Episode 160: Role of Immunotherapy in Metastatic Triple Negative Breast Cancer

Welcome back to this final part in this series on Triple Negative Breast Cancer. In the first episodes, what we've done is looked at the role in adjuvant and neo-adjuvant for immunotherapy. We've talked about the importance of pathological response rate, and we've talked about a 13% improvement by giving the immunotherapy. We then went on to talk about some of the challenges of giving immunotherapy and chemotherapy together. We started to think about some of the toxicities, and what was really nice is Anna then described how actually in both lung and breast cancer, maybe we should be setting up specific pathways so that we can work to get patients to this surgical date. We finished by Pete really talking us through why it's still important as of today in June 2025 that we still get patients to surgery because that is a standard treatment option. What I want to do in this episode is move to the metastatic setting. We know that immunotherapy now has a role in the metastatic setting for Triple Negative Breast Cancer. We know if we look across the world that different immunotherapy drugs are being used in terms of PD1 versus PDL1 blockage. I want to think about that. Also, then what I get into thinking about is the role for re-challenge immunotherapy is PDL1 important. Finally, I want to talk about ADC briefly, just to introduce it, although I know that we're going to cover this in other podcasts going forward. Finally, I want to think about the future from immunotherapy, where is the real excitement by specifics till CARD and how are we going to build on the success that we're currently seeing? The Triple Negative Breast Cancer again doesn't have the targeted treatment options. They are able to work at the issue, except the positive ones have the endocrine therapy and the other two targeted therapies. The main stage of Triple Negative Breast Cancer Medestatic setting has been chemotherapy. The most patients who become metastatic, the vast majority actually have had early breast cancer. Quite often, these patients have already had chemotherapy in an early setting, so an anticycle and usually a taxing. Then it depends on their time from when they finish that early breast cancer treatment to when they become metastatic, to exactly what we do. Certainly, with anticyclin, there's a small risk in the future of heart problems, and so there's a lifetime maximum you can have of that. By and large, your patients have had an anticycle in the early breast cancer. We don't tend to give it, certainly not in the first line for the metastatic setting. If a metastatic triple negative breast cancer is stoically the treatment, it's tended to be a taxa, a newsy-packed, tax-based treatment. Then what's changed? What are we now doing? If we're giving a immunotherapy as part of that, what are the stipulations? Is there a PDL-1 element to who's eligible? What kind of benefit do we think we're getting? Either upfront in terms of response or PFS or that more durable part of the curve that we're really interested in? There's been two pivotal trials in this area. The first trial that came along was in Passion-130. This was followed by Kino-355. Both of them looked at so that you use the control arm, which again was the current standard of care, so you use the attack-same-based chemotherapy, but added in immunotherapy. A tesolizamab together with a version of a pact, a contract called NABPACT-the-taxle. We perhaps have been interested in that we can talk about why they did that in a moment. It was Pemberlizamab with Kino-355. The data showed that for these trials, they took all patients, but then they did a subgroup analysis according to their PDL-1 expression, and both of you slightly different assays, slightly different cut-offs, but there was a definition of PDL-1 positive versus negative. When they did the subgroup analysis, it was only the PDL-1 positive patients who benefited from the chemotherapy plus immunotherapy in these settings. That was both in terms of a progression-free survival, but also in terms of an overall survival as well, although because of the way the Empassion 130 was designed in its statistical plan, it was in a formal analysis of the overall survival benefit. There was a clinically meaningful increase, so for Empassion 130, there was a seven-month improvement on average of the overall survival with the immunotherapy in the PDL-1 population compared to chemotherapy alone. On the basis of that, that's our standard of care in the UK at the moment. There's the way of assessing PDL-1 positivity differed between the two trials. There's about a 10% of patients who, if they're negative by the Empassion 130 method, are positive by the keynote 355 method, so there's not a complete overlap between them. In the UK, again, this does differ around the world, but the protocol for treating at the moment is we test to see whether they're suitable for immunotherapy based on the autismism at plus and now practice, that's only in patch 130. If that's negative, then you test to see if that's suitable for keynote 355. Okay, and so if I'm the patient in the middle of that PDL-1 dilemma, if you biopsy and it comes back at low PDL-1, does that mean I can't have a autism app? If it does, can't you just go and biopsy something else until you find me a PDL-1 number that's good enough? So it's a good question. There is evidence that certain organs may have lower PDL-1 expression. So it's an epitastics of in a particular organ may have a lower PDL-1 expression. There is a have a greater therapy, again, for example, may have a lower PDL-1 expression. So yes, it can alter the outcome. Time is probably the main question here, and also obviously the safety for the patient in terms of how easy it is to get the biopsy. So sometimes we, again, perhaps more, not look so much like if the PDL-1, but sometimes patients are having another biopsy perhaps to confirm the diagnosis, sometimes to recheck the receptor status, which can sometimes change. And so we do sometimes test multiple sites if we've got them and we can get them in a timely manner to see if they're PDL-1 positive. And if any of them are PDL-1 positive, then we will give the immunotherapy alongside the chemotherapy. Okay, but presumably the nice improvement reimbursement says there have positive PDL-1 to be able to have a T-ZO, or is it just that we want to know because it'll guide us, but everyone can have it regardless, PDL-1. It's going to be clear on that. Yeah, so no. So the evidence based on the trial data, I mean, how well it works, but also, as you said, the the nice reimbursement of funding is that there has to be the patients have to be PDL-1 positive. And there are there's definitions based on particular assays within the laboratory about what that means. And so no, you can't be given to everybody they have to meet that positivity criteria. Okay, so Anna, I don't want to get into the sort of why nice would choose one, not the other, because I think that's, you know, way out of our time sort of ballpark today. But we talking renal about the PDL-1 versus PD-1 story and the, you know, there's this feeling, I'm not as convinced, but there's this feeling that PD-1 does better than PDL-1. Do we know anything in the breast cancer space about the class of drug and do we think it has any impact? Probably not. There is, I mean, obviously the two drugs that we're talking about in combination, do you do work differently with paembolism, I've talked to PD-1 and tells us I'm talking PDL-1. And the bit that interacts with does, does, is different. So PDL-1 is expressed on the surface of the tumor, hence why we stain for it. PD-1 is generally expressed by the immune cells. And there's a bit of cross, cross-expression and there's some funky scores that you can use to sort of get a, get a composite score. So the theory is that if you use a PD-1 that you'll get a fact across PDL-1 and PDL-2, whereas if you use a PD-1, you'll have a more targeted effect. But in terms of efficacy, there doesn't appear to be a difference. And there are subtle differences in the trial designs. You will never do a head-to-head comparison. So I don't think there's particular significant differences in terms of which axis that you're targeting. They're probably fairly similar. The thought is that because of the fact that PDL-1 drugs are a bit more targeted, that you actually possibly see slightly less toxicity. And that probably plays out in the analysis and sort of overall sort of real-world experience of a tezonesumab versus other PC-1 drugs. But again, it's probably not in a particularly significant manner. And you would still consider and see all the toxicity you see with a PD-1, just maybe slightly lower frequent thing. Okay. So PDL-1 is designed clear. So in the metastatic setting for triple negative. Are we getting And only one bite at IO is it essentially just in the front line and then no later lines. And if that is the case, is there any data in the rechallens space, either in the private patients or in trials? Do we know if there's any benefit in going again? So, currently it is just in the first line setting. The trial data certainly looking at later line use of it of immunotherapy, so far as it's been negative, it's been no better than chemotherapy in that setting. The rechallenge at the moment again is not routinely done. Again, I'm sure there's a particular, maybe some small data around this, but again, this is very much areas of active research about how actually we can improve the response rate best in the first line setting, but also actually particularly again, how can we continue that in later line treatments of the way? And as said, there's active research in this area, but we don't have the clear answers yet. OK, so look, in the final sort of 10, 15 minutes, I just want to think about other types of immunotherapy, because Anna and I talk ad nauseam about the fact that this is no longer just checkpoint inhibitors. What are the things I want to come to kill, car, see, vaccines, etc. What are the things Anna that we've never really talked about is ADCs, which means I've got no idea what they are. And we had a brief conversation over some wine one day, where you were trying to convince me that ADCs could be considered as an immune modulator, and therefore that we should start talking about them. I'm not sure I'd bought it that day, but I don't know anything about them. So, sell me the ADC concept, and sell me why you think I should think about this through the lens of the immune system. OK. OK, so just a quick way of the fact that ADCs are used in breast cancer, but they're used in specific types, to subtypes of breast cancer, but in terms of what they are, so ADC stands for an antibody drug conjugate, and I like them because they're pharmacologically elegant. So essentially you have one clinical antibody, then something called a linker, and then you have something called a payload, which generally speaking is a chemotherapy pipe drug. And the idea is that actually by using a monoclonal antibody, you kind of use it like a sniffer dog. So essentially the monoclonal antibody finds the protein that's being expressed in the particular cancer, and then binds to it, dragging the chemotherapy with it into the into the region where it needs to be effective. So the monoclonal antibody searches out the cancer that's over expressing a particular target and takes the chemotherapy to it, which is very obliging a bit. And then the chemotherapy cycles through and becomes effective in that space. And the idea is, essentially you can get higher concentrations of the active agent at the level of the cancer way you need it. And there are lots of ADCs that are coming out into clinical practice across multiple different tumor groups. Mostly based is that there's a little bit of variability in the type of payload through the type of chemotherapy type drug you're using. But the big variability is in the target of the ADC, the protein that the monoclonal antibody is binding to. So theoretically the monoclonal is your work a bit. It's the bit that takes the drug that's actually going to do something to the places meant to be. However, there is some evidence, translational evidence that suggests that there is some immune activity that happens by the presence and binding of the antibody drug conjugate, that when it binds, you probably do get some degree of immune activation. Also, we know that some of the targets, so this is an anti-herde drug, so not used in triple-nose breast cancer, used in a herde-positive recommend that. But N-herde, who binds to her tube, and we know her to, particularly in certain tissues, suppress acidity activity. So by essentially binding to it, it probably does inherently increase the immune system activity. And also, what we recognise is that some of the toxicities we see of ADCs are almost certainly inflammatory and immune-based. And we know that because they respond to immunosuppression and corticosteroid use. So all that wrapped into one is suggested the fact that, although the ADC is essentially utilising the immune system as a way of marking out a cancer and getting a higher concentration of treatment way you want it, it's not going to affect probably how quite have sort of slightly unintended or not primary immune mechanisms. And certainly the toxicities we see are of an immune-based. And I think if we tether that to the fact that we are increasingly in starting to see combinations of ADCs and checkpoint inhibitors coming through, we will see a very interesting time coming forth, I think, where understanding the importance of the different parts of the immune system and how they're involved within the patient is something that we're going to have to traverse more and more. And ADCs are expanding at pace. We don't talk about, we haven't talked about it particularly much so far, but there is a huge number of blood in the market in lots of different cancers because they are showing benefit in a lot of circumstances. So more on ADCs to come, I think, but certainly there is, they're very interesting therapeutic and pharmacologically very exciting. OK, sold. I like it. OK. Pete, so let's think about other forms of immunotherapy then in triple negative breast. Is there any ongoing work? Is there cancer vaccines a thing, or on-collytic viruses a thing, a tilse, a thing, a carchew thing? What's going on in that wider immunotherapy space? So they're all areas of active research. But because breast cancer traditionally has been viewed as a less immunogenic cancer type, we've, as Anna said, we tended to lag behind a little bit in these areas. And so the trials that tend to be going on with this, certainly with the CAR-T, TILs, side of things, tends to be more in the phase one, so smaller studies at the moment, but they certainly work ongoing from that side. And we'll see how that develops over time. There has been some vaccine work done as well, and there's been some of our kind of specialized vaccines again, which has had some success, but again, hasn't kind of certainly come through to a certain mainstream treatment at this point, but again. So again, ongoing work from that side. I think the areas of that are going to show development by specific antibodies. So we have some interesting trials at the moment looking at PDR1 with other targets, particularly there's with trial running with PDR1 plus VGF by specific antibody again. So I think these are the way that things are certainly in the breast cancer field will move first, and then things like the cell-based therapies and vaccine-based efforts will come along a little bit later. OK. And that by specific, because we talked about triple negative, and this may be a really city or basic question, but we talked about triple negative not really having many things to sort of on the surface, other by specifics in the triple negative space. And if they are, what are they bind into if we don't have the other things like the other receptors that we've talked about or heard to? How do I are using by specifics in triple negative? And if so, what are the targets that we're trying to use to get the immune system activated? So some of this is based around previous, combined if you're almost actually previous treatments and that. For example, with the VGF side of things, there is a drug called Bebacism app, which has had some evidence of benefit in triple negative breast cancer. The data is a bit mixed, so it's not using the NHS, but certainly it is used in other settings. But again, there's evidence of perhaps that as well as affecting the blood vessel, the vascular, it kind of system. And so there's a rationale for combining that side of things. In terms of other targets, there is obviously things like Tidget, for example, expressed as well. There is work ongoing in this area. Obviously, things like the Tidget story across cancer in general has been mixed in terms of the responses. And so some companies have pulled out of that space. Some companies are continuing. Again, the trust tends to be an earlier phase at the moment. Again, we're still waiting the phase to be dated. So kind of, yeah, your name from that side. Okay, so let me kind of push you for the sort of final couple of minutes. What are you most excited about in the immunotherapy space in triple negative breast cancer? If you're a better man and you're going to put your money somewhere, where's the next step change coming from? So I think we're starting to see the first step change coming with the ADCs as we've spoken about. They will become the partner, the chemotherapy, if you like partner of choice for the immunotherapy. So at Asco this year, the Ascent 4 trial data was presented. And this was using their, this particular company's ADC called second two is my plus pembolism versus the standard chemotherapy plus pembolism. And it was better. There's an increase in the progression for you survival. And so that's the first step that that kind of there's as Anna was saying, there's other plus immunotherapy combinations in trial. These are moving into the early breast cancer setting as well. So there's trials ongoing, for example, the neoadjuvant space. And I think in terms of they will see what the results come from there, but I'm going to be very interested whether they both improve outcomes in terms of pathological. completely responsible and survival, but also whether they allow us to avoid chemotherapy drugs like the anthocytes, which if for some patients be associated with longer toxicities as well. So I think the ADC combination is going to be very interesting. I do think actually the bi-specific as well coming through as well, and obviously eventually I'm sure that they will all get combined as these things tend to do from that side. So I think those two are particularly interesting areas to keep an eye on at the moment. And then maybe if I just come to you to finish. So in terms of predicting response to IO or predicting chance of toxicity, is there anything in the triple negative breast cancer space that we're aware of, except in the fact that we talked before about IL-6, IL-7, different epigenetics and other things? Is there anything particular in the triple negative breast cancer that can help us either work out who's going to respond or ultimately in our world reduce the chance of getting toxicity? Not really to be honest. In terms of all of the things that we've talked about in other patient groups is very valid. I think we need to, we do need to understand the immunology a little bit more. So as we've talked about throughout, things like there is presence of teaming and photocell lymphocytes in different negative breast cancer. But it's not particularly defined. One of the things that's very interesting is we always look at median overall survival when we look at study curves and when we look at whether trials are positive or not. And we know that patients with PCL-1 positive breast cancer, different types of breast cancer, get the best outcomes with the combination of napakotaxle and metaselism together. However, there are some patients that get long javelties here of response. So you get that, you do get the tail on the curve. So understanding a bit more about that patient population, I think is something that's really crucial for us going forward. Why do those patients get long-term responses? I know of patients that have been on treatment for in a number of years. So what is it about them that makes it different? And it would be very useful to be thinking about how we look at their pre-treatment biopsies and then sort of further ongoing evaluation. Because there's something different about that subgroup that we probably need to analyse a little bit more clearly. And I think that's useful because the other question we have is obviously we talk about using checkpoint inhibitors particularly in the second line. And we don't see a positive benefit and that's probably because we get a relatively modest benefit in the first line. And we know that if we go down, see a real line to treatment that we get less benefit from the immunotherapy in the in nilial cancer. But is there something about a particular patient group we could identify who would get benefit in subsequent lines of treatment that we haven't necessarily identified in the mechanisms and the modalities that we look at now? So I think that's important. In terms of the regime, at the moment, it's quite interesting. So in the neo-antibid space, these packletacles are one of the four chemotherapy drugs that we use alongside Pembralismab and in the mess data setting when we think about the Pembralismab they use napakletaxle. And one of the things that's quite interesting, we've talked before under the podcast is the fact that we know that checkpoint inhibitors increase your likelihood of hypersensitivity. And so you do wonder whether actually the reason you use napakletaxle, which essentially is a modified packletaxle agent that is like Pizzoimal and so therefore it's meant to cause less hypersensitivity, that's how it was marketed in the first instance. And so you wonder whether there is a hypersensitivity element of some of the toxicity we see in the particularly in the neo-agent space because we don't see these sort of slightly bizarre different toxicity profiles in the in the mess data status. That might be because the patients are generally a bit more immunosuppressed, but it is very interesting that there is stark contrast between those being treated neo-agentently and those being treated methodically. It might be that as they part of this is optimising the chemotherapy regime and thinking about the interaction between the two modalities that were giving in combination that might help us get to a place where we've got less toxicity in patients, but it's all very theoretical at the moment and no certainty. Okay, and then Peter, finally we haven't talked about anti-CTLA for drugs like Iphe today. Does the data, has that a presume it's been explored, the CTLA story in in breast, but I'm guessing that the data just didn't come out strong enough for us to think it should be used? Yes, I think that's right actually. Though I'm sure it has been used, I have to say that again it certainly has not made it to be a clinical practice and it's not used, it's not a partner in any of the ongoing trials from that side of things. I don't know the data in detail which suggests me that it probably wasn't very impressive. Yeah, no fine, good. Okay, so look, in the interest of time, let's bring this to a close. I want to say a massive thank you, as always, for Anna, who's currently in Seattle, I think at about midnight here at time, maybe later now. And a really massive thank you to Pete for coming on and giving us a tour de force of triple negative breast because it's an area that I struggle to understand a much clearer now on what it is. And actually, it sounds like I always made a difference and it sounds like we've got things coming down the line which is really exciting. So thank you both, have a lovely day and look forward to seeing you both again soon. Thank you. Thank you.