Denise A. Yardley, MD, discusses key data presented at the 2018 SABCS and the impact of the SOLAR-1 findings.
Denise Yardley, MD
The encouraging findings with the alpha-specific PI3K inhibitor alpelisib in patients with PIK3CA-mutant breast cancer coincide with the refined, personalized approach being implemented in breast cancer treatment, explained Denise A. Yardley, MD.
In the primary analysis of the phase III SOLAR-1 trial, the combination of alpelisib and fulvestrant (Faslodex) was associated with a median progression-free survival (PFS) of 11.0 months in patients with PIK3CA-mutant advanced breast cancer compared with 5.7 months for those who received placebo plus fulvestrant at a median follow-up of 20 months. This translated to a 35% reduction in the risk of disease progression or death (HR, 0.65; P = .00065).1
Additional analyses of the trial, which were presented at the 2018 San Antonio Breast Cancer Symposium, showed that alpelisib plus fulvestrant extended PFS versus fulvestrant alone in this patient population, regardless of line of therapy or prior CDK4/6 inhibitor treatment.2 Moreover, the median OS has not been reached in the alpelisib arm, according to an interim analysis.
“Opportunities are there. There are lots of drugs, the science is fabulous, and the industry is really continuing to offer drugs for our patients on clinical trials,” said Denise Yardley, MD. “This year, we are going to see some FDA approvals and it’s an exciting time in 2019.”
In an interview during the 2019 OncLive® State of the Science Summit™ on Breast Cancer, Yardley, senior investigator, Breast Cancer Research Program, Sarah Cannon Research Institute, discussed key data presented at the 2018 SABCS and the impact of the SOLAR-1 findings.Yardley: SABCS continues to build on a changing standard of practice for patients facing a diagnosis of breast cancer. What we are continuing to see, as a big message, is trying to define our treatment recommendations. For early-stage patients, it is trying to decide on which patients need chemotherapy, who can avoid chemotherapy, and then for those who are going to benefit from endocrine therapy, [who should receive] the extended endocrine therapy. We are seeing not the one-size-fits-all approach anymore; it’s really tailoring it on a case-by-case basis. In my practice, my discussions become longer and longer trying to assimilate the data and bring the patients into that patient-physician partnership to try to make these treatment decisions.
In the metastatic setting, we are also seeing the ability to try and refine our treatments. As we see more and more trials with niche populations in the metastatic breast cancer setting, we are learning that genomic profiling of breast cancer tumors is extremely important—in the metastatic setting, even upfront, even for the hormone receptor (HR)—positive patients. We had updates with the SOLAR-1 data, which were initially presented at the 2018 ESMO Congress, looking at the importance of PIK3CA mutations. Even though we [had data with] the PI3K/ATM/mTOR pathway with everolimus (Afinitor) in the BOLERO-2 trial, now we have the SOLAR-1 data. [It showed that], yes, there is benefit from these targeted agents and this is a reason to profile—to identify patients with the PIK3CA mutations.
We saw exciting data with immunotherapy for the first time—we saw that enter the realm of breast cancer with a strong signal. I have had partners in our practice at Sarah Cannon Research Institute that have a longstanding history in lung cancer with immunotherapy. But now, breast cancer actually rocks with immunotherapy. That is confined to triple-negative breast cancer (TNBC) in the first-line setting. On top of that, it is for PD-L1—positive tumors. Therefore, we are really learning to tailor our treatment recommendations for different subtypes and the precision of different mutations in breast cancer. Making those treatment decisions are really hinging on having those data available. I see patients really struggling with the data. Various patients come in with newspaper clippings, and all have some pertinence to immunotherapy—whether it’s a signal or whether it’s as bench work in the basic science labs. It is more challenging to explain to them why this [class of] drugs, which are approved in many other solid tumors, has been struggling in breast cancer. I take the dialogue that breast cancer is not a one-size-fits-all [approach]. There are multiple subtypes, and the biology of these subtypes are very well etched out; we are seeing how therapies work and don’t work in these specific subtypes.
With immunotherapy, when you look at breast cancer as a whole, it was hard to see that signal when you took out the TNBC population. We further went on to test those in the [IMpassion130 trial, which is where] we saw that signal of benefit. What is interesting is that it raises the point that there was a PFS advantage, but that was not nearly as overwhelming and exciting as the overall survival (OS) advantage.
Talking about OS advantages in the metastatic setting really aren’t the premise of my discussions and interactions—it is more so PFS. But now, I have this exciting new therapy, and we are talking about how it works differently, the benefits are different, and the OS advantage was really eye-opening in that it is different than what we have been seeing to date.Trying to figure out who to subtype is the most important thing. We are still in this huge uphill learning phase of what to do with the information. I tell a lot of patients that I may molecularly profile [their tumor] to find out how their tumor works and “talks,” but a lot of times they just get back noise—not things that are actionable or will allow them to get on a clinical trial.
The interesting thing is now we [are seeing] a whole host of these basket trials. [If there is] a BRAF mutation in a patient with breast cancer, now [that opens] the opportunity for the patient to receive treatment with a drug targeted toward that. It may not [be] a breast cancer—specific trial, but more of those basket trials, or tumor-agnostic trials. That becomes an important decision-making [factor] for patients and what to do with that data.
We are learning that there is relevance in some of the drugs becoming available, like those for the PIK3CA or ESR1 mutations that may allow us to make decisions on endocrine therapy as single agents. It is becoming more of a discussion with patients. It has to be appropriate; a patient has to be accepting of the potential of a trial from some of the data we might get from the profiling.All of us are learning about the biosimilars. I personally don’t have experience, and I see that these approvals are coming. Our own institution and group make policies on that. Certainly, it becomes more competitive with pricing, too; that may increase advantages and opportunities for patients. The biosimilars are here to stay, so we are all going to have to roll up our sleeves and we are going to have to figure out how to implement them in the practice. Are they a complete substitution [of the reference drug]? Are there caveats with these agents? Those are all things that our institution, program, and myself are starting to struggle with and trying to figure out. They are here; we have to figure out how to integrate them. But today, I don’t have that experience to pull them into my daily practice. We are going to be welcoming new drugs to the treatment armamentarium. The FDA is going to be hopefully looking at 1 or 2 drugs for their approvals in TNBC, an entity we recognize has long needed a specific drug. We are going to look at sacituzumab govitecan; hopefully that will be approved.
We are going to see the immunotherapy approval with atezolizumab for TNBC as well, so it’s going to be quite exciting for that specific patient subtype. The PI3K pathway is a pathway that has been looked at in breast cancer over and over; the hindrance has been, whether [the optimal drug] is a pan-PI3K inhibitor for all of the isoforms, or it’s a beta-sparing , or if it’s alpelisib. That will show a resonating signal that merits approval in those HR-positive patients. Just out of the gate, 2019 already has 3 promising drugs at the heels of the FDA to be approved for breast cancer to continue to extend the treatment options for these patients with advanced disease. One of the other focuses that will be seen in 2019 has been the excitement with the CDK4/6 inhibitors. While they have graciously taken hold of the first-line HR-positive/HER2-negative breast cancer space as a standard of care, and even in second- or later-line settings, the excitement now is moving them into the neoadjuvant and adjuvant settings.
In the metastatic setting, while they have offered patients, on average, 2 years of controlled disease, we do see resistance to these agents. We are learning more about whether that is cyclin E or the FGFR pathway, so we are going to learn a lot more about overcoming that resistance—perhaps we need a PI3K inhibitor in combination.
The TRINITI-1 trial looked at giving a CDK4/6 inhibitor after a CDK4/6 inhibitor and adding everolimus, so we are going to learn now how the CDK4/6 inhibitors have changed the face of the HR-positive patients. However, there is also a domino effect of how all of our other therapies fit downstream. It is an exciting time.