IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42400-5.html
   My bibliography  Save this article

Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial

Author

Listed:
  • Maria Pouyiourou

    (University of Heidelberg
    University of Heidelberg
    University of Heidelberg)

  • Bianca N. Kraft

    (University of Heidelberg
    University of Heidelberg)

  • Timothy Wohlfromm

    (University of Heidelberg)

  • Michael Stahl

    (Evangelische Kliniken Essen-Mitte)

  • Boris Kubuschok

    (Augsburg University Medical Center and Bavarian Cancer Research Center (BZKF), Partner Cite Augsburg)

  • Harald Löffler

    (Marienhospital Stuttgart)

  • Ulrich T. Hacker

    (University Cancer Center Leipzig (UCCL), Leipzig University Medical Center)

  • Gerdt Hübner

    (Ameos Krankenhausgesellschaft Ostholstein)

  • Lena Weiss

    (University of Munich)

  • Michael Bitzer

    (University Hospital Tübingen)

  • Thomas Ernst

    (Jena University Hospital)

  • Philipp Schütt

    (Onkologische Gemeinschaftspraxis)

  • Thomas Hielscher

    (German Cancer Research Center (DKFZ))

  • Stefan Delorme

    (German Cancer Research Center (DKFZ))

  • Martina Kirchner

    (University of Heidelberg
    University of Heidelberg)

  • Daniel Kazdal

    (University of Heidelberg
    University of Heidelberg)

  • Markus Ball

    (University of Heidelberg
    University of Heidelberg)

  • Klaus Kluck

    (University of Heidelberg
    University of Heidelberg)

  • Albrecht Stenzinger

    (University of Heidelberg
    University of Heidelberg)

  • Tilmann Bochtler

    (University of Heidelberg
    University of Heidelberg
    University of Heidelberg)

  • Alwin Krämer

    (University of Heidelberg
    University of Heidelberg
    University of Heidelberg)

Abstract

Cancer of unknown primary has a dismal prognosis, especially following failure of platinum-based chemotherapy. 10-20% of patients have a high tumor mutational burden (TMB), which predicts response to immunotherapy in many cancer types. In this prospective, non-randomized, open-label, multicenter Phase II trial (EudraCT 2018-004562-33; NCT04131621), patients relapsed or refractory after platinum-based chemotherapy received nivolumab and ipilimumab following TMBhigh vs. TMBlow stratification. Progression-free survival (PFS) represented the primary endpoint; overall survival (OS), response rates, duration of clinical benefit and safety were the secondary endpoints. The trial was prematurely terminated in March 2021 before reaching the preplanned sample size (n = 194). Among 31 evaluable patients, 16% had a high TMB ( > 12 mutations/Mb). Overall response rate was 16% (95% CI 6-34%), with 7.7% (95% CI 1-25%) vs. 60% (95% CI 15-95%) in TMBlow and TMBhigh, respectively. Although the primary endpoint was not met, high TMB was associated with better median PFS (18.3 vs. 2.4 months) and OS (18.3 vs. 3.6 months). Severe immune-related adverse events were reported in 29% of cases. Assessing on-treatment dynamics of circulating tumor DNA using combined targeted hotspot mutation and shallow whole genome sequencing as part of a predefined exploratory analysis identified patients benefiting from immunotherapy irrespective of initial radiologic response.

Suggested Citation

  • Maria Pouyiourou & Bianca N. Kraft & Timothy Wohlfromm & Michael Stahl & Boris Kubuschok & Harald Löffler & Ulrich T. Hacker & Gerdt Hübner & Lena Weiss & Michael Bitzer & Thomas Ernst & Philipp Schüt, 2023. "Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42400-5
    DOI: 10.1038/s41467-023-42400-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42400-5
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-42400-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Viktor A. Adalsteinsson & Gavin Ha & Samuel S. Freeman & Atish D. Choudhury & Daniel G. Stover & Heather A. Parsons & Gregory Gydush & Sarah C. Reed & Denisse Rotem & Justin Rhoades & Denis Loginov & , 2017. "Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    2. David Capper & David T. W. Jones & Martin Sill & Volker Hovestadt & Daniel Schrimpf & Dominik Sturm & Christian Koelsche & Felix Sahm & Lukas Chavez & David E. Reuss & Annekathrin Kratz & Annika K. We, 2018. "DNA methylation-based classification of central nervous system tumours," Nature, Nature, vol. 555(7697), pages 469-474, March.
    3. Guangchun Han & Guoliang Yang & Dapeng Hao & Yang Lu & Kyaw Thein & Benjamin S. Simpson & Jianfeng Chen & Ryan Sun & Omar Alhalabi & Ruiping Wang & Minghao Dang & Enyu Dai & Shaojun Zhang & Fengqi Nie, 2021. "9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    4. Daniel S. Chen & Ira Mellman, 2017. "Elements of cancer immunity and the cancer–immune set point," Nature, Nature, vol. 541(7637), pages 321-330, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Aleix Prat & Fara Brasó-Maristany & Olga Martínez-Sáez & Esther Sanfeliu & Youli Xia & Meritxell Bellet & Patricia Galván & Débora Martínez & Tomás Pascual & Mercedes Marín-Aguilera & Anna Rodríguez &, 2023. "Circulating tumor DNA reveals complex biological features with clinical relevance in metastatic breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Aditi Sahu & Kivanc Kose & Lukas Kraehenbuehl & Candice Byers & Aliya Holland & Teguru Tembo & Anthony Santella & Anabel Alfonso & Madison Li & Miguel Cordova & Melissa Gill & Christi Fox & Salvador G, 2022. "In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Xi Lu & Naga Prathyusha Maturi & Malin Jarvius & Irem Yildirim & Yonglong Dang & Linxuan Zhao & Yuan Xie & E-Jean Tan & Pengwei Xing & Rolf Larsson & Mårten Fryknäs & Lene Uhrbom & Xingqi Chen, 2022. "Cell-lineage controlled epigenetic regulation in glioblastoma stem cells determines functionally distinct subgroups and predicts patient survival," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Claire Vinel & Gabriel Rosser & Loredana Guglielmi & Myrianni Constantinou & Nicola Pomella & Xinyu Zhang & James R. Boot & Tania A. Jones & Thomas O. Millner & Anaelle A. Dumas & Vardhman Rakyan & Je, 2021. "Comparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    5. Shaoshuai Tang & Yunzhi Wang & Rongkui Luo & Rundong Fang & Yufeng Liu & Hang Xiang & Peng Ran & Yexin Tong & Mingjun Sun & Subei Tan & Wen Huang & Jie Huang & Jiacheng Lv & Ning Xu & Zhenmei Yao & Qi, 2024. "Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    6. Alexandra Gyurdieva & Stefan Zajic & Ya-Fang Chang & E. Andres Houseman & Shan Zhong & Jaegil Kim & Michael Nathenson & Thomas Faitg & Mary Woessner & David C. Turner & Aisha N. Hasan & John Glod & Ro, 2022. "Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. E. H. Puttock & E. J. Tyler & M. Manni & E. Maniati & C. Butterworth & M. Burger Ramos & E. Peerani & P. Hirani & V. Gauthier & Y. Liu & G. Maniscalco & V. Rajeeve & P. Cutillas & C. Trevisan & M. Poz, 2023. "Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Mingyun Bae & Gyuhee Kim & Tae-Rim Lee & Jin Mo Ahn & Hyunwook Park & Sook Ryun Park & Ki Byung Song & Eunsung Jun & Dongryul Oh & Jeong-Won Lee & Young Sik Park & Ki-Won Song & Jeong-Sik Byeon & Bo H, 2023. "Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Heng-Jia Liu & Heng Du & Damir Khabibullin & Mahsa Zarei & Kevin Wei & Gordon J. Freeman & David J. Kwiatkowski & Elizabeth P. Henske, 2023. "mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    10. Jonathan C. M. Wan & Dennis Stephens & Lingqi Luo & James R. White & Caitlin M. Stewart & Benoît Rousseau & Dana W. Y. Tsui & Luis A. Diaz, 2022. "Genome-wide mutational signatures in low-coverage whole genome sequencing of cell-free DNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    11. Feng Xie & Xiaoxue Zhou & Peng Su & Heyu Li & Yifei Tu & Jinjin Du & Chen Pan & Xiang Wei & Min Zheng & Ke Jin & Liyan Miao & Chao Wang & Xuli Meng & Hans Dam & Peter Dijke & Long Zhang & Fangfang Zho, 2022. "Breast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    12. Omar Alhalabi & Jianfeng Chen & Yuxue Zhang & Yang Lu & Qi Wang & Sumankalai Ramachandran & Rebecca Slack Tidwell & Guangchun Han & Xinmiao Yan & Jieru Meng & Ruiping Wang & Anh G. Hoang & Wei-Lien Wa, 2022. "MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    13. Kate E. Stanley & Tatjana Jatsenko & Stefania Tuveri & Dhanya Sudhakaran & Lore Lannoo & Kristel Calsteren & Marie Borre & Ilse Parijs & Leen Coillie & Kris Bogaert & Rodrigo Almeida Toledo & Liesbeth, 2024. "Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    14. Yaping Liu & Sarah C. Reed & Christopher Lo & Atish D. Choudhury & Heather A. Parsons & Daniel G. Stover & Gavin Ha & Gregory Gydush & Justin Rhoades & Denisse Rotem & Samuel Freeman & David W. Katz &, 2024. "FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    15. Mengxue Zhou & Jiaxin Wang & Jiaxing Pan & Hui Wang & Lujia Huang & Bo Hou & Yi Lai & Fengyang Wang & Qingxiang Guan & Feng Wang & Zhiai Xu & Haijun Yu, 2023. "Nanovesicles loaded with a TGF-β receptor 1 inhibitor overcome immune resistance to potentiate cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    16. Meriem Messaoudene & Stéphanie Ferreira & Nathalie Saint-Lu & Mayra Ponce & Caroline Truntzer & Romain Boidot & Clément Bescop & Thomas Loppinet & Tanguy Corbel & Céline Féger & Karine Bertrand & Arie, 2024. "The DAV132 colon-targeted adsorbent does not interfere with plasma concentrations of antibiotics but prevents antibiotic-related dysbiosis: a randomized phase I trial in healthy volunteers," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    17. Matthew E. Stokes & Kerstin Wenzl & C. Chris Huang & María Ortiz & Chih-Chao Hsu & Matthew J. Maurer & Nicholas Stong & Yumi Nakayama & Lei Wu & Hsiling Chiu & Ann Polonskaia & Samuel A. Danziger & Fa, 2024. "Transcriptomic classification of diffuse large B-cell lymphoma identifies a high-risk activated B-cell-like subpopulation with targetable MYC dysregulation," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    18. Nicolette M. Fonseca & Corinne Maurice-Dror & Cameron Herberts & Wilson Tu & William Fan & Andrew J. Murtha & Catarina Kollmannsberger & Edmond M. Kwan & Karan Parekh & Elena Schönlau & Cecily Q. Bern, 2024. "Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    19. Charlotte K. Y. Ng & Eva Dazert & Tuyana Boldanova & Mairene Coto-Llerena & Sandro Nuciforo & Caner Ercan & Aleksei Suslov & Marie-Anne Meier & Thomas Bock & Alexander Schmidt & Sylvia Ketterer & Xuey, 2022. "Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    20. Shunli Fu & Lili Chang & Shujun Liu & Tong Gao & Xiao Sang & Zipeng Zhang & Weiwei Mu & Xiaoqing Liu & Shuang Liang & Han Yang & Huizhen Yang & Qingping Ma & Yongjun Liu & Na Zhang, 2023. "Temperature sensitive liposome based cancer nanomedicine enables tumour lymph node immune microenvironment remodelling," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42400-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.