Pub Date : 2024-08-01DOI: 10.1016/S1470-2045(24)00075-5
Connor Lynch, Sean P Pitroda, Ralph R Weichselbaum
Radiotherapy exerts immunostimulatory and immunosuppressive effects, both locally, within the irradiated tumour microenvironment, and systemically, outside the radiation field. Inspired by preclinical data that showed synergy between radiotherapy and immune checkpoint inhibitors, multiple clinical trials were initiated with the hypothesis that combined treatment with radiotherapy and immune checkpoint inhibitors could stimulate a robust systemic immune response and improve clinical outcomes. However, despite early optimism, radioimmunotherapy trials in the curative and metastatic settings have met with little success. In this Review, we summarise the immunostimulatory effects of radiotherapy that provided the theoretical basis for trials of combination radiotherapy and immune checkpoint inhibitors. We also discuss findings from clinical trials incorporating radiotherapy and immune checkpoint inhibitors and examine the success of these trials in the context of the immunosuppressive effects of radiotherapy. We conclude by highlighting targets for relieving radiotherapy-induced immunosuppression with the goal of enhancing the combined effects of radiotherapy and immune checkpoint inhibitors.
{"title":"Radiotherapy, immunity, and immune checkpoint inhibitors.","authors":"Connor Lynch, Sean P Pitroda, Ralph R Weichselbaum","doi":"10.1016/S1470-2045(24)00075-5","DOIUrl":"https://doi.org/10.1016/S1470-2045(24)00075-5","url":null,"abstract":"<p><p>Radiotherapy exerts immunostimulatory and immunosuppressive effects, both locally, within the irradiated tumour microenvironment, and systemically, outside the radiation field. Inspired by preclinical data that showed synergy between radiotherapy and immune checkpoint inhibitors, multiple clinical trials were initiated with the hypothesis that combined treatment with radiotherapy and immune checkpoint inhibitors could stimulate a robust systemic immune response and improve clinical outcomes. However, despite early optimism, radioimmunotherapy trials in the curative and metastatic settings have met with little success. In this Review, we summarise the immunostimulatory effects of radiotherapy that provided the theoretical basis for trials of combination radiotherapy and immune checkpoint inhibitors. We also discuss findings from clinical trials incorporating radiotherapy and immune checkpoint inhibitors and examine the success of these trials in the context of the immunosuppressive effects of radiotherapy. We conclude by highlighting targets for relieving radiotherapy-induced immunosuppression with the goal of enhancing the combined effects of radiotherapy and immune checkpoint inhibitors.</p>","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":"25 8","pages":"e352-e362"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875175","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 : 2024-08-01DOI: 10.1016/S1470-2045(24)00270-5
Yi-Long Wu, Valentina Guarneri, Pei Jye Voon, Boon Khaw Lim, Jin-Ji Yang, Marie Wislez, Cheng Huang, Chong Kin Liam, Julien Mazieres, Lye Mun Tho, Hidetoshi Hayashi, Nguyen Viet Nhung, Puey Ling Chia, Filippo de Marinis, Jo Raskin, Qinghua Zhou, Giovanna Finocchiaro, Anh Tuan Le, Jialei Wang, Christophe Dooms, Terufumi Kato, Ernest Nadal, How Soon Hin, Egbert F Smit, Martin Wermke, Daniel Tan, Masahiro Morise, Aurora O'Brate, Svenja Adrian, Boris M Pfeiffer, Christopher Stroh, Dilafruz Juraeva, Rainer Strotmann, Kosalaram Goteti, Karin Berghoff, Barbara Ellers-Lenz, Niki Karachaliou, Xiuning Le, Tae Min Kim
Background: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population.
Methods: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete).
Findings: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea.
Interpretation: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated.
{"title":"Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.","authors":"Yi-Long Wu, Valentina Guarneri, Pei Jye Voon, Boon Khaw Lim, Jin-Ji Yang, Marie Wislez, Cheng Huang, Chong Kin Liam, Julien Mazieres, Lye Mun Tho, Hidetoshi Hayashi, Nguyen Viet Nhung, Puey Ling Chia, Filippo de Marinis, Jo Raskin, Qinghua Zhou, Giovanna Finocchiaro, Anh Tuan Le, Jialei Wang, Christophe Dooms, Terufumi Kato, Ernest Nadal, How Soon Hin, Egbert F Smit, Martin Wermke, Daniel Tan, Masahiro Morise, Aurora O'Brate, Svenja Adrian, Boris M Pfeiffer, Christopher Stroh, Dilafruz Juraeva, Rainer Strotmann, Kosalaram Goteti, Karin Berghoff, Barbara Ellers-Lenz, Niki Karachaliou, Xiuning Le, Tae Min Kim","doi":"10.1016/S1470-2045(24)00270-5","DOIUrl":"10.1016/S1470-2045(24)00270-5","url":null,"abstract":"<p><strong>Background: </strong>Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population.</p><p><strong>Methods: </strong>This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete).</p><p><strong>Findings: </strong>Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea.</p><p><strong>Interpretation: </strong>Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated.</p><p><strong>Funding: </strong>Merck (CrossRef Funder ID: 10.13039/100009945).</p>","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":"25 8","pages":"989-1002"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875177","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 : 2024-08-01Epub Date: 2024-06-20DOI: 10.1016/S1470-2045(24)00369-3
Emma Wilkinson
{"title":"Cancer priorities set out in manifestos as organisations warn of worsening standards.","authors":"Emma Wilkinson","doi":"10.1016/S1470-2045(24)00369-3","DOIUrl":"10.1016/S1470-2045(24)00369-3","url":null,"abstract":"","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"957"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442980","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 : 2024-08-01Epub Date: 2024-07-01DOI: 10.1016/S1470-2045(24)00274-2
Shilpa S Murthy, Dario Trapani, Bochen Cao, Freddie Bray, Shashanka Murthy, Thomas Peter Kingham, Chandrakanth Are, André M Ilbawi
<p><strong>Background: </strong>Cancer is a leading cause of mortality worldwide. By 2040, over 30 million new cancers are predicted, with the greatest cancer burden in low-income countries. In 2015, the UN passed the Sustainable Development Goal 3.4 (SDG 3.4) to tackle the rising burden of non-communicable diseases, which calls for a reduction by a third in premature mortality from non-communicable diseases, including cancer, by 2030. However, there is a paucity of data on premature mortality rates by cancer type. In this study, we examine annual rates of change for cancer-specific premature mortality and classify whether countries are on track to reach SDG 3.4 targets.</p><p><strong>Methods: </strong>This is a retrospective, cross-sectional, population-based study investigating premature mortality trends from 2000-19 using the WHO Global Health Estimates data. All cancers combined and thirteen individual cancers in 183 countries were examined by WHO region, World Bank income level, and sex. The risk of premature mortality was calculated for ages 30-69 years, independent of other competing causes of death, using standard life table methods. The primary objective was to compute average annual rate of change in premature mortality from 2000 to 2019. Secondary objectives assessed whether this annual rate of change would be sufficient to reach SDG 3.4. targets for premature mortality by 2030.</p><p><strong>Findings: </strong>This study was conducted using data retrieved for the years 2000-19. Premature mortality rates decreased in 138 (75%) of 183 countries across all World Bank income levels and WHO regions, however only eight (4%) countries are likely to meet the SDG 3.4 targets for all cancers combined. Cancers where early detection strategies exist, such as breast and colorectal cancer, have higher declining premature mortality rates in high-income countries (breast cancer 48 [89%] of 54 and colorectal cancer 45 [83%]) than in low-income countries (seven [24%] of 29 and four [14%]). Cancers with primary prevention programmes, such as cervical cancer, have more countries with declining premature mortality rates (high-income countries 50 [93%] of 54 and low-income countries 26 [90%] of 29). Sex-related disparities in premature mortality rates vary across WHO regions, World Bank income groups, and by cancer type.</p><p><strong>Interpretation: </strong>There is a greater reduction in premature mortality for all cancers combined and for individual cancer types in high-income countries compared with lower-middle-income and low-income countries. However, most countries will not reach the SDG 3.4 target. Cancers with early detection strategies in place, such as breast and colorectal cancers, are performing poorly in premature mortality compared with cancers with primary prevention measures, such as cervical cancer. Investments toward prevention, early detection, and treatment can potentially accelerate declines in premature mortality.</p><p><strong>Fund
{"title":"Premature mortality trends in 183 countries by cancer type, sex, WHO region, and World Bank income level in 2000-19: a retrospective, cross-sectional, population-based study.","authors":"Shilpa S Murthy, Dario Trapani, Bochen Cao, Freddie Bray, Shashanka Murthy, Thomas Peter Kingham, Chandrakanth Are, André M Ilbawi","doi":"10.1016/S1470-2045(24)00274-2","DOIUrl":"10.1016/S1470-2045(24)00274-2","url":null,"abstract":"<p><strong>Background: </strong>Cancer is a leading cause of mortality worldwide. By 2040, over 30 million new cancers are predicted, with the greatest cancer burden in low-income countries. In 2015, the UN passed the Sustainable Development Goal 3.4 (SDG 3.4) to tackle the rising burden of non-communicable diseases, which calls for a reduction by a third in premature mortality from non-communicable diseases, including cancer, by 2030. However, there is a paucity of data on premature mortality rates by cancer type. In this study, we examine annual rates of change for cancer-specific premature mortality and classify whether countries are on track to reach SDG 3.4 targets.</p><p><strong>Methods: </strong>This is a retrospective, cross-sectional, population-based study investigating premature mortality trends from 2000-19 using the WHO Global Health Estimates data. All cancers combined and thirteen individual cancers in 183 countries were examined by WHO region, World Bank income level, and sex. The risk of premature mortality was calculated for ages 30-69 years, independent of other competing causes of death, using standard life table methods. The primary objective was to compute average annual rate of change in premature mortality from 2000 to 2019. Secondary objectives assessed whether this annual rate of change would be sufficient to reach SDG 3.4. targets for premature mortality by 2030.</p><p><strong>Findings: </strong>This study was conducted using data retrieved for the years 2000-19. Premature mortality rates decreased in 138 (75%) of 183 countries across all World Bank income levels and WHO regions, however only eight (4%) countries are likely to meet the SDG 3.4 targets for all cancers combined. Cancers where early detection strategies exist, such as breast and colorectal cancer, have higher declining premature mortality rates in high-income countries (breast cancer 48 [89%] of 54 and colorectal cancer 45 [83%]) than in low-income countries (seven [24%] of 29 and four [14%]). Cancers with primary prevention programmes, such as cervical cancer, have more countries with declining premature mortality rates (high-income countries 50 [93%] of 54 and low-income countries 26 [90%] of 29). Sex-related disparities in premature mortality rates vary across WHO regions, World Bank income groups, and by cancer type.</p><p><strong>Interpretation: </strong>There is a greater reduction in premature mortality for all cancers combined and for individual cancer types in high-income countries compared with lower-middle-income and low-income countries. However, most countries will not reach the SDG 3.4 target. Cancers with early detection strategies in place, such as breast and colorectal cancers, are performing poorly in premature mortality compared with cancers with primary prevention measures, such as cervical cancer. Investments toward prevention, early detection, and treatment can potentially accelerate declines in premature mortality.</p><p><strong>Fund","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"969-978"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534745","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 : 2024-08-01Epub Date: 2024-06-26DOI: 10.1016/S1470-2045(24)00269-9
Ceren Sunguc, David L Winter, Emma J Heymer, Gavin Rudge, Angela Polanco, Katherine A Birchenall, Melanie Griffin, Richard A Anderson, W Hamish B Wallace, Michael M Hawkins, Raoul C Reulen
<p><strong>Background: </strong>There are limited data on the risks of obstetric complications among survivors of adolescent and young adult cancer with most previous studies only reporting risks for all types of cancers combined. The aim of this study was to quantify deficits in birth rates and risks of obstetric complications for female survivors of 17 specific types of adolescent and young adult cancer.</p><p><strong>Methods: </strong>The Teenage and Young Adult Cancer Survivor Study (TYACSS)-a retrospective, population-based cohort of 200 945 5-year survivors of cancer diagnosed at age 15-39 years from England and Wales-was linked to the English Hospital Episode Statistics (HES) database from April 1, 1997, to March 31, 2022. The cohort included 17 different types of adolescent and young adult cancers. We ascertained 27 specific obstetric complications through HES among 96 947 women in the TYACSS cohort. Observed and expected numbers for births and obstetric complications were compared between the study cohort and the general population of England to identify survivors of adolescent and young adult cancer at a heighted risk of birth deficits and obstetric complications relative to the general population.</p><p><strong>Findings: </strong>Between April 1, 1997, and March 31, 2022, 21 437 births were observed among 13 886 female survivors of adolescent and young adult cancer from England, which was lower than expected (observed-to-expected ratio: 0·68, 95% CI 0·67-0·69). Other survivors of genitourinary, cervical, and breast cancer had under 50% of expected births. Focusing on more common (observed ≥100) obstetric complications that were at least moderately in excess (observed-to-expected ratio ≥1·25), survivors of cervical cancer were at risk of malpresentation of fetus, obstructed labour, amniotic fluid and membranes disorders, premature rupture of membranes, preterm birth, placental disorders including placenta praevia, and antepartum haemorrhage. Survivors of leukaemia were at risk of preterm delivery, obstructed labour, postpartum haemorrhage, and retained placenta. Survivors of all other specific cancers had no more than two obstetric complications that exceeded an observed-to-expected ratio of 1·25 or greater.</p><p><strong>Interpretation: </strong>Survivors of cervical cancer and leukaemia are at risk of several serious obstetric complications; therefore, any pregnancy should be considered high-risk and would benefit from obstetrician-led antenatal care. Despite observing deficits in birth rates across all 17 different types of adolescent and young adult cancer, we provide reassurance for almost all survivors of adolescent and young adult cancer concerning their risk of almost all obstetric complications. Our results provide evidence for the development of clinical guidelines relating to counselling and surveillance of obstetrical risk for female survivors of adolescent and young adult cancer.</p><p><strong>Funding: </strong>Children wit
{"title":"Risks of adverse obstetric outcomes among female survivors of adolescent and young adult cancer in England (TYACSS): a population-based, retrospective cohort study.","authors":"Ceren Sunguc, David L Winter, Emma J Heymer, Gavin Rudge, Angela Polanco, Katherine A Birchenall, Melanie Griffin, Richard A Anderson, W Hamish B Wallace, Michael M Hawkins, Raoul C Reulen","doi":"10.1016/S1470-2045(24)00269-9","DOIUrl":"10.1016/S1470-2045(24)00269-9","url":null,"abstract":"<p><strong>Background: </strong>There are limited data on the risks of obstetric complications among survivors of adolescent and young adult cancer with most previous studies only reporting risks for all types of cancers combined. The aim of this study was to quantify deficits in birth rates and risks of obstetric complications for female survivors of 17 specific types of adolescent and young adult cancer.</p><p><strong>Methods: </strong>The Teenage and Young Adult Cancer Survivor Study (TYACSS)-a retrospective, population-based cohort of 200 945 5-year survivors of cancer diagnosed at age 15-39 years from England and Wales-was linked to the English Hospital Episode Statistics (HES) database from April 1, 1997, to March 31, 2022. The cohort included 17 different types of adolescent and young adult cancers. We ascertained 27 specific obstetric complications through HES among 96 947 women in the TYACSS cohort. Observed and expected numbers for births and obstetric complications were compared between the study cohort and the general population of England to identify survivors of adolescent and young adult cancer at a heighted risk of birth deficits and obstetric complications relative to the general population.</p><p><strong>Findings: </strong>Between April 1, 1997, and March 31, 2022, 21 437 births were observed among 13 886 female survivors of adolescent and young adult cancer from England, which was lower than expected (observed-to-expected ratio: 0·68, 95% CI 0·67-0·69). Other survivors of genitourinary, cervical, and breast cancer had under 50% of expected births. Focusing on more common (observed ≥100) obstetric complications that were at least moderately in excess (observed-to-expected ratio ≥1·25), survivors of cervical cancer were at risk of malpresentation of fetus, obstructed labour, amniotic fluid and membranes disorders, premature rupture of membranes, preterm birth, placental disorders including placenta praevia, and antepartum haemorrhage. Survivors of leukaemia were at risk of preterm delivery, obstructed labour, postpartum haemorrhage, and retained placenta. Survivors of all other specific cancers had no more than two obstetric complications that exceeded an observed-to-expected ratio of 1·25 or greater.</p><p><strong>Interpretation: </strong>Survivors of cervical cancer and leukaemia are at risk of several serious obstetric complications; therefore, any pregnancy should be considered high-risk and would benefit from obstetrician-led antenatal care. Despite observing deficits in birth rates across all 17 different types of adolescent and young adult cancer, we provide reassurance for almost all survivors of adolescent and young adult cancer concerning their risk of almost all obstetric complications. Our results provide evidence for the development of clinical guidelines relating to counselling and surveillance of obstetrical risk for female survivors of adolescent and young adult cancer.</p><p><strong>Funding: </strong>Children wit","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"1080-1091"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469145","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 : 2024-08-01Epub Date: 2024-06-28DOI: 10.1016/S1470-2045(24)00249-3
Salomon Tendler, Mark P Dunphy, Matthew Agee, Joseph O'Donoghue, Rania G Aly, Noura J Choudhury, Adam Kesner, Assen Kirov, Audrey Mauguen, Marina K Baine, Heiko Schoder, Wolfgang A Weber, Natasha Rekhtman, Serge K Lyashchenko, Lisa Bodei, Michael J Morris, Jason S Lewis, Charles M Rudin, John T Poirier
<p><strong>Background: </strong>Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [<sup>89</sup>Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer.</p><p><strong>Methods: </strong>We conducted an open-label, first-in-human study of immunoPET-CT imaging with [<sup>89</sup>Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [<sup>89</sup>Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [<sup>89</sup>Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [<sup>89</sup>Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741.</p><p><strong>Findings: </strong>Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [<sup>89</sup>Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [<sup>89</sup>Zr
{"title":"Imaging with [<sup>89</sup>Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial.","authors":"Salomon Tendler, Mark P Dunphy, Matthew Agee, Joseph O'Donoghue, Rania G Aly, Noura J Choudhury, Adam Kesner, Assen Kirov, Audrey Mauguen, Marina K Baine, Heiko Schoder, Wolfgang A Weber, Natasha Rekhtman, Serge K Lyashchenko, Lisa Bodei, Michael J Morris, Jason S Lewis, Charles M Rudin, John T Poirier","doi":"10.1016/S1470-2045(24)00249-3","DOIUrl":"10.1016/S1470-2045(24)00249-3","url":null,"abstract":"<p><strong>Background: </strong>Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [<sup>89</sup>Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer.</p><p><strong>Methods: </strong>We conducted an open-label, first-in-human study of immunoPET-CT imaging with [<sup>89</sup>Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [<sup>89</sup>Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [<sup>89</sup>Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [<sup>89</sup>Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741.</p><p><strong>Findings: </strong>Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [<sup>89</sup>Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [<sup>89</sup>Zr","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"1015-1024"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476907","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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