≥66 years with resection after primary diagnosis of stage 2 or 3 EC/GEJC between 2009 and 2017 were analyzed (N = 925; median follow-up 26.2 months). Surrogacy was assessed by evaluating individual level associations between DFS and OS using Spearman’s rank correlation and the association between treatment effects by Pearson’s correlation coefficient. To evaluate the association between treatment effects, patients were classified in synthetic clusters based on treatments received. Propensity score matching addressed imbalances in baseline characteristics between treatment and control groups in the clusters. Predictive performance of the surrogacy equation was assessed internally for the generated clusters via leave-one-out cross-validation and externally via predictions for 26 clinical trials of early-stage EC/GEJC.
Results
Patients were mostly male (84%), non-Hispanic white (89.3%), with median age 71.8 years, and cancer stages 2 (50.4%) and 3 (49.6%). Cancer types were adenocarcinoma (76.1%), squamous cell carcinoma (10.4%), and other types (13.5%). Most patients 766/925 (82.8%) received neoadjuvant therapy (680/766 chemoradiotherapy versus 86/766 chemotherapy alone) while 23.6% of the patients received adjuvant therapy. Within each treatment setting, most [705/766 (92.0%) of neoadjuvant therapy and 178/218 (81.7%) of adjuvant therapy] received multi-agent chemotherapy. The individual level correlation was 0.76 (95% confidence interval 0.70-0.80). The correlation between treatment effects was 0.96 (95% confidence interval 0.80-0.99) with a corresponding surrogate threshold effect of 0.71. Both internal (91%) and external (89%) validation of the model demonstrated high predictive accuracy.
Conclusions
Correlations between DFS and OS were meaningful at both individual and treatment effect level. The derived surrogacy equation enables reliable early assessments of OS benefit from the observed DFS benefit for early-stage EC/GEJC treatments in real-world settings.
{"title":"Disease-free survival as surrogate for overall survival in real-world settings for esophageal cancer: an analysis of SEER-Medicare data","authors":"J.A. Ajani , L. Leung , S. Kanters , P. Singh , M. Kurt , I. Kim , M.-M. Pourrahmat , H.S. Friedman , P. Navaratnam , G. Reardon","doi":"10.1016/j.esmoop.2024.103934","DOIUrl":"10.1016/j.esmoop.2024.103934","url":null,"abstract":"<div><h3>Background</h3><div>Establishing surrogate endpoints for overall survival (OS) may expedite assessment of new therapies in esophageal cancer (EC) and gastroesophageal junction cancer (GEJC). This study aimed to evaluate disease-free survival (DFS) as a surrogate endpoint for OS.</div></div><div><h3>Methods</h3><div>Patients from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database aged ≥66 years with resection after primary diagnosis of stage 2 or 3 EC/GEJC between 2009 and 2017 were analyzed (<em>N</em> = 925; median follow-up 26.2 months). Surrogacy was assessed by evaluating individual level associations between DFS and OS using Spearman’s rank correlation and the association between treatment effects by Pearson’s correlation coefficient. To evaluate the association between treatment effects, patients were classified in synthetic clusters based on treatments received. Propensity score matching addressed imbalances in baseline characteristics between treatment and control groups in the clusters. Predictive performance of the surrogacy equation was assessed internally for the generated clusters via leave-one-out cross-validation and externally via predictions for 26 clinical trials of early-stage EC/GEJC.</div></div><div><h3>Results</h3><div>Patients were mostly male (84%), non-Hispanic white (89.3%), with median age 71.8 years, and cancer stages 2 (50.4%) and 3 (49.6%). Cancer types were adenocarcinoma (76.1%), squamous cell carcinoma (10.4%), and other types (13.5%). Most patients 766/925 (82.8%) received neoadjuvant therapy (680/766 chemoradiotherapy versus 86/766 chemotherapy alone) while 23.6% of the patients received adjuvant therapy. Within each treatment setting, most [705/766 (92.0%) of neoadjuvant therapy and 178/218 (81.7%) of adjuvant therapy] received multi-agent chemotherapy. The individual level correlation was 0.76 (95% confidence interval 0.70-0.80). The correlation between treatment effects was 0.96 (95% confidence interval 0.80-0.99) with a corresponding surrogate threshold effect of 0.71. Both internal (91%) and external (89%) validation of the model demonstrated high predictive accuracy.</div></div><div><h3>Conclusions</h3><div>Correlations between DFS and OS were meaningful at both individual and treatment effect level. The derived surrogacy equation enables reliable early assessments of OS benefit from the observed DFS benefit for early-stage EC/GEJC treatments in real-world settings.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"9 11","pages":"Article 103934"},"PeriodicalIF":7.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.esmoop.2024.103984
V. Tuninetti , J.A. Marín-Jiménez , G. Valabrega , E. Ghisoni
Poly-ADP-ribose polymerase inhibitors (PARPis) have revolutionized the management of BRCA-mutated (BRCAmut) and homologous recombination deficiency (HRD)-positive ovarian cancer (OC). While long-term analyses clearly support the use of PARPi as maintenance therapy after first-line chemotherapy, recent data have raised concerns on detrimental overall survival (OS) in non-BRCAmut OC, a greater incidence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and unfavorable outcomes following subsequent platinum-based chemotherapy in pretreated OC patients. In this report we discuss the long-term follow-up results from phase III trials in pretreated OC patients, which led to the Food and Drug Administration’s withdrawal of PARPi indications in this setting. We summarize the newly available evidence concerning the risk of MDS/AML and the post-progression efficacy results after PARPi. We emphasize the importance of long-term follow-up and real-world data coming from international registries to define the efficacy and safety of stopping PARPi at relapse at a pre-specified time. To this point, biomarkers able to identify the patients who will experience long-term remission with PARPi maintenance or develop early resistance are urgently needed to guide treatment decision and duration.
{"title":"Long-term outcomes of PARP inhibitors in ovarian cancer: survival, adverse events, and post-progression insights","authors":"V. Tuninetti , J.A. Marín-Jiménez , G. Valabrega , E. Ghisoni","doi":"10.1016/j.esmoop.2024.103984","DOIUrl":"10.1016/j.esmoop.2024.103984","url":null,"abstract":"<div><div>Poly-ADP-ribose polymerase inhibitors (PARPis) have revolutionized the management of <em>BRCA</em>-mutated (<em>BRCA</em><sup>mut</sup>) and homologous recombination deficiency (HRD)-positive ovarian cancer (OC). While long-term analyses clearly support the use of PARPi as maintenance therapy after first-line chemotherapy, recent data have raised concerns on detrimental overall survival (OS) in non-<em>BRCA</em><sup>mut</sup> OC, a greater incidence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and unfavorable outcomes following subsequent platinum-based chemotherapy in pretreated OC patients. In this report we discuss the long-term follow-up results from phase III trials in pretreated OC patients, which led to the Food and Drug Administration’s withdrawal of PARPi indications in this setting. We summarize the newly available evidence concerning the risk of MDS/AML and the post-progression efficacy results after PARPi. We emphasize the importance of long-term follow-up and real-world data coming from international registries to define the efficacy and safety of stopping PARPi at relapse at a pre-specified time. To this point, biomarkers able to identify the patients who will experience long-term remission with PARPi maintenance or develop early resistance are urgently needed to guide treatment decision and duration.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"9 11","pages":"Article 103984"},"PeriodicalIF":7.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.esmoop.2024.103976
S.S. Datta , V. Sharma , A. Mukherjee , S. Agrawal , B. Sirohi , B. Gyawali
Background
The importance of surrogate endpoints, magnitude of clinical benefit of cancer drugs, and their prices have often been debated in the oncology world. No study, however, has systemically explored oncologists’ perception regarding these issues.
Methods
We conducted a mixed-methods study including in-depth qualitative interviews of medical oncologists prescribing cancer drug therapy in India. Quantitative data were collected using a predetermined proforma. Qualitative in-depth interviews were audio-recorded, transcribed verbatim, anonymized, subsequently coded, and analyzed by generating basic and global themes.
Results
We interviewed 25 medical oncologists. Twenty-eight percent of oncologists rarely used cancer drugs that improved response rate (RR) but not overall survival (OS), and an equal percentage mostly/often used such drugs. For cancer drugs that improved progression-free survival (PFS) but not OS, 20% never/rarely used them while 48% mostly/often used them. Oncologists in India considered a 4.5-month (range, 1.5-12 months) advantage in median PFS as meaningful, and considered price of ∼120 United States Dollars (USD) per month (range, 48-720 USD per month) for those PFS gains as justified. For OS, median gains of 4.5 months (range, 2-24 months) and at a monthly price of ∼360 USD (range, 48-900 USD) was considered justified. Oncologists in India were aware and concerned that RR only meant tumour shrinkage not survival benefit, but many assumed that tumour shrinkage meant better quality of life. Many oncologists acknowledged the limitations of PFS but would use a drug with PFS benefit if it was cheaper than the drug with OS benefit.
Conclusions
Oncologists in India showed awareness of the limited surrogacy between RR/PFS and OS but assumed that RR/PFS correlated with improved quality of life and acknowledged price as a factor in deciding treatment choices. This is the first study providing a benchmark for minimum clinical benefit (4.5 months in PFS or OS) and maximum monthly price (120 USD for PFS, 360 USD for OS) deemed justifiable by oncologists practicing in low-and-middle-income countries.
{"title":"What constitutes meaningful benefit of cancer drugs in the context of LMICs? A mixed-methods study of oncologists’ perceptions on endpoints, benefit, price, and value of cancer drugs","authors":"S.S. Datta , V. Sharma , A. Mukherjee , S. Agrawal , B. Sirohi , B. Gyawali","doi":"10.1016/j.esmoop.2024.103976","DOIUrl":"10.1016/j.esmoop.2024.103976","url":null,"abstract":"<div><h3>Background</h3><div>The importance of surrogate endpoints, magnitude of clinical benefit of cancer drugs, and their prices have often been debated in the oncology world. No study, however, has systemically explored oncologists’ perception regarding these issues.</div></div><div><h3>Methods</h3><div>We conducted a mixed-methods study including in-depth qualitative interviews of medical oncologists prescribing cancer drug therapy in India. Quantitative data were collected using a predetermined proforma. Qualitative in-depth interviews were audio-recorded, transcribed verbatim, anonymized, subsequently coded, and analyzed by generating basic and global themes.</div></div><div><h3>Results</h3><div>We interviewed 25 medical oncologists. Twenty-eight percent of oncologists rarely used cancer drugs that improved response rate (RR) but not overall survival (OS), and an equal percentage mostly/often used such drugs. For cancer drugs that improved progression-free survival (PFS) but not OS, 20% never/rarely used them while 48% mostly/often used them. Oncologists in India considered a 4.5-month (range, 1.5-12 months) advantage in median PFS as meaningful, and considered price of ∼120 United States Dollars (USD) per month (range, 48-720 USD per month) for those PFS gains as justified. For OS, median gains of 4.5 months (range, 2-24 months) and at a monthly price of ∼360 USD (range, 48-900 USD) was considered justified. Oncologists in India were aware and concerned that RR only meant tumour shrinkage not survival benefit, but many assumed that tumour shrinkage meant better quality of life. Many oncologists acknowledged the limitations of PFS but would use a drug with PFS benefit if it was cheaper than the drug with OS benefit.</div></div><div><h3>Conclusions</h3><div>Oncologists in India showed awareness of the limited surrogacy between RR/PFS and OS but assumed that RR/PFS correlated with improved quality of life and acknowledged price as a factor in deciding treatment choices. This is the first study providing a benchmark for minimum clinical benefit (4.5 months in PFS or OS) and maximum monthly price (120 USD for PFS, 360 USD for OS) deemed justifiable by oncologists practicing in low-and-middle-income countries.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"9 11","pages":"Article 103976"},"PeriodicalIF":7.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号