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