Combination Approaches in PD-L1–Positive Metastatic Triple Negative Breast Cancer

[MUSIC] >> Hello, and welcome back to the "Eunquality Brothers" podcast. I'm Rohit Gossane, here with my brother and co-host, Rahul Gossane, and we are both practicing community medical oncologists. And like many of you, we are trying to keep up with the rapidly changing treatment landscape, so we can deliver the best care to our patients close to home. Today, we are diving into evolving frontline treatment landscape for triple negative breast cancer. >> Well, a triple negative breast cancer has to be one of the most challenging diseases we see. But we're starting to see more and more treatment options here. In frontline settings, this has gone from chemo only to chemo with immunotherapy, and now we're awaiting approvals for ADCs with immunotherapy. Detoxification to the cron standard of care and how antibody drug conjugates, such as acetismab and data at the XD could potentially change this. We're excited to welcome Dr. Shereen Lloyd, a leading breast medical oncologist from Australia. Shereen, thanks so much for joining us. >> Hi guys, thanks for having me, please to be here. >> Shereen, welcome. Let me paint a bit of the background where we stand today, and then we'll dive in, particularly in metastatic space. For early stage triple negative breast cancer, we have keynote 522 base regimen, that is IO plus chemotherapy, followed by surgery and then completion of additional immunotherapy to complete that one year time. Here, the data supports use of immunotherapy in all comers, which is not PDL1 score dependent. However, this is different in metastatic triple negative breast cancer, where the treatment options are driven based on the PDL1 status in score. As community onc, we are rather used to seeing the PDL1 positivity, different scores, different cutoffs, even in lung cancer and upper GI malignancies. With regards to metastatic triple negative breast cancer, Shereen, could you start us off? How do you define PDL1 positivity and what assays do we have available here? >> Yes, so as you know, triple negative breast cancer is very challenging to treat. I think the whole scene change of immunotherapy, particularly in the advanced setting, has caused a lot of confusion. We are very reliant on our pathologists more than ever now. I think that's a key note that we have to have reliable pathologists and pathologists that you can have a dialogue with and that you trust their results, because obviously the patient's treatment and their lives kind of depend on that. At the moment, the approval for pen-relison embolias on the CPS assay, which is a combined positive score, and that looks at a mean-staining of PDL1, mainly in a mean-cells in breast cancer. That's very different from lung cancer where it's on the tumor cells. At the moment, the approval is of a CPS 10 or more for pen-relison embolias, and there's this gray area of 1 to 10, which in the phase 3 study did actually have a small benefit, but it was just not deemed statistically significant by the pre-specified protocol and statistical analysis. So I think the pre-boost for 10 or more, but the problem is that there's this gray area, and we know that PDL1 testing can be quite different between the laboratories and between the pathologists. Also, it's not really a binary factor, even though we treated it as a binary factor. So I think they're key things to just keep in mind when we interpret the CPS result. One thing I like to do is look at the immune cells, as well as the PDL1 staining, because sometimes you can have a lot of immune cells, and if your CPS is less than 10, that may be something to question the pathologist, because again, the patient might be missing out on benefit to pen-relison embolias. And also, I try to push my pathologist to give me a binary score. You know, is it 10 or more or less than one? Because if you're sitting at around 8 to 9, then I think it's very reasonable to ask the pathologist to look to see other areas of the tumor could be 10 or more, because that patient's almost certainly going to benefit from pen-relison embolias. And we know that first-line treatment is the most important for these patients. So it's really important that they don't miss out on pen-relison embolias, because not only does it extend their overall survival, many patients don't get to second-line treatment, but also pen-relison embolias, we've seen, actually improves response to the second-line setting, as well, if they get a good response in the first-line setting. So it's really important that they don't miss out. Previously, we've used SP142, but a TISILIT NISMAB is no longer used in the United States from what I understand. It can be used in Europe. It's a very different school. It reports less patients as pd-on-positive, so I personally think people should probably stick to CPS and also ask the pathologist to look at percentage of immune cell infiltration, as well, just as like a positive or negative kind of benchmark. What's that makes sense? Yeah, no, thanks for that background. And that's really helpful. Something to appreciate you briefly touched on this. I actually testing can be very subjective, and we know that the data supports that pd-on-positive disease when pen-relison embolias is used, you have better outcomes. So you're brought up pushing our pathologist and making sure we have that CPS score of 10 and above so that we're using immunotherapy in the right settings. So again, these biomarkers have significant clinical relevance. And more recently, based off Ascente-3 and Ascente-4, we seen Sacitosamabgovote can affront and based off Troopar on Bresto2, we seen DatoDXD come in frontline settings. Over the next few minutes, let's focus on pd-on-positive disease. This is where Ascente-4 trial becomes important. Shrin, can you walk us through the study design and its findings here? Yeah, So Ascente-4 was really designed to go up front with the keynote 355 regimen against chemotherapy and pen-relisonment. Again, it was the CPS 10 or more. This was centrally reviewed, which I think is a problem because there is a difference between metastatic and early biobsties as well. So I think this will influence some of the key trials that are coming out as well. It was a phase three open label, randomized, international study, large study, one-to-one randomisation. And basically, it was reported and just actually outpublished in New England that it hit its primary endpoint, which was progression-free survival by blinded independent review and an investigational arm of Sassid-2zemaab with hembalizemaab was superior to the standard of care, which is the chemotherapy of physician's choice. And pen-relisonment is around about a third improvement with regards to the hazard ratio. So it's significant. And interestingly, the objective response rate was not too dissimilar between the arms, which I think was quite interesting, despite the much longer PFS as well as the much longer median duration of response that we saw in the investigation at the reporting. The initial reporting, of course, over a survival is quite immature. And that will be interesting because, of course, patients were allowed to cross-over Sassid-2zemaab in the second line setting, which I think is really important for these studies in the future to allow a cross-over because we know that it has an overall survival benefit. I think the adjunct Vic really congratulated on allowing that. And I think there was quite extensive cross-over. But personally, I'm a believer in up-front hembalizemaab, so I personally believe it will hit the OS because of the immunotherapy component. So yeah, I think this is a good improvement in the first line setting. We still have a lot of work to do. I think it's still -- The still doing very poorly, the median PFS, or something like 11 months. So actually not too dissimilar, not much more than the original keynote studies, which I think reflects what we're doing now in the early stage. So there's still a lot of work to do, but it's clear that ADCs plus immunotherapy seems to be better than traditional chemotherapy lines. I think that's a good step forward. Well, thanks very much for recovering, Old Ashirin. There's quite a bit to unpack here. One, I want to go back to your point, which you initially stated. That is that we have a very little window with triple negative breast cancer. So we have to use stronger treatment options in front-line therapies. So checking for that PDL-1 score is the key. And as you stated, that not enough patients are even making it do second line. So that's another reason. We have seen that for small-so-long cancer. So again, keeping that the strongest option up in front-line options is important. Now, what's going to do with the Ascent 04? The comparator arm, as you stated, was chemo plus pembrolismab, which is in fact the current standard of care. And this is rather important because in trials that we see sometimes the standard of care arm is rather obsolete or not the current treatment arm. So that is the key aspect that was seen with this trial. And also, there was crossover with Sassitude Zubam, especially given that we have benefit in later lines of this. Also, Sassitude Zubam was rather approved in later lines for bladder cancer, but this was pulled away because of neutropenic related mortality. So keeping that growth factor in mind is extremely important. So that's a good set way to cover the side effects here. Shereen, can you touch on some of the common side effects that we do see with Sassitude Zubam, Avgovatecan? Yes. So in the later line settings in particular, but also in the first line setting, the diarrhea and the neutropenia is significant. I think all grades were 70% diarrhea. And grade three at higher was, I think, was like 40%. That was despite the use of growth factor. So Sassitude Zubam app causes diarrhea. We know that. And particularly the day one, day eight, dosing. Patients need to be aware of that, particularly in the third week. It can be quite severe. I've had patients with, you know, toxic collitis and up in intensive care. So diarrhea combined in the neutropenia can be significant toxicity. So patients need to be warned about the diarrhea, obviously. and given, you know, we all send these patients home with a gastrostop with some other antidireal agent and they need to let their physician know if they're running into trouble. The other thing that can contribute to the severity of the diuret is the neutropenia and certainly we now have learned to give primary prophylaxis with long acting GCSF. We give that on day 9 generally and that generally prevents the neutropenia and you know some patients will require a dose reduction. At the start GCSF was not mandated in the trial but I think in the end it was pretty extensively used as well. So the interesting thing about the trial in general however that there was not seemingly a substantial proportion of collitis, immune collitis related to the investigational which is interesting and it suggests that the type of diuret of SSE2's map is not a direct toxic effect that we see with chemotherapy potentially. So I think that was encouraging that we're not getting lots of immune collitis for these patients. It's just your typical diuret and so potentially you can manage that in the community setting with an upfront perhaps dose reductions that is 7.5 rather than 10 if the patient is elderly, frail as comorbidies or I think has had a lot of prior treatment in the early stage setting because I think their bow marrow will be a little bit you know not as fit as patients who are do no bow and using GCSF on day 9 as standard of care as well. I say I think they're really important messages and good education with the patient and a nurse or nurse practitioner to follow up with the patient during the first cycle. Shreen thank you so much on touching these common side effects particularly neutropenia and diarrhea given that the incidence is so high. A few other things to keep in mind with SSE2's map govati can alopecia fatigue and nausea. Shreen while we're talking about these side effects can you dive in a little more into some of the clinical pearls in managing these side effects particularly your diarrhea and neutropenia. Roll of growth factors what about skipping that day 8 can we do every other week what about the dose reduction here. Yeah so you can I mean the first thing to do is a dose reduction I think I actually have been more prone to start I didn't favor studying at the 7.5 or the 8 milligrams per kilogram. I mean patients that I'm a bit worried about who might live further away from the hospital for example. There it has definitely been talked about the fortnightly dosing and certainly in my experience that definitely is associated with lexatoxicity and less neutropenia and patients certainly feel better on it. As I understand Gilead are formally testing that schedule but I know many people around the world are certainly using it if patients can't tolerate the day with day one day eight scheduling so that certainly improves. As I understand a pharmacokinetics you know there hasn't been and we're not sure the pharmacokinetics supports that type of scheduling which is why Gilead is actually doing a formal trial I understand it at the moment but certainly my experience patients do feel much better on the fortnightly dosing. Absolutely and before we run away one last thing about diarrhea proflactic antiderials are you starting that upfront or at the time of their first episode. Generally if the patient is reliable at the time of when they first get it and then aggressively if they continue to have diarrhea. Yeah. Generally my feeling is the neutropenia does make that worse so it's important to get on top of the neutropenia as well. Absolutely and again when it comes to triple negative breast cancer Schrin we're often running into visceral disease or liver involvement. How is sassid to the MAP govetic ant cleared? Can I safely use this for patients with significant liver involvement? Let's say with elevated AST and ALT but normal belly rubin I know we have to be mindful even with Pembrolyzumab with these DERRANGE LFTs but what about sassid tozumab govetic ant? Well that's a good question. I mean in the study we use the typical eligibility criteria. I certainly would be where your patients have you know grade three or higher LFT derangement. I think it is related to disease and in the first line sitting I would certainly start at the lower dose and see how that goes and watch the LFTs carefully but obviously if it's related disease you want to get a good response right so if you're getting a 60% response right so you definitely want to be giving sassid tozumab at the dose that is therapeutic. Obviously if the belly rubin is up I would be getting some advice about that because you don't want to tip them over obviously into liver failure from the medication. Yep. Shrin I just wanted to get more clarity on the side effect management itself. Now we did touch on diarrhea in some aspect of transaminitis as well but now how are you deciding is it sassid tozumab causing it or pemberal isumab causing it and which one are you dose adjusting? Are you going to dose adjust and continue on with pemberal isumab or get rid of pemberal isumab and then dose the just sassid tozumab. Yeah so interestingly in breast cancer patients and I'm not sure why this is but immunocalyptus is actually quite rare so I think you know we can be reasonably confident that the diaries related to sassid tozumab and so certainly you know from first principles you would hold both drugs until it resolves and then if it's severe enough you would start with the dose reduction of the sassid tozumab with GCFF. You might want to hold the pemberal for a cycle just to introduce one at a time and then I would but generally and in the trial that was consistent that a mean colliders per se is it's quite rare I think it's reasonable to push on with both unless of course there's other immune related toxicity that need managing. Perfect thanks so much for covering that so at this point in time data is clearly positive as we have discussed and after this discussion I'm feeling comfortable with managing some of these side effects. On approval for that pdl1 positive disease this would be our preferable approach given the results we have but if we are using this broadly is there a particular patient that you would not use this upfront? Um it's a good question I mean I think sassid tozumab is quite similar to chemotherapy our traditional types of chemotherapy so I think if a patient is malar suppressed or has you know chronic diarrhea such as diverticulitis etc or a history of you know dosy taxil mediated diarrhea collitis or tiffilitis I think you might be a little bit cautious saying that I think in the real world setting you can start the lower dose you can give a fortnightly dose you can see how it goes I think it is important to get the ADC in you're probably going to get similar side effects from you know a tax saying um you know maybe not a weekly tax saying but certainly in that page can cause diarrhea um so you mate I think this survival advantage is too great not to try at least one at a lower you know at a lower dose and what do you want to do just the neutropenia as well again we tend to do the longer acting after the day eight regimen itself now if one has experienced neutropenia by the day eight are you skipping that are you starting a rather the growth factor for short acting at that point in time how are you maneuvering through that? Yeah so generally I would skip the day eight if they're already neutropenic and then start again at a lower dose at the day at the next cycle okay and when it comes to that pdl1 negative disease we have covered this aspect in another episode where data dhd will likely become available as well and we'll be left with cross trial comparisons here and patient shared decision making is going to be the key but here for pdl1 positive disease any ongoing trials that do look promising while we await sassitudes map approval the pdl1 positive obviously there's the tropian five I think which is ongoing which is the data dhd equivalent um there are I think that's pretty much the only one I know of with an immunotherapy agent there are plenty going in this pdl1 negative or immunotherapy not eligible space um including some novel ADCs um so the biantech pdl1 vegetin inhibitor there's also the BMS edf r per 3 ADC both of these sorry the BMS also has a tope one payload so at the moment I think most of the interest is in the pdl1 oh sorry the immunotherapy in eligible space firstly I'm finding that with kinet 5d2 there are less patients fulfilling that pdl1 positive criteria um compared to when we conducted the impassion 130 study um so I think that means that we're curing more patients in the early stage setting and those that recur are recurring earlier and more aggressive and pdl1 or immun low disease which makes sense because we know their patients who are immune high or have an active immune response so the ones doing better right so they're more likely to be cured and then we're left with the ones that are you know um immune cold or have more aggressive phenotypes so I think you know probably that's the space that we need to develop I think with the newer ADCs it may be that cps1 to 10 are going to see benefit from immunotherapy so I would encourage you know the companies to develop in that space um because I feel that these pd1 ages are managing to reinvigorate these patients immune system and that's important ultimately for longer survival so I think that we might see more development with immun therapies in the lower pdl1 space in the future and the one thing I forgot to mention is that don't forget there's heterogeneity between the primary and the medicine that it's like with regards to biopsies and pdl1 status so I think it's probably preferable to look at the primary cancer If you have access to it and there's lots of technical issues as well, you know how long it sat around before they put it in Boyman when it was looked at for PDM on testing that can also influence your PDM on one positivity result as well So there's just too many things going on. I think just to take one value one you know one positive or negative test that goes value Actually, this is a good point to bring up as well as we're talking about by a marker Sassi Tuzmab is a trope to antibody drop conjugate. There's no utility of checking for that trope to expression here Correcturing because the benefit is regardless of that trope to expression Yes, yes, well, I'm kind of a bit glad about that because at least we don't have another pathological test to rely on About saying that it's always nice, you know, I think as we go forward other targets for ADCs to have a biomarker defined population I think there's some data coming out from our scent 0-4 next this year with three guards to how a trope to Be haste when it does seem that it's quite ubiquitous along in triple negative breast cancers So does seem a bit like her too, you know her too seems to be present in most the breast cancers. So that at least You know, we have one list test to rely on As well, but we'll wait and see how I guess the treatment landscape evolves a little bit because then we might be confused about what drug to use when Absolutely, you know as we start to wrap this conversation a few things to keep in mind What do you start it off with keynote 52 now that we're exposing the disease with immunotherapy that perhaps is changing the biology when we seeing that recurrent relapse disease For denolvo it's important to keep that pd01 pdl negative in mind when we're selecting chemo with immunotherapy or ADC with immunotherapy Shureen before we close any final thoughts here for upfront treatment options for triple negative breast cancer In the meta static sitting in the meta static settings Yeah, I mean, I think now we have proof of principle ADC's will change the landscape in the upfront advanced um disease sitting We certainly didn't see any additive immune toxicity And it certainly is plausible that the toxicity profile will be better with an ADC because it targets a certain part of the cell right rather than being generic like traditional chemotherapy has The different ADCs will have different side effect profiles So that might help us in the future choosing which ADCs to go with when combined with an immunotherapy and hopefully we'll get better immunotherapy agents, you know, I think they combine pd01 bjf inhibitors look quite promising Particularly in the advanced sitting in patients who recurred after you know pymbalizamab as of course as you imply that I think we're going to be seeing a different type of disease phenotype um that recurred and we really haven't not much idea about that um and certainly I think traditional chemotherapies not going to help us Given that we're using it all upfront um in the early stage sitting Well, this is certainly exciting and we'll see how the field plays out Shureen this conversation has been rather very helpful and very insightful for us We appreciate you taking the time to walk us through the new data at hand and our currently treatment landscape For the frontline metastatic triple negative breast cancer patient population For listeners, let us go over a quick recap from today's discussion Today with Dr. Shureen Lloyd a breast medical oncologist we focus on evolving frontline treatment landscape For pd01 positive metastatic triple negative breast cancer We talked about how the pd01 scoring plays a role where in earlier stage we are not dependent on that However for metastatic space it is important because our treatment implications tied to it That is pemberlizmab can only be combined with chemotherapy or sassitude map in that pd01 positive patient population And that's where we dived into ascent 04 where we are seeing sassitude map in combination with immunotherapy With median pfs in favor of sassitude map 11.2 months versus 7.8 months with has a ratio of 0.65 Rahul what did you think about the conversation and thoughts here? Yeah, I wrote the big thing here is treatment is with palliative and time so we took quite a few Minutes here to dive into side effects and importantly some clinical pros in managing that two big things that came out Neutropenia and diarrhea More than half had some great of Neutropenia in diarrhea so managing these side effects is critical We're also covering pd01 negative disease in frontline settings for triple negative breast cancer So make sure to check out that upcoming episode as well Thanks for tuning in. We are The Oncology Brothers.