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.
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 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.