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Hope S. Rugo, MD, discusses a variety of agents for the treatment of patients with ER-positive breast cancer, such as mTOR inhibitors, PI3K inhibitors, and CDK4/6 inhibitors, in addition to novel targeted therapies being investigated in TNBC.
Hope Rugo, MD
Reversing hormone resistance for estrogen receptor (ER)-positive breast cancer and introducing new targeted therapies for patients with triple-negative breast cancer (TNBC) are vital points of discussion in the community, according to Hope S. Rugo, MD.
“It's clear there's a lot going on in the field of breast cancer. [There are some] really exciting areas,” said Rugo in an interview during the 2017 OncLive® State of the Science SummitTM on Breast Cancer, of which she was the chair. “The audience was excited to hear about some of these advances and look to the future, as well.”
In an interview during the meeting, Rugo, a professor of medicine and director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, discussed a variety of agents for the treatment of patients with ER-positive breast cancer, such as mTOR inhibitors, PI3K inhibitors, and CDK4/6 inhibitors, in addition to novel targeted therapies being investigated in TNBC.Rugo: We had a great program [at the] 2017 State of the Science SummitTM on Breast Cancer…we had a number of different talks that really covered the different biologic subtypes of breast cancer from our clinical faculty.
I spoke about 2 different areas. One was advances in reversing hormone resistance in hormone receptor (HR)-positive metastatic breast cancer—focusing on inhibitors of mTOR and PI3K—where we are now, where we're going, and then looked at CDK4/6 inhibitors of which there are 3 approved. These are palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) in the treatment of [patients with] metastatic disease. I spoke a bit about where we are going in terms of reversing resistance with combination therapies and how we can moderate and manage toxicity from these agents, as well. It's an exciting time in HR-positive breast cancer. It was interesting to discuss it afterward and talk about some of the questions regarding these agents.
The other area that I spoke about was advances in TNBC in terms of new targeted therapies. This fit in very nicely after the talk by Dr Melanie Majure about optimal chemotherapy regimens for TNBC. I spoke about a number of different agents, PARP inhibitors, and the recent presentation and publication of the OlympiA trial as well as the ABRAZO trial with talazoparib.
The ongoing OlympiA trial [is] continuing to study olaparib (Lynparza) in the adjuvant setting [and] the mechanism of resistance. We'll be seeing a phase III trial with talazoparib in the metastatic settings, similar to OlympiA, hopefully in the next few months. We will wait and see. We need to see if we reach all the endpoints in order to report it. The other areas that I spoke about, which are of great interest, include antibody-drug conjugates, of which there are several novel agents that are being tested and are in phase III trials. Glembatumumab vedotin and sacituzumab govitecan [are] really exciting agents. We spoke about some of the data leading up to these phase III studies.
We spoke about immunotherapy—everybody's exciting area of study and a big buzzword, both in the lay press as well as our [medical] publications. Some data would show us that patients respond better to checkpoint inhibitors earlier in the course of their disease. First-line metastatic data, and then the I-SPY neoadjuvant data, [are] showing even higher pathologic complete response (pCR) rates in patients receiving immunotherapy.
There are a number of ongoing trials studying that, as well as small-molecule inhibitors that may be given in combination with immunotherapy to try to enhance the immune response.We don’t understand this idea of latency with late recurrences in HR-positive disease, and that’s a huge challenge. There are a lot of people studying it. We have focused [on] trying to find agents that make hormone therapy work better. By doing that, we may inadvertently solve the latency problem. It remains to be seen, but the advent of the CDK4/6 inhibitors and the PI3K inhibitors [is] very exciting because, hopefully, we'll be able to figure out who should be treated in the adjuvant setting.
I added up all of the different patients who will be enrolled in adjuvant trials, and there are more than 15,000 women who will be enrolled in adjuvant or post-neoadjuvant clinical trials with CDK4/6 inhibitors versus either placebo or standard of care. We're going to learn lot about what those agents do now.
Waiting for 20 years [is] never our strong point, but we'll know something about these patients. The trials have all focused on higher-risk disease by amount of cancer and some about biology, so maybe we'll get an endpoint a little bit earlier. Whether or not this is the key to preventing late recurrences remains to be seen.Well, we've made a lot of progress this last year—really since the 2017 ASCO Annual Meeting. If you looked at the preclinical data and some data that was presented in one of the educational science talks at the 2016 San Antonio Breast Cancer Symposium, I had already understood that, as cancers progress, mutational load increases neoantigens. That may increase immune response, but there’s a second part of that which is, if you have a tumor that has an increased mutational load, great. [However,] as the tumor progresses and develops more resistance, it develops mechanisms of avoiding an immune response that are beyond a checkpoint inhibitor.
[When] these cancers stop bringing in immune cells, they have a way of becoming less and less immune activating, so then they become more immunologically cold. What we've learned is that treating cancers earlier makes a difference. We get much higher response rates in the first-line setting than later-line settings. If you look at tumors that have tumor-infiltrating lymphocytes above the median, they seem to have a much higher response, particularly in the first-line setting. The neoadjuvant data are very, very encouraging, showing these marked improvements in estimated pCR rate. What we are learning is that it's not the same as giving chemotherapy, where we see a response in the metastatic setting, so we will try [to get FDA] approval there and then we’ll move it earlier.
We're doing this with all these drugs, but sometimes where we really may see the best response is very early. We really need to get those drugs much earlier into that setting.