Pub Date : 2026-03-01DOI: 10.1016/j.esmoop.2026.106089
J. Bedke , M.S. van der Heijden , G. Sonpavde , M.D. Galsky , W. Liao , L. Shi , S.I. Blum , S. Mitra , M.Y. Patel , T. Powles
Background
In the phase III CheckMate 901 trial, nivolumab plus standard-of-care gemcitabine–cisplatin chemotherapy followed by nivolumab monotherapy significantly prolonged overall survival and progression-free survival versus gemcitabine–cisplatin alone in cisplatin-eligible patients with unresectable or metastatic urothelial carcinoma (UC). Here, using patient-reported outcome (PRO) data from CheckMate 901, we report effects of adding nivolumab to gemcitabine–cisplatin on health-related quality of life (HRQoL).
Patients and methods
PRO assessments [European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire—Core 30 (EORTC QLQ-C30) and EuroQol 5-Dimension 5-Level (EQ-5D-5L)] were scheduled for both arms through the first 6 months of treatment (combination phase), and for the nivolumab plus gemcitabine–cisplatin arm thereafter (monotherapy phase). The prespecified primary PRO scale of interest was QLQ-C30 global health status/quality of life (QoL). Secondary scales of interest included QLQ-C30 physical functioning, role functioning, and fatigue, and the EQ-5D-5L visual analog scale. Noninferiority analysis involved a mixed-effect model for repeated measures to estimate differences in least-squares mean changes from baseline to week 16. The proportions of patients with meaningful changes were calculated using prespecified thresholds.
Results
In total, 524 patients were analyzed (nivolumab plus gemcitabine–cisplatin, n = 276; gemcitabine–cisplatin alone, n = 248). Overall least-squares mean changes through week 16 indicated the noninferiority of nivolumab plus gemcitabine–cisplatin versus gemcitabine–cisplatin alone for global health status/QoL and all secondary scales. At week 16, the proportions of patients with meaningful changes in global health status/QoL (improvement, 29.2% versus 23.0%; deterioration, 28.3% versus 30.4%) and all secondary PRO scales were similar in both arms.
Conclusions
Adding nivolumab to gemcitabine–cisplatin did not worsen HRQoL compared with gemcitabine–cisplatin alone in the first 16 weeks of therapy. These findings support nivolumab plus gemcitabine–cisplatin as standard first-line therapy for cisplatin-eligible patients with unresectable or metastatic UC.
{"title":"Nivolumab plus gemcitabine–cisplatin for unresectable or metastatic urothelial carcinoma: health-related quality-of-life analyses from the phase III CheckMate 901 trial☆","authors":"J. Bedke , M.S. van der Heijden , G. Sonpavde , M.D. Galsky , W. Liao , L. Shi , S.I. Blum , S. Mitra , M.Y. Patel , T. Powles","doi":"10.1016/j.esmoop.2026.106089","DOIUrl":"10.1016/j.esmoop.2026.106089","url":null,"abstract":"<div><h3>Background</h3><div>In the phase III CheckMate 901 trial, nivolumab plus standard-of-care gemcitabine–cisplatin chemotherapy followed by nivolumab monotherapy significantly prolonged overall survival and progression-free survival versus gemcitabine–cisplatin alone in cisplatin-eligible patients with unresectable or metastatic urothelial carcinoma (UC). Here, using patient-reported outcome (PRO) data from CheckMate 901, we report effects of adding nivolumab to gemcitabine–cisplatin on health-related quality of life (HRQoL).</div></div><div><h3>Patients and methods</h3><div>PRO assessments [European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire—Core 30 (EORTC QLQ-C30) and EuroQol 5-Dimension 5-Level (EQ-5D-5L)] were scheduled for both arms through the first 6 months of treatment (combination phase), and for the nivolumab plus gemcitabine–cisplatin arm thereafter (monotherapy phase). The prespecified primary PRO scale of interest was QLQ-C30 global health status/quality of life (QoL). Secondary scales of interest included QLQ-C30 physical functioning, role functioning, and fatigue, and the EQ-5D-5L visual analog scale. Noninferiority analysis involved a mixed-effect model for repeated measures to estimate differences in least-squares mean changes from baseline to week 16. The proportions of patients with meaningful changes were calculated using prespecified thresholds.</div></div><div><h3>Results</h3><div>In total, 524 patients were analyzed (nivolumab plus gemcitabine–cisplatin, <em>n</em> = 276; gemcitabine–cisplatin alone, <em>n</em> = 248). Overall least-squares mean changes through week 16 indicated the noninferiority of nivolumab plus gemcitabine–cisplatin versus gemcitabine–cisplatin alone for global health status/QoL and all secondary scales. At week 16, the proportions of patients with meaningful changes in global health status/QoL (improvement, 29.2% versus 23.0%; deterioration, 28.3% versus 30.4%) and all secondary PRO scales were similar in both arms.</div></div><div><h3>Conclusions</h3><div>Adding nivolumab to gemcitabine–cisplatin did not worsen HRQoL compared with gemcitabine–cisplatin alone in the first 16 weeks of therapy. These findings support nivolumab plus gemcitabine–cisplatin as standard first-line therapy for cisplatin-eligible patients with unresectable or metastatic UC.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"11 3","pages":"Article 106089"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147303734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01DOI: 10.1016/j.esmoop.2026.106091
K. Jhaveri , F.C. Bidard , K. Kalinsky , P. Neven , H.S. Rugo , S.M. Tolaney , L.M. Litchfield , C.C. von Laue , S. Traore , F. Sapunar , Y. Li , J. O’Shaughnessy
Background
The EMBER-3 trial demonstrated significant progression-free survival (PFS) benefit for imlunestrant + abemaciclib versus imlunestrant alone in patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) with disease recurrence/progression during prior aromatase inhibitor ± cyclin-dependent kinase 4/6 inhibitor (AI ± CDK4/6i) treatment. The phase III MONARCH 2 and postMONARCH trials demonstrated the superiority of fulvestrant + abemaciclib versus fulvestrant in CDK4/6i-naïve and pretreated patients, respectively. The efficacy of imlunestrant + abemaciclib versus fulvestrant + abemaciclib has not been directly evaluated in randomized controlled trials. In the absence of head-to-head trial data, indirect treatment comparison (ITC) analyses allow fair evaluation of between-trial efficacy. This study aimed to determine the relative efficacy of imlunestrant + abemaciclib versus fulvestrant + abemaciclib through ITC of the EMBER-3, MONARCH 2, and postMONARCH trials.
Materials and Methods
To compare investigator-assessed PFS between imlunestrant + abemaciclib and fulvestrant + abemaciclib, three ITC methods—Bucher, matching-adjusted indirect comparison (MAIC), and propensity score matching (PSM)—were employed using individually matched patient-level data from the EMBER-3, MONARCH 2, and postMONARCH trials. Ten prognostic and predictive factors were selected as baseline covariates. The standard Bucher method had no population adjustment, whereas PSM and MAIC were population-adjusted. The MAIC analysis adjusted the pooled MONARCH 2/postMONARCH population to match the EMBER-3 population. The PSM matched the propensity score between the EMBER-3 and pooled MONARCH 2/postMONARCH populations.
Results
Baseline characteristics were well balanced across adjusted populations by MAIC and PSM. Though not powered for formal hypothesis testing, PFS favored imlunestrant + abemaciclib versus fulvestrant + abemaciclib across all three ITC methods. Hazard ratios (95% confidence intervals) for Bucher, MAIC, and PSM were 0.77 (0.58-1.04), 0.77 (0.55-1.06), and 0.83 (0.56-1.22), respectively.
Conclusion
In this ITC analysis of patient-level data from three phase III trials, although not powered for formal hypothesis testing, the all-oral targeted combination therapy imlunestrant + abemaciclib showed a consistent numerical reduction in the risk of disease progression or death compared with fulvestrant + abemaciclib in patients with ER-positive/HER2-negative ABC previously treated with endocrine therapy ± CDK4/6i.
{"title":"Imlunestrant plus abemaciclib versus fulvestrant plus abemaciclib in ER-positive, HER2-negative advanced breast cancer: an indirect treatment comparison of three phase III trials","authors":"K. Jhaveri , F.C. Bidard , K. Kalinsky , P. Neven , H.S. Rugo , S.M. Tolaney , L.M. Litchfield , C.C. von Laue , S. Traore , F. Sapunar , Y. Li , J. O’Shaughnessy","doi":"10.1016/j.esmoop.2026.106091","DOIUrl":"10.1016/j.esmoop.2026.106091","url":null,"abstract":"<div><h3>Background</h3><div>The EMBER-3 trial demonstrated significant progression-free survival (PFS) benefit for imlunestrant + abemaciclib versus imlunestrant alone in patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) with disease recurrence/progression during prior aromatase inhibitor ± cyclin-dependent kinase 4/6 inhibitor (AI ± CDK4/6i) treatment. The phase III MONARCH 2 and postMONARCH trials demonstrated the superiority of fulvestrant + abemaciclib versus fulvestrant in CDK4/6i-naïve and pretreated patients, respectively. The efficacy of imlunestrant + abemaciclib versus fulvestrant + abemaciclib has not been directly evaluated in randomized controlled trials. In the absence of head-to-head trial data, indirect treatment comparison (ITC) analyses allow fair evaluation of between-trial efficacy. This study aimed to determine the relative efficacy of imlunestrant + abemaciclib versus fulvestrant + abemaciclib through ITC of the EMBER-3, MONARCH 2, and postMONARCH trials.</div></div><div><h3>Materials and Methods</h3><div>To compare investigator-assessed PFS between imlunestrant + abemaciclib and fulvestrant + abemaciclib, three ITC methods—Bucher, matching-adjusted indirect comparison (MAIC), and propensity score matching (PSM)—were employed using individually matched patient-level data from the EMBER-3, MONARCH 2, and postMONARCH trials. Ten prognostic and predictive factors were selected as baseline covariates. The standard Bucher method had no population adjustment, whereas PSM and MAIC were population-adjusted. The MAIC analysis adjusted the pooled MONARCH 2/postMONARCH population to match the EMBER-3 population. The PSM matched the propensity score between the EMBER-3 and pooled MONARCH 2/postMONARCH populations.</div></div><div><h3>Results</h3><div>Baseline characteristics were well balanced across adjusted populations by MAIC and PSM. Though not powered for formal hypothesis testing, PFS favored imlunestrant + abemaciclib versus fulvestrant + abemaciclib across all three ITC methods. Hazard ratios (95% confidence intervals) for Bucher, MAIC, and PSM were 0.77 (0.58-1.04), 0.77 (0.55-1.06), and 0.83 (0.56-1.22), respectively.</div></div><div><h3>Conclusion</h3><div>In this ITC analysis of patient-level data from three phase III trials, although not powered for formal hypothesis testing, the all-oral targeted combination therapy imlunestrant + abemaciclib showed a consistent numerical reduction in the risk of disease progression or death compared with fulvestrant + abemaciclib in patients with ER-positive/HER2-negative ABC previously treated with endocrine therapy ± CDK4/6i.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"11 3","pages":"Article 106091"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147364530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-03-11DOI: 10.1016/j.esmoop.2026.106081
K. Khaddour , P. Kote, M. Liu, A. Giobbie-Hurder, I. Dryg, A. Goyal, J.P. Guenette, J.D. Schoenfeld, D.N. Margalit, R.B. Tishler, E.M. Rettig, R.K.V. Sethi, D.J. Annino, L.A. Goguen, R. Uppaluri, C. Yoon, M. de Simone, N.A. Ran, J. Stevens, A.H. Waldman, G.J. Hanna
Background
Anti-programmed cell death protein 1 (PD-1) therapy is the cornerstone for managing advanced cutaneous squamous-cell carcinoma (CSCC). Nevertheless, many patients experience treatment failure. Limited data exist regarding outcomes following anti-PD-1 failure. This study investigates progression patterns and clinical outcomes in CSCC patients post-anti-PD-1 therapy.
Patients and methods
We conducted a retrospective analysis of CSCC patients treated with anti-PD-1 at the Dana-Farber Cancer Institute. We evaluated clinicopathological features and outcomes. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan–Meier method. CSCC-specific mortality was estimated using cumulative incidence. Multivariate regression was used to investigate prognostic factors.
Results
Among 238 patients receiving immunotherapy, 72 exhibited anti-PD-1 failure with a median age of 72 years; 22% were female and 29% were immunosuppressed. Median follow-up was 23 months [95% confidence interval (CI) 19-37 months] and median duration of immunotherapy was 3 months (range 1-44 months). Progression after anti-PD-1 failure occurred as local (21%), locoregional (37%), or distant metastatic (42%). Primary resistance was observed in 62.5%, while 37.5% developed secondary resistance. Patients with primary resistance exhibited a significantly lower tumor mutational burden (TMB) (P = 0.03). Among 61 patients receiving subsequent treatment, cetuximab-based therapy and local treatments each were administered in 31%. Complete and partial responses were achieved in 5% and 25%, respectively, while 6% had stable disease, 28% progressed, and 36% were non-assessable. Median OS was 44.1 months (95% CI 17.4 months-not achieved) and median EFS2 (time from starting subsequent treatment post-anti-PD-1 until recurrence, progression, or death) was 7.1 months (95% CI 3.2-12.2 months). CSCC-specific death was 50% at 5 years (95% CI 30% to 67%). Prior chemotherapy was associated with poorer OS (hazard ratio 2.87, 95% CI 1.03-7.98, P = 0.04).
Conclusions
In this cohort of patients with CSCC, distant metastatic and locoregional progression were the predominant patterns following anti-PD-1 failure, with lower TMB linked to primary resistance. Prior chemotherapy was associated with poorer OS. Select patients benefited from subsequent treatments, including cetuximab and local therapy.
{"title":"Progression patterns and clinical outcomes in patients with cutaneous squamous-cell carcinoma following anti-PD-1 therapy failure","authors":"K. Khaddour , P. Kote, M. Liu, A. Giobbie-Hurder, I. Dryg, A. Goyal, J.P. Guenette, J.D. Schoenfeld, D.N. Margalit, R.B. Tishler, E.M. Rettig, R.K.V. Sethi, D.J. Annino, L.A. Goguen, R. Uppaluri, C. Yoon, M. de Simone, N.A. Ran, J. Stevens, A.H. Waldman, G.J. Hanna","doi":"10.1016/j.esmoop.2026.106081","DOIUrl":"10.1016/j.esmoop.2026.106081","url":null,"abstract":"<div><h3>Background</h3><div>Anti-programmed cell death protein 1 (PD-1) therapy is the cornerstone for managing advanced cutaneous squamous-cell carcinoma (CSCC). Nevertheless, many patients experience treatment failure. Limited data exist regarding outcomes following anti-PD-1 failure. This study investigates progression patterns and clinical outcomes in CSCC patients post-anti-PD-1 therapy.</div></div><div><h3>Patients and methods</h3><div>We conducted a retrospective analysis of CSCC patients treated with anti-PD-1 at the Dana-Farber Cancer Institute. We evaluated clinicopathological features and outcomes. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan–Meier method. CSCC-specific mortality was estimated using cumulative incidence. Multivariate regression was used to investigate prognostic factors.</div></div><div><h3>Results</h3><div>Among 238 patients receiving immunotherapy, 72 exhibited anti-PD-1 failure with a median age of 72 years; 22% were female and 29% were immunosuppressed. Median follow-up was 23 months [95% confidence interval (CI) 19-37 months] and median duration of immunotherapy was 3 months (range 1-44 months). Progression after anti-PD-1 failure occurred as local (21%), locoregional (37%), or distant metastatic (42%). Primary resistance was observed in 62.5%, while 37.5% developed secondary resistance. Patients with primary resistance exhibited a significantly lower tumor mutational burden (TMB) (<em>P</em> = 0.03). Among 61 patients receiving subsequent treatment, cetuximab-based therapy and local treatments each were administered in 31%. Complete and partial responses were achieved in 5% and 25%, respectively, while 6% had stable disease, 28% progressed, and 36% were non-assessable. Median OS was 44.1 months (95% CI 17.4 months-not achieved) and median EFS2 (time from starting subsequent treatment post-anti-PD-1 until recurrence, progression, or death) was 7.1 months (95% CI 3.2-12.2 months). CSCC-specific death was 50% at 5 years (95% CI 30% to 67%). Prior chemotherapy was associated with poorer OS (hazard ratio 2.87, 95% CI 1.03-7.98, <em>P</em> = 0.04).</div></div><div><h3>Conclusions</h3><div>In this cohort of patients with CSCC, distant metastatic and locoregional progression were the predominant patterns following anti-PD-1 failure, with lower TMB linked to primary resistance. Prior chemotherapy was associated with poorer OS. Select patients benefited from subsequent treatments, including cetuximab and local therapy.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"11 3","pages":"Article 106081"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147385910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-03-10DOI: 10.1016/j.esmoop.2026.106092
O. Kimpel , D. Cosentini , A. Calabrese , A. Jouinot , B. Altieri , S. Kircher , G. Di Dalmazi , Y.S. Elhassan , D. Vassiliadi , K. Chrysoula , S. Puglisi , K. Coscia , N.V. Gallego , P. Loli , M. Boudina , M. Lagana , V. Cremaschi , D. Pignatelli , E. Rios , C.A. Villavicencio , M. Fassnacht
Background
In 2022, the World Health Organization (WHO) classified adrenal cortical carcinoma (ACC) into four subtypes: conventional, oncocytic, myxoid, and sarcomatoid. The differences in prognosis among these subtypes remain unclear. This European Network for the Study of Adrenal Tumours (ENSAT) multicentre study examines the differences not only in outcomes but also in the clinical management of patients with different ACC subtypes.
Patients and methods
Patient characteristics and survival data were retrospectively collected and analysed using Kaplan–Meier, multivariate Cox regression, and matched propensity score analyses (1 : 3 ratio) to compare recurrence-free survival (RFS) and overall survival (OS) for each subtype against conventional ACC. RFS was investigated only in patients after R0 resection, whereas OS was evaluated in the whole cohort. Matching was done for sex, age, and ENSAT tumour stage.
Results
The study included 1098 conventional, 179 oncocytic, 28 myxoid, and 10 sarcomatoid ACCs. RFS (in 653 conventional, 127 oncocytic, 15 myxoid, and 6 sarcomatoid ACCs) and OS (in all patients) were significantly longer in oncocytic ACC compared with the other groups, which was confirmed by multivariate Cox regression analyses {hazard ratio (HR) for RFS using conventional ACC as reference: oncocytic 0.47 [95% confidence interval (CI) 0.34-0.66], myxoid 0.92 (0.49-1.71), and sarcomatoid 0.83 (0.13-2.13) and for OS: oncocytic 0.37 (0.22-0.61), myxoid 1.02 (0.50-2.1), and sarcomatoid 0.82 (0.11-5.94)}. Similar results were seen after propensity score matching. RFS and OS were significantly longer in oncocytic ACC compared with the matched conventional ACC (RFS HR 0.41, 95% CI 0.29-0.55, P < 0.001; OS HR 0.35, 95% CI 0.24-0.52, P < 0.001).In metastatic oncocytic ACC, mitotane was similarly effective as in conventional tumours, but platinum-based chemotherapy seemed to result in longer progression-free survival.
Conclusion
Stage-adjusted outcome in oncocytic ACC is better than in other subtypes.
2022年，世界卫生组织（WHO）将肾上腺皮质癌（ACC）分为四种亚型：常规型、嗜瘤型、黏液型和肉瘤样。这些亚型之间的预后差异尚不清楚。这项欧洲肾上腺肿瘤研究网络（ENSAT）多中心研究不仅考察了不同ACC亚型患者的预后差异，还考察了不同亚型患者的临床管理差异。患者和方法回顾性收集患者特征和生存数据，并使用Kaplan-Meier、多变量Cox回归和匹配倾向评分分析（1:3比）进行分析，比较各亚型与常规ACC的无复发生存期（RFS）和总生存期（OS）。RFS仅在R0切除后的患者中进行研究，而OS在整个队列中进行评估。性别、年龄和ENSAT肿瘤分期进行匹配。结果纳入1098例常规acc， 179例嗜瘤细胞acc， 28例黏液样acc， 10例肉瘤样acc。在653例常规ACC、127例癌性ACC、15例黏液性ACC和6例肉瘤样ACC中，癌性ACC的RFS（所有患者）和OS（所有患者）明显较其他组更长，多因素Cox回归分析证实了这一点。以常规ACC为参照，RFS的风险比（HR）为：癌性ACC 0.47[95%可信区间（CI） 0.34-0.66]、黏液性ACC 0.92（0.49-1.71）、肉瘤样ACC 0.83 (0.13-2.13), OS：嗜瘤细胞0.37(0.22-0.61)，黏液样1.02(0.50-2.1)，肉瘤样0.82（0.11-5.94）。倾向评分匹配后也看到了类似的结果。与匹配的常规ACC相比，嗜瘤细胞ACC的RFS和OS明显更长（RFS HR 0.41, 95% CI 0.29-0.55, P < 0.001; OS HR 0.35, 95% CI 0.24-0.52, P < 0.001）。在转移性癌细胞性ACC中，米托坦与常规肿瘤相似，但基于铂的化疗似乎导致更长的无进展生存期。结论癌细胞型ACC分期调整预后优于其他亚型。
{"title":"Current clinical management and outcome of patients with adrenal cortical carcinoma (ACC) with rare histological subtypes—an ENSAT cohort study","authors":"O. Kimpel , D. Cosentini , A. Calabrese , A. Jouinot , B. Altieri , S. Kircher , G. Di Dalmazi , Y.S. Elhassan , D. Vassiliadi , K. Chrysoula , S. Puglisi , K. Coscia , N.V. Gallego , P. Loli , M. Boudina , M. Lagana , V. Cremaschi , D. Pignatelli , E. Rios , C.A. Villavicencio , M. Fassnacht","doi":"10.1016/j.esmoop.2026.106092","DOIUrl":"10.1016/j.esmoop.2026.106092","url":null,"abstract":"<div><h3>Background</h3><div>In 2022, the World Health Organization (WHO) classified adrenal cortical carcinoma (ACC) into four subtypes: conventional, oncocytic, myxoid, and sarcomatoid. The differences in prognosis among these subtypes remain unclear. This European Network for the Study of Adrenal Tumours (ENSAT) multicentre study examines the differences not only in outcomes but also in the clinical management of patients with different ACC subtypes.</div></div><div><h3>Patients and methods</h3><div>Patient characteristics and survival data were retrospectively collected and analysed using Kaplan–Meier, multivariate Cox regression, and matched propensity score analyses (1 : 3 ratio) to compare recurrence-free survival (RFS) and overall survival (OS) for each subtype against conventional ACC. RFS was investigated only in patients after R0 resection, whereas OS was evaluated in the whole cohort. Matching was done for sex, age, and ENSAT tumour stage.</div></div><div><h3>Results</h3><div>The study included 1098 conventional, 179 oncocytic, 28 myxoid, and 10 sarcomatoid ACCs. RFS (in 653 conventional, 127 oncocytic, 15 myxoid, and 6 sarcomatoid ACCs) and OS (in all patients) were significantly longer in oncocytic ACC compared with the other groups, which was confirmed by multivariate Cox regression analyses {hazard ratio (HR) for RFS using conventional ACC as reference: oncocytic 0.47 [95% confidence interval (CI) 0.34-0.66], myxoid 0.92 (0.49-1.71), and sarcomatoid 0.83 (0.13-2.13) and for OS: oncocytic 0.37 (0.22-0.61), myxoid 1.02 (0.50-2.1), and sarcomatoid 0.82 (0.11-5.94)}. Similar results were seen after propensity score matching. RFS and OS were significantly longer in oncocytic ACC compared with the matched conventional ACC (RFS HR 0.41, 95% CI 0.29-0.55, <em>P</em> < 0.001; OS HR 0.35, 95% CI 0.24-0.52, <em>P</em> < 0.001).In metastatic oncocytic ACC, mitotane was similarly effective as in conventional tumours, but platinum-based chemotherapy seemed to result in longer progression-free survival.</div></div><div><h3>Conclusion</h3><div>Stage-adjusted outcome in oncocytic ACC is better than in other subtypes.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"11 3","pages":"Article 106092"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147385973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01DOI: 10.1016/j.esmoop.2026.106087
L. Paracchini , A. Velle , P. Di Gennaro , L. Mannarino , L. Ancona , D. Lorusso , S.C. Cecere , N. Colombo , L. Beltrame , A. Fagotti , G. Tasca , M. Piemontese , L. Arenare , D. Califano , F. Galdiero , R. Zadro , P. Chiodini , F. Perrone , E. Biagioli , M. D’Incalci , S. Marchini
Background
Advanced-stage epithelial ovarian cancer (EOC) remains a therapeutic challenge due to high relapse rates and limited survival, while standard post-surgical parameters such as residual tumor (RT) incompletely capture minimal residual disease (MRD) and offer limited insight into tumor evolution. To address this gap, we investigated whether a multimodal, tumor-agnostic analysis of circulating tumor DNA (ctDNA)—integrating tumor fraction (TF) and genome-wide fragmentomic profiles (PF)—could refine early risk stratification after cytoreductive surgery and enable longitudinal monitoring during therapy.
Materials and methods
A total of 393 plasma samples from 173 patients in the phase IV MITO16a/MaNGO-OV2a trial were analyzed by shallow whole-genome sequencing at three time points: post-surgery/pre-chemotherapy (B1), post-chemotherapy (B2), and at the end of maintenance therapy or upon disease progression during maintenance (B3). Associations with progression-free survival (PFS) and overall survival (OS) were assessed using multivariable Cox models adjusted for clinical covariates.
Results
TF was detectable in 97% of patients at B1, including those classified as optimally debulked, and outperformed established clinical covariates in predicting survival [PFS: hazard ratio (HR) 1.02, P = 0.008; OS: HR 1.04, P = 0.005]. PF provided independent prognostic values (PFS: HR 1.06, P = 0.010; OS: HR 1.10, P = 0.005), and combined TF/PF modeling identified subgroups with distinct survival trajectories beyond clinical predictors (PFS: HR 1.76, P = 0.015; OS: HR 2.06, P = 0.029). Longitudinal copy number profiling revealed dynamic remodeling under treatment pressure, with recurrent 19q13.42 amplification emerging at B2 and B3.
Conclusions
Together, these findings establish multimodal ctDNA profiling as a sensitive, non-invasive strategy for MRD detection and longitudinal surveillance in advanced EOC, refining prognostic assessment beyond clinical and surgical factors while paving the way for precision-guided therapeutic management.
背景：晚期上皮性卵巢癌（EOC）由于高复发率和有限的生存期仍然是一个治疗挑战，而标准的术后参数，如残余肿瘤（RT）不能完全捕获最小残留疾病（MRD），并且对肿瘤演变的了解有限。为了解决这一差距，我们研究了循环肿瘤DNA （ctDNA）的多模式、肿瘤不确定分析——整合肿瘤分数（TF）和全基因组片段组谱（PF）——是否可以改进细胞减少手术后的早期风险分层，并在治疗期间进行纵向监测。材料和方法：通过浅全基因组测序分析来自173名IV期MITO16a/MaNGO-OV2a试验患者的393份血浆样本，在三个时间点：手术后/化疗前（B1）、化疗后（B2）、维持治疗结束或维持期间疾病进展（B3）。使用经临床协变量调整的多变量Cox模型评估与无进展生存期（PFS）和总生存期（OS）的关系。结果：97%的B1级患者可检测到TF，包括那些被分类为最佳减体积的患者，并且在预测生存方面优于已建立的临床协变量[PFS：风险比（HR） 1.02, P = 0.008；Os: hr 1.04, p = 0.005]。PF提供了独立的预后值（PFS: HR 1.06, P = 0.010; OS: HR 1.10, P = 0.005），联合TF/PF模型确定了超越临床预测因子的不同生存轨迹的亚组（PFS: HR 1.76, P = 0.015; OS: HR 2.06, P = 0.029）。纵向拷贝数分析显示在处理压力下动态重构，在B2和B3处出现19q13.42重复扩增。总之，这些发现确立了多模态ctDNA分析作为一种敏感、无创的MRD检测和晚期EOC纵向监测策略，在临床和手术因素之外改进预后评估，同时为精确指导治疗管理铺平道路。
{"title":"Multimodal tumor-agnostic ctDNA analysis for minimal residual disease detection and risk stratification in ovarian cancer: results from the MITO16a/MaNGO-OV2 trial","authors":"L. Paracchini , A. Velle , P. Di Gennaro , L. Mannarino , L. Ancona , D. Lorusso , S.C. Cecere , N. Colombo , L. Beltrame , A. Fagotti , G. Tasca , M. Piemontese , L. Arenare , D. Califano , F. Galdiero , R. Zadro , P. Chiodini , F. Perrone , E. Biagioli , M. D’Incalci , S. Marchini","doi":"10.1016/j.esmoop.2026.106087","DOIUrl":"10.1016/j.esmoop.2026.106087","url":null,"abstract":"<div><h3>Background</h3><div>Advanced-stage epithelial ovarian cancer (EOC) remains a therapeutic challenge due to high relapse rates and limited survival, while standard post-surgical parameters such as residual tumor (RT) incompletely capture minimal residual disease (MRD) and offer limited insight into tumor evolution. To address this gap, we investigated whether a multimodal, tumor-agnostic analysis of circulating tumor DNA (ctDNA)—integrating tumor fraction (TF) and genome-wide fragmentomic profiles (PF)—could refine early risk stratification after cytoreductive surgery and enable longitudinal monitoring during therapy.</div></div><div><h3>Materials and methods</h3><div>A total of 393 plasma samples from 173 patients in the phase IV MITO16a/MaNGO-OV2a trial were analyzed by shallow whole-genome sequencing at three time points: post-surgery/pre-chemotherapy (B1), post-chemotherapy (B2), and at the end of maintenance therapy or upon disease progression during maintenance (B3). Associations with progression-free survival (PFS) and overall survival (OS) were assessed using multivariable Cox models adjusted for clinical covariates.</div></div><div><h3>Results</h3><div>TF was detectable in 97% of patients at B1, including those classified as optimally debulked, and outperformed established clinical covariates in predicting survival [PFS: hazard ratio (HR) 1.02, <em>P</em> = 0.008; OS: HR 1.04, <em>P</em> = 0.005]. PF provided independent prognostic values (PFS: HR 1.06, <em>P</em> = 0.010; OS: HR 1.10, <em>P</em> = 0.005), and combined TF/PF modeling identified subgroups with distinct survival trajectories beyond clinical predictors (PFS: HR 1.76, <em>P</em> = 0.015; OS: HR 2.06, <em>P</em> = 0.029). Longitudinal copy number profiling revealed dynamic remodeling under treatment pressure, with recurrent 19q13.42 amplification emerging at B2 and B3.</div></div><div><h3>Conclusions</h3><div>Together, these findings establish multimodal ctDNA profiling as a sensitive, non-invasive strategy for MRD detection and longitudinal surveillance in advanced EOC, refining prognostic assessment beyond clinical and surgical factors while paving the way for precision-guided therapeutic management.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"11 3","pages":"Article 106087"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147303719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-10DOI: 10.1016/j.esmoop.2026.106067
A. Grinshpun , D. Dustin , M. Cai , M. Hughes , M. DiLullo , M. Moore , D. Yardley , I.A. Mayer , W.F. Symmans , E.L. Mayer , E.P. Winer , N.U. Lin , S.M. Tolaney , O. Metzger , R. Jeselsohn
Background
Neoadjuvant endocrine therapy (NET) is used in hormone receptor (HR)-positive, HER2-negative breast cancer to reduce tumor burden before surgery. However, robust biomarkers to predict benefit from NET are lacking.
Patients and methods
We evaluated the potential of circulating tumor DNA (ctDNA) before treatment and the dynamics during NET to guide treatment decisions for patients receiving NET. In this retrospective analysis, ctDNA before and after NET from patients enrolled in the phase II PELOPS trial, was assessed using the tissue-free Guardant Reveal assay.
Results
ctDNA was detected at the pre-NET timepoint in 37.5% of patients (18/48) and 13.6% (6/44) of patients following NET. Pre-NET ctDNA detection was associated with higher pathological stage and higher residual cancer burden scores after NET. Patients with persistent ctDNA detected pre-surgery had a higher risk of distant recurrence.
Conclusions
Taken together, these results support the potential of ctDNA to predict tumor burden before surgery after NET and provide insights into long-term prognosis.
{"title":"Circulating tumor DNA in neoadjuvant endocrine therapy for early breast cancer","authors":"A. Grinshpun , D. Dustin , M. Cai , M. Hughes , M. DiLullo , M. Moore , D. Yardley , I.A. Mayer , W.F. Symmans , E.L. Mayer , E.P. Winer , N.U. Lin , S.M. Tolaney , O. Metzger , R. Jeselsohn","doi":"10.1016/j.esmoop.2026.106067","DOIUrl":"10.1016/j.esmoop.2026.106067","url":null,"abstract":"<div><h3>Background</h3><div>Neoadjuvant endocrine therapy (NET) is used in hormone receptor (HR)-positive, HER2-negative breast cancer to reduce tumor burden before surgery. However, robust biomarkers to predict benefit from NET are lacking.</div></div><div><h3>Patients and methods</h3><div>We evaluated the potential of circulating tumor DNA (ctDNA) before treatment and the dynamics during NET to guide treatment decisions for patients receiving NET. In this retrospective analysis, ctDNA before and after NET from patients enrolled in the phase II PELOPS trial, was assessed using the tissue-free Guardant Reveal assay.</div></div><div><h3>Results</h3><div>ctDNA was detected at the pre-NET timepoint in 37.5% of patients (18/48) and 13.6% (6/44) of patients following NET. Pre-NET ctDNA detection was associated with higher pathological stage and higher residual cancer burden scores after NET. Patients with persistent ctDNA detected pre-surgery had a higher risk of distant recurrence.</div></div><div><h3>Conclusions</h3><div>Taken together, these results support the potential of ctDNA to predict tumor burden before surgery after NET and provide insights into long-term prognosis.</div></div><div><h3>Clinical trial number</h3><div>ClinicalTrials.gov <span><span>NCT02764541</span><svg><path></path></svg></span></div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"11 3","pages":"Article 106067"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01DOI: 10.1016/j.esmoop.2025.106043
T. Macarulla , R.Pazo Cid , M.S. Womack (4th) , A. Cubillo Gracian , A. Zervoudakis , H. Hatoum , V. Chung , A. Patel , A.S. Paulson , S. Pant , E.M. O’Reilly , R.A. Hubner , E. Van Cutsem , T. Bekaii-Saab , L. Zhang , J. Li , H. Chen , F. Maxwell , Z.A. Wainberg , D. Melisi
Background
The phase III NAPOLI 3 trial established liposomal irinotecan in combination with 5-fluorouracil/leucovorin plus oxaliplatin (NALIRIFOX) as a superior first-line (1L) treatment option compared with gemcitabine plus nab-paclitaxel (Gem + NabP) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC), without imposing an upper age limit on enrollment. The current analysis of the NAPOLI 3 data investigated the potential impact of older age on the efficacy and safety of NALIRIFOX.
Patients and methods
Adults with previously untreated mPDAC were randomly assigned in a 1 : 1 ratio to receive NALIRIFOX or Gem + NabP. This post hoc analysis compared outcomes for patients aged ≥70 years versus <70 years. Endpoints included overall survival (OS), progression-free survival (PFS), and safety. No statistical comparison was carried out.
Results
Of the 770 patients in the NAPOLI 3 population, 553 were aged <70 years and 217 were aged ≥70 years. Median OS and median PFS with NALIRIFOX were 11.7 months and 7.4 months, respectively, in the <70 years subgroup (n = 275) and 10.0 months and 7.3 months, respectively, in the ≥70 years subgroup (n = 108). The benefit of NALIRIFOX versus Gem + NabP was preserved in the older versus younger subgroup. There was no evidence of increased treatment-related toxicity in the older (versus younger) subgroup.
Conclusions
NALIRIFOX improved mPDAC survival versus Gem + NabP irrespective of patient age, with no signals for reduced tolerability in the older (versus younger) patients. The results provide reassurance that triplet therapy with NALIRIFOX is an efficacious and tolerable regimen in older treatment-naive patients with mPDAC who were fit enough for inclusion in NAPOLI 3, supporting consideration of its use as 1L therapy in this population.
{"title":"NALIRIFOX versus nab-paclitaxel and gemcitabine in older patients with treatment-naive metastatic pancreatic cancer: a subgroup analysis of the pivotal NAPOLI 3 trial","authors":"T. Macarulla , R.Pazo Cid , M.S. Womack (4th) , A. Cubillo Gracian , A. Zervoudakis , H. Hatoum , V. Chung , A. Patel , A.S. Paulson , S. Pant , E.M. O’Reilly , R.A. Hubner , E. Van Cutsem , T. Bekaii-Saab , L. Zhang , J. Li , H. Chen , F. Maxwell , Z.A. Wainberg , D. Melisi","doi":"10.1016/j.esmoop.2025.106043","DOIUrl":"10.1016/j.esmoop.2025.106043","url":null,"abstract":"<div><h3>Background</h3><div>The phase III NAPOLI 3 trial established liposomal irinotecan in combination with 5-fluorouracil/leucovorin plus oxaliplatin (NALIRIFOX) as a superior first-line (1L) treatment option compared with gemcitabine plus nab-paclitaxel (Gem + NabP) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC), without imposing an upper age limit on enrollment. The current analysis of the NAPOLI 3 data investigated the potential impact of older age on the efficacy and safety of NALIRIFOX.</div></div><div><h3>Patients and methods</h3><div>Adults with previously untreated mPDAC were randomly assigned in a 1 : 1 ratio to receive NALIRIFOX or Gem + NabP. This <em>post hoc</em> analysis compared outcomes for patients aged ≥70 years versus <70 years. Endpoints included overall survival (OS), progression-free survival (PFS), and safety. No statistical comparison was carried out.</div></div><div><h3>Results</h3><div>Of the 770 patients in the NAPOLI 3 population, 553 were aged <70 years and 217 were aged ≥70 years. Median OS and median PFS with NALIRIFOX were 11.7 months and 7.4 months, respectively, in the <70 years subgroup (<em>n</em> = 275) and 10.0 months and 7.3 months, respectively, in the ≥70 years subgroup (<em>n</em> = 108). The benefit of NALIRIFOX versus Gem + NabP was preserved in the older versus younger subgroup. There was no evidence of increased treatment-related toxicity in the older (versus younger) subgroup.</div></div><div><h3>Conclusions</h3><div>NALIRIFOX improved mPDAC survival versus Gem + NabP irrespective of patient age, with no signals for reduced tolerability in the older (versus younger) patients. The results provide reassurance that triplet therapy with NALIRIFOX is an efficacious and tolerable regimen in older treatment-naive patients with mPDAC who were fit enough for inclusion in NAPOLI 3, supporting consideration of its use as 1L therapy in this population.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"11 3","pages":"Article 106043"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146194391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01DOI: 10.1016/j.esmoop.2026.106076
E.S.M. van Aken , S.M. O’Cathail , A.K. Gandhi , J. Bussink , L. Castelo-Branco , J.G. Eriksen , G. Argilés , C.T. Hiley , V. Atkinson , J. Kaźmierska , A. Calles , K. Konopa , E. Le Rhun , F. McDonald , G. Mountzios , P.M. Putora , B. Muoio , U. Ricardi , C.B. Westphalen , A. Wrona , A. Prelaj
Background
Combining radiotherapy (RT) with targeted agents may lead to improved treatment outcomes across various tumor types. However, there is a risk of increased toxicity. Unfortunately, high-quality toxicity data are scarce, contributing to a lack of evidence-based guidelines.
Design
ESMO and ESTRO launched a series of systematic literature reviews and evidence-based, multidisciplinary Delphi consensus recommendations on the safety of combining RT with targeted agents. The current paper addresses the safety of combining EGFR, ALK, and BRAF/MEK inhibitors with RT, regardless of (solid) tumor histology. During the two Delphi consensus rounds with 19 international experts, 57 clinical scenarios were evaluated by systematically covering different drug classes and irradiated areas. Based on the systematic literature reviews, safety statements were developed for all scenarios.
Results
During the systematic literature review process for EGFR, ALK, and BRAF/MEK inhibitors, 2745 records were screened, and 110 reports were included in the final literature reviews and the database. Over the course of the subsequent Delphi consensus rounds, agreement was reached on all 57 scenario-specific safety statements.
Conclusions
For most scenarios, concurrently combining RT with targeted agents may lead to increased toxicity. Therefore, we recommend a drug interruption, a drug dosage reduction, or a major RT adaptation in various scenarios.
{"title":"ESMO-ESTRO consensus statements on the safety of combining radiotherapy with EGFR, ALK, or BRAF/MEK inhibitors","authors":"E.S.M. van Aken , S.M. O’Cathail , A.K. Gandhi , J. Bussink , L. Castelo-Branco , J.G. Eriksen , G. Argilés , C.T. Hiley , V. Atkinson , J. Kaźmierska , A. Calles , K. Konopa , E. Le Rhun , F. McDonald , G. Mountzios , P.M. Putora , B. Muoio , U. Ricardi , C.B. Westphalen , A. Wrona , A. Prelaj","doi":"10.1016/j.esmoop.2026.106076","DOIUrl":"10.1016/j.esmoop.2026.106076","url":null,"abstract":"<div><h3>Background</h3><div>Combining radiotherapy (RT) with targeted agents may lead to improved treatment outcomes across various tumor types. However, there is a risk of increased toxicity. Unfortunately, high-quality toxicity data are scarce, contributing to a lack of evidence-based guidelines.</div></div><div><h3>Design</h3><div>ESMO and ESTRO launched a series of systematic literature reviews and evidence-based, multidisciplinary Delphi consensus recommendations on the safety of combining RT with targeted agents. The current paper addresses the safety of combining EGFR, ALK, and BRAF/MEK inhibitors with RT, regardless of (solid) tumor histology. During the two Delphi consensus rounds with 19 international experts, 57 clinical scenarios were evaluated by systematically covering different drug classes and irradiated areas. Based on the systematic literature reviews, safety statements were developed for all scenarios.</div></div><div><h3>Results</h3><div>During the systematic literature review process for EGFR, ALK, and BRAF/MEK inhibitors, 2745 records were screened, and 110 reports were included in the final literature reviews and the database. Over the course of the subsequent Delphi consensus rounds, agreement was reached on all 57 scenario-specific safety statements.</div></div><div><h3>Conclusions</h3><div>For most scenarios, concurrently combining RT with targeted agents may lead to increased toxicity. Therefore, we recommend a drug interruption, a drug dosage reduction, or a major RT adaptation in various scenarios.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"11 3","pages":"Article 106076"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01DOI: 10.1016/j.esmoop.2026.106088
Y. Komatsu , N. Taira , Y. Kurokawa , Y. Honma , A. Sawaki , Y. Naito , S. Iwagami , T. Takahashi , Y. Hirano , Y. Tanaka , T. Nishida , T. Doi
Background
Health-related quality of life (HRQoL) has emerged as an important outcome following the introduction of tyrosine kinase inhibitors for metastatic gastrointestinal stromal tumors (GISTs). We report the HRQoL results from the randomized, placebo-controlled, phase III CHAPTER-GIST-301 study evaluating pimitespib as fourth-line therapy for metastatic GIST.
Patients and methods
HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (EORTC QLQ-C30) v3.0 and EuroQol Five Dimensions Questionnaire-5L (EQ-5D-5L) at baseline and scheduled study visits during the blinded period. Between-group change from baseline scores were compared using a mixed model repeated measure model. The percentage of patients with a clinically meaningful deterioration (≥10 point change from baseline) in HRQoL was calculated for each EORTC QLQ-C30 item. Time to deterioration (TTD) was calculated using the Kaplan–Meier method.
Results
Overall, 86 patients were randomized to receive pimitespib (n = 58) or placebo (n = 28) in the CHAPTER-GIST-301 study. Compliance across all HRQoL questionnaires exceeded 80% by week 18. Least-squares mean changes from baseline were generally similar between pimitespib and placebo treatment groups, with the exception of diarrhea and appetite loss. Items associated with a ≥10 point difference in EORTC QLQ-C30 were diarrhea (hazard ratio 4.82, 95% confidence interval 2.17-10.71), with almost no difference in other items.
Conclusion
Pimitespib as a new treatment option in the fourth-line setting did not negatively impact HRQoL overall, with the exception of diarrhea and appetite loss, in patients with metastatic GIST.
{"title":"Quality-of-life outcomes with pimitespib in patients with advanced gastrointestinal stromal tumor: results from the randomized, double-blind, placebo-controlled, phase III, CHAPTER-GIST-301 study","authors":"Y. Komatsu , N. Taira , Y. Kurokawa , Y. Honma , A. Sawaki , Y. Naito , S. Iwagami , T. Takahashi , Y. Hirano , Y. Tanaka , T. Nishida , T. Doi","doi":"10.1016/j.esmoop.2026.106088","DOIUrl":"10.1016/j.esmoop.2026.106088","url":null,"abstract":"<div><h3>Background</h3><div>Health-related quality of life (HRQoL) has emerged as an important outcome following the introduction of tyrosine kinase inhibitors for metastatic gastrointestinal stromal tumors (GISTs). We report the HRQoL results from the randomized, placebo-controlled, phase III CHAPTER-GIST-301 study evaluating pimitespib as fourth-line therapy for metastatic GIST.</div></div><div><h3>Patients and methods</h3><div>HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (EORTC QLQ-C30) v3.0 and EuroQol Five Dimensions Questionnaire-5L (EQ-5D-5L) at baseline and scheduled study visits during the blinded period. Between-group change from baseline scores were compared using a mixed model repeated measure model. The percentage of patients with a clinically meaningful deterioration (≥10 point change from baseline) in HRQoL was calculated for each EORTC QLQ-C30 item. Time to deterioration (TTD) was calculated using the Kaplan–Meier method.</div></div><div><h3>Results</h3><div>Overall, 86 patients were randomized to receive pimitespib (<em>n</em> = 58) or placebo (<em>n</em> = 28) in the CHAPTER-GIST-301 study. Compliance across all HRQoL questionnaires exceeded 80% by week 18. Least-squares mean changes from baseline were generally similar between pimitespib and placebo treatment groups, with the exception of diarrhea and appetite loss. Items associated with a ≥10 point difference in EORTC QLQ-C30 were diarrhea (hazard ratio 4.82, 95% confidence interval 2.17-10.71), with almost no difference in other items.</div></div><div><h3>Conclusion</h3><div>Pimitespib as a new treatment option in the fourth-line setting did not negatively impact HRQoL overall, with the exception of diarrhea and appetite loss, in patients with metastatic GIST.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"11 3","pages":"Article 106088"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147364184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-03-10DOI: 10.1016/j.esmoop.2026.106305
F. Tettamanzi , C. De Carlo , C. Cappadona , D. Giuliano , V. Rimoldi , C. Piombo , L.G. Cecchi , S. Zanella , G. Marulli , E. Voulaz , G. Veronesi , S. Marchini , L. Di Tommaso , P.A. Zucali , R. Asselta
Background
Thymic carcinoma (TC) is a rare and aggressive neoplasm of thymic epithelial origin, with no currently available biomarkers to guide treatment or prognosis. In this study, we aimed at characterizing the genomic landscape of a cohort of TCs, at somatic and germline levels.
Materials and methods
Whole-exome sequencing was carried out on 25 TC archival samples and 17 histologically normal adjacent tissues. Genomic characteristics and their association with clinical outcomes were assessed.
Results
High tumor mutational burden (TMB) and microsatellite instability were present in 8% and ∼30% of the study cohort. Somatic mutations in 20 core genes of DNA damage response (DDR) were associated with high TMB (P = 0.005) and worse overall survival (OS) [hazard ratio 5.05 (95% confidence interval 1.49-17.20), P = 0.010]. Putative pathogenic variants in the core DDR genes were frequently detected in the germline as well (35%). Among somatic alterations, driver genes included POLE, MTOR, and ATR (12%). Notably, ∼30% of patients harbored mutations matching biomarkers of response to currently available therapies such as poly (ADP-ribose) polymerase inhibitors. Somatic copy number profiles were heterogeneous; however, several amplification and deletion events were identified as recurrent across tumors.
Conclusions
TC appears to be a heterogeneous disease, exhibiting varying genomic alteration rates. Several somatic and germline aberrations, some of which have been reported in this article for the first time, warrant further investigation for their hinted prognostic value and clinical implications.
{"title":"Somatic and germline genomic variation in thymic carcinomas","authors":"F. Tettamanzi , C. De Carlo , C. Cappadona , D. Giuliano , V. Rimoldi , C. Piombo , L.G. Cecchi , S. Zanella , G. Marulli , E. Voulaz , G. Veronesi , S. Marchini , L. Di Tommaso , P.A. Zucali , R. Asselta","doi":"10.1016/j.esmoop.2026.106305","DOIUrl":"10.1016/j.esmoop.2026.106305","url":null,"abstract":"<div><h3>Background</h3><div>Thymic carcinoma (TC) is a rare and aggressive neoplasm of thymic epithelial origin, with no currently available biomarkers to guide treatment or prognosis. In this study, we aimed at characterizing the genomic landscape of a cohort of TCs, at somatic and germline levels.</div></div><div><h3>Materials and methods</h3><div>Whole-exome sequencing was carried out on 25 TC archival samples and 17 histologically normal adjacent tissues. Genomic characteristics and their association with clinical outcomes were assessed.</div></div><div><h3>Results</h3><div>High tumor mutational burden (TMB) and microsatellite instability were present in 8% and ∼30% of the study cohort. Somatic mutations in 20 core genes of DNA damage response (DDR) were associated with high TMB (<em>P</em> = 0.005) and worse overall survival (OS) [hazard ratio 5.05 (95% confidence interval 1.49-17.20), <em>P</em> = 0.010]. Putative pathogenic variants in the core DDR genes were frequently detected in the germline as well (35%). Among somatic alterations, driver genes included <em>POLE</em>, <em>MTOR</em>, and <em>ATR</em> (12%). Notably, ∼30% of patients harbored mutations matching biomarkers of response to currently available therapies such as poly (ADP-ribose) polymerase inhibitors. Somatic copy number profiles were heterogeneous; however, several amplification and deletion events were identified as recurrent across tumors.</div></div><div><h3>Conclusions</h3><div>TC appears to be a heterogeneous disease, exhibiting varying genomic alteration rates. Several somatic and germline aberrations, some of which have been reported in this article for the first time, warrant further investigation for their hinted prognostic value and clinical implications.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"11 3","pages":"Article 106305"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147386287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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