Moffitt Cancer Center is currently working to develop a host of novel therapeutic treatments within the breast cancer space, from immunotherapeutics to personalized cancer vaccines.
Moffitt Cancer Center is currently working to develop a host of novel therapeutic treatments within the breast cancer space, from immunotherapeutics to personalized cancer vaccines, according to Hatem Soliman, MD.
Findings from the KEYNOTE-355 trial show that pembrolizumab (Keytruda) induced positive outcomes in the first-line setting. The PD-1 inhibitor improved progression-free survival (PFS) when combined with chemotherapy in patients with metastatic triple negative breast cancer (TNBC). Soliman added that is also worth exploring the agent in a more curative setting.
“Even more exciting, and this is where I think a lot of the field is going to go is that Peter Schmid, MD, and investigators presented data at ESMO 2019 on the KEYNOTE-522 trial,” he said. “That was actually taking a drug like pembrolizumab and moving it up into the curative setting. Women who had high-risk TNBC who had not metastasized yet had pembrolizumab added to [their] preoperative chemotherapy regimen. The addition of pembrolizumab was found to significantly increase the likelihood that a woman would have a complete response (CR) and the complete eradication of her tumor.”
The FDA approved pembrolizumab plus chemotherapy as neoadjuvant treatment for patients with early-stage TNBC on July 27 based on data from the phase 3 KEYNOTE-522 (NCT03036488). Patients assigned neoadjuvant regimen followed by pembrolizumab monotherapy as adjuvant treatment after surgery demonstrated a statistically significant event-free survival benefit (HR, 0.63; 95% CI, 0.48-0.82; P = .00031) compared with placebo.1
Investigators at Moffitt are also exploring the use of personalized cancer vaccines. The vaccines are created by taking autologous cells from a patient that can either be administered directly to the tumor tumor or the lymph nodes.
“The idea is to try and boost that immune response to get it attacking the tumor cells and cooperating with some of the systemic therapies we use in order to improve their outcomes and cure rates. That has been a key focus of ours over the past 3 or 4 years,” Soliman said.
In an interview with OncLive, Soliman, medical director of the Clinical Trials Office and a medical oncologist specializing in breast cancer in the Center for Women’s Oncology at Moffitt Cancer Center, discusses the use of intratumoral agents in patients with TNBC, the promising early phase results of triplet immunotherapy regimens, and the benefit of using pembrolizumab in first line. Jennifer Wlach, a partner at Mercury who helps with Moffitt’s media relations, also joined the interview.
Hatem Soliman: On the therapeutic side, we have been particularly interested in trying to become a mecca of sorts for novel treatments that try to recruit a woman's immune system to better fight off cancer.
These kinds of approaches have dual benefits in that they can be performed usually with less toxicity in some cases when compared to some of our chemotherapeutic agents. But the immune system can also provide durable benefit for a patient over an extended period of time compared to, say, targeted agents or certain chemotherapeutic drugs. This is because the immune system can adapt and change over time to try and address some of the threats posed by residual cancer cells that may be left in a woman's body that can lead to recurrence over time.
Our department has been very focused on launching a whole raft of different studies using personalized cancer vaccines where we take a woman's cells out of her body and load those cells with specific antigens. We actually produce those vaccines at Moffitt for each patient individually using their own cells and administer it either to their tumor of lymph nodes. The idea is to try and boost that immune response to get it attacking the tumor cells and cooperating with some of the systemic therapies we use in order to improve their outcomes and cure rates. That has been a key focus of ours over the past 3 or 4 years.
We have also been spearheading a number of trials where we use other types of agents that will help to energize the immune system. The tumor cells use a lot of mechanisms to try and cloak themselves and hide from the immune system, but a lot of the drugs we're rolling out now try to pierce that veil and make the cancer cells more visible to the immune system it's able to target them more effectively. We combine it typically with chemotherapy agents, albeit with schedules that are typically less toxic or with lower doses so that they can synergize with those agents and potentially help with improving responses over time. We have a number of those trials that are ongoing with patients who have both metastatic disease and also with early-stage disease; we're seeing some interesting results with that approach.
One of our key projects that both Bethany Niell, MD, PhD, a radiology specialist at Moffitt, and I have worked on together closely is the use of oncolytic viruses as another way to try and recruit the immune system. They're genetically engineered viruses that specifically target tumor cells and cause them to burst open while leaving normal tissue alone. [Essentially], we can take these engineered viruses, inject them into a woman's breast cancer tumors and cause the destruction of those tumors while at the same time altering their immune system—[all of] that during their curative therapy.
Dr Niell and I worked closely together on this because she has been responsible for helping to localize those injections in the tumor. We do this under imaging guidance, so this is a key example of multidisciplinary research, whereby we take different team members—the surgeons, radiologists, medical oncologists—and work together in order to deliver these cutting-edge treatments.
There are a number of agents that have made some real in-roads in the world of breast cancer. Obviously the 1 that has the most data behind it from a clinical trial perspective are PD-1 or PD-L1 agents. This includes drugs such as atezolizumab (Tecentriq) and pembrolizumab, which many patients and [physicians] are familiar with because they have gotten a lot of use across a variety of different cancers.
For atezolizumab, you do have an approval based on the IMpassion130 trial, which took women with metastatic TNBC. [The trial] took [atezolizumab] and combined it with paclitaxel (Taxol) chemotherapy in the first-line setting. For women who are PD-L1–positive, that has shown a clinical benefit in PFS and a trend towards improved overall survival, as well. That has been a standard of practice now for well over a year and half. It has been a significant development in the field and opened the door to other similar approaches.
We also have some emerging data with pembrolizumab. Recently there was a metastatic trial KEYNOTE-355, which showed similar clinical benefit for PFS [when] combining pembrolizumab and chemotherapy for women with TNBC in the first line. That has also been exciting.
But even more exciting, and this is where I think a lot of the field is going to go, is that Peter Schmid, MD, and investigators presented data at ESMO 2019 with the KEYNOTE-522 trial. That was actually taking a drug like pembrolizumab and moving it up into the curative setting. Women who had high-risk TNBC that has not metastasized yet had pembrolizumab added to the preoperative chemotherapy regimen. The addition of pembrolizumab was found to significantly increase the likelihood that a woman would have a CR and the complete eradication of her tumor. Up to 64% of the women who got that combination treatment achieved a CR compared to the 50% or so in just chemotherapy alone.
The early data favored a survival benefit too, although that was still immature. But that really raises the exciting prospect that some of these immunotherapy drugs can be used in the curative setting where you really get more bang for your buck to rid the tumor up front and improve the likelihood that the woman has a durable cure.
That’s where most of the data is right now in terms of clinical trials, however, there are a number of early phase trials that are very exciting using triplets [adding] another targeted agent to drugs like pembrolizumab or atezolizumab. We’re seeing some very dramatic increases in the response rates when we add a targeted agent that, in essence, can cooperate with immunotherapy and make it work better. We’re seeing much better response rates compared to just chemotherapy with immunotherapy.
Those trials are ongoing and we're looking to see whether those results hold up over time because then we may be able to select women for a little bit more of an aggressive approach where we need to get their tumors to respond using a combination of agents.
Finally, something I'm particularly excited about is the use of some of these intratumoral agents where we can inject the tumors directly. Some of our data that we presented at the AACR Annual Meeting in Atlanta showed that when we injected TNBC tumors with the oncolytic virus talimogene laherparepvec (T-VEC; Imlygic) in combination with standard chemotherapy, we were able to increase the pathologic CR rate to 55% and the near-CR rate plus pathogenic CR was close to 80%. This is a highly active agent that I feel is benefitting a number of women. We just completed accrual to the phase 2 portion of that study and we're analyzing the data as we speak to see how the response rates hold up over a larger cohort of women.
What’s exciting is the plethora of novel targeted agents that are being developed using a lot of different technologies, [including] antibody-drug conjugates. We have seen some pretty remarkable agents developed starting with ado-trastuzumab emtansine (T-DM1; Kadcyla), but more recently within HER2 with sacituzumab govitecan (Trodelvy), which is showing some remarkable activity in some very difficult-to-treat women with metastatic TNBC who have not responded well to prior agents.
You also have drugs like abemaciclib (Verzenio) that has been used for quite some time now within metastatic hormone receptor (HR)-positive breast cancer that just reported a positive result in the curative setting. Giving that drug to [patients with] high-risk, HR-positive cancer, they had a lower risk of recurrence, thereby increasing the likelihood that they were cured when we were able to treat them with that agent.
New agents [are] starting to emerge from our clinical trials that are really starting to have an impact on the survivability of breast cancer and the benefits are quite substantial. If I want to put in a call to action for Breast Cancer Awareness Month, it’s that we can't bring these new agents to women unless they participate on a clinical trial. Unfortunately, a very small number of women participate in clinical trials in the US; it's number that has historically been below 10% and has stayed there for quite some time.