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TONIC: PD-1 Blockade in Metastatic Triple-Negative Breast Cancer

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Key Points

  • In the overall cohort, the objective response rate (ORR) per iRECIST was 20%.
  • The majority of responses were observed in the cisplatin (ORR = 23%) and doxorubicin (ORR = 35%) cohorts.
  • After doxorubicin and cisplatin induction, the investigators detected an upregulation of immune-related genes involved in PD-1/PD-L1 and T-cell cytotoxicity pathways.

Clinical and translational data from the TONIC trial, published in a research letter by Voorwerk et al in Nature Medicine, indicated that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to programmed cell death protein 1 (PD-1) blockade in triple-negative breast cancer.

Researchers wrote that efficacy of PD-1 blockade in metastatic triple-negative breast cancer is low. They emphasized a need for strategies to render the tumor microenvironment more sensitive to PD-1 blockade, and preclinical research has suggested immunomodulatory properties for chemotherapy and radiotherapy.

TONIC Data

In the first stage of TONIC, an adaptive, noncomparative phase II trial, 67 patients with metastatic triple-negative breast cancer were randomly assigned to receive nivolumab without induction or with 2-week low-dose induction, or with irradiation (3  ×  8  Gy), cyclophosphamide, cisplatin, or doxorubicin, all followed by nivolumab.

In the overall cohort, the objective response rate (ORR) per iRECIST was 20%. The majority of responses were observed in the cisplatin (ORR = 23%) and doxorubicin (ORR = 35%) cohorts.

After doxorubicin and cisplatin induction, the investigators detected an upregulation of immune-related genes involved in PD-1/programmed cell death ligand 1 (PD-L1) 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.

The authors concluded, “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 triple-negative breast cancer. These data warrant confirmation in triple-negative breast cancer and exploration of induction treatments prior to PD-1 blockade in other cancer types.”

Disclosure: This study received funding from BMS/II-ON, the Dutch Cancer Society, Pink Ribbon, and the Breast Cancer Research Foundation. For full disclosures of the study authors, visit nature.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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