Burris Discusses Pivotal Data, Next Steps in Breast Cancer

Partner | Cancer Centers | <b>Sarah Cannon</b>

Howard A. “Skip” Burris, MD, highlights some of the exciting updates from the 2018 San Antonio Breast Cancer Symposium and what can be expected in the breast cancer field in the year ahead.

Howard A. “Skip” Burris, MD

Recent pivotal breast cancer data presented at the 2018 San Antonio Breast Cancer Symposium (SABCS), particularly with immunotherapy, are just the start of promising directions for researchers, said Howard A. “Skip” Burris, MD.

An updated biomarker analysis from the phase III IMpassion130 trial—data from which were initially presented at the 2018 ESMO Congress—showed that progression-free and overall survival (OS) improvements with the combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) in patients with metastatic triple-negative breast cancer (TNBC) or inoperable locally advanced TNBC were exclusive to those patients with PD-L1 expression ≥1% on immune cells.

Other biomarkers, which included PD-L1 expression on tumor cells, intratumoral CD8-positive T cells, stromal tumor-infiltrating lymphocytes, and BRCA1/2 mutation status, also confirmed the importance of PD-L1 expression on immune cells in predicting clinical benefit derived from the atezolizumab combination.

Based on the initial IMpassion130 findings, the FDA granted a priority review designation to a supplemental biologics license application for the frontline atezolizumab combination for patients with unresectable locally advanced or metastatic PD-L1—positive TNBC. The initial data showed that there was a 38% reduction win the risk of progression or death with atezolizumab plus nab-paclitaxel versus nab-paclitaxel alone in this patient population. Under the Prescription Drug User Fee Act, the FDA is scheduled to decide on the application by March 12, 2019.

“The data are changing so quickly, it’s difficult to keep up, and folks are certainly interested in seeing how the disease-specific experts are applying this information in their practices,” said Burris.

Looking ahead, Burris said the breast cancer community should expect a focus on molecular profiling as well as upfront testing with PARP and CDK4/6 inhibitors.

OncLive: Reflecting on the recent breast cancer advances, how are these pivotal data informing treatment decisions?

In an interview during the 2019 OncLive® State of the Science Summit™ on Breast Cancer, Burris, chief medical officer of Sarah Cannon Research Institute, and president-elect of ASCO, highlighted some of the exciting updates from the 2018 SABCS and what can be expected in the breast cancer field in the year ahead.Burris: The data coming out of SABCS and the conversations [at the State of the Science Summit™] were different than prior years, because we have exciting affirmation in all the various subtypes, as well as the various stages of breast cancer. We have promising and almost practice-changing data in HER2-positive breast cancer, TNBC, and in the realm of the estrogen receptor (ER)—positive breast cancer. It was fascinating to see, in one of the presentations at SABCS this year, a wonderful case-based discussion where Dr Cliff Hudis of ASCO moderated and Dr Hal Burstein of Dana-Farber Cancer Institute and Dr Dan Hayes of University of Michigan—all breast cancer experts—debated the strategy.

What practice-changing data in HER2/TNBC did you find were most exciting?

I thought what was interesting was how crowded the room was and how thirsty the audience was for how people were going to apply the new knowledge going forward. [It covered] what to do with molecular profiling, how to do the prognostic assays, and where they might incorporate the treatment.In the HER2-positive breast cancer treatment paradigm, we have, for many years, really liked T-DM1. The antibody-drug conjugate has been well tolerated, active, and a lot of the data in the adjuvant and neoadjuvant settings have been accruing. It’s been hard to sort out when that might emerge.

With the 2018 SABCS, the KATHERINE data, and seeing T-DM1 so positive over trastuzumab (Herceptin) in the [adjuvant] population was a great win. It makes sense to give additional chemotherapy in that setting, and it makes sense to continue trastuzumab-based therapy. That is the idea behind T-DM1: this “smart bomb,” better-tolerated approach of having chemotherapy linked to an active monoclonal antibody, so that is absolutely going to be something that will be quickly adopted, incorporated, and yield even greater outcomes.

On the TNBC front, we had some wins with positive trials with PARP inhibitors in the metastatic setting. We had some wins with positive trials with antibody-drug conjugates. There are a few new ones coming along and, if the immunotherapy store was going to make sense in breast cancer, most people thought it would be in TNBC. The IMpassion130 data, with atezolizumab in combination with nab-paclitaxel were presented—[the findings were originally shown] at the 2018 ESMO Congress, there are a lot of data there.

Are there any emerging data with PARP inhibitors slated to read out this year?

The overall results were statistically positive. It is clear that the subgroups, particularly the PD-L1— positive group, have the greatest benefit. Once again, [this is] another trial that is promising because the difference in response rate and PFS were important, but the real difference was what was seen in overall survival. That is a premature endpoint at this point, but the survival difference still looks even more impressive measured in many, many months and possibly approaching 1 year. Therefore, we’ll see where that ends up, but that will be a story to watch. Frankly, in the field of breast cancer, while we’re learning how to give immunotherapy and where it should be given, it’s certainly nice to get a positive result to keep the enthusiasm moving forward.I’m hopeful that, what’s next with the PARP inhibitors, is we see them move forward. We had many results, and it’s great to help those patients who have limited options or have disease resistant to chemotherapy. However, the real advance for drugs like that is to utilize them upfront. There are some neoadjuvant trials ongoing, where we’ll get some results around response rates fairly early. That will be a nice next step, but it’s clear that in the setting of using a drug that has the ability to kill cancer cells, that giving it in the first-line setting without additional drugs is where the impact will be.

You mentioned molecular profiling. What advice can you give to community oncologists on how they can become more familiar with that?

Chronic oral therapy with those would be attractive, or maybe almost a different paradigm too far from giving hormonal therapy as the initial treatment—or a combination treatment in ER-positive breast cancer. If we could do that with the PARP inhibitors in some of these TNBCs, especially in some of these “BRCA-ish” groups, we know these patients benefit. However, it turns out that there is probably a growing group of patients being identified as “BRCA-ish” where it might really play a role.How to utilize next-generation sequencing (NGS) or molecular profiling in your practice is a great debate. I’ve taken a position and have surveyed our community oncologists about what they would want for themselves or their loved ones [if they had breast cancer], and almost uniformly—each of them in the setting of having a relapsed or resistant tumor—they would want to know the molecular profile.

That being said, how to handle the data and where it’s applicable remains a bit confusing. However, this is a place where it might be the most important information—we learn the individual’s tumor. My advocacy has been that for patients who have recurrent or relapsed disease, that NGS approach should be part of their treatment decision-making. You’re doing it for the individual patient—to increase the odds that they get in a clinical trial. You won’t know until you search for those mutations.

Three biosimilars have been approved in the breast cancer field thus far. What are your thoughts on the wave of these agents?

Lastly, it’s going to be what’s needed for the field. The more patients with resistant or recurrent disease that undergo molecular profiling, the better we'll understand where to utilize these drugs. While we don’t know the answer yet around some prognostic factors, such as the microsatellite instability-high or the high tumor mutational burden, where those cuts are made remain of some debate. However, that is OK. There is still a growing body of evidence to suggest that the more mutations, the more unstable the tumor, and the greater likelihood the patients are going to benefit with checkpoint inhibitor therapy. Right now, for many patients who are trying to participate on a clinical trial, it certainly helps point the patient to the right clinical study.The biosimilars are here. It is a place where we need to get comfortable with. My only personal struggle with biosimilars is how to participate in a clinical trial while, at the same time, I’m saying, “We need to have clinical trials.” We need to make sure these drugs hold up. It’s not quite as similar as making an oral generic therapy, so the biosimilars do need a bit more work.

What do you expect to see in the field by the end of 2019?

At Sarah Cannon Research Institute, we have been very focused on new drugs—investigational drugs—so we have not really fit the biosimilars into our clinical trial menu. That being said, with the cost of medicine where it is, I think this is one step in that direction. [These biosimilars are] coming; trastuzumab [biosimilars] are coming, and there are more that will be on the way. Within the next 2 to 3 years, we are all going to get very comfortable with biosimilars.In breast cancer in particular, we are going to have some additional answers around resistance in the ER-positive group. We have seen the CDK4/6 inhibitors move into the frontline setting. What do we do next in that population? What sort of resistance patterns are emerging? We are going to learn much more about that. We are learning about these oral [selective estrogen receptor degraders] in development. Several of those look promising. We are closer to having an oral drug that will work in that setting and that could be a possible role [for them].

Some hints of activity [have been seen] from the PI3K-alpha inhibitors. A couple of those [have been observed] with positive trials, we'll see how those data roll through the registration and approval pathways. However, after a lull from the approval of everolimus (Afinitor), we now have a couple drugs in that pathway that we’re going to see [if] they get approved or not. Then, we all know that once these drugs make it out to the market, then some of the real research starts about where and how to utilize these agents.

What would you caution?

Lately, the IMpassion130 data with atezolizumab is going to create some renewed energy around studying breast cancer. That is going to be a nice change in terms of how we are approaching these trials, and there will be so much more accrual in the setting of breast cancer with the checkpoint inhibitors and other immunotherapy agents.The most important thing, I would say, for breast cancer is while we have had such great advances and improvements in how patients are doing, improvements in OS, and positive trial results, it is probably more important than ever to consider a clinical trial for your patient. When trastuzumab got approved in the adjuvant setting 15 years ago, we thought we were loosely on the way to being done with that subset of patients. Yet now, we have T-DM1 data [in the adjuvant setting]. We know there is a ways to go, to continue to improve that subpopulation.

In TNBC, these positive results are sort of the first step. [There is] all of the enthusiasm, and all the newly approved drugs in breast cancer. If we just follow what has happened in the past, this is the time to step on the gas and use this momentum to get more clinical research done and have better results for our patients.