Phase III Trial of Breast Cancer Vaccine Nelipepimut-S Now Fully Enrolled, Mittendorf Discusses Next Steps

Elizabeth A. Mittendorf, MD, PhD

Enrollment is now complete for the phase III PRESENT trial examining nelipepimut-S (NeuVax) in patients with breast cancer, according to Galena Biopharma, the company developing the vaccine. Researchers have now accrued 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).

Nelipepimut-S comprises a peptide derived from HER2 protein combined with GM-CSF. Patients receive it monthly for 6 months and then every 6 months thereafter for up to 3 years. Early data have shown that the immunotherapy could offer a promising new option for breast cancer patients with low-to-intermediate HER2 expression.

In a phase I/II trial that examined 187 women with tumors that expressed any degree of HER2, the 5-year rate of disease-free survival (DFS) was 89.7% overall for those who received nelipepimut-S compared with 80.2% for those who did not. For optimally dosed patients, the DFS rate rose to 94.6%.

The phase III international PRESENT trial is a randomized, double-blind, placebo-controlled study being conducted at over 140 sites. The primary endpoint is 3-year DFS.

To learn more about PRESENT and the potential impact of nelipepimut-S in breast cancer, OncLive spoke with the trial’s principal investigator, Elizabeth A. Mittendorf, MD, PhD, associate professor, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center.

OncLive: Now that enrollment is complete, can you discuss the plans for the phase III PRESENT trial? What are your expectations?

Dr Mittendorf: We have to do a couple of things to ensure we have a successful trial. First, those who have been randomized need to be taken through their vaccinations. This usually includes monthly injections for 6 months and then booster shots after 3 years. It is also important to have patients continue into the follow-up period, because the follow-up data will really lead to our endpoint. The trial is written in such a way that the endpoint will be achieved after 3 years or about 140 reoccurrences. By mapping that out, it appears those two things may happen at about the same time.

So far, we have seen some reoccurrences. However, I am blinded to if those reoccurrences are occurring in vaccinated or controlled patients. I can only base my enthusiasm on the data that we have from our earlier phase trials. For patients who received the appropriate dose in the phase I/II studies, which is the dose we are using in this phase III study, the vaccine reduced reoccurrence by about 50%. If we continue to see those sorts of results in the phase III trial, it will be a positive trial.

There are plenty examples of trials that have done well in phase II and have not been proven in phase III, so that is a possibility here. However, the way the trial is designed with the very specific patient population we identified, I am cautiously optimistic based on what we’ve learned from previous studies.

How does this current trial differ from prior research?

When we did our phase I/II studies, we allowed patients with any degree of HER2 expression. Since those trials started, trastuzumab became standard of care for HER2 3+ disease, so the PRESENT trial is only enrolling HER2 1+ and 2+ patients. In order to have a population that has an approximate 20% risk of reoccurrence, this trial is only enrolling patients with node-positive disease, where as the earlier trials enrolled patients with node-negative disease.

Those are the two biggest differences in our patient population. The phase III patient population was chosen from what we learned in the earlier studies. Specifically, it was those patients with lower HER2 expression who seemed to have the most robust immune response. When we looked at the number of immune cells in their blood that were generated after vaccination, it was higher than the HER2 3+ patients.

What are the biggest challenges in treating someone with low-to-intermediate HER2 expression?

The challenge for the HER2 1+ 2+ patients is that, other than endocrine therapy for those who also happen to be HR positive, we don’t have any treatment for them after they finish their chemotherapy. They just go into their follow-up phase. We’ve gone back and looked at our data, and HER2 1+ 2+ have a worse disease-free survival than 3+ because they don’t have trastuzumab to fall back on. The vaccine may represent an opportunity for an immunotherapy in HER2 1+ 2+ patients. I actually consider trastuzumab to be a form of immunotherapy for the 3+ group. I think there are immunological mechanisms of trastuzumab that we are just now learning about.

Are there any patients who should not receive nelipepimut-S, or are there any challenging toxicities that result from the treatment?

The vaccine is incredibly well tolerated; it is not something that you’d have any hesitation to give to patients with comorbidities. We are not trying to replace anything that we know works. We are not trying to replace chemotherapies, surgery, or radiation. What we are offering is an option for a very well tolerated, simple shot. Most patients just get a little bit of redness and itchiness at the injection site and may have a little bit of fatigue and bone pain. For fairly minimal toxicity, this is an agent that could decrease your risk of reoccurrence by about 50%. There is a lot of enthusiasm from patients and providers to consider this, rather than using another chemotherapy agent for these patients, which would increase toxicity. This offers a lifelong immune response. It is not like a chemo drug that once it is out of your system and the half-life is past, there is no more benefit. Once you get the vaccine, this is potentially a lifelong protection.

Do you ever see a role for this vaccine in the metastatic setting?

If you look at similar vaccines that have been investigated in the metastatic setting, they have been unsuccessful. The reason for that is because the metastatic microenvironment is so hostile to the immune system. There are cells that counter immune responses and there are cytokines that dampen immune responses. If we were to ever take the vaccine into the metastatic setting, it would need to be done in combination with another immunotherapeutic agent. There has been a lot of enthusiasm about checkpoint blockades, and that could be something to be used in combination with the vaccine in the metastatic setting. However, as a monotherapy, I don’t see that working.

In general, what do you see as the future for immunotherapy in breast cancer?

Historically, it has been suggested that breast cancer is not an immunogenic disease. We have emerging data that suggest that is not the case. Within 10 years, I personally believe that every patient with breast cancer will have some form of immunotherapy as part of his or her standard treatment plan. It is going to be a matter of finding the correct immunotherapy for the correct disease stage. We are just at the beginning of a very exciting time.