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Kevin Kalinsky, MD, MS: Hello. I'm Dr Kevin Kalinsky. Welcome to Medscape's InDiscussion podcast series on triple-negative breast cancer (TNBC). Today we're wrapping up our first season of this podcast series by looking beyond TROP2, with our guest, Dr Filipa Lynce. Dr Lynce is the director of the Inflammatory Breast Cancer Center at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School.
Her research focuses on inflammatory breast cancer, TNBC, BRCA-associated breast cancers, and novel therapies in the treatment of breast cancer. Dr Lynce, it's really a pleasure to have you on this podcast and for us to pull everything together and think about therapies beyond what are currently approved.
Filipa Lynce, MD: Thank you, Kevin. It's a real pleasure to be here today with you.
Kalinsky: We'll start by focusing on inflammatory breast cancer (IBC), because I know that this is an active area of research for you. Let's think big-picture about where we are with IBC, such as differences in biology, differences in therapeutic approaches, and any updates on treating what we've historically thought of as a challenging breast cancer to treat.
Lynce: That's a great way to start. I think that there has been a lot of discussion on this topic. We all agree that IBC has a clinically distinct and unique presentation and behavior when compared with noninflammatory breast cancer and adjusting for the same subtype.
It remains unclear whether it is a biologically distinct entity. We all know that some characteristics are unique to IBC. More often, you find patients with IBC who have HER2-positive or triple-negative disease. You have a higher number of patients presenting with upfront stage IV disease compared with non-IBC.
We recently reported a higher proportion of patients with CNS metastasis, but we haven't been able to show from a biologic standpoint whether this is a distinct entity. So far, transcriptomic work has been relatively unrevealing, perhaps with the exception of TGF beta signaling, and there has been some important work in that field, as well as the JAK-STAT pathway, led by Dr Kornelia Polyak from Dana-Farber.
There was an interesting paper published 2 years ago, where a group from MD Anderson and Yale compared results of whole exome sequencing of 20 IBC samples with paired germline to match non-IBC samples from The Cancer Genome Atlas, and they found similar genomic alterations between the two groups, with the exception of a possible enrichment of germline alterations in TGF beta.
Recently we did a similar study, but using our own CLIA-certified, tumor-only, targeted hybrid-capture DNA sequencing platform, OncoPanel, and we compared 140 IBC cases. It is a large dataset with 2300 non-IBC cases, all of them profiled using OncoPanel. We'll be presenting our data in San Antonio. But I think we need to do better, and moving forward we need to go beyond somatic DNA level changes. We need to focus really on the tumor microenvironment. There are some preclinical data suggesting that the tumor microenvironment might have a specific role in IBC. We need to look at germline somatic interactions as well. Is it something unique to the host that makes the breast cancer present the way it does in patients who present with IBC?
Kalinsky: Do we have data on how patients with IBC are responding to antibody drug conjugates (ADC)?
Lynce: Not yet. These patients were included from the trials that evaluated ADCs in the metastatic setting. I am not familiar with subset analysis focused on IBC, given that IBC represents 2%-3% of all the breast cancer cases.
However, now that ADCs are being moved to the neoadjuvant setting and the early-stage setting, that is certainly a concern, as most of the time, patients with T4d disease — that is the definition of IBC — are excluded from most of the neoadjuvant trials.
The same applies when you are talking about immunotherapy. We don't know the response of IBC, in particular triple-negative IBC, to immunotherapy. There are interesting data coming from different centers, more real-world data. We do acknowledge that this is a really important point. I think our industry partners acknowledge that as well. It makes sense to move ADCs to the early-stage setting and include and study the patients with a higher risk for recurrence. IBC patients are part of that group.
For example, here at Dana-Farber, we have two studies that are dedicated to IBC, looking at the combination of ADCs with IO in patients with inflammatory breast cancer. One is the TRUDI study, evaluating trastuzumab deruxtecan plus durvalumab in the neoadjuvant setting, both for patients with HER2-positive and HER2-low IBC. It is eight cycles in the neoadjuvant setting followed by surgery. It's currently open at Dana-Farber and MD Anderson. Cohort C in the NeoSTAR study, that already presented some of their initial results, is fully dedicated to patients with HER2-negative IBC. In this study, patients receive sacituzumab with pembrolizumab for four cycles, followed by AC and pembrolizumab. Almost all of our patients with IBC have a clinical trial opportunity so that we can learn more about the role of ADCs in this particular disease.
Kalinsky: That's great. I know in I-SPY that there's a plan to look at some of these less common subtypes of breast cancer, including metaplastic. I don't know if IBC is also being evaluated in that analysis, but I know that there's an ongoing look at some of the rare cancers that were in I-SPY.
I'm going to move along from talking about IBC to focus a bit on where we think the field could be going in terms of novel therapies. I thought we would start from recent data that we saw at ESMO 2023, looking at, for instance, B7-H4, in ADCs.
I wanted to get your sense of what you thought of those data. Do you think that this is a target that is worthy of investigation? Are there any other ADCs that have piqued your interest, including the HER3 ADC?
Lynce: I think many of us were excited with the results of two novel ADCs that have B7-H4 as the target. Those two ADCs were HS20089 and SGN-B7H4V. For those who are listening to us, B7-H4 is a transmembrane glycoprotein of the B7 family that inhibits the function of activated T cells.
It has a role in the immune response. It is known that it's expressed at low levels in normal tissue and upregulated in solid tumors. There are different ADCs that have as targets B7-H4 and are being developed not only in breast cancer, but in other tumors. I think that we saw some exciting results of two first-in-human dose-escalation studies that were presented very recently at ESMO.
The first one was HS-20089. In these ADCs, the target is B7-H4; the payload in these is a topoisomerase-1 inhibitor. This is a common payload in the ADCs we are currently using in breast cancer. The number of patients with TNBC that were enrolled was significant, with 28 patients. The overall response rate they saw was about 29% with a disease control rate of 75%. Patients who had received prior PARP inhibitors had a fantastic response, an overall response rate of 75%, and that might say something about the homologous recombination status of these tumors.
Something that we are all looking forward is the efficacy data. We are currently using ADCs in the clinic, but we are always looking for how can we improve efficacy with manageable safety. That's what I think was very exciting. This was a relatively well-tolerated drug. As expected with these payloads, most of the grade 1 and grade 2 toxicity was neutropenia. Grade 3 and 4 was also neutropenia, decreased platelets counts; and nausea and vomiting were seen in a very small number of patients. So these studies are moving forward, and I think that it will be nice to see how it plays out in a larger number of patients and beyond TNBC.
We also saw results of another ADC that has B7-H4 as the target. This was SGN-B7H4V. Here we have a different payload — not a topoisomerase 1 inhibitor but a monomethyl auristatin E, which is a potent microtubule inhibitor that we have seen on other ADCs.
We saw the results of the phase 1 dose escalation being presented at ESMO, including many different solid tumors and hormone receptor–positive and TNBC. We saw the results of the safety profile of this drug that were comparable to other ADCs that include the same payload, and was peripheral neuropathy, cytopenias, nausea, and disease. This safety profile is further being developed.
There is more to come. This is still phase 1 dose escalation, but I think it is a promising target. I know that you discussed this on prior episodes, but there are still questions, like, how do we sequence and how do we find out if the resistance is to the payload or the antibody? Having different ADCs in our portfolio that have very different payloads will be of benefit and interest to our patients.
Kalinsky: I think we see clearly across different phase 3 trials that ADCs are better than chemotherapy in various settings. The major issue is that not all ADCs are the same, even though they may have the same payload or the same target. The linkers can be different, and so we're seeing different toxicities and different levels of activity. While we've seen some exciting activity with agents you just mentioned, the question's going to become, how do we best sequence these? We also know that our patients may have toxicity, such as neuropathy, from other agents. We have to think about whether we can give additional potentially neurotoxic agents to patients. There is interesting research activity around this in breast cancer and in gynecologic cancers.
Lynce: It's the same with bone marrow toxicity. As these patients are more heavily pretreated, figuring out how much they can tolerate in terms of agents that will cause bone marrow toxicity remains a challenge.
Kalinsky: The one other takeaway that I had from ESMO is that it's quite clear that ADCs are here to stay. There are so many ADCs that are currently in development, including other TROP2 ADCs and other HER2-targeted ADCs. This is going to be a continued area of interest with lots of trials in various spaces.
The last thing I want to touch upon is combining ADCs.
Lynce: Great, great question. Going back to ESMO, we saw results of a very interesting and provocative study that was presented by one of my colleagues here at Dana-Farber, Dr Bradley McGregor, where they showed the results of combining two ADCs for patients with treatment-resistant metastatic urothelial cancer.
In this case, they combined sacituzumab govitecan, which we are all very familiar with in breast cancer, with enfortumab vedotin. It was pretty impressive that in a treatment-resistant patient with metastatic urothelial cancer, they reported an overall response rate of 70% with three CRs and 13 partial responses.
I know that a similar approach of combining different ADCs is being explored by different groups in breast cancer. This could be a way of potentially overcoming resistance or being able to deliver more payload, depending on the ADCs that you combine.
I do worry, of course, with using ADCs in the clinic. What will the toxicity profile be? Is it going to be a concomitant approach or more of a sequential approach as we think about ADCs and PARP inhibitors? There is more to come, but I was very excited seeing the results of this trial.
Kalinsky: I agree. Financial toxicity is important to consider as well.
Lynce: Yes.
Kalinsky: We think about toxicity in general. I agree, it's an area of real interest. Well, thank you, Dr Filipa Lynce, for joining us today for InDiscussion and talking about TNBC and looking beyond TROP2. This was a great conversation and a great way for us to conclude the first season of this podcast.
Thank you so much for joining us. This is Dr Kevin Kalinsky for InDiscussion.
Resources
Inflammatory Breast Cancer: What You Should Know
JAK-STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States
TRUDI: TDXD+Durva in HER2+/Low IBC (TRUDI)
381O First-in-Human/Phase I Trial of HS-20089, a B7-H4 ADC, in Patients With Advanced Solid Tumors
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Cite this: Thinking Beyond TROP2 at ESMO 2023 - Medscape - Dec 05, 2023.
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