ORLANDO (FRONTLINE MEDICAL NEWS) – The novel combination of entinostat and nivolumab with or without ipilimumab showed encouraging safety, tolerability, and antitumor activity in early results from an ongoing phase 1 trial of patients with advanced breast cancer.

Of 30 patients who were enrolled and treated in the dose-escalation phase of the study as of Feb. 24, 2018, 20 had evaluable responses, and of those, 3 had a partial response for an overall response rate of 15%. An additional 12 had stable disease, and 5 had disease progression, Roisin M. Connolly, MD , reported in a poster at the annual conference of the National Comprehensive Cancer Network.

All patients received 5 mg of entinostat during a 2-week run-in period. After that, dose level 1 (DL1) patients received 3 mg of entinostat weekly plus 3 mg/kg of nivolumab every 2 weeks, dose level 2 (DL2) patients received 5 mg of entinostat weekly and 3 mg/kg of nivolumab every 2 weeks, dose level 3 (DL3) patients received 3 mg of entinostat weekly plus 3 mg/kg nivolumab every 2 weeks and 1 mg/kg of ipilimumab every 6 weeks for up to four doses, and dose level 4 (DL4) patients received 5 mg of entinostat weekly plus 3 gm/kg nivolumab every 2 weeks and 1 mg/kg of ipilimumab every 6 weeks for up to four doses.

Responses were seen in all 3 DL1 patients, 12 of 14 DL2 patients, 3 of 4 DL3 patients, and 2 of 9 (with 4 pending first restaging) DL4 patients. Dose-limiting toxicities included one case of pneumonitis at DL2 and an allergic reaction in one DL4 patient, said Dr. Connolly of Johns Hopkins University, Baltimore.

The most common treatment-associated adverse events occurring in 6 or more patients included anemia, fatigue, neutropenia, nausea, and rash, with each occurring in 12 to 22 patients, including grade 3 anemia in 7 patients, grade 3 fatigue in 4 patients, and grade 3 neutropenia in 5 patients. Grade 4 adverse events included lymphopenia in one patient and elevated lipase in one patient, she said.

Possible immune-related adverse events included hypothyroidism in 2 DL2 patients and 3 DL3 patients, hyperthyroidism in 1 DL3 patient, colitis in 1 DL2 and 1 DL3 patient, pneumonitis in 4 DL2 patients, rash in 10 DL2-DL4 patients, and meningoencephalitis and myasthenia gravis in 1 DL3 patient.

Study participants were adults with a mean age of 60 years with metastatic or unresectable solid tumors for which standard treatments did not exist or were no longer effective, or for which treatment with anti–programmed cell death ligand1/cytotoxic T-lymphocyte antigen 4 treatment was appropriate. All had good performance status and adequate organ and pulmonary function, less than 30% liver involvement, and any brain metastases were stable. Those with active autoimmune disease or a history of autoimmune disease that might recur were excluded, as were patients treated within 14 days of enrollment.

“The rationale for the study was based on preclinical work suggesting that epigenetic modifiers might be able to enhance the efficacy of immune therapies, and this would be particularly important for ‘colder’ tumor types like breast cancer that might not have the same sort of responses that we see in other tumor types,” Dr. Connolly explained in an interview. “The lab work suggested, for example, that the [histone deacetylase] inhibitor entinostat might affect myeloid-derived suppressor and regulatory T cells that might prevent cytotoxic T cells from fighting the cancer.”

There may be other mechanisms for this activity as well, she noted.

The run-in period with entinostat alone allowed collection of pre- and posttreatment biopsies to examine the effects on the tissues, such as whether treatment affects T cells, myeloid-derived suppressor cells, or their pathways, she said.

“We’re seeing [the] same types of toxicities seen with combination immune-oncology strategies, and we’re seeing some tumor responses that are of interest. Now we will delve into the tissue biopsies and blood samples we’ve collected to explore the mechanisms in more detail. In the near future we will open our breast cancer expansion cohort to look in more detail at what these drugs might be doing in breast cancer,” she added.

Specifically, she and her colleagues are evaluating the effects of treatment on immune-related biomarkers, measuring tumor-specific mutations and mutant neoantigens recognized by patient T cells in tumor biopsies, evaluating changes in the frequency of T cells recognizing tumor-specific mutant neoantigens in peripheral blood lymphocytes pre- and posttherapy, and looking at epigenetic changes pre- and posttherapy.

These preliminary findings suggest that the combination of entinostat and nivolumab with or without ipilimumab is safe and tolerable, with expected rates of immune-related adverse events, Dr. Connolly said, noting that the recommended phase 2 dose to be used in the dose expansion phase of the study has yet to be determined.

The findings, should they be confirmed as the trial progresses, could have important implications because immune checkpoint inhibitors, which work best in patients with immunogenic cancers that naturally attract T-cell infiltration into their tumor microenvironment, have limited single-agent activity in tumors, such as breast cancer, that are not believed to be immunogenic, she reported. Such cancers have thus far had only modest responses to single-agent immune checkpoint inhibition in advanced triple-negative and HER2+ breast cancer, with overall response rates of 5%-20%.

However, women who do respond to immune checkpoint inhibition tend to have durable and sustainable responses, she said, explaining that suboptimal immune responsiveness is likely a result of a lack of tumor antigen expression and/or recognition, as well as multiple suppressive signals in the tumor microenvironment.

Should the novel strategy tested in this study for converting breast cancers into immune responsive tumors facilitate improved response to immune checkpoint agents, it has the potential to significantly extend survival in breast cancer patients, she concluded.

This study was funded by grants from the National Institutes of Health, Bloomberg Kimmel Institute for Immunotherapy, NCCN, and the Mary Kay Foundation, as well as a V Foundation award. Dr. Connolly reported having no disclosures.

SOURCE: Connolly RM et al. NCCN, Poster 3 .


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