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.
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.
- 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