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Banu Arun, MD: Hello. I'm Banu Arun, a medical oncologist from the University of Texas MD Anderson Cancer Center. Welcome to Medscape's InDiscussion series on advanced and metastatic breast cancer. Today, we'll discuss immunotherapy in advanced metastatic breast cancer. First, let me introduce my guest, Dr Kevin Kalinsky. Dr Kalinsky is an associate professor in medicine at Emory University, where he serves as a director of breast medical oncology at the Glenn Family Breast Center and holds the Luisa and Rand Glenn Family Chair in Breast Cancer Research. Dr Kalinsky is the lead author in The New England Journal of Medicine publication of RxPONDER and an active breast cancer translational researcher. Welcome to InDiscussion.
Kevin Kalinsky, MD, MS: Thank you.
Arun: Dr Kalinsky, today we really have a very special topic for metastatic breast cancer: immunotherapy. Can you give us just a little bit of background on how after so many years, all of the sudden, we got here?
Kalinsky: We saw the advances that immunotherapy, particularly checkpoint inhibition, was having in other disease types. We had seen approvals in other types of cancers, like melanoma and other subtypes, before we had seen approval in metastatic breast cancer. When it came to immunotherapy, there were some smaller studies. We saw some single-agent activity. We also had seen that there seems to be an increase in response when we were combining checkpoint inhibition along with chemotherapy. Our first approval had been with atezolizumab for those patients who had frontline triple-negative programmed death–ligand 1 (PD-L1)–positive breast cancers by the SP142 assay. That led to the approval for IMpassion130 for atezolizumab. We ultimately saw that the approval did not remain after we saw the results of IMpassion131, which is a study with paclitaxel, which was not a positive study. However, we do have pembrolizumab based upon the KEYNOTE-355 study, which is a study giving taxanes or gemcitabine and carboplatin along with pembrolizumab or just compared to chemotherapy, where we saw for the PD-L1–positive population an improvement in progression free survival and overall survival based upon the 22C3 assay, if the patient's combined positive score was 10% or greater.
Arun: Wonderful. Do you want to expand a little bit on the KEYNOTE-355 study and how that affected our standard-of-care for our patients?
Kalinsky: I think one of the things that we learned early in the development of checkpoint inhibition in breast cancer is that the earlier we're utilizing the immunotherapy, the more the clinical activity seems to be because there have been some other studies that were looking at giving immunotherapy later on, and we weren't seeing the same sort of responses. When we are giving immunotherapy in metastatic triple-negative breast cancer, it is based upon the KEYNOTE-355 regimen. This is a frontline study where patients were randomized to get paclitaxel or nab-paclitaxel or carboplatin and gemcitabine vs those chemotherapies with pembrolizumab. For those patients who had the combined positive score of 10% or greater, which is about 40% of the patients that we see with metastatic triple-negative breast cancer, we saw that there was this improvement in both progression free survival and overall survival. When we have a patient with metastatic triple-negative breast cancer, it is critical that we check for PD-L1 status, specifically with the 22C3 assay, to see if patients are candidates for immunotherapy or not.
Arun: Thank you very much. This is very helpful. We are dealing with a stage IV metastatic cohort and, of course, quality of life is very important. What can you tell us about side effects of immunotherapy and how you approach the side effects in clinic? I know that this is a very extensive discussion, but please offer a summary for our listeners.
Kalinsky: As opposed to chemotherapy, where often, the side effects are predictable and the timeframe in which we see those side effects can be predictable, with immunotherapy, it can be less predictable. There are some patients who have no side effects, but the most common side effect that we can see with immunotherapy can be thyroid dysfunction or other sorts of endocrinopathies. There are rare side effects that we can see, like pneumonitis, colitis, diabetes or aplastic anemia, where the rates are low but if they happen, they can be significant. It's always important to reiterate to patients some of those rare toxicities. The other thing that can be difficult from the clinician perspective is that those sorts of side effects can be side effects like fatigue or things that can be masked by things that we may attribute to something else. It should always be top of mind. Also, when we're giving immunotherapy, it's important that we're regularly checking things like thyroid function just to make sure that we're not missing the beginning of either hyper or hypothyroidism.
Arun: Indeed. We face these issues in the clinic, and I find myself as an oncologist maybe not being on top of some of the internal medicine related side effects. I'm trying to team up with some internal medicine providers and faculty at my institution. What are your thoughts on that? I think it is complicated and it might be even cardiology or endocrinology. What are your thoughts about that?
Kalinsky: I think we're finding that caring for patients with cancer really requires multiple disciplines. It's really a team approach and requires conversations with internists, endocrine experts, cardiology, neurology, or hematology. With some of the agents that we're giving, we're seeing these side effects that really require a multidisciplinary care. What I will also say, just in terms of the adverse effects that we can see with immunotherapy, what we do really depends on the severity of the side effects as well as also where you're seeing those side effects. For instance, if you're having that rare myopathy or neurologic dysfunction, that's the kind of circumstance where you may have some real reservation about reintroducing immunotherapy as opposed to thyroid dysfunction, where you may just give replacement with thyroid medications and continue the patient on immunotherapy.
Arun: It's a dynamic interaction and requires continuous follow-up depending on the type of side effects. I completely agree. One important aspect that we oncologists, and in fact any healthcare provider, are very aware of is that these new drugs are rather expensive, and there is insurance coverage. But does everybody have access to these drugs?
Kalinsky: That's an excellent question. I think that some of the agents that we have approved in triple-negative breast cancer, including antibody drug conjugates (ADCs), are not globally available. When there is lack of access, that can lead to disparities of care where some patients have other opportunities that others may not have. I also think, just for a patient who has metastatic triple-negative breast cancer, that there are some things that are really critical that we are doing for all of our patients. We need to be checking PD-L1 status at the time of diagnosis. Does it matter if it's the primary tumor or the metastatic tumor? We need to do that. We need to check for BRCA mutations. Oftentimes, looking at hereditary testing beyond BRCA, looking for germline PALB2. It's important that we do this. We should really be looking to see if patients are HER2-low or not because our definition is based upon trastuzumab deruxtecan (T-DXd), we don't think in terms of HER2-positive or HER2-negative. Now it's HER2-negative and HER2-low and HER2-positive, even though that paradigm is likely to change as well, where we may have a HER2–ultra low population. But right now, in this time period, it is important that we do that for all of our patients. That's also where disparities of care can really kick in if providers are not routinely checking this on their patients.
Arun: You really touch base on a very important aspect because with all of the molecular diagnostics and the targeted therapies, it's very important that providers think about it and are used to ordering it and that there's coverage. This was really a great segue into my next question about ADC. Our listeners will remember that in episode one, we had a discussion with Dr Filipa Lynce related to ADCs but specifically for this episode, how do you think we should think about sacituzumab, T-DXd, as well as poly (ADP-ribose) polymerase (PARP) inhibitors and BRCA germline–positive patients?
Kalinsky: It's an excellent question. I think it also reflects how the field is changing and I suspect will continue to change. Right now, as of this moment, ADC's are not given as frontline therapy. For a patient who has a PD-L1 positive tumor, I think the standard is often to give chemo and immunotherapy. I'll touch on patients who have hereditary mutations in just a moment. The next step would be to give an ADC right now. I would lean toward giving sacituzumab govitecan, given we see this overall survival advantage. There was a large randomized phase 3 trial with ASCENT that demonstrated this doubling of progression free survival and overall survival. If a patient has a HER2-low tumor, I think it's reasonable to give T-DXd after that. However, we don't have data in terms of sequencing. These drugs are moving rapidly in trials in the frontline setting. For instance, there are studies like the ASCENT trials, the ASCENT-03, which is a PD-L1–negative population comparing chemo vs sacituzumab govitecan. There was also a frontline study, ASCENT 04, which is comparing chemotherapy with pembrolizumab and sacituzumab with pembrolizumab because there are data that may be giving an ADC along with PARP inhibition that there may be some synergy that's there. We will see. The other thing that's important to keep in mind is that sacituzumab govitecan is a TROP2 ADC. Datopotamab deruxtecan (dato DXd), which is another TROP2 ADC that is given once every 3 weeks, has completed one randomized phase three trial. This is ongoing now in triple-negative breast cancer. It is possible that we'll have more than one TROP2 ADC for our patients with HER2-negative disease. If you have a patient who has a hereditary BRCA mutation, there remains an important question. We are starting to get some randomized data of PARP inhibitor plus or minus checkpoint inhibition. For instance, at San Antonio in 2022, we saw the results of the DORA study. I think that there are some preclinical data demonstrating the potential synergy of giving those two agents together. I'm commonly giving checkpoint inhibition as frontline. If I have a patient with a BRCA mutation, that may be a patient that I may think about as my chemotherapy option, giving something like carboplatin. I am awaiting additional randomized data. The reason I give checkpoint inhibition early is because that's a population that I'm hoping may have some durability of the response, that we see some leveling off in that tail of the curve. It is important to note that with PARP inhibition, we see real responses, notable responses, and of course compared with chemotherapy, an improvement in progression free survival.
Arun: And durable responses.
Kalinsky: And some durability of the responses. The question is when you give immunotherapy plus PARP inhibition, whether you can improve the durability of the responses. I'm curious about your approach and whether you think about this similarly, or if you have a different sort of approach.
Arun: I think we all have the same dilemma. My approach is very similar, but sometimes I deviate a little bit from your approach. If we have a germline BRCA–positive patient because the prospective trial really was done only in that population, regardless of PD-L1 expression and regardless of triple negativity, that is a pretty straightforward indication to many of us. Like everyone, I go back and forth between whether I should use the PARP inhibitor as first-line or second-line after immunotherapy, I think I tend to give it first-line first. One of the reasons is also, for example, if I use carboplatin and gemcitabine with immunotherapy in the germline BRCA mutation carrier, maybe I am reducing the response after platinum to PARP inhibitors. I am saying this very carefully because we don't have comparative prospective data for all of these things I'm saying. But those are some of the things I think about in my head algorithmically when I try to make clinical decisions.
Kalinsky: I think that makes a lot of sense. I was reflecting on data that Nick Turner had presented when he was presenting the talazoparib data, which demonstrated that the further away from platinum that you were when you got the PARP inhibitor, the more the likelihood for a response. It does ask the question of timing of a platinum and then utilization of a PARP inhibitor. I'm going to veer us off topic for a second because we're also giving immunotherapy in the early stage setting regardless of PD-L1 status based upon KEYNOTE-522. If I had a patient who had a BRCA mutation, who has residual disease, instead of giving something like capecitabine, often, I'm giving those patients olaparib and I'm combining immunotherapy with the olaparib in the adjuvant setting. Not that we have specific data. We have safety data, but not data in that particular setting. But that is a combination that I would utilize in that circumstance.
Arun: I agree with that. In the post-neoadjuvant with residual disease, I do the same. Rather than jumping to capecitabine, I either continue the 6 months of immunotherapy and then do the 1-year of olaparib or now, with the recent combination data, we can combine it. Adding another year of capecitabine without any data and prolonging the adjuvant therapy to 2.5 years does not seem very practical to me. We don't have any data on this. But there are great choices out there. I'm also very excited about the combinations you mentioned. I even heard of triplet combination ADCs, immunotherapy, and PARP inhibitors. We are eagerly awaiting the results but, of course, also understanding the toxicities. One last area is resistance, and I know there's not that much data, but with all of the antibody drug conjugates, I think the resistance discussion will be really important.
Kalinsky: I agree. I think we're getting some data. For instance, our colleagues Leif Ellisen and Aditya Bardia had some data that were published in Cancer Discovery just about TROP2 and mechanisms of resistance to sacituzumab govitecan. I think it remains an important question within the field. We don't have a great predictor of response; TROP2 expression by itself - most tumors express TROP2 with the antibody that we're utilizing. TROP2 expression doesn't seem to be an indicator for who's going to respond. The other question you mention is what about the time of resistance? This is also where this question has come up in terms of sequencing, because though T-DXd is targeting HER2, the payload is also a topoisomerase inhibitor, right? It is a similar payload to what we see with sacituzumab govitecan. Part of the question is what if you're targeting something differently but the payload is the same? Are we going to see the same sort of responses? That's an area that I anticipate we'll get some data. We just don't have any data right now.
Arun: Correct. Thank you so much for being with us today.
Kalinsky: Thanks for having me.
Arun: Today we've talked with Dr Kevin Kalinsky about immunotherapy in advanced and metastatic breast cancer. Take a moment to download the Medscape app to listen and subscribe to this podcast series in advanced and Metastatic Breast Cancer. This is Banu Arun and for InDiscussion.
Primary results From IMpassion131, a Double-Blind, Placebo-Controlled, Randomised Phase III Trial of First-Line Paclitaxel With or Without Atezolizumab for Unresectable Locally Advanced/Metastatic Triple-Negative Breast Cancer
Pembrolizumab Plus Chemotherapy Versus Placebo Plus Chemotherapy for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple-Negative Breast Cancer (KEYNOTE-355): A Randomised, Placebo-Controlled, Double-Blind, Phase 3 Clinical Trial
Study of Sacituzumab Govitecan-hziy and Pembrolizumab Versus Treatment of Physician's Choice and Pembrolizumab in Patients With Previously Untreated, Locally Advanced Inoperable or Metastatic Triple-Negative Breast Cancer (ASCENT-04)
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Cite this: Immunotherapy in Advanced and Metastatic Breast Cancer: Recent Studies, Disparities in Care and Rare Side Effects - Medscape - Jun 07, 2023.