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Kevin Kalinsky, MD: Hello. I'm Dr Kevin Kalinsky, and welcome to Medscape's InDiscussion series on triple-negative breast cancer. Today, we're discussing the optimization of neoadjuvant therapy selection with Dr Priyanka Sharma. Dr Sharma is a professor of medicine at the University of Kansas Medical Center, an assistant director of clinical research and co–program leader for the Drug Discovery, Delivery and Experimental Therapeutics Program at the University of Kansas Cancer Center. Dr Sharma, thank you for joining us.
Priyanka Sharma, MD: It's my pleasure to be part of this discussion.
Kalinsky: Dr Sharma, I thought maybe we would just start off with talking about our current approach for patients in terms of neoadjuvant therapy when you're utilizing immunotherapy. This will be a good segue for us to talk about some of your data with NeoPACT, etc. And really just your general approach now and what the standard of care is now for our patients in terms of neoadjuvant therapy for triple-negative disease.
Sharma: I think we all recognize that KEYNOTE-522 is the standard of care for neoadjuvant therapy for patients with triple-negative breast cancer, at least with stage 2 and 3 disease, with the combination of polychemotherapy and pembrolizumab. KEYNOTE-522 included four chemotherapy drugs: carboplatin (carbo), paclitaxel, and AC (doxorubicin-cyclophosphamide) given concurrently with pembrolizumab. That's become the de facto standard of care. Some may argue the merits of adding or not adding carbo in the regimen, but that's how KEYNOTE-522 studied it and the comparator arm was also the four-drug polychemotherapy regimen. In my practice, that has been the de facto standard of care, unless we have a clinical trial that offers something different or is studying a particular subset of patients.
Having said that, I do think about it a little bit harder in patients with T2N0 cancer, especially those with cancers that are 2-3 cm. I do wonder about overtreating with five drugs in these patients. We've had the NeoPACT trial open for a while. That's a trial that was attractive, especially for patients with node-negative disease. There are the studies that are looking at de-escalated chemotherapy regimens that are not that intense and do not include that many drugs. I would say in most practices, the KEYNOTE-522 regimen has become standard of care.
We all have our favorites in terms of whether we're using weekly carbo vs every 3 weeks, what dose we're using, whether we're using dose-dense AC or not; KEYNOTE-522 had every 3 weeks. We've all adopted the dose-dense strategy based on the superiority from randomized studies. So, going back to every 3 weeks kind of felt like tracking back. In our practice, we have two different KEYNOTE-522 plans built, one with dose-dense and one with non–dose-dense AC, because our group was divided in what they wanted to use. Both groups had a strong rationale for how and why they wanted to do so. We didn't feel like we needed to force one group to join the other group.
We were fortunate that we were able to have two different beacon plans, and you can pick one or the other. I typically do dose-dense, and then just the regular dose to finish it fast. It's just so long to start with. If you start doing every 3 weeks, the treatment feels like it's so much longer than we used to do before.
Kalinsky: I am smiling because we had a similar discussion within Emory where we talked about, "Should we be doing dose-dense therapy or every 3 weeks?" and a number of the providers leaned towards doing every 3 weeks because we're seeing this real benefit with that every-3-week regimen. Of course, we know dose-dense therapy can be beneficial for patients, and then the conversation came up with giving every-3-week pembrolizumab and patients being off cycle. I feel like at each of our institutions, we've really been debating this. Do you have a preference of how you're giving the carboplatin? Do you tend to give it every 3 weeks? Do you give it weekly?
Sharma: I'm one of those people that prefer to give both the taxane and platinum every 3 weeks. You can get both of those in, and to be honest, some of our regimens we've been altering to substitute paclitaxel to docetaxel. We can give both of those drugs every 3 weeks. We're in a place where we have a demand for it. We're in the rural part of the state. A lot of patients travel from a distance to come get treatment and they don't like traveling every week, especially every week with the uncertainty of whether you're going to get treated or not. We have weekly carbo, weekly paclitaxel. They show up; the counts are good or not; and sometimes they get treated, sometimes not, and then they have to come back 3 days later. That just gets to be very disruptive. I prefer the every-3-week carbo, personally, but it would be at the area under the curve (AUC) 5 if I'm doing it with the weekly paclitaxel, just like in KEYNOTE-522. If you miss doses, that's one thing with this regimen you should be cognizant about, especially if you're doing both the drugs weekly. You may get through some drugs because some of them are fully delivered in 12 weeks, but some aren't. I think it's important to deliver as close to 12 doses as possible for the weekly carbo/paclitaxel. We've learned from CALGB 40603 that if you compromise on your paclitaxel doses while giving carbo, there actually is a negative impact on pathologic complete response (pCR). It often takes about 15 or 16 weeks to get through that first part, and not 12 weeks, if you want to deliver all the doses. At least that's what I've seen in my practice.
Kalinsky: That's a really fair point. We've mentioned the NeoPACT study. I was hoping you would spend a little bit of time talking about the results of that study and the design because it also has implications for other research that you are doing.
Sharma: The NeoPACT study was designed and started while KEYNOTE-522 accrual was winding down. It wasn't complete yet, but clearly we didn't have results. That built on our initial data on anthracycline-free, neoadjuvant chemotherapy of docetaxel and carboplatin given every 3 weeks for six cycles.
The NeoPACT regimen included docetaxel and carbo, both given every 3 weeks, along with pembrolizumab given every 3 weeks for six cycles. The study did not have any adjuvant pembrolizumab because it was done and almost accrued before KEYNOTE-522 results came out and pembrolizumab was approved in early-stage triple-negative breast cancer.
The trial enrolled 115 eligible patients. It allowed patients with stage 1 disease — not all stage 1, but T1c, and then also stage 2 and stage 3 patients. About 12 to 13% of patients that enrolled were stage T1c. We allowed enrollment of patients with estrogen receptor/progesterone receptor (ER/PR) expression up to 10%, as long as adjuvant endocrine therapy was not intended to be given. About 12% of patients fell in this category.
That's another difference from KEYNOTE-522, where the strict 0N and zero ER/PR [DS2] expression criteria were used. The overall pCR rate was 58%, and pCR plus residual cancer burden (RCB)-1 was 68% in the 115 enrolled patients. The regimen was fairly well tolerated. The discontinuation of any one of the three drugs was at 12%, which compares quite favorably with five-drug regimens, and I think that's intuitive. The more drugs you have, the higher the chance that a drug isn't delivered completely.
Immune adverse events (AEs), grade 3, or more were noted in about 3.5% of patients. There were no cases of adrenal insufficiency. The grade 3 and 4 AEs were mainly colitis, and one of them was neurologic AE. If we look at long-term outcomes, the 3-year estimated event-free survival is at about 85%; if we look at patients who achieved a pCR, that 3-year event-free survival is 98%, and this is in absence of adjuvant pembrolizumab because the study did not include adjuvant pembrolizumab.
In terms of patients with residual disease, a good proportion of them got some sort of adjuvant therapy. You know, with the capecitabine being standard of care and endorsed in National Comprehensive Cancer Network (NCCN) guidelines. A lot of patients got that therapy. But again, a majority of them didn't get adjuvant pembro because that wasn't part of standard of care.
Kalinsky: The data that you're mentioning are intriguing for a few reasons. One, this high rate of pCR in the absence of giving an anthracycline, which of course we get concerned about in terms of some concerning long-term toxicities, including cardiac toxicity. It also raises this point about how patients with pCR do — that they have an improved event-free survival. Though it's a smaller study, it further highlights the need for us to accrue to the OPTIMICE-pCR study, which we talked about in another episode. That study is asking the question of whether patients need a full year of pembrolizumab or not.
Before we talk about other studies, like the SCARLET study, in your practice, in the absence of patients for whom there's a contraindication for utilizing an anthracycline, do you sometimes utilize the NeoPACT study? Do you feel like it needs additional data in a larger setting — for example, something along the lines of the SCARLET trial? For which patients are you considering utilizing NeoPACT off of a clinical trial?
Sharma: NeoPACT was a phase 2 study, so it would need validation, but it was a decent-sized phase 2 trial. In my practice, as you mentioned, for patients who have contraindications to or who have strong wishes to avoid anthracycline, this is a go-to regimen. I am also discussing patients like I talked to you about, those with T2 tumors that are 2-3 cm. That's a situation where you want to add immunotherapy, but you don't feel like you need to throw the kitchen sink with five drugs at these patients. For patients that don't have a pCR, they can always get AC after surgery. It isn't like we are taking it away as an option permanently. If about 6 out of 10 of these patients are having a pCR, then typically, they can avoid an anthracycline. I wouldn't say that that would be standard of care in many patients, because again, this is coming off of a phase 2 trial.
I would also like to point out that our current practice is based on KEYNOTE-522, but we've had other immunotherapy trials and await results of other phase 3 studies that have looked at AC/T and atezolizumab. If you look at the IMpassion study, the pCR rate there was 58%, and it's a randomized phase 2 trial. If you look at the atezo arm of that group, it's not that dissimilar in size from NeoPACT. If one was debating whether to exclude some chemotherapy drug from this four-drug regimen — whether you avoid carbo or whether you avoid anthracycline — we've got data from two separate studies that can support that. Clearly, to change practice and to apply it to all patients, we need a large randomized study that demonstrates noninferiority of a less intense chemotherapy regimen when we deliver it with pembrolizumab.
Kalinsky: I just wanted to touch upon one thing, because this is something that came up in our multidisciplinary clinic this past week, for those patients who have T1c tumors, do you often give them neoadjuvant therapy? What is your general cutoff for when you think about for a patient with triple-negative breast cancer, having them go straight to surgery as opposed to giving them neoadjuvant therapy?
Sharma: Typically for patients with T1c disease, we've been early adopters of neoadjuvant chemotherapy, and I typically offer them neoadjuvant chemotherapy for a few reasons. The prognostic impact of pCR is still relevant for them. The adjuvant capecitabine decisions are still relevant for these patients. CREATE-X didn't exclude patients that started out with T1c disease, so they would still be eligible for adjuvant capecitabine. If you are treating them neoadjuvantly, you can consider doing some sort of a de-escalated regimen as opposed to when you're doing adjuvantly, then you are stuck with some sort of a standard adjuvant regimen.
The other piece of information that affects their local therapy is when we look at T1c/T2, clinically node-negative patients (we published these data) and compare the patients that went to surgery first or that went to neoadjuvant therapy, about 15%-20% of those that go into surgery first will have node-positive disease. You clear occult axillary disease, at least in the high-risk biologies where the risk for having node positivity is higher.
I think the third reason for some of the patients is they have risk factors for carrying a BRCA mutation. They've undergone testing. They're waiting for those results, and based on that, they're making decisions about the extent of surgery. This gives them time to plan those things and make the right choices, and consult with the right subspecialist without feeling the need to jump into surgery. As a group, we're doing neoadjuvant chemotherapy for patients with T1c disease.
I haven't adopted immunotherapy for these patients yet, though. The approval for pembrolizumab leaves it vague with high-risk disease. I go with what was included in KEYNOTE-522. Dr Kalinsky, what are you doing with your patients with T1c disease and pembrolizumab?
Kalinsky: We use the same sort of approach where for those patients, we'll talk about neoadjuvant chemotherapy without immunotherapy. It's also a risk-benefit discussion. The first patient in whom I utilized neoadjuvant pembrolizumab had one of those very rare side effects where she had red cell aplasia. This is anecdotal, but it was a significant reaction that she had. It highlights that we need to be thoughtful in terms of when we're utilizing agents. For patients with T1c N0 disease, I tend to not give immunotherapy.
Sharma: As we use immunotherapy more in a curative disease setting, we all have seen these really severe side effects in just the 2 years we've been using it. I've had a patient with renal failure on dialysis. I've had to give rituximab for a rash that just wouldn't go away. We couldn't taper the steroids down. We all have patients like that, where you see some of these very severe side effects. Some of them are going to be life-altering and permanent for our patients.
Kalinsky: I want to make sure that we have some time to talk about the SCARLET study, because this is a phase 3 trial that's being opened through the cooperative groups. I want to make sure that we talk about the rationale for this study and the design, because it is an important study that we'll have open at our sites. If you don't mind, can you talk us through the trial?
Sharma: SCARLET is taking the NeoPACT data, and it is the randomized phase 3 confirmation trial that will compare the NeoPACT regimen, which is carbo/docetaxel pembro for six cycles, vs the KEYNOTE-522 regimen. Eligible patients are those that have stage 2 and 3 triple-negative breast cancer. It does exclude patients with high anatomical risks, like those with inflammatory breast cancer and those with N3 disease, because we felt that may not be the group in which to try to de-escalate preoperative treatment. The primary endpoint of the trial is long-term outcomes with event-free survival. It's a noninferiority trial looking at these two regimens and ensuring that we are not compromising long-term outcomes.
The adjuvant therapy for patients in SCARLET is standard of care and is pragmatic. The trial also allows co-enrollment and optimized pCR for patients that have a pCR. We wanted to make sure that the two trials were coordinated, such that the patients could avail themselves of both trials. For patients who have residual disease in SCARLET, their providers can prescribe capecitabine or AC, or both of them if they wish to; adjuvant pembrolizumab is suggested for these patients. The overall hypothesis of the trial is that when immunotherapy is included in our neoadjuvant regimen, then an anthracycline-free chemoimmunotherapy will be noninferior to an anthracycline-based chemoimmunotherapy for patients that don't have a pCR can get AC after the surgery, so they can "be rescued." It's a pretty large trial because it's a noninferiority trial. It has an aim to enroll 2400 patients over 4 years. We hope that we get endorsement and support from the larger community. There's no requirement for any biological specimens for the patients to enroll and start treatment.
There's a requirement to submit a slide for tumor-infiltrating lymphocytes (TILs) way down the line, but the patients can enroll and be randomized and start the treatment before that happens. We understand that many of these patients feel an urgency to get started on treatment and don't feel like they should wait a few weeks for some sample submission or analysis.
Kalinsky: We think about, for instance, HER2-positive disease, where we've moved away from giving anthracyclines based on the TRAIN-2 study. Given how robust the response can be with HER2-targeted therapies, it really would be nice if we can get away from anthracyclines with the incorporation of immunotherapy. As you mentioned, this has the potential to be practice-changing.
You mentioned the biomarker work and TILs. In the remaining minutes, could you talk about some of the lessons that you've learned from NeoPACT and how that's being incorporated into the SCARLET trial?
Sharma: For all our chemoimmunotherapy trials and neoadjuvant trials, what we've seen from them is that immune upregulation, whether we assess it through gene expression assays or through TILs, is associated with higher response to chemotherapy and chemoimmunotherapy. It may not necessarily identify subgroups that have preferential benefit from immunotherapy. But it identifies subgroups that have a very high pCR with chemoimmunotherapy.
For example, in NeoPACT in patients who had high TILs, the pCR rate was over 70% or 75%. That's a pretty high number, and that's the information we are taking to SCARLET now. Through the process of biomarkers, we hope to learn and identify subgroups that have very high pCR rates, even with a de-escalated chemoimmunotherapy, and that sets the stage for future trials — could we possibly de-escalate therapy in those subgroups even more? Those that have low immune microenvironments may need more, and we will learn more from SCARLET, as we do more tissue and blood biomarkers.
Kalinsky: It's a really exciting study. We would encourage listeners also to be enrolling patients in the study. A lot of great work has led up to this point, and it's been a great conversation.
There are lots of other things that we could talk about as well, but ultimately, congratulations on getting SCARLET off the ground, and we look forward to having a conversation on a podcast in the future, talking about the results of that particular study.
Sharma: Yes.
Kalinsky: Today we had Priyanka Sharma discussing optimization of neoadjuvant therapy. Thank you so much for joining us. This is Dr Kevin Kalinsky for InDiscussion.
Resources
Pembrolizumab for Early Triple-Negative Breast Cancer
NCCN Guidelines® Insights: Breast Cancer, Version 4.2023
Adjuvant Capecitabine for Breast Cancer After Preoperative Chemotherapy
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Cite this: How Do You Optimize Neoadjuvant Therapy Selection? - Medscape - Sep 06, 2023.
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