Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial

• Published in: Nature medicine Vol. 25; no. 6; pp. 920 - 928
• Main Authors: Voorwerk, Leonie, Slagter, Maarten, Horlings, Hugo M., Sikorska, Karolina, van de Vijver, Koen K., de Maaker, Michiel, Nederlof, Iris, Kluin, Roelof J. C., Warren, Sarah, Ong, SuFey, Wiersma, Terry G., Russell, Nicola S., Lalezari, Ferry, Schouten, Philip C., Bakker, Noor A. M., Ketelaars, Steven L. C., Peters, Dennis, Lange, Charlotte A. H., van Werkhoven, Erik, van Tinteren, Harm, Mandjes, Ingrid A. M., Kemper, Inge, Onderwater, Suzanne, Chalabi, Myriam, Wilgenhof, Sofie, Haanen, John B. A. G., Salgado, Roberto, de Visser, Karin E., Sonke, Gabe S., Wessels, Lodewyk F. A., Linn, Sabine C., Schumacher, Ton N., Blank, Christian U., Kok, Marleen
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2019; Nature Publishing Group
• Subjects: 631/250/251; 631/67/1347; 692/308/2779/109/2425; 692/308/53; 692/308/575; Adult; Aged; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents, Immunological - administration & dosage; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cell death; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Combined Modality Therapy; Cyclophosphamide; Cyclophosphamide - administration & dosage; Cytotoxicity; Doxorubicin; Doxorubicin - administration & dosage; Female; Genes; Humans; Immunomodulation; Immunotherapy; Infectious Diseases; Irradiation; Letter; Lymphocytes; Lymphocytes T; Metabolic Diseases; Metastases; Metastasis; Methods; Middle Aged; Molecular Medicine; Monoclonal antibodies; Neoplasm Metastasis - genetics; Neoplasm Metastasis - immunology; Neoplasm Metastasis - therapy; Neurosciences; Nivolumab - administration & dosage; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Radiotherapy, Adjuvant; Sensitivity enhancement; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Targeted cancer therapy; Testing; Toxicity; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - therapy; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology; Tumor necrosis factor-α; Tumors
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-019-0432-4

The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low 1 – 5 , highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation 6 – 13 . In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST 14 ) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1–PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK–STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types. A pick-the-winner clinical trial design in patients with metastatic triple-negative breast cancer shows that immune induction with doxorubicin or cisplatin may improve clinical responses to PD-1 blockade and induce a more favorable tumor microenvironment.