Burris Talks Research and Regulatory Advances in TNBC

Immunotherapy, PARP inhibitors, and antibody-drug conjugates (ADCs) have become pillars of treatment in triple-negative breast cancer (TNBC), explained Howard A. “Skip” Burris, III, MD, FASCO, FACP, who added that the pipeline is rich with research regarding neoadjuvant treatment strategies, biomarkers of response, and potential new targets.

“In the field of TNBC, we’re beginning to see some remarkable advances, mostly centering around 3 paradigms that have become so attractive for the treatment of patients with cancer,” said Burris. “There’s a reason to be optimistic about the future for this previously very difficult-to-treat subset of patients with breast cancer.”

In an interview with OncLive® during the 2020 International Perspectives in Cancer on Breast Cancer, Burris, chief medical officer and president of Clinical Operations at Sarah Cannon Research Institute, and a 2014 Giant of Cancer Care® in Drug Development, discussed research regarding immunotherapy, PARP inhibitors, and ADCs and the importance of molecular profiling in matching patients with the optimal therapy.

OncLive: Could you highlight some of the recent advances that have been made in TNBC?

Burris: In TNBC, we [have access to] immunotherapy and targeted biologics, the latter of which are the PARP inhibitors primarily, which target specific mutational profiles. There’s also ADCs, which are based on the idea of delivering chemotherapy via an antibody, or the “smart bomb” approach, targeting the tumor, minimizing collateral damage, and more effectively delivering a toxin to the cells to create cell death.

Now, [sacituzumab govitecan (Trodelvy)] is FDA approved, becoming the first ADC to receive regulatory approval in TNBC, which has generated great excitement. There’s a lot of promise there.

Also on the triple-negative front [is the concept of neoadjuvant therapy]. Many of our early-stage patients would benefit from neoadjuvant therapy. Because most patients with TNBC are not going to receive hormonal therapy or HER2-based therapy, they are going to be candidates for chemotherapy. Continuing to work on neoadjuvant and adjuvant strategies remains the focus of many trial efforts. In the area of neoadjuvant therapy, the addition of checkpoint inhibitors to chemotherapy has generated some promising results. We’ve seen the addition of pembrolizumab (Keytruda) in this setting. Some of the clinical trials that have come out to date look quite promising, particularly in terms of deep responses. Pathological complete response is the current standard. Though, longer follow-up is needed to look at overall benefits with regard to whether these patients might need further treatment.

On the PARP inhibitor front, we are seeing great competition among the various PARP inhibitors, which makes for exciting clinical trials and innovative advances to try to integrate these types of biologics into the treatment of diseases such as TNBC. The PARP inhibitors are very effective in patients who have inherited or acquired BRCA-type mutations, or those who have homologous recombination repair (HRR) deficiency. Molecular profiling with next-generation sequencing (NGS) is being done more commonly [to identify] these patients. Certainly, this is something we can do to identify patients that are likely to receive benefit from the addition of these pills, which in general have been fairly well tolerated. We continue to explore the best approaches for adding PARP inhibitors to the triple-negative armamentarium. It’s certainly a very promising advance for these patients.

What are your thoughts on the positive topline results from the IMpassion031 trial, which showed a benefit with the addition of atezolizumab (Tecentriq) to chemotherapy, irrespective of PD-L1 expression?

From the Impassion031 trial and the effects we’re seeing with atezolizumab in this population of patients with regard to a biomarker [tells us that we have to] continue to try to understand which patients might benefit. We have several opportunities there thinking about PD-L1 overexpression, tumor mutational burden (TMB), and then microsatellite instability.

We know that chemotherapy works fairly well in TNBC, it’s just the adverse effects and then how long can you take it? How much do you need to give? The idea of using chemotherapy to create neoantigens, that stimulate an immune response, probably is part of the reason we’re seeing some of the attractive results that we are [in the neoadjuvant setting].

Could pembrolizumab also be incorporated into the neoadjuvant setting, based on the results of the KEYNOTE-522 trial?

This trial evaluated pembrolizumab in the neoadjuvant setting. With pembrolizumab added to a chemotherapy-based regimen, we do see more complete responses and broader tumor effect. I think it bodes well [for this idea of neoadjuvant therapy in TNBC]. We need to continue to understand which patients should receive this type of therapy, but in general, the regimen is well tolerated. There’s going to be continued research in this area. I firmly believe that if immunotherapy is going to play a role in TNBC, [it is best used in the earlier settings This idea of giving pembrolizumab and atezolizumab in the neoadjuvant setting is quite encouraging.

Given that we saw a benefit with pembrolizumab in PD-L1–positive patients but not with atezolizumab, do you think PD-L1 is a drug-dependent biomarker?

It’s a great question, and it’s something that comes up in a variety of different tumor types. PD-L1 overexpression does give you some encouragement about potentially prescribing these drugs. There are some differences with the various checkpoint inhibitors. It’s going to require more patience and more study to sort that out. When we look at the IMpassion130 trial with atezolizumab in the metastatic setting, we found that in subset analysis, patients that overexpressed PD-L1 did better with the treatment. It’s possibly quite different with neoadjuvant therapy in de novo untreated patients [with] recurrent disease; it might be a different setting.

We also saw positive results from the KEYNOTE-355 trial in the metastatic setting. If that regimen is approved, how might you navigate between atezolizumab and pembrolizumab? Would the decision come down to tolerability?

It will be interesting to see how that plays out. Having grown up many years ago, in the docetaxel versus paclitaxel days and the various comparisons we’ve had, there will obviously be some physician preferences on what they’re comfortable with and how those [regimens] are prescribed. It will be very interesting to see how it plays out. Both drugs are impressively active in this setting. [Patient and provider discussion regarding which] regimen the patient is going to receive will probably drive a lot of the decision making. This is where our participation in clinical trials is so important. Those physicians that have gotten comfortable with giving that particular regimen in the clinical trial setting will probably continue to stick with that drug.

How have you incorporated sacituzumab govitecan into your practice since its approval?

Sacituzumab govitecan is something we’ve been prescribing [at Sarah Cannon Research Institute] during July and early August. Several patients have been treated [with sacituzumab govitecan] already in my clinic and many more in our practice. So far, it has gone very well. It’s a drug that does require the use of some premedication, so antiemetics are given. In general, patients have done quite well. We’re already seeing some encouraging signs of activity with improvement in liver function test. Some patients are seeing improvement in cancer-related symptoms.

We have known that camptothecin has activity in this type of breast cancer. Many studies looked at our irinotecan in this setting over the years. Having that active payload and then tying it to an antibody to get to the cells, I’m quite optimistic that the impact will be substantial for our patients.

The administration is going fairly well. We’re keeping our eye on patients and learning how to use [the drug]. Diarrhea was one of the concerns from the clinical trial, so patients are educated in that direction.

Are there any PARP inhibitor trials in particular that you would like to shed light on?

There are several that are continuing to accrue. If you go back and look at the backbone of the OlympiAD trial with olaparib (Lynparza) [and the benefit] we saw in that setting, we saw that olaparib had comparable activity to platinum-based therapy. That is quite impressive in that regard.

The [EMBRACA] study with talazoparib (Talzenna) showed great activity in terms of responses. It’s good for patients to continue to see this class of drugs develop and to see the comparative results that come out. [Each PARP inhibitor] is a little different with regard to toxicity and how it’s handled. The competition works out well for the patients with regard to seeing how they can best be studied, best be utilized, and what combinations might lie in front of us.

Are there any other emerging agents or approaches that people should be aware of?

We are seeing a number of targets coming up for ADCs. This idea of being able to target other markers on the cancer cell by way of having an antibody deliver a payload is something that’s being studied quite extensively. A number of ADCs are in the clinic, and then there are also some novel biologics that are coming along. We are going to see some novel biologics beyond the PARP inhibitors that might play a role either alone or combination in TNBC. With NGS, we’re beginning to identify subsets of patients with TNBC that are likely to benefit from targeted therapies.

How has the coronavirus disease 2019 (COVID-19) pandemic impacted your treatment recommendations for patients, if at all?

We at Sarah Cannon Cancer Institute and Tennessee Oncology have tried to stay safe but stay the course. We were early adopters of aggressive personal protective equipment. We have limited visitors and used telehealth. Some of the oral therapies can be shipped [straight to the patient], which has been very attractive. That has been real satisfying to the patients, regardless of distance. Patients who live down the street or live further away, they like telehealth and minimizing the number of trips to the clinic.

We’ve also been on little more aggressive about educating our patients with regard to their own safety. Our experience, though, with having had patients be COVID-19 positive as well as some of the health care workers, that the masking, the handwashing, the social distancing does work. With regard to having some positive cases, we’ve had very little impact in terms of additional folks in the clinic or other patients being infected, so those steps do really work. It has created some anxiety for the patients and their families, as one would expect.

It certainly has been overall disruptive to not hug your patients and not shake hands. Taking care of patients with cancer [creates] a special bond with that group, and you often have a bond with their family. That’s a part that the patients really miss, giving their nurse or physician a hug, but we’ve continued along. Our patients are so grateful, and they’re so adaptable. They will do what it takes to get their treatment done. We’re also seeing patients continue to want to pursue clinical trial options, so that has been a positive as well.

What is your take-home message for your colleagues?

Most importantly, consider a clinical trial for your patients with TNBC. We have better regimens in front of us and coming forward in the neoadjuvant and metastatic settings. Secondly, we encourage all of our relapsed and recurring patients with TNBC to receive molecular profiling. We need to know which patients have BRCA or HRR mutational profiles, as well as those patients with have high TMB or PD-L1 overexpression. These [markers] are really important to know as we better ascertain what types of patients are going to respond to what types of therapy. Lastly, with regard to the future, it’s bright. There are many drugs are entering into the clinic into our phase 1 programs.