Triple Negative Breast Cancer (TNBC) Treatment Algorithm: Dr. Tiffany Traina

Hello and welcome back to the oncology brothers podcast. I'm Rahul Gossane here with Rohit Gossane to practicing community medical oncologist with Hope to bridge the gaps between academic research and community practice where majority of our cancer patients get treatment today. Today we're continuing with our breast cancer treatment algorithm series and focus is on triple negative breast cancer. Right Rahul this is one place where we do need more and more treatment options though we are seeing some advancements here but we need to at least from community standpoint get comfortable with managing these side effects so our patients can stay on these therapies longer and to appreciate all that we have at hand from current treatment algorithm for triple negative breast cancer we are thrilled to have Dr. Tiffany Traina a breast medical oncologist from Memorial Sloan Kettering Cancer Center. Tiffany thanks so much for joining us today. Thank you for the invitation and a pleasure to be here. Tiffany welcome let's start at the beginning of the algorithm with early stage disease. Let's hit you with a few questions here. What is your lower limit size for that tumor where you thinking of adjuvant chemotherapy who gets adriamisin in that T1 end-zero disease? And who do you lean towards for that new adjuvant treatment or Kino 522 for this particular early disease? terrific questions. I do follow and adhere to NCCN guidelines because the spirit of that guideline is trying to strike the balance between risk and benefit of our interventions. Even though we acknowledge triple negative breast cancers are slightly higher risk when we're talking about 5 millimeters of tumor in the node negative setting there really is equipois where the potential that the toxicity of those interventions could outweigh any small benefit we're gaining. So I adhere to a greater than 5 millimeter of invasive TNBC if the patient has negative nodes to consider chemotherapy. Usually if I'm in that low 5 millimeter to 1 centimeter range I'm thinking about this as a place where I could deescalate think about a regimen like Tc even at MSK for some of our older patients with lots of comorbidities who might even look at CMF where we really want to balance risk benefit. I think the other end of the spectrum is easy to address as well when those tumors are 2 centimeters or greater or node positive or absolutely embracing Kino 522 regimen we could talk a little bit about the scheduling and how we do that in a bit. So really looking at neo-adjuvant therapy for our larger tumors. I think a bit of the gray zone is in the 1 centimeter to 2 centimeter node negative. The rationale for thinking about neo-adjuvant therapy is that desire to have an in vivo response to chemotherapy to be able to really personalize who needs escalation of care and who may have an excellent prognosis and be able to get away with a simpler regimen. I still lean towards upfront surgery unless the tumor size is getting really close to 2 centimeters. 1.9 2 centimeters depending on the imaging modality. I really tend to go with either upfront surgery in which case in the adjuvant setting I'm using regimens like ACT, Dostincy CT, sometimes TC or I'm classifying them as high risk enough that they're getting neo-adjuvant therapy in which case I'm incorporating pemberlism app as well. Thanks so much for touching on that. Building on this theme of keynote 522 which is rather the standard of care for T2 or any node positive disease given the improvement in path CR as well as overall survival data we have with this. But again this regimen chemotherapy plus pemberlism app is given differently in each institution as you were saying in your practice Tiffany do you give Dostincy AC for this part of the portion or even for AC initially and then TC or vice versa? How are you maneuvering through this? Yeah happy to share because as we know in the study you had the option of giving either Q3 week carbo or weekly we've seen the schedule be leading with AC as well as leading with tax on cargo. In my practice what I have found to be really tolerable and also try to squeak out the greatest efficacy is weekly pachla taxal weekly cargo platen with every 3 week pemberlism app. Once I'm through that 12 week regimen I switch to Dostincy AC because we know from multiple studies now that Dostincy administration is improving survival and these are some of our highest risk patients. So with AC number one I dose pemberlism app with a Q6 week dose which is more patient friendly for scheduling. AC number two AC number three two weeks apart on their own and then when they come back for AC number four I dose pemberlism app again with a six week dose that is usually sufficient time for them to get to surgery and come back to me six weeks later with their pathology to review. If you thanks for touching on that I am doing AC every three weeks often with TCF front and then AC later this is not the easiest regimen and it has its fair share of side effects but given triple negative breast cancer ends up being very unforgiving we're trying our best to give everything upfront. After new adjuvant treatment and surgery what if we have that residual disease? What is that threshold for starting capesite to be? Is any residual disease benefiting from capesite to be? This is all happening concurrently with pemberlism app and we're extrapolating that data. Exactly I have a very low bar and for me any amount of residual disease and triple negative breast cancer after having seen four of our best chemotherapies and checkpoint inhibitor I have that discussion with all of my patients. I tend to dose capesite to be in a one week on one week off schedule for six months I find that to be manageable and tolerable we've had safety data we've had efficacy data there so I've brought that from the metastatic setting to use in the adjuvant space here. Remember also for those patients who might have a germline bronch amutation instead of capesite to be and I would be giving a year of elaborate overlapping with the remainder of their pemberlism app any amount of invasive residual disease I would offer additional systemic therapy. Tiffany when you are administering a radiation are you concurrently adding any of these agents or is this after radiation is done that is pemberlism app in cases of residual disease capesite to be and also laparib. Brilliant brilliant question so pemberlism app I have comfort with safety overlapping with radiation I tend to get the radiation done with and then begin the additional systemic therapy I don't overlap those. Okay and with regards to a patient who does qualify for olympia and has residual disease where the options are pemberlism app capesite to be and elaborate how are you sequencing that approach. I lean into the biomarker of that germline bronch amutation and the data we have for adjuvant elaborate is so compelling that I would use elaborate for a year rather than capesite of being and overlap with the pemberlism app. Just to read a few things a laparib data is coming from olympia where we have overall survival whereas capesite to being data is coming from createx also overall survival benefit in both settings. All right now on to metastatic disease and here it's either relapse or recurrent disease or the novel metastatic disease can we start off with that recurrent relapse disease especially after that affron chemo and immunotherapy. I feel like we've changed that biology and patients that have recurrent disease it's an aggressive disease because they've seen all that chemo and immunotherapy upfront. Tiffany outside trials what next for this recurrent relapse disease after chemo 5-2 regimen. I think as you described it these patients that are recurring now after having seen keynote really have such refractory difficult to treat disease especially when that disease free interval is short less than a year. This is a high area of unmet need fortunately we're seeing fewer of these patients in our clinics and hopefully you are as well feeling the benefits of keynote with fewer patients recurring later but when it does happen this is a place where even before we had some of the data from a center 3 I was moving those ADCs up sooner for this patient population because they are certainly at higher risk. When we look at some of the trials that have been practiced changing you'll see that about a third of the patients on those trials have denovo metastatic triple negative breast cancer and that always feels a little bit higher than what I would have expected in clinical practice but I do think we're seeing a shift in what our patients are looking like with advanced disease as a result of what we're doing in the early stage setting. Something that I want to clarify here that in keynote 5-2-2 regimen we are administering pemberalism app despite the pdl1 score while in metastatic disease that's only approved for pdl1 positive which is cps more than or equal to 10. Tiffany with that particular patient we're talking about if the disease was to progress while on pemberalism app of course we will be adding chemotherapy or an ADC but are you going to continue with immunotherapy or take that off. Let's take a step back for a minute and just say what are the data that we have right now. When we're approaching first line metastatic triple negative breast cancer we need to know pdl1 status as you described and for those patients who have pdl1 positive tumors we have historically had keynote 3-5-5 the combination of either taxing or gem carbo with pemberalism app significantly improving outcomes and that had been our go to standard. The question about should we use a checkpoint inhibitor upon progression after seeing a checkpoint inhibitor we really don't have data for. We have yet to see that data in the metastatic setting we don't have data about how to address this right now as patients are progressing on their neo-adjuvant or adjuvant pembero. In my own practice, if somebody is recurring on their adjuvant pembro, it isn't clear to me that they're deriving much benefit from that if they've developed metastatic disease in that setting. And now we have some compelling alternatives as we talk about the PDL-1 negative setting. For folks who've had a longer disease-free interval longer than a year, I would be inclined to re-challenge with the checkpoint inhibitor there if they had a PDL-1 positive tumor. Thanks for the clarification, Tiffany. What we are seeing here with Ascent or even Tropion Breast Trials, that Sassetusumab and DataDXE come up front in our frontline settings, which is part of NCCN guidelines. Now, if you don't mind touching what we are seeing from these trials itself, that is AscentO3, AscentO4, and the Tropion BreastO2. Happy to. So in the PDL-1 negative camp, the definition was those patients who were not candidates for checkpoint inhibitor, we have two different studies. One that looked at moving Sassetusumab, GovTKN, into the first line setting, and the other using DataDXE in the first line setting. These trials have unique differences that are important to call out. When we look at AscentO3, this was Sassetusumab up against either taxane or gem-carbocombination, or key design feature here is this trial-allowed crossover. For patients randomized to standard of care chemotherapy, if they progressed, they were provided Sassetusumab upon progression. That's important because we know Sassetusumab has an overall survival advantage in later line. When we interpret a secondary endpoint of overall survival for AscentO3, we may not see one even though this is a powerful option to have in the first line setting. But when we look at the study results, Sassetusumab out-preformed standard of care chemotherapy in terms of progression-free survival, you're seeing almost ten-month median progression-free survival, overall survival, difficult to interpret, and really immature. Response rates were pretty comparable, about 50 percent whether you got Sassetusumab or traditional chemotherapy. They used PFS2 as a surrogate endpoint for overall survival. PFS2 was prolonged with Sassetusumab almost a year and a half compared to just about a year with standard of care chemotherapy. So almost by every metric using the ADC was superior to chemotherapy. When we looked at TROPEAN Bresto2, this was using DATO-DXD, so another anti-trop2 ADC, but a payload similar to TresTusumab directs to CAN. And DATO-DXD is administered once every three weeks, so nice schedule, a bit different than Sassetusumab day 1, day 8, shorter infusion time, and a different side effect profile. So TROPEAN Bresto2's control arm was a bit different. It really required that patients had seen prior taxing. If they didn't have a prior taxing or had a long disease-free interval, they had to get taxing. About 80 percent of folks on the control arm were getting a taxing, and then far fewer either a ribulane or single-agent carboplatin. Similarly, DATO-DXD was quite superior to standard of care chemotherapy, so progression-free survival, almost 11 months compared to about 5 and a half months, overall survival was significantly improved. Media and overall survival was about two years compared to about a year and a half with traditional chemotherapy. There was no crossover in TROPEAN Bresto2 because we had no data that DATO-DXD in a later line would improve survival. So those design elements may make it a little bit trickier, interpreting an overall survival endpoint here. But these were really high-risk patients. In TROPEAN Bresto2, there was no lower limit to disease-free interval. About 15 percent of patients were progressing within six months of their adjuvant or neo-adjuvant therapy, and about 20 percent were progressing within a year. These are our toughest patients to treat today. Stephanie, thank you so much for touching on all that. In terms of data, I wrote this down so that I don't mess it up with a cento-for, with SACITISMAB and PEMBERALISMAB, we saw improved progression-free survival from 7.8 months to 11.2 months, in a cento-3, we saw improved progression-free survival from 6.9 months to 9.7 months, and with data-DXD, we saw improved progression-free survival from 5.6 months to 10.8 months. As you pointed out, we also saw overall survival with data-DXD, but that crossover was not allowed. That's right. I do want to come back to side effects because they differ. But here, what next if the disease was to progress after one ADC? Another trope to ADC using our available chemotherapy? I feel we're in data-free zone here. Yes. We are, unfortunately, in a data-free zone. We have several retrospective analyses that are out in the literature and have been presented from institutional experiences. And in general, ADC number two doesn't perform as well as ADC number one. So the limitation in all of these ADCs that we have available, whether we're talking about Sessatusumab or DatodexD or even TDxD in those patients with a hereto-low tumor, all of these have Topo-1 payloads. So although the targets may differ, these payloads are similar in their mechanism of action. There was some provocative data, again, retrospective, that would suggest a sandwich approach might be better. Meaning, in between your two ADCs use a traditional chemotherapy with a non-cross-resistant mechanism of action, expand the benefits of using all the ADCs that we have. But nobody right now can say what the optimal sequence is. There are some studies ongoing trying to answer that question. Now, that's full of. So, before we go on, Tiffany, with regards to the PDL-1 positive group, this trial, Centro for chemotherapy plus pembrolizumab versus Sessatusumab plus pembrolizumab for that PDL-1 positive group. In your settings currently, are you relying on this or waiting for the approval because we are seeing is a benefit for that PDL-1 positive group? Right. And again, as we're talking about, how are you picking one ADC over another today in your clinical practice? I think this will be a good segue to your touch on some of the side effects as well. Certainly. The Sessatusumab pembrolizumab combination was flagged as a preferred option in the updated NCCN guidelines just about a week ago. I think we have it available to us for a patient that has large burden of disease, metastatic first-line setting, PDL-1 positive. I would embrace those data, seeing a really profound improvement in medium progression free survival of almost a year is really impressive for this patient population. I do think it's meaningful to have improved PFS because the other data point that is really sobering and triple negative breast cancer is 40 to 50 percent of patients do not make it to second-line therapy. So this concept of saving your best drugs for later really doesn't apply in this patient population. Absolutely. Absolutely. And I'm setting the same thing for the small cell lung cancer we have seen. We need to use the best for the front line. And in that PDL-1 negative, how are you picking amongst data, DXD and Sassy? I think it's wonderfully refreshing to have two amazing options for our patients, neither of which require a biomarker, which is fabulous for this patient population, but just keeps hearing about the markers they don't have for treatment. There are some distinct differences in the toxicity between these agents. Sassy Tuse-Mab has a wealth of data and experience, right? Indicated in other tumor types. We've been using it for years already in later line TNBC. So there is comfort and familiarity around how to manage the neutropenia, how to prophylax for the diarrhea. I'll call out the prime study that looked at primary prophylaxis for both neutropenia with growth factor and emotium for diarrhea. And that's significantly reduced grade three talks. It enabled patients to stay on therapy longer. So I think there's a comfort with Sassy Tuse-Mab and there is clear data across subtypes to show benefit there. The schedule of day one, day eight sometimes is difficult for our patients who are traveling from a great distance. The infusion time can be long. So I think there are certain characteristics in shared decision making with our patients to say, you know what, maybe this isn't a perfect fit for you because some of your preexisting GI talks are because I know you had difficulty with your accounts when you were getting through keynote. We can try to use growth factor, but we could also think about Sassy in the second line setting where data is dosing schedule is once every three weeks. Epinia tends not to be an issue there. ILD rates were incredibly low, less than one percent risk. Data DXD does have stomatitis and mucusitis and requires prophylaxing with oral steroid rinse, cryotherapy, even sucking on some ice chips during infusion. That could be a deterrent for some patients. And then the other unique adverse event is dry eye. So in the label, it is recommended that patients see either an ophthalmologist or an optometrist, sometime around initiating therapy. We've interpreted it as sometime within cycle one. It shouldn't be a barrier to getting started on therapy, but you do want to have just a baseline assessment. There's no finding on that baseline assessment that would stop you from using the drug. It's just important to have that as a benchmark. And then usually recommending lubricants, eye drops for the eye avoiding contact lenses and having an annual ophthalm exam is recommended. They're just unique side effect profiles and that's where we have to have the open conversations with our patients. The overall survival data is compelling, but in a Cento-3 design doesn't allow us to see an overall survival difference potentially. Again, two active ADCs. We have to keep these side effects in my Neutropenia Diaria where. the stacetismab, dry eyes, mucosidus. Even a small hint of ILD where data with the XD, these are the things that should be on our radar. Tiffany, thank you so much for taking the time to touch on your current treatment algorithm for triple negative breast cancer. For our listeners, let's go over a quick recap. In this discussion with Dr. Tiffany Trayna, we covered triple negative breast cancer, starting off with early disease. Selectively, we also use new adjuvant chemotherapy for high risk T1C lesion, though approval of chemo-munotherapy based off Kino 52 is for T2 and above, or any node positive disease. Roll out your thoughts here. - Rahul, we also touched on how are we administering the Kino 52 regimen, that is, chemotherapy plus immunotherapy. And we acknowledge that every institution administers this differently. At least for my clinic, I'm still using the AC portion of it Q3 weeks with Pembrolyzumab. For the initial part, I tried with TC first, plus Pembrolyzumab administering this treatment weekly. Then we touched on the adjuvant treatment portion, where we have Cape Cytabine for residual disease, where we have that survival benefit, and then also Olaprib based on Olympia study again, that additional survival benefit, which we are combining with Pembrolyzumab in adjuvant setting. - Yeah, I wrote after early and locally advanced disease, we talked to metastatic disease. Here we're seeing some new ADCs come in front line settings. Sacitus Mab Govotecan, which was initially approved in second line and beyond, now based off a Cento-3, a Cento-4 is coming here in front line settings. Dato-DXD, based off Tropion, Bresto-2, is coming in front line settings. Something to keep in mind, here, the use of Pembrolyzumab is indicated based off CPS score of 10 or above. What to do for that disease that is progressing in these ADCs is still a big unmet need. Thanks for tuning in. Be sure to check out our other breast cancer episodes in this series, and as always, send us your questions and cases. We love hearing from you and how you're applying all this in real life. We are the oncology brothers, and we'll see you next time.