Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study

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Abstract

Purpose

Agents targeting programmed death receptor 1 (PD-1) or its ligand (PD-L1) have shown antitumor activity in the treatment of metastatic breast cancer (MBC). The aim of this study was to assess the activity of avelumab, a PD-L1 inhibitor, in patients with MBC.

Methods

In a phase 1 trial (JAVELIN Solid Tumor; NCT01772004), patients with MBC refractory to or progressing after standard-of-care therapy received avelumab intravenously 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Membrane PD-L1 expression was assessed by immunohistochemistry (Dako PD-L1 IHC 73-10 pharmDx).

Results

A total of 168 patients with MBC, including 58 patients with triple-negative breast cancer (TNBC), were treated with avelumab for 2–50 weeks and followed for 6–15 months. Patients were heavily pretreated with a median of three prior therapies for metastatic or locally advanced disease. Grade ≥ 3 treatment-related AEs occurred in 13.7% of patients, including two treatment-related deaths. The confirmed objective response rate (ORR) was 3.0% overall (one complete response and four partial responses) and 5.2% in patients with TNBC. A trend toward a higher ORR was seen in patients with PD-L1+ versus PD-L1− tumor-associated immune cells in the overall population (16.7% vs. 1.6%) and in the TNBC subgroup (22.2% vs. 2.6%).

Conclusion

Avelumab showed an acceptable safety profile and clinical activity in a subset of patients with MBC. PD-L1 expression in tumor-associated immune cells may be associated with a higher probability of clinical response to avelumab in MBC.

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Most cited references 40

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New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

E A Eisenhauer, P Therasse, J. Bogaerts … (2009)

Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.

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Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

Y Iwai, M. Ishida, Y. Tanaka … (2002)

PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.

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Immune checkpoint blockade: a common denominator approach to cancer therapy.

Suzanne Topalian, Charles Drake, Drew M Pardoll (2015)

The immune system recognizes and is poised to eliminate cancer but is held in check by inhibitory receptors and ligands. These immune checkpoint pathways, which normally maintain self-tolerance and limit collateral tissue damage during anti-microbial immune responses, can be co-opted by cancer to evade immune destruction. Drugs interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, anti-PD-L1, and others in early development, can unleash anti-tumor immunity and mediate durable cancer regressions. The complex biology of immune checkpoint pathways still contains many mysteries, and the full activity spectrum of checkpoint-blocking drugs, used alone or in combination, is currently the subject of intense study. Copyright © 2015 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Luc Y. Dirix:

ORCID: http://orcid.org/0000-0002-7792-9964

luc.dirix@gza.be

Istvan Takacs: takacs.istvan@med.semmelweis-univ.hu

Guy Jerusalem: g.jerusalem@chu.ulg.ac.be

Petros Nikolinakos: pnikolinakos@universitycancer.com

Hendrik-Tobias Arkenau: Tobias.Arkenau@HCAHealthcare.co.uk

Andres Forero-Torres: aforero@uab.edu

Ralph Boccia: rboccia@ccbdmd.com

Marc E. Lippman: mlippman@med.miami.edu

Robert Somer: somer-robert@cooperhealth.edu

Martin Smakal: msmakal@gmail.com

Leisha A. Emens: emensle@jhmi.edu

Borys Hrinczenko: borys.hrinczenko@hc.msu.edu

William Edenfield: jedenfield@ghs.org

Jayne Gurtler: drgurtler@metairieoncologists.org

Anja von Heydebreck: Anja.von.Heydebreck@merckgroup.com

Hans Juergen Grote: hans-juergen.grote@merck.de

Kevin Chin: kevin.chin@emdserono.com

Erika P. Hamilton: ehamilton@tnonc.com

Journal

Journal ID (nlm-ta): Breast Cancer Res Treat

Journal ID (iso-abbrev): Breast Cancer Res. Treat

Title: Breast Cancer Research and Treatment

Publisher: Springer US (New York )

ISSN (Print): 0167-6806

ISSN (Electronic): 1573-7217

Publication date (Electronic): 23 October 2017

Publication date PMC-release: 23 October 2017

Publication date (Print): 2018

Volume: 167

Issue: 3

Pages: 671-686

Affiliations

[1 ]ISNI 0000 0001 0790 3681, GRID grid.5284.b, Sint Augustinus-University of Antwerp, ; Antwerp, Belgium

[2 ]ISNI 0000 0001 0942 9821, GRID grid.11804.3c, Semmelweis University, ; Budapest, Hungary

[3 ]ISNI 0000 0000 8607 6858, GRID grid.411374.4, CHU Sart Tilman Liege and Liege University, ; Liege, Belgium

[4 ]GRID grid.477676.3, University Cancer & Blood Center, LLC, ; Athens, GA USA

[5 ]ISNI 0000 0004 0459 7684, GRID grid.477834.b, Sarah Cannon Research Institute, ; London, UK

[6 ]ISNI 0000000121901201, GRID grid.83440.3b, University College London Cancer Institute, ; London, UK

[7 ]ISNI 0000000106344187, GRID grid.265892.2, University of Alabama, ; Birmingham, AL USA

[8 ]GRID grid.477919.5, Center for Cancer and Blood Disorders, ; Bethesda, MD USA

[9 ]ISNI 0000 0004 1936 8606, GRID grid.26790.3a, University of Miami Miller School of Medicine, ; Miami, FL USA

[10 ]ISNI 0000 0004 0384 9827, GRID grid.411896.3, Cooper Hospital University Medical Center, ; Camden, NJ USA

[11 ]Nemocnice Horovice, Onkologicke Oddelení, Horovice, Czech Republic

[12 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, The John Hopkins University School of Medicine, ; Baltimore, MD USA

[13 ]ISNI 0000 0001 2150 1785, GRID grid.17088.36, Michigan State University, ; East Lansing, MI USA

[14 ]ISNI 0000 0004 0406 7499, GRID grid.413319.d, Greenville Hospital System, ; Greenville, SC USA

[15 ]Metairie Oncologist LLC, Metairie, LA USA

[16 ]ISNI 0000 0001 0672 7022, GRID grid.39009.33, Merck KGaA, ; Darmstadt, Germany

[17 ]ISNI 0000 0004 0412 6436, GRID grid.467308.e, EMD Serono, ; Billerica, MA USA

[18 ]ISNI 0000 0004 0459 5478, GRID grid.419513.b, Sarah Cannon Research Institute, ; Nashville, TN USA

Author information

Luc Y. Dirix http://orcid.org/0000-0002-7792-9964

Article

Publisher ID: 4537

DOI: 10.1007/s10549-017-4537-5

PMC ID: 5807460

PubMed ID: 29063313

SO-VID: bc253e16-5fb2-4b70-9ab1-ecfbefa38775

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 29 September 2017

Date accepted : 6 October 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009945, Merck KGaA;

Funded by: FundRef http://dx.doi.org/10.13039/100004319, Pfizer;

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: avelumab,metastatic breast cancer,triple-negative breast cancer,pd-l1,second-line

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: avelumab, metastatic breast cancer, triple-negative breast cancer, pd-l1, second-line

Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study

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UCL: UN SDG 03 Good Health and Well-Being

Most cited references 40

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

Immune checkpoint blockade: a common denominator approach to cancer therapy.

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