Short-term treatment with doxorubicin or cisplatin may favorably condition the tumor microenvironment in women with metastatic triple-negative breast cancer (TNBC), making response to PD-1 blockade more likely, according to the results of a phase 2 study.1

“Preclinical and clinical studies have shown that low-dose chemotherapy or irradiation may be utilized to stimulate anticancer immune responses,” researchers wrote in the study.

In this analysis, the researchers tested hypofractionated irradiation and low-dose cyclophosphamide, cisplatin, and doxorubicin in patients with TNBC to see if any could serve as a “priming strategy” to improve the efficacy of PD-1/PD-L1 blockade.

During the first stage of the trial, 67 patients with TNBC were randomly assigned to a 2-week waiting period, or irradiation, cyclophosphamide, cisplatin, or doxorubicin, all followed by nivolumab.

Related Articles

The overall response rate was 20%, which the researchers noted was higher than other studies that showed a response rate of only 5% to 10%. However, the majority of responses occurred in patients assigned to cisplatin (23%) or doxorubicin (35%). Patients with no induction had an overall response rate of 17%.

“To our knowledge, TONIC is the first trial to evaluate the concept of [tumor microenvironment modulation] using chemotherapy or irradiation prior to PD-1/PD-L1 blockade,” the researchers wrote.

After induction with cisplatin or doxorubicin, the researchers detected upregulation of immune-related genes involved in PD-1/PD-L1 and T cell cytotoxicity pathways. This was supported by “enrichment among upregulated genes related to inflammation, JAK-STAT, and TNF-alpha signaling after doxorubicin.”

“Our data provide substantial evidence that induction with cisplatin or doxorubicin can prime tumors for response to anti-PD-1, based on high response rates to anti–PD-1 and upregulation of immune-related gene sets,” the researchers concluded.

In the next phase of the study, researchers will validate these results using a nivolumab monotherapy, as well as an arm in which patients would be administered doxorubicin followed by nivolumab.

Reference

  1. Voorwerk L, Slagter M, Horlings HM, et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial [published online May 13, 2019]. Nat Med. doi: 10.1038/s41591-019-0432-4