Pub Date : 2025-01-27DOI: 10.1016/j.ejca.2025.115263
Josephine G.M. Strijker , Guillem Pascual-Pasto , Grant P. Grothusen , Yannine J. Kalmeijer , Elisavet Kalaitsidou , Chunlong Zhao , Brendan McIntyre , Stephanie Matlaga , Lindy L. Visser , Marta Barisa , Courtney Himsworth , Rivani Shah , Henrike Muller , Linda G. Schild , Peter G. Hains , Qing Zhong , Roger R. Reddel , Phillip J. Robinson , Xavier Catena , María S. Soengas , Judith Wienke
Introduction
Chimeric antigen receptor (CAR) T-cell therapy is a promising and innovative cancer therapy. However, immunosuppressive tumor microenvironments (TME) limit T cell persistence and durable efficacy. Here, we aimed to identify and target immunosuppressive factors in the TME of neuroblastoma, a pediatric extracranial solid tumor, to improve CAR-T efficacy.
Methods
Immunosuppressive factors were identified using a multi-omics approach, including single-cell RNA sequencing (scRNA-seq) of 24 neuroblastoma tumors, published bulk-RNA sequencing datasets, and mass-spectrometry of patient-derived tumoroid models. Candidate targets were validated with functional assays in vitro and in vivo. Protein degradation of the top immunosuppressive target by PROTAC technology was used to evaluate the effect on CAR T-cell activity.
Results
ScRNA-seq revealed 13 immunosuppressive interactions in the TME of neuroblastoma, two effectors of which, Midkine (MDK) and Macrophage Migration Inhibitory Factor (MIF), were validated as candidate targets across multiple published datasets. Both factors were among the top 6 % of most abundantly secreted factors by patient-derived tumoroid models, substantiating their potential relevance in the TME. In vitro and in vivo functional assays confirmed MIF to be a potent inhibitor of CAR T-cell activation and killing capacity. To translate these findings into a potentially clinically applicable treatment, we explored MIF targeting by PROTAC technology, which significantly enhanced activation of CAR T-cells targeting GPC2 and B7-H3.
Conclusion
By defining the immunosuppressive effects of neuroblastoma’s TME on CAR T-cell efficacy, revealing the pivotal role of MIF, we provide an analytic pipeline and therapeutic strategy for improving adoptive cell therapies for this pediatric malignancy and potentially other solid tumors.
{"title":"Blocking MIF secretion enhances CAR T-cell efficacy against neuroblastoma","authors":"Josephine G.M. Strijker , Guillem Pascual-Pasto , Grant P. Grothusen , Yannine J. Kalmeijer , Elisavet Kalaitsidou , Chunlong Zhao , Brendan McIntyre , Stephanie Matlaga , Lindy L. Visser , Marta Barisa , Courtney Himsworth , Rivani Shah , Henrike Muller , Linda G. Schild , Peter G. Hains , Qing Zhong , Roger R. Reddel , Phillip J. Robinson , Xavier Catena , María S. Soengas , Judith Wienke","doi":"10.1016/j.ejca.2025.115263","DOIUrl":"10.1016/j.ejca.2025.115263","url":null,"abstract":"<div><h3>Introduction</h3><div>Chimeric antigen receptor (CAR) T-cell therapy is a promising and innovative cancer therapy. However, immunosuppressive tumor microenvironments (TME) limit T cell persistence and durable efficacy. Here, we aimed to identify and target immunosuppressive factors in the TME of neuroblastoma, a pediatric extracranial solid tumor, to improve CAR-T efficacy.</div></div><div><h3>Methods</h3><div>Immunosuppressive factors were identified using a multi-omics approach, including single-cell RNA sequencing (scRNA-seq) of 24 neuroblastoma tumors, published bulk-RNA sequencing datasets, and mass-spectrometry of patient-derived tumoroid models. Candidate targets were validated with functional assays <em>in vitro</em> and <em>in vivo</em>. Protein degradation of the top immunosuppressive target by PROTAC technology was used to evaluate the effect on CAR T-cell activity.</div></div><div><h3>Results</h3><div>ScRNA-seq revealed 13 immunosuppressive interactions in the TME of neuroblastoma, two effectors of which, Midkine (MDK) and Macrophage Migration Inhibitory Factor (MIF), were validated as candidate targets across multiple published datasets. Both factors were among the top 6 % of most abundantly secreted factors by patient-derived tumoroid models, substantiating their potential relevance in the TME. <em>In vitro</em> and <em>in vivo</em> functional assays confirmed MIF to be a potent inhibitor of CAR T-cell activation and killing capacity. To translate these findings into a potentially clinically applicable treatment, we explored MIF targeting by PROTAC technology, which significantly enhanced activation of CAR T-cells targeting GPC2 and B7-H3.</div></div><div><h3>Conclusion</h3><div>By defining the immunosuppressive effects of neuroblastoma’s TME on CAR T-cell efficacy, revealing the pivotal role of MIF, we provide an analytic pipeline and therapeutic strategy for improving adoptive cell therapies for this pediatric malignancy and potentially other solid tumors.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"218 ","pages":"Article 115263"},"PeriodicalIF":7.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143098572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.ejca.2025.115254
Jeremy Mo , Anne Zaremba , Andrisha-Jade Inderjeeth , Perla El Zeinaty , Ao Li , Alexandre Wicky , Nicholas Della Marta , Caroline Gaudy Marqueste , Ann-Sophie Bohne , Margarida Matias , Nicholas McNamee , Lucia Festino , Charley Chen , Sydney Ch’ng , Alexander C.J. van Akkooi , Laetitia Da Meda , John J. Park , Paolo A. Ascierto , Axel Hauschild , Jenny H. Lee , Ines Pires da Silva
Aim
Merkel Cell Carcinoma (MCC) is a rare skin cancer with a rising incidence worldwide. Anti-programmed death-1/ligand-1 (anti-PD-(L)1) therapies are effective for the treatment of advanced MCC. This study examines patterns of response / progression of advanced MCC to anti-PD-(L)1 therapies and describes subsequent management.
Method
This is a multi-centre international retrospective cohort study with data collected up to May 2023 from 17 centres across 6 countries. Outcomes included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) for anti-PD-(L)1 and subsequent therapy.
Results
One-hundred and eighty-five advanced MCC patients received anti-PD-(L)1 therapy. At median follow-up of 28.7 months (95 % CI: 21.4–38.3), ORR was 57.3 %, median DOR was 42.8 months (95 % CI, 25.8 – not reached (NR)), median PFS was 14 months (95 % CI, 8.1– 19.8), and median OS was 42.8 months (95 % CI, 30.3 – NR). One-hundred and eight patients (59 %) experienced progressive disease; 50 % (n = 54/108) with primary resistance and 26 % (n = 28/108) with secondary resistance. Fifty patients (27 %; n = 50/185) received subsequent systemic therapies (+/- local therapy) with response data; 18 (36 %; n = 18/50) received doublet platinum chemotherapy (ORR 67 %, DOR 5.0 months [95 % CI; 3.7 - NR]) and 16 (32 %; n = 16/50) were rechallenged with anti-PD-(L)1 (ORR 56 %, DOR 20.2 months [95 % CI; 8.3 - NR]).
Conclusion
The most common subsequent treatment for patients with primary resistance was chemotherapy, while those with secondary resistance most frequently underwent further anti-PD-(L)1 therapy in combination with other therapies. Despite both therapies demonstrating promising ORR, doublet platinum chemotherapy had a poorer DOR compared to anti-PD-(L)1 rechallenge.
{"title":"Clinical outcomes and management following progressive disease with anti-PD-(L)1 therapy in patients with advanced Merkel Cell Carcinoma","authors":"Jeremy Mo , Anne Zaremba , Andrisha-Jade Inderjeeth , Perla El Zeinaty , Ao Li , Alexandre Wicky , Nicholas Della Marta , Caroline Gaudy Marqueste , Ann-Sophie Bohne , Margarida Matias , Nicholas McNamee , Lucia Festino , Charley Chen , Sydney Ch’ng , Alexander C.J. van Akkooi , Laetitia Da Meda , John J. Park , Paolo A. Ascierto , Axel Hauschild , Jenny H. Lee , Ines Pires da Silva","doi":"10.1016/j.ejca.2025.115254","DOIUrl":"10.1016/j.ejca.2025.115254","url":null,"abstract":"<div><h3>Aim</h3><div>Merkel Cell Carcinoma (MCC) is a rare skin cancer with a rising incidence worldwide. Anti-programmed death-1/ligand-1 (anti-PD-(L)1) therapies are effective for the treatment of advanced MCC. This study examines patterns of response / progression of advanced MCC to anti-PD-(L)1 therapies and describes subsequent management.</div></div><div><h3>Method</h3><div>This is a multi-centre international retrospective cohort study with data collected up to May 2023 from 17 centres across 6 countries. Outcomes included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) for anti-PD-(L)1 and subsequent therapy.</div></div><div><h3>Results</h3><div>One-hundred and eighty-five advanced MCC patients received anti-PD-(L)1 therapy. At median follow-up of 28.7 months (95 % CI: 21.4–38.3), ORR was 57.3 %, median DOR was 42.8 months (95 % CI, 25.8 – not reached (NR)), median PFS was 14 months (95 % CI, 8.1– 19.8), and median OS was 42.8 months (95 % CI, 30.3 – NR). One-hundred and eight patients (59 %) experienced progressive disease; 50 % (n = 54/108) with primary resistance and 26 % (n = 28/108) with secondary resistance. Fifty patients (27 %; n = 50/185) received subsequent systemic therapies (+/- local therapy) with response data; 18 (36 %; n = 18/50) received doublet platinum chemotherapy (ORR 67 %, DOR 5.0 months [95 % CI; 3.7 - NR]) and 16 (32 %; n = 16/50) were rechallenged with anti-PD-(L)1 (ORR 56 %, DOR 20.2 months [95 % CI; 8.3 - NR]).</div></div><div><h3>Conclusion</h3><div>The most common subsequent treatment for patients with primary resistance was chemotherapy, while those with secondary resistance most frequently underwent further anti-PD-(L)1 therapy in combination with other therapies. Despite both therapies demonstrating promising ORR, doublet platinum chemotherapy had a poorer DOR compared to anti-PD-(L)1 rechallenge.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"217 ","pages":"Article 115254"},"PeriodicalIF":7.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oligometastatic disease in head and neck squamous cell carcinoma (HNSCC) is a rare setting. Local ablative therapies are the most adopted strategies although no evidence-based recommendations are currently published. We report on long-term clinical outcomes of a cohort of HNSCC patients treated with stereotactic body radiotherapy (SBRT) for lung-only oligometastatic disease. Material and Methods: Eligible patients had 1–5 lung metastases. The oligometastatic pattern was classified as “de novo” or “induced oligoprogressive”. We evaluated time to progression (TTP) as the time from the last day of SBRT to disease progression or death from any cause. Predictive factors of better clinical outcome and survival analysis were performed. Results: A cohort of 50 patients (52 metastases) was retrospectively evaluated. The median age was 68 years and 45 patients had an ECOG PS 0–1. Oropharynx cancer was the primary tumor subsite in 20 patients and HPV positive status was reported in 13 patients. “De novo” oligometastatic pattern was observed for the majority of patients. After a median follow up of 24,5 months, median TTP and overall survival (OS) from the end of SBRT were 17 months and 46 months, respectively. The 2-years LC rates was 86 %. At univariate analysis, patients aged > 70 years reported a better TTP (0.03). Conclusion: Our findings suggested that SBRT may improve clinical outcome prolonging time to progression in a properly selected cohort of HNSCC patients with lung-only oligometastatic disease. Distant metastases from HPV-related primary HNSCC should be tested for p16/HPV status.
{"title":"Stereotactic body radiotherapy for lung-only oligometastatic head and neck squamous cell carcinoma: Long-term clinical outcome and favorable predictive factors","authors":"Viola Salvestrini , Ilaria Bonaparte , Carlotta Becherini , Isacco Desideri , Saverio Caini , Annarita Palomba , Niccolò Bertini , Chiara Mattioli , Gabriele Simontacchi , Giulio Francolini , Daniela Greto , Mauro Loi , Vanessa Di Cataldo , Lorenzo Livi , Pierluigi Bonomo","doi":"10.1016/j.ejca.2025.115260","DOIUrl":"10.1016/j.ejca.2025.115260","url":null,"abstract":"<div><h3>Background</h3><div>Oligometastatic disease in head and neck squamous cell carcinoma (HNSCC) is a rare setting. Local ablative therapies are the most adopted strategies although no evidence-based recommendations are currently published. We report on long-term clinical outcomes of a cohort of HNSCC patients treated with stereotactic body radiotherapy (SBRT) for lung-only oligometastatic disease. <em>Material and Methods</em>: Eligible patients had 1–5 lung metastases. The oligometastatic pattern was classified as “de novo” or “induced oligoprogressive”. We evaluated time to progression (TTP) as the time from the last day of SBRT to disease progression or death from any cause. Predictive factors of better clinical outcome and survival analysis were performed. <em>Results</em>: A cohort of 50 patients (52 metastases) was retrospectively evaluated. The median age was 68 years and 45 patients had an ECOG PS 0–1. Oropharynx cancer was the primary tumor subsite in 20 patients and HPV positive status was reported in 13 patients. “De novo” oligometastatic pattern was observed for the majority of patients. After a median follow up of 24,5 months, median TTP and overall survival (OS) from the end of SBRT were 17 months and 46 months, respectively. The 2-years LC rates was 86 %. At univariate analysis, patients aged > 70 years reported a better TTP (0.03). <em>Conclusion</em>: Our findings suggested that SBRT may improve clinical outcome prolonging time to progression in a properly selected cohort of HNSCC patients with lung-only oligometastatic disease. Distant metastases from HPV-related primary HNSCC should be tested for p16/HPV status.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"218 ","pages":"Article 115260"},"PeriodicalIF":7.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143098574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.ejca.2025.115259
Annette Leibetseder , Maximilian J. Mair , Anika Simonovska Serra , Zoltan Spiro , Martin Aichholzer , Georg Widhalm , Franziska Eckert , Adelheid Wöhrer , Raimund Helbok , Serge Weis , Matthias Preusser , Josef Pichler , Anna Sophie Berghoff
Background
A significant proportion of women in reproductive age are diagnosed with diffuse gliomas, resulting in the need to address the safety of pregnancy in patient consultation. However, data on glioma progression after and during pregnancy are sparse and controversial.
Methods
Female adult patients in their reproductive years (≥18 years and <46 years) with histological diagnosis of glioma between 01/01/2000 and 01/12/2019 from 2 academic centers have been included in the study. Re-classification according to the 2021 WHO classification of CNS tumours was performed. The cohort was divided into 3 groups, defined as (A) nulliparae, (B) primi-/multiparae before glioma diagnosis, and (C) primi-/multiparae after glioma diagnosis. Survival analyses were performed in a time-dependent manner with parity as time-dependent covariate.
Results
159/368 females met our inclusion criteria, resulting in 47 (29.6 %) nulliparae, 88 (55.3 %) primi-/multiparae before glioma diagnosis and 24 (15.1 %) primi-/multiparae after glioma diagnosis. Median follow-up was 127.4 months (range 0.7–341.9), and median overall survival and progression free survival were 247.6 months (range 0.4–269.1) and 67.9 months (range 0.7–341.9), respectively. Overall, 113/159 (71.1 %) patients had tumour progression and 53/159 (33.3 %) deceased. In total, 57.4 % of the nullipara, 76.1 % of the primi-/multipara before glioma diagnosis and 79.1 % of the primi-/multipara after glioma diagnosis groups experienced tumour progression (p > 0.05). In multivariate time-dependent analysis, primi-/multiparae after glioma diagnosis presented with shorter progression free (HR 2.45, p = 0.0079), but not overall survival (HR 0.54, p > 0.05) in comparison to the other two groups.
Conclusion
Pregnancy after glioma diagnosis was associated with shorter progression free survival. Longer follow-up as well as larger cohorts are needed to investigate a potential impact on overall survival.
{"title":"Association of pregnancy with tumour progression in patients with glioma","authors":"Annette Leibetseder , Maximilian J. Mair , Anika Simonovska Serra , Zoltan Spiro , Martin Aichholzer , Georg Widhalm , Franziska Eckert , Adelheid Wöhrer , Raimund Helbok , Serge Weis , Matthias Preusser , Josef Pichler , Anna Sophie Berghoff","doi":"10.1016/j.ejca.2025.115259","DOIUrl":"10.1016/j.ejca.2025.115259","url":null,"abstract":"<div><h3>Background</h3><div>A significant proportion of women in reproductive age are diagnosed with diffuse gliomas, resulting in the need to address the safety of pregnancy in patient consultation. However, data on glioma progression after and during pregnancy are sparse and controversial.</div></div><div><h3>Methods</h3><div>Female adult patients in their reproductive years (≥18 years and <46 years) with histological diagnosis of glioma between 01/01/2000 and 01/12/2019 from 2 academic centers have been included in the study. Re-classification according to the 2021 WHO classification of CNS tumours was performed. The cohort was divided into 3 groups, defined as (A) nulliparae, (B) primi-/multiparae before glioma diagnosis, and (C) primi-/multiparae after glioma diagnosis. Survival analyses were performed in a time-dependent manner with parity as time-dependent covariate.</div></div><div><h3>Results</h3><div>159/368 females met our inclusion criteria, resulting in 47 (29.6 %) nulliparae, 88 (55.3 %) primi-/multiparae before glioma diagnosis and 24 (15.1 %) primi-/multiparae after glioma diagnosis. Median follow-up was 127.4 months (range 0.7–341.9), and median overall survival and progression free survival were 247.6 months (range 0.4–269.1) and 67.9 months (range 0.7–341.9), respectively. Overall, 113/159 (71.1 %) patients had tumour progression and 53/159 (33.3 %) deceased. In total, 57.4 % of the nullipara, 76.1 % of the primi-/multipara before glioma diagnosis and 79.1 % of the primi-/multipara after glioma diagnosis groups experienced tumour progression (p > 0.05). In multivariate time-dependent analysis, primi-/multiparae after glioma diagnosis presented with shorter progression free (HR 2.45, p = 0.0079), but not overall survival (HR 0.54, p > 0.05) in comparison to the other two groups.</div></div><div><h3>Conclusion</h3><div>Pregnancy after glioma diagnosis was associated with shorter progression free survival. Longer follow-up as well as larger cohorts are needed to investigate a potential impact on overall survival.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"218 ","pages":"Article 115259"},"PeriodicalIF":7.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1016/j.ejca.2025.115256
Jérôme Doyen , Anne Dompmartin , Coralie Cruzel , Dinu Stefan , Jean-Philippe Arnault , Alexandre Coutte , Alexandra Picard-Gauci , Sandrine Mansard , Baptiste Gleyzolle , Eric Fontas , Elodie Long-Mira , Xavier Mirabel , Laurent Mortier , Henri Montaudié
Background
Radiotherapy is thought to enhance anti-tumor immunity, particularly when delivered in a hypofractionated and multisite manner. Therefore, we investigated the effects of combining radiotherapy with nivolumab in patients with advanced melanoma.
Methods
This was a multicenter, non-randomized, phase 2 trial that enrolled patients with treatment-naïve metastatic melanoma. They received nivolumab (240 mg / 2 weeks) plus radiotherapy (day 15, 6 Gy × 3). When feasible, one target from each organ was irradiated (no irradiation of all targets). The primary endpoint was 1-year overall survival (OS).
Results
This trial included 64 patients between March 2017 and July 2019. The median follow-up was 23.5 (2.3–43.8) months. The median age was 68 (35–95) years, patients were mostly male (67 %) with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0 (72 %), stage IV-M1c disease (47 %), and were BRAF-wild-type (67 %). The 2-year OS and 1-year PFS rates were 65.2 % and 56 %, respectively (P = 0.22 and P = 0.03, vs. 58 % and 43 %, respectively, in the Checkmate 066 study). Thirty-seven (58 %) and twenty-seven (42 %) patients were irradiated at one and multiple targets, respectively. The ECOG-PS (1 vs. 0; HR = 3.5; P = 0.005) was an independent prognostic factor for OS. Irradiating more than one site and irradiating a smaller cumulative tumor volume tended to correlate with better outcome. Grade 3–4 treatment-related adverse events occurred in 21.9 % of the patients (no grade 5).
Conclusions
Combined immunotherapy and hypofractionated radiotherapy did not improve survival compared to historical cohorts. The radiotherapy schedule needs to be optimized in order to improve these results.
{"title":"Nivolumab and hypofractionated radiotherapy in patients with advanced melanoma: A phase 2 trial","authors":"Jérôme Doyen , Anne Dompmartin , Coralie Cruzel , Dinu Stefan , Jean-Philippe Arnault , Alexandre Coutte , Alexandra Picard-Gauci , Sandrine Mansard , Baptiste Gleyzolle , Eric Fontas , Elodie Long-Mira , Xavier Mirabel , Laurent Mortier , Henri Montaudié","doi":"10.1016/j.ejca.2025.115256","DOIUrl":"10.1016/j.ejca.2025.115256","url":null,"abstract":"<div><h3>Background</h3><div>Radiotherapy is thought to enhance anti-tumor immunity, particularly when delivered in a hypofractionated and multisite manner. Therefore, we investigated the effects of combining radiotherapy with nivolumab in patients with advanced melanoma.</div></div><div><h3>Methods</h3><div>This was a multicenter, non-randomized, phase 2 trial that enrolled patients with treatment-naïve metastatic melanoma. They received nivolumab (240 mg / 2 weeks) plus radiotherapy (day 15, 6 Gy × 3). When feasible, one target from each organ was irradiated (no irradiation of all targets). The primary endpoint was 1-year overall survival (OS).</div></div><div><h3>Results</h3><div>This trial included 64 patients between March 2017 and July 2019. The median follow-up was 23.5 (2.3–43.8) months. The median age was 68 (35–95) years, patients were mostly male (67 %) with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0 (72 %), stage IV-M1c disease (47 %), and were <em>BRAF</em>-wild-type (67 %). The 2-year OS and 1-year PFS rates were 65.2 % and 56 %, respectively (<em>P</em> = 0.22 and <em>P</em> = 0.03, vs. 58 % and 43 %, respectively, in the Checkmate 066 study). Thirty-seven (58 %) and twenty-seven (42 %) patients were irradiated at one and multiple targets, respectively. The ECOG-PS (1 vs. 0; HR = 3.5; <em>P</em> = 0.005) was an independent prognostic factor for OS. Irradiating more than one site and irradiating a smaller cumulative tumor volume tended to correlate with better outcome. Grade 3–4 treatment-related adverse events occurred in 21.9 % of the patients (no grade 5).</div></div><div><h3>Conclusions</h3><div>Combined immunotherapy and hypofractionated radiotherapy did not improve survival compared to historical cohorts. The radiotherapy schedule needs to be optimized in order to improve these results.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"217 ","pages":"Article 115256"},"PeriodicalIF":7.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1016/j.ejca.2025.115222
O. Metzger Filho , F. Cardoso , C. Poncet , C. Desmedt , S. Linn , J. Wesseling , F. Hilbers , S. Delaloge , J.-Y. Pierga , E. Brain , S. Vrijaldenhoven , P.A. Neijenhuis , E.J.Th Rutgers , M. Piccart , L.J. van ’t Veer , G. Viale
Background
Evaluation of the prognostic performance and clinical utility of the MammaPrint 70-gene signature in early-stage invasive lobular carcinoma (ILC) for whom such analyses in a randomized trial is awaited.
Patients and methods
Exploratory subgroup analysis of MINDACT trial patients with centrally assessed histology (n = 5929) with invasive breast cancer of no-special-type (NST), or pure ILC. In the trial patients were categorized based on the 70-gene signature for genomic risk and modified Adjuvant!Online for clinical risk. Survival outcomes at 8.7 years median follow-up by 70-gene signature were compared between NST and ILC for Distant Metastasis-Free Survival (DMFS), Disease-Free Survival (DFS) and Overall Survival (OS).
Results
5313 patients were ILC (n = 487) or NST (n = 4826). ILC was further classified into classic ILC (n = 255) or ILC variants (n = 232). The 70-gene signature classified 16.2 % of ILC and 39.1 % of NST as genomic high-risk (gH). Survival outcomes for ILC vs. NST revealed similar estimates according to genomic risk overall and across subsets. The 70-gene signature classified 10.2 % of classic ILC and 22.8 % of ILC variants as gH. 5-yr DFS estimates for ILC variants 88.4 % (95 %CI: 83.1–92.1) was inferior to classic ILC 93.0 % (95 %CI: 88.7–95.7).
Conclusions
Sixteen percent of ILC were classified high genomic risk by the 70-gene signature, with unfavorable survival outcomes. Survival estimates were similar for patients with ILC and NST classified as either low- or high-genomic risk, suggesting that the 70-gene signature also has prognostic value in ILC and may be a clinically useful tool for adjuvant treatment decision-making in ILC.
{"title":"Survival outcomes for patients with invasive lobular cancer by MammaPrint: Results from the MINDACT phase III trial","authors":"O. Metzger Filho , F. Cardoso , C. Poncet , C. Desmedt , S. Linn , J. Wesseling , F. Hilbers , S. Delaloge , J.-Y. Pierga , E. Brain , S. Vrijaldenhoven , P.A. Neijenhuis , E.J.Th Rutgers , M. Piccart , L.J. van ’t Veer , G. Viale","doi":"10.1016/j.ejca.2025.115222","DOIUrl":"10.1016/j.ejca.2025.115222","url":null,"abstract":"<div><h3>Background</h3><div>Evaluation of the prognostic performance and clinical utility of the MammaPrint 70-gene signature in early-stage invasive lobular carcinoma (ILC) for whom such analyses in a randomized trial is awaited.</div></div><div><h3>Patients and methods</h3><div>Exploratory subgroup analysis of MINDACT trial patients with centrally assessed histology (n = 5929) with invasive breast cancer of no-special-type (NST), or pure ILC. In the trial patients were categorized based on the 70-gene signature for genomic risk and modified Adjuvant!Online for clinical risk. Survival outcomes at 8.7 years median follow-up by 70-gene signature were compared between NST and ILC for Distant Metastasis-Free Survival (DMFS), Disease-Free Survival (DFS) and Overall Survival (OS).</div></div><div><h3>Results</h3><div>5313 patients were ILC (n = 487) or NST (n = 4826). ILC was further classified into classic ILC (n = 255) or ILC variants (n = 232). The 70-gene signature classified 16.2 % of ILC and 39.1 % of NST as genomic high-risk (gH). Survival outcomes for ILC vs. NST revealed similar estimates according to genomic risk overall and across subsets. The 70-gene signature classified 10.2 % of classic ILC and 22.8 % of ILC variants as gH. 5-yr DFS estimates for ILC variants 88.4 % (95 %CI: 83.1–92.1) was inferior to classic ILC 93.0 % (95 %CI: 88.7–95.7).</div></div><div><h3>Conclusions</h3><div>Sixteen percent of ILC were classified high genomic risk by the 70-gene signature, with unfavorable survival outcomes. Survival estimates were similar for patients with ILC and NST classified as either low- or high-genomic risk, suggesting that the 70-gene signature also has prognostic value in ILC and may be a clinically useful tool for adjuvant treatment decision-making in ILC.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"217 ","pages":"Article 115222"},"PeriodicalIF":7.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-21DOI: 10.1016/j.ejca.2025.115255
K. Laktionov , A. Smolin , D. Stroyakovskiy , V. Moiseenko , M. Dvorkin , T. Andabekov , Y. Cheng , B. Liu , V. Kozlov , S. Odintsova , S. Dvoretsky , A. Mochalova , M. Urda , T. Yi , X. Li , U. László , V. Müller , K. Bogos , N. Fadeeva , G. Musaev , F. Kryukov
Background
Prolgolimab is an IgG1 anti-PD-1 monoclonal antibody with the Fc-silencing ‘LALA’ mutation. The phase III DOMAJOR study assessed efficacy and safety of prolgolimab in combination with pemetrexed and platinum-based chemotherapy vs placebo in combination with pemetrexed and platinum-based chemotherapy as first-line treatment for advanced non-small cell lung cancer (NSCLC).
Methods
292 patients with advanced non-squamous NSCLC were randomized 1:1 to receive 4 cycles of pemetrexed, platinum-based drug and either prolgolimab (3 mg/kg Q3W) or placebo followed by prolgolimab/placebo with pemetrexed until disease progression or toxicity (≤36 months). The primary endpoint was overall survival (OS).
Results
After a median follow-up of 18 months, the median OS was not reached (95 % CI, 22.28 – NA) in the prolgolimab-combination group vs 14.6 months (95 % CI, 11.73 – 19.15) in the placebo-combination group (HR, 0.51; 95 % CI, 0.35 – 0.73, p = 0.0001). The OS improvement was independent of PD-L1 status. Median progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) was 7.7 months in the prolgolimab-combination group and 5.5 months in the placebo-combination group (HR, 0.65; 95 % CI, 0.49 – 0.85, p = 0.0004). The only adverse events that were reported in at least 10 % of the patients that were significantly more frequent in the prolgolimab-combination group were blood creatinine increased and dyspnoea.
Conclusion
Among patients with advanced NSCLC the addition of prolgolimab to pemetrexed and a platinum-based drug increased OS and PFS, with no new safety concerns. This benefit was retained in patients with PD-L1 negative tumors. (ClinicalTrials.gov, NCT03912389)
{"title":"Prolgolimab with chemotherapy as first-line treatment for advanced non-squamous non-small-cell lung cancer","authors":"K. Laktionov , A. Smolin , D. Stroyakovskiy , V. Moiseenko , M. Dvorkin , T. Andabekov , Y. Cheng , B. Liu , V. Kozlov , S. Odintsova , S. Dvoretsky , A. Mochalova , M. Urda , T. Yi , X. Li , U. László , V. Müller , K. Bogos , N. Fadeeva , G. Musaev , F. Kryukov","doi":"10.1016/j.ejca.2025.115255","DOIUrl":"10.1016/j.ejca.2025.115255","url":null,"abstract":"<div><h3>Background</h3><div>Prolgolimab is an IgG1 anti-PD-1 monoclonal antibody with the Fc-silencing ‘LALA’ mutation. The phase III DOMAJOR study assessed efficacy and safety of prolgolimab in combination with pemetrexed and platinum-based chemotherapy vs placebo in combination with pemetrexed and platinum-based chemotherapy as first-line treatment for advanced non-small cell lung cancer (NSCLC).</div></div><div><h3>Methods</h3><div>292 patients with advanced non-squamous NSCLC were randomized 1:1 to receive 4 cycles of pemetrexed, platinum-based drug and either prolgolimab (3 mg/kg Q3W) or placebo followed by prolgolimab/placebo with pemetrexed until disease progression or toxicity (≤36 months). The primary endpoint was overall survival (OS).</div></div><div><h3>Results</h3><div>After a median follow-up of 18 months, the median OS was not reached (95 % CI, 22.28 – NA) in the prolgolimab-combination group vs 14.6 months (95 % CI, 11.73 – 19.15) in the placebo-combination group (HR, 0.51; 95 % CI, 0.35 – 0.73, p = 0.0001). The OS improvement was independent of PD-L1 status. Median progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) was 7.7 months in the prolgolimab-combination group and 5.5 months in the placebo-combination group (HR, 0.65; 95 % CI, 0.49 – 0.85, p = 0.0004). The only adverse events that were reported in at least 10 % of the patients that were significantly more frequent in the prolgolimab-combination group were blood creatinine increased and dyspnoea.</div></div><div><h3>Conclusion</h3><div>Among patients with advanced NSCLC the addition of prolgolimab to pemetrexed and a platinum-based drug increased OS and PFS, with no new safety concerns. This benefit was retained in patients with PD-L1 negative tumors. (ClinicalTrials.gov, NCT03912389)</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"217 ","pages":"Article 115255"},"PeriodicalIF":7.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-21DOI: 10.1016/j.ejca.2025.115253
Sidsel Pedersen , Emma Lund Johansen , Karen Louise Højholt , Marie Wett Pedersen , Anne Mark Mogensen , Søren Kjær Petersen , Charlotte Aaquist Haslund , Marco Donia , Henrik Schmidt , Lars Bastholt , Rasmus Friis , Inge Marie Svane , Eva Ellebaek
Introduction
Advances in modern therapies have improved outcomes for patients with melanoma brain metastases (MBM), though prognosis remains poor. The optimal treatment strategy for patients who do not meet clinical trial inclusion criteria is unclear.
Methods
This study included all patients with MBM diagnosed in Denmark between 2015 and 2022, identified through the Danish Metastatic Melanoma Database (DAMMED) and local surgical and radiotherapy records. Data were collected from electronic patient records.
Results
A total of 838 patients were included, with a median overall survival (OS) of 9.0 months. Of these, 112 (19.4 %) survived beyond 3 years post-diagnosis. Patients treated with immune checkpoint inhibitors (ICI) as first line treatment, specifically ipilimumab + nivolumab, demonstrated an intracranial overall response rate (icORR) of 46 % and a 2-year OS of 49 %. Those treated with BRAF/MEK inhibitors (BRAF/MEKi) had an icORR of 56 % but a 2-year OS of 20 %. Patients with leptomeningeal disease (LMD, n = 67) had a median OS of 8.4 months. Systemic therapy was associated with a superior OS for patients with LMD, though no survival benefit was seen with ICI compared to BRAF/MEKi. Among the 230 patients who underwent surgery, 30 received postoperative stereotactic radiosurgery (SRS); however, there was no difference in OS or intracranial progression-free survival between the groups.
Conclusion
A considerable proportion of patients with brain metastases diagnosed after 2015 survived more than 3 years. Patients with LMD appeared to obtain limited benefit of ICI with only few patients alive > 3 years post-diagnosis.
{"title":"Survival improvements in patients with melanoma brain metastases and leptomeningeal disease in the modern era: Insights from a nationwide study (2015–2022)","authors":"Sidsel Pedersen , Emma Lund Johansen , Karen Louise Højholt , Marie Wett Pedersen , Anne Mark Mogensen , Søren Kjær Petersen , Charlotte Aaquist Haslund , Marco Donia , Henrik Schmidt , Lars Bastholt , Rasmus Friis , Inge Marie Svane , Eva Ellebaek","doi":"10.1016/j.ejca.2025.115253","DOIUrl":"10.1016/j.ejca.2025.115253","url":null,"abstract":"<div><h3>Introduction</h3><div>Advances in modern therapies have improved outcomes for patients with melanoma brain metastases (MBM), though prognosis remains poor. The optimal treatment strategy for patients who do not meet clinical trial inclusion criteria is unclear.</div></div><div><h3>Methods</h3><div>This study included all patients with MBM diagnosed in Denmark between 2015 and 2022, identified through the Danish Metastatic Melanoma Database (DAMMED) and local surgical and radiotherapy records. Data were collected from electronic patient records.</div></div><div><h3>Results</h3><div>A total of 838 patients were included, with a median overall survival (OS) of 9.0 months. Of these, 112 (19.4 %) survived beyond 3 years post-diagnosis. Patients treated with immune checkpoint inhibitors (ICI) as first line treatment, specifically ipilimumab + nivolumab, demonstrated an intracranial overall response rate (icORR) of 46 % and a 2-year OS of 49 %. Those treated with BRAF/MEK inhibitors (BRAF/MEKi) had an icORR of 56 % but a 2-year OS of 20 %. Patients with leptomeningeal disease (LMD, n = 67) had a median OS of 8.4 months. Systemic therapy was associated with a superior OS for patients with LMD, though no survival benefit was seen with ICI compared to BRAF/MEKi. Among the 230 patients who underwent surgery, 30 received postoperative stereotactic radiosurgery (SRS); however, there was no difference in OS or intracranial progression-free survival between the groups.</div></div><div><h3>Conclusion</h3><div>A considerable proportion of patients with brain metastases diagnosed after 2015 survived more than 3 years. Patients with LMD appeared to obtain limited benefit of ICI with only few patients alive > 3 years post-diagnosis.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"217 ","pages":"Article 115253"},"PeriodicalIF":7.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-20DOI: 10.1016/j.ejca.2025.115257
Eva Ellebaek, Marco Donia, Inge Marie Svane
Groundbreaking studies have reshaped the treatment landscape for patients with resectable stage ≥IIIB melanoma by demonstrating the benefits of neoadjuvant therapy. Data from the NADINA and SWOG S1801 trials reveal substantial improvements in event-free survival compared to adjuvant therapy alone. These studies employed distinct neoadjuvant immunotherapy approaches — ipilimumab plus nivolumab in NADINA and anti-PD-1 monotherapy in SWOG S1801 — highlighting potential differences in efficacy and toxicity. The integration of biomarkers may improve the risk/benefit ratio by enabling personalized treatment selection between ipilimumab plus nivolumab versus anti-PD-1 monotherapy. In metastatic melanoma, molecular biomarkers such as BRAF mutational status and intratumoral PD-L1 expression can help guide treatment decisions; however, their, and other biomarkers’, role in the neoadjuvant context has yet to be fully investigated. This commentary underscores the need to investigate whether these molecular markers, along with other biomarkers and clinical parameters, can inform neoadjuvant therapy in resectable stage ≥IIIB melanoma. We propose a coordinated effort involving retrospective analyses of current trials and prospective clinical studies, to define the role of biomarkers. A biomarker-guided approach could optimize efficacy and reduce toxicity, offering personalized treatment options for patients with resectable melanoma. As implementation of neoadjuvant therapy rapidly gains global adoption, we advocate for robust research to ensure that each patient receives the most effective and least toxic therapeutic option.
{"title":"Neoadjuvant or perioperative immunotherapy for resectable melanoma: The need for biomarkers","authors":"Eva Ellebaek, Marco Donia, Inge Marie Svane","doi":"10.1016/j.ejca.2025.115257","DOIUrl":"10.1016/j.ejca.2025.115257","url":null,"abstract":"<div><div>Groundbreaking studies have reshaped the treatment landscape for patients with resectable stage ≥IIIB melanoma by demonstrating the benefits of neoadjuvant therapy. Data from the NADINA and SWOG S1801 trials reveal substantial improvements in event-free survival compared to adjuvant therapy alone. These studies employed distinct neoadjuvant immunotherapy approaches — ipilimumab plus nivolumab in NADINA and anti-PD-1 monotherapy in SWOG S1801 — highlighting potential differences in efficacy and toxicity. The integration of biomarkers may improve the risk/benefit ratio by enabling personalized treatment selection between ipilimumab plus nivolumab versus anti-PD-1 monotherapy. In metastatic melanoma, molecular biomarkers such as <em>BRAF</em> mutational status and intratumoral PD-L1 expression can help guide treatment decisions; however, their, and other biomarkers’, role in the neoadjuvant context has yet to be fully investigated. This commentary underscores the need to investigate whether these molecular markers, along with other biomarkers and clinical parameters, can inform neoadjuvant therapy in resectable stage ≥IIIB melanoma. We propose a coordinated effort involving retrospective analyses of current trials and prospective clinical studies, to define the role of biomarkers. A biomarker-guided approach could optimize efficacy and reduce toxicity, offering personalized treatment options for patients with resectable melanoma. As implementation of neoadjuvant therapy rapidly gains global adoption, we advocate for robust research to ensure that each patient receives the most effective and least toxic therapeutic option.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"217 ","pages":"Article 115257"},"PeriodicalIF":7.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-20DOI: 10.1016/j.ejca.2025.115236
Thomas U. Schulz , Sarah Zierold , Michael M. Sachse , Giulia Pesch , Dirk Tomsitz , Katharina Schilbach , Katharina C. Kähler , Lars E. French , Lucie Heinzerling
{"title":"Corrigendum to “Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients' health-related quality of life” [Eur J Cancer 176 (2022) 88–99]","authors":"Thomas U. Schulz , Sarah Zierold , Michael M. Sachse , Giulia Pesch , Dirk Tomsitz , Katharina Schilbach , Katharina C. Kähler , Lars E. French , Lucie Heinzerling","doi":"10.1016/j.ejca.2025.115236","DOIUrl":"10.1016/j.ejca.2025.115236","url":null,"abstract":"","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"217 ","pages":"Article 115236"},"PeriodicalIF":7.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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