Mittendorf Explains What's New With NeuVax in Breast Cancer

Elizabeth A. Mittendorf, MD, PhD, discusses nelipepimut-S (NeuVax), a peptide derived from HER2 protein combined with granulocyte-macrophage colonystimulating factor that is currently being investigated as a single-agent, in combination with standard-of-care therapies, and in multiple settings and subtypes of breast cancer.

Elizabeth A. Mittendorf, MD, PhD

Nelipepimut-S (NeuVax), a peptide derived from HER2 protein combined with granulocyte-macrophage colonystimulating factor (GM-CSF), is currently being investigated as a single-agent, in combination with standard-ofcare therapies, and in multiple settings and subtypes of breast cancer.

upon reaching 141 events with 3 years minimum follow-up. According to lead study author Elizabeth A. Mittendorf, MD, PhD, both endpoints are expected to happen in 2018. Mittendorf presented the talk Immunotherapy Update: Biology and Early Results: Vaccines on Friday at the Miami Breast Cancer Conference. Nelipepimut-S is also being considered in combination. Two ongoing trials are investigating trastuzumab (Herceptin) with nelipepimut-S in patients with varying levels of HER2 positivity.

“These trials are looking at if trastuzumab may actually make nelipepimut-S more effective,” says Mittendorf, associate professor, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center. “There is a lot of pre-clinical data to suggest that there would be synergy between vaccines that elicit a CD8 T-cell response and trastuzumab.”

One study, a phase IIb trial, is evaluating trastuzumab and nelipepimut-S in node positive and triple-negative, nodenegative breast cancer patients with immunohistochemistry HER2 1+/2+ expressing tumors who are disease-free after standard-of-care therapy. The trial is ongoing. A second phase II trial, which is also ongoing and currently recruiting participants, is evaluating combination immunotherapy with nelipepimut-S and trastuzumab in high-risk HER2-positive 3+ breast cancer patients. Both HER2 1+ 2+ and HER2 3+ patients seem to benefit from the combination regimen, says Mittendorf.

“The immune data from the early trials suggest that both groups do generate an immune response,” says Mittendorf. “However, response appears to be a bit more robust in the low expressers. The rational for that may be because the high expressers have had enough antigen that patients have developed a little bit of tolerance, making it more difficult for vaccination to be effective.”

New Therapies Under Development

Other combination regimens with nelipepimut-S are on the horizon.

“It is also likely that these vaccines may be able to find their place in the metastatic setting in combination with other drugs that are either agonizing the T-cell stimulatory molecules or antagonizing T-cell inhibitory molecules,” says Mittendorf.

Nelipepimut-S is also being investigated in ductal carcinoma in situ (DCIS).

A randomized phase II trial of nelipepimut-S plus GMCSF vaccine therapy versus sargramostim (Leukine), a type of GM-CSF, alone in DCIS patients will soon begin recruiting participants and will include patients from MD Anderson, Memorial Sloan Kettering, Dana-Farber, and Columbia University medical centers.

Patients diagnosed with DCIS will get 3 cycles of the vaccine prior to surgery, undergo surgery, and then compete 3 more vaccines post-surgery, explains Mittendorf. “The goal of the study is to see if we can increase the number of T-cells circulating in the patients that recognize the HER2 antigen,” says Mittendorf. “Because the vaccine is being given before surgery, it will also give us an opportunity using the surgical specimens to determine if we have induced the T-cell infiltrate into the tumor area.”

If the vaccine is effective in patients at the earliest stage of the disease in DCIS, it may be investigated as a preventative therapy, says Mittendorf. However, investigating the agent in the preventative setting will be a challenge.

“I think that the DCIS trial is the first step towards moving into primary prevention,” she says. “However, the logistics around doing preventative trials in a primary population are fairly significant based on the number of patients required and the length of follow-up. What we are hoping for is that we will be able to develop the immunologic markers that will show us who is responding that could be used as endpoints for those kinds of studies.”

Similar vaccines to nelipepimut-S are also on the horizon. These include GP2, a novel HER2-derived peptide vaccine designed to stimulate CD8+ cytotoxic T-lymphocytes and reduce the rate of breast cancer recurrence. In a multicenter phase II randomized study of 180 women with high-risk breast cancer, GP2 vaccine recipients with the highest overexpression of HER2 had no recurrences after completing trastuzumab therapy.

“This suggests that for the HER2-positive 3+ group to have the optimal response with vaccination, they need to receive it in combination with trastuzumab,” says Mittendorf.

Other breast cancer vaccines may be coming soon, including PANVAC, a poxviral-based cancer vaccine, which has shown clinical efficacy and immunologic activity in some patients with breast, ovarian, and colorectal cancer. A Folate Receptor Alpha (FRα) peptide vaccine is also being evaluated mixed with GM-CSF as a vaccine adjuvant, with or without an immune priming with cyclophosphamide, as a consolidation therapy after neoadjuvant or adjuvant treatment of patients with Stage IIb-III triplenegative breast cancer (TNBC).

Mittendorf’s research team is also beginning to investigate the concept of personalized vaccines, which utilize the patient’s own tumor to dictate what should be targeted. “There is lot going on in the world of vaccines in breast cancer,” says Mittendorf. “The technology is advancing rapidly. I think there is going to be a role for vaccines, but how we choose to use it is going to be dictated by the stage of disease.”

The phase III PRESENT trial is examining nelipepimut- S in 758 women with early-stage node-positive breast cancer with low-to-intermediate HER2 expression (HER2 1+ by IHC or HER2 2+ by IHC/FISH) at over 140 sites. The primary analysis endpoint will be trigged