Efficacy of the eribulin, pertuzumab, and trastuzumab combination therapy for human epidermal growth factor receptor 2–positive advanced or metastatic breast cancer: a multicenter, single arm, phase II study (JBCRG-M03 study)

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Purpose To date, it is not clear which anticancer agent is useful in combination with trastuzumab and pertuzumab As the first and second selective regimens for advanced or metastatic breast cancer (AMBC), this multicenter, open-label, phase II trial (JBCRG-M03: UMIN000012232) presents a prespecified analysis of eribulin in combination with pertuzumab and trastuzumab. Methods We enrolled 50 patients with no or single prior chemotherapy for HER2-positive AMBC during November 2013–April 2016. All patients received adjuvant or first-line chemotherapy with trastuzumab and a taxane. The treatment comprised eribulin on days 1 and 8 of a 21-day cycle and trastuzumabplus pertuzumab once every 3 weeks, all administered intravenously. While the primary endpoint was the progression-free survival (PFS), secondary endpoints were the response rate and safety. Results Of 50 patients, 49 were eligible for safety analysis, and the full analysis set (FAS) included 46 patients. We treated 8 (16%) and 41 (84%) patients in first- and second-line settings, respectively. While 11 patients (23.9%) had advanced disease, 35 (76.1%) had metastatic disease. The median PFS was 9.2 months for all patients [95% confidence interval (CI): 7.0–11.4]. In the FAS, 44 patients had the measurable lesions and the complete response rate (CR) was 17.4%, and partial response rate (PR) was 43.5%. The grade 3/4 adverse events were neutropenia (5 patients, 10.2%), including febrile neutropenia (2 patients, 4.1%), hypertension (3 patients, 6.1%), and other (1 patient). The average of the left ventricular ejection fraction did not decline markedly. No symptomatic left ventricular systolic dysfunction was observed. Conclusions In patients with HER2-positive AMBC, eribulin, pertuzumab, and trastuzumab combination therapy exhibited substantial antitumor activity with an acceptable safety profile. Hence, we have started a randomized phase III study comparing eribulin and a taxane in combination with pertuzumab and trastuzumab for the treatment of HER2-positive AMBC. Trial registration ID: UMIN-CTR: UMIN000012232.

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Most cited references 33

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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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TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells

Sanjeev Mariathasan, Shannon Turley, Dorothee Nickles … (2018)

Therapeutic antibodies that block the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer (mUC) 1–5 . However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here, we examined tumours from a large cohort of mUC patients treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). Lack of response was associated with a signature of transforming growth factor β (TGF-β) signalling in fibroblasts, particularly in patients with CD8+ T cells that were excluded from the tumour parenchyma and instead found in the fibroblast- and collagen-rich peritumoural stroma—a common phenotype among patients with mUC. Using a mouse model that recapitulates this immune excluded phenotype, we found that therapeutic administration of a TGF-β blocking antibody together with anti–PD-L1 reduced TGF-β signalling in stromal cells, facilitated T cell penetration into the centre of the tumour, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding outcome in this setting and suggests that TGF-β shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T cell infiltration.

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TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis

Daniele V F Tauriello, Sergio Palomo-Ponce, Diana Stork … (2018)

Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity or increased TGFβ levels predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden, T-cell exclusion and TGFβ-activated stroma. Inhibition of the PD-1-PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFβ unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1-PD-L1 therapy. Our data show that increased TGFβ in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the TH1-effector phenotype. Immunotherapies directed against TGFβ signalling may therefore have broad applications in treating patients with advanced colorectal cancer.

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Author and article information

Contributors

Toshinari Yamashita:

ORCID: https://orcid.org/0000-0002-6479-1660

tyamashita@kcch.jp

Journal

Journal ID (nlm-ta): Invest New Drugs

Journal ID (iso-abbrev): Invest New Drugs

Title: Investigational New Drugs

Publisher: Springer US (New York )

ISSN (Print): 0167-6997

ISSN (Electronic): 1573-0646

Publication date (Electronic): 24 August 2020

Publication date PMC-release: 24 August 2020

Publication date (Print): 2021

Volume: 39

Issue: 1

Pages: 217-225

Affiliations

[1 ]GRID grid.414944.8, ISNI 0000 0004 0629 2905, Department of Breast and Endocrine Surgery, , Kanagawa Cancer Center, ; 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515 Japan

[2 ]GRID grid.416592.d, ISNI 0000 0004 1772 6975, Department of Breast Surgery, , Matsuyama Red Cross Hospital, ; Matsuyama, Japan

[3 ]GRID grid.416803.8, ISNI 0000 0004 0377 7966, Department of Surgery, Breast Oncology, , NHO Osaka National Hospital, ; Osaka, Japan

[4 ]GRID grid.413955.f, ISNI 0000 0004 0489 1533, Breast Disease Center, , Asahikawa Medical University Hospital, ; Asahikawa, Japan

[5 ]GRID grid.413045.7, ISNI 0000 0004 0467 212X, Breast and Thyroid Surgery, , Yokohama City University Medical Center, ; Yokohama, Japan

[6 ]GRID grid.410800.d, ISNI 0000 0001 0722 8444, Department of Breast Oncology, , Aichi Cancer Center, ; Nagoya, Japan

[7 ]GRID grid.489169.b, Department of Medical Oncology, , Osaka International Cancer Institute, ; Osaka, Japan

[8 ]GRID grid.417001.3, ISNI 0000 0004 0378 5245, Department of Breast Surgery, , Osaka Rosai Hospital, ; Sakai, Japan

[9 ]GRID grid.414973.c, Department of Medical Oncology, , Kansai Electric Power Hospital, ; Osaka, Japan

[10 ]GRID grid.459677.e, ISNI 0000 0004 1774 580X, Department of Breast and Endocrine Surgery, , Japanese Red Cross Kumamoto Hospital, ; Kumamoto, Japan

[11 ]GRID grid.411321.4, ISNI 0000 0004 0632 2959, Department of General Surgery, , Chiba University Hospital, ; Chiba, Japan

[12 ]GRID grid.20515.33, ISNI 0000 0001 2369 4728, Breast and Endocrine Surgery, Faculty of Medicine, , University of Tsukuba, ; Tsukuba, Japan

[13 ]GRID grid.174567.6, ISNI 0000 0000 8902 2273, Department of Surgery, , Nagasaki University Graduate School of Biomedical Sciences, ; Nagasaki, Japan

[14 ]Department of Breast Surgery, Hirosaki Municipal Hospital, Hirosaki, Japan

[15 ]GRID grid.418490.0, ISNI 0000 0004 1764 921X, Department of Breast Surgery, , Chiba Cancer Center, ; Chiba, Japan

[16 ]Breast Surgery, Sagara Hospital, Kagoshima, Japan

[17 ]GRID grid.258799.8, ISNI 0000 0004 0372 2033, Department of Biomedical Statistics and Bioinformatics, , Graduate School of Medicine Kyoto University, ; Kyoto, Japan

[18 ]GRID grid.486756.e, ISNI 0000 0004 0443 165X, Center of Breast Oncology, , The Cancer Institute Hospital of JFCR, ; Tokyo, Japan

[19 ]GRID grid.258799.8, ISNI 0000 0004 0372 2033, Department of Surgery (Breast Surgery), , Graduate School of Medicine Kyoto University, ; Kyoto, Japan

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Toshinari Yamashita https://orcid.org/0000-0002-6479-1660

Article

Publisher ID: 991

DOI: 10.1007/s10637-020-00991-6

PMC ID: 7851001

PubMed ID: 32833136

SO-VID: 674b1699-2183-4523-8334-76a0c5f791f9

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 23 July 2020

Date accepted : 18 August 2020

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: metastatic breast cancer,chemotherapy,anti-her2 drug,eribulin,pertuzumab

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: metastatic breast cancer, chemotherapy, anti-her2 drug, eribulin, pertuzumab

Efficacy of the eribulin, pertuzumab, and trastuzumab combination therapy for human epidermal growth factor receptor 2–positive advanced or metastatic breast cancer: a multicenter, single arm, phase II study (JBCRG-M03 study)

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Karger: Oncology

Most cited references 33

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

TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells

TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis

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