Alpha-TEA and Concurrent Trastuzumab Under Exploration in Refractory HER2+ Breast Cancer

Concurrent treatment with α-tocopheryloxyacetic acid (α-TEA) and trastuzumab (Herceptin) could possess the potential to induce clinical activity and augment type 1 (Th1) antitumor immunity in patients with HER2-positive metastatic breast cancer who have progressed on HER2-directed therapies, investigators of an ongoing phase 1 trial have hypothesized.

In the dose-escalation trial, investigators aim to enroll 24 patients with progressive metastatic HER2-positive breast cancer who have previously progressed on trastuzumab/pertuzumab (Perjeta) and ado-trastuzumab emtansine (T-DM1; Kadcyla). In the trial, patients will receive 1 of 4 sequential doses of α-TEA: 0.6 mg/kg, 1.2 mg/kg, 2.4 mg/kg, and 4.8 mg/kg. Investigators will determine the safety of the 4 escalating doses of α-TEA with concurrent trastuzumab, evaluate the clinical response of this approach, and determine whether the combination increases activity of effector memory CD4+ and CD8+ T cells.

“We anticipate that this will be a fairly safe therapy and safe combination,” William R. Gwin III, MD, lead study investigator, said. “Right now, unfortunately, data are premature, so certainly ongoing follow-up of these patients and their lab values will be critical. Alpha-TEA has the potential to provide a new type of immune therapy that's delivered via pill that patients take home and, hopefully, augment antitumor immunity while working synergistically with ongoing therapies.”

In an interview with OncLive, Gwin, an assistant professor at both the Seattle Cancer Care Alliance and the University of Washington Cancer Vaccine Institute, further discussed the ongoing trial examining this novel combination and provided insight into the next steps for this research.

OncLive: Could you discuss the rationale for this regimen, including the reasoning behind the dose-escalation?

Gwin: The rationale is two-fold: We've known for a while that α-TEA, which is the truncated name of this molecule, has antitumor activity. It is known as an ether derivative of alpha-tocopherol, which is vitamin E. We know that vitamin E, unfortunately, has not shown the antitumor activity that we had hoped for. Alpha-TEA is distinctly different in that it is directly cytotoxic to tumor cells; it has demonstrated this in mostly preclinical, studies. Now, we have an ongoing, single-agent phase 1 study where it has also demonstrated antitumor activity in patients with cancer; this activity appears to be mediated by the generation of reactive oxygen species, which then leads to apoptotic cell death. [Alpha-TEA] seems to be particularly selective for tumor cells, as opposed to what we see with more traditional cytotoxic chemotherapies. That's the basis of what we previously knew about α-TEA.

More recently, as interest in immunotherapy increases, there was an investigation [to determine whether] α-TEA mediates some immune properties, as well. Interestingly enough, it does. Alpha-TEA has immunostimulatory activities, particularly in the tumor immune microenvironment. Preclinical studies have shown that it can increase the frequencies of activated CD4 and CD8 T cells, which are critical immune cells in mediating antitumor activity. This was highlighted in depletion studies where if you would knock out the CD4 and CD8 T cells, you see a loss of the antitumor activity of the α-TEA.

In addition to this, we, as a group, recognize that there is a particular type of immune response that’s needed to generate antitumor immunity; this is called Type 1 or Th1 immunity. We recognize [that this is] Type 1 immunity is lost in many tumors. Alpha-TEA appears to augment that Th1 immunity by increasing not only the CD8 and CD4 T cells, but also boosting cytokines that are associated with Th1, such as interferon-gamma.

A group in Portland has an ongoing phase 1 study with the single-agent α-TEA where they have reported some of these same immune responses in a clinical trial [setting] with reported increases in activated CD8 T cells in both effector memory and effector CD8 T cell subsets. All this is to say that α-TEA does mediate antitumor effects, but it does so through a couple of different mechanisms. For one, it results in the generation of reactive oxygen species which leads to apoptosis, as well as through an immune-mediated component through augmentation of the level of CD4 and CD8 T cells.

Considering what we can combine it with in areas of clinical need in oncology, certainly, we have many HER2 agents out there, particularly in the metastatic setting, which is great for patients. The challenge we continue to face is, despite these agents, patients continue to progress. We need additional agents with new mechanisms of action to mediate better antitumor efficacy. We recognize that, particularly in breast cancer, which is my area of clinical and research interest, there's a recognized immune component to HER2-driven cancers. Interestingly, you lose HER2-specific immune responsiveness as patients’ diseases move through oncogenesis. Our interest in combining these two therapies (α-TEA and trastuzumab) is that in HER2-positive breast cancers we see both loss of HER2 immunity , as well as loss of Th1 immunity. Thus, if we can combine agents that augments Th1 immunity as well as HER2 specific immunity, we hope to see a synergistic and complementary effect in this population.

Our phase 1 single-agent study is ongoing, it is a dose-escalation study, where all dose levels will be getting α-TEA plus trastuzumab. Eligible patients must be refractory to trastuzumab, pertuzumab, as well as T-DM1. Also, they can have received lapatinib (Tykerb) in the past.

What did you present at the 2020 ASCO Virtual Scientific Program?

Our interest is presenting [the study] to the scientific community as an ongoing trial, and then highlighting our goals of this study, which are to look at the safety of the combination of α-TEA and trastuzumab in this HER2 treatment-refractory population. We also want to examine whether there’s any clinical benefit of this combination. From a scientific and immunologic standpoint, are we able to see, with this combination, a reversal of some of the effects or defects in the immune system that we know is present in HER2-driven breast cancers? Do we see an increase in HER2-specific T cells? Do we see an increase in this type 1 immunity with this combination?

Recognizing one of the real detriments in these immunologically- and HER2-driven breast cancer, is a decrease in the level and activity of natural killer (NK) cells, which are critical in mediating antitumor immunity. In this study do we see an increase in that level and/or do we see an increase in the activity of these NK cells? The presentation itself is to highlight and hopefully get increasing interest in patient participation and referrals for this study, but also looking for long-term collaborations.

Have any common adverse events (AEs) previously been reported with α-TEA?

To date, patients on the single agent α-TEA trial have gone through 3 dose levels. In the first 2 dose levels, the approach has actually been quite well tolerated with mostly only grade 1 and 2 AEs reported. The one unexpected finding was that there was an increase in the incidence of atrial fibrillation, but it appears that those patients who had that develop, actually had atrial fibrillation in the past. As such these patients were predisposed to again develop atrial fibrillation. That being said, as part of this study, unfortunately, we are going to have to exclude patients who have had a history of atrial fibrillation because of that correlation. Other than that, it's actually been quite well-tolerated. It does also highlight the potential of α-TEA to be an alternative agent to traditional cytotoxic chemotherapies.

What is the main question you hope to answer with this research?

The main question to answer, and always the most critical one is: “Is the combination safe?” This trial will answer that question. Then, [it’s worth asking], “Does this provide benefit?” I hope it does. If it's a safe combination with low toxicity, then it is an interesting drug to advance, and even potentially use in an earlier-line setting. Our hope is that we also start identifying additional mechanisms for how to [best] manipulate the immune environment, which we believe in HER2-positive disease is actually quite critical. This study will provide us with additional insights into that and the mechanisms [required] to achieve that goal. I'm most interested to see what effects are on NK cells in regards toactivity changes and level changes as this is an area of unmet need, particularly in the HER2 population.

What next steps are being taken with this agent?

We feel that if we're able to provide evidence of both safety and clinical efficacy, as well as immune efficacy with this combination, that will likely translate into a phase 2 study. We also think it is worthwhile to consider this agent in earlier-stage disease. Right now, we're focusing on the metastatic setting, but are there end points in earlier stage disease that taking this oral drug may be able to augment? [For example], increasing pathologic complete response (pCR) in neoadjuvant HER2 disease or decreasing the risk of recurrence in the adjuvant setting. Many more opportunities exist within HER2 disease.

We also believe that α-TEA likely has activity well beyond HER2. We have ongoing efforts to develop a study in triple-negative breast cancer (TNBC) examining the use of α-TEA in combination with checkpoint blockade. We want to try to use 2 agents that both have immune-mediated properties and determine whether those properties are synergistic in the triple negative population. Those efforts are moving forward and likely will spin-off additional areas of investigation.

Is there anything else from this trial that you wanted to highlight?

The promise for α-TEA is that it has low toxicity and is an oral therapy that you take daily for 2 weeks at a time. We believe that both preclinical and early clinical evidence suggests that there is anticancer activity. We believe that the agent is going to be synergistic based on some of the striking data from our preclinical studies of the combination with trastuzumab. We are cautiously optimistic that it is safe and will provide the clinical benefit that's so needed in this population.

Are there any other significant research efforts being made in this space that you're excited about?

There are many areas of interest. One effort that we are targeting at the UW CVI/SCCA is the utilization of HER2 targeted vaccines to restore HER2-specific immunity that I mentioned earlier that appears to be lost through HER2 oncogenesis. We have vaccine trials in the adjuvant HER2 setting, and we'll be opening a trial of vaccination during neoadjuvant chemotherapy shortly. In this neoadjuvant study we are integrating vaccination in a very specific manner with chemotherapy to try and boost this anti-HER2 immune responsiveness with the goals of both improving pCR and decreasing the risk of recurrence in the long run.

Work that caught my eye in this realm from ASCO was the bispecific DART antibody targeting PD-1 and LAG-3. Given in combination with margetuximab, which is a HER2 monoclonal antibody that has been manipulated through its Fc portion to augment antibody-dependent cellular cytotoxicity (ADCC). We believe that ADCC is an important immune mechanism in treating HER2-positive breast cancer. The findings from this study were in patients who were treatment refractory and revealed that even if the patients who had PD-L1–negative tumors, the overall response rate was 43%, which is quite impressive. This response rate is better than what we've seen in some of the other treatment trials with checkpoint blockade, particularly the PANACEA trial in HER2-positive breast cancer.

Reference

1. Gwin WR, Childs J, Higgins D, et al. A phase I dose-escalation trial of alpha-tocopheryloxyacetic acid and concurrent trastuzumab in patients with treatment refractory HER2+ metastatic breast cancer. J Clin Oncol.2020;38(suppl 15):TPS1103. doi:10.1200/JCO.2020.38.15_suppl.TPS1103