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

Nat Med. 2019 Jun;25(6):920-928. doi: 10.1038/s41591-019-0432-4. Epub 2019 May 13.


The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low1-5, 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 irradiation6-13. 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; iRECIST14) 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.

Publication types

  • Adaptive Clinical Trial
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Immunological / administration & dosage
  • B7-H1 Antigen / antagonists & inhibitors
  • Cisplatin / administration & dosage
  • Combined Modality Therapy
  • Cyclophosphamide / administration & dosage
  • Doxorubicin / administration & dosage
  • Female
  • Humans
  • Middle Aged
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / immunology
  • Neoplasm Metastasis / therapy
  • Nivolumab / administration & dosage
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Radiotherapy, Adjuvant
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • 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


  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • CD274 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Nivolumab
  • Doxorubicin
  • Cyclophosphamide
  • Cisplatin