Outstanding Questions in Neoadjuvant Therapy

An interview with Dr. Lisa Carey from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, NC, panel member on "Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk, Early-stage Triple Negative Breast Cancer: ASCO Guideline Rapid Recommendation Update." Dr. Carey discusses the updated recommendation on the use of pembrolizumab for patients with T1cN1-2 or T2-4N0 (stage II or III), early-stage triple negative breast cancer. For more information, visit, www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Lisa Carey from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, expert panel member on Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk Early-stage Triple-negative Breast Cancer: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Carey.

Dr. Lisa Carey: It's a pleasure to be here, Brittany. Thank you!

Brittany Harvey: Great! First, I like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Carey, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Lisa Carey: I do not.

Brittany Harvey: Thank you. Then what prompted this rapid update to the Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline, which was last published in 2021?

Dr. Lisa Carey: You know, what prompted it where there were a number of changes that had come out, particularly things like the use of immune checkpoint inhibitors, and the adoption of the neoadjuvant strategy that really made us feel that these were overdue for practice guidelines. And in particular, there were some very important changes that came out early this year, particularly with the pembrolizumab use.

Dr. Brittany Harvey: Great, so, based on these changes in the pembrolizumab use, what is the updated recommendation from the guideline panel?

Dr. Lisa Carey: The recommendation actually is for patients who fulfilled the KEYNOTE-522 trial criteria. KEYNOTE-522 was a seminal trial in early triple-negative breast cancer, meaning, treatment-naive of the use of pembrolizumab incorporated into a chemotherapy-based regimen given neoadjuvantly, and then with the continuation of the immune checkpoint inhibitor pembrolizumab adjuvantly.

This was important because we had been using, for a couple of years now, immune checkpoint inhibitors in PD-L1 positive or immune-activated triple-negative breast cancers in the metastatic setting. But we had not had evidence of improved survival or outcomes in early triple-negative breast cancer, so that's where KEYNOTE-522 comes in. This was a trial in which patients with early untreated triple-negative breast cancer, who fulfilled at least greater than T1N0, - and I want to make that pretty clear, this is a pretty broad net for early triple-negative breast cancer; the vast majority of triple negatives will be eligible for this treatment based on the population that was studied - and they receive four chemotherapy drugs, so, a taxane plus platinum, followed by an anthracycline-based regimen, either with or without pembrolizumab throughout the entire neoadjuvant course. They then went to surgery, and then they went on to receive adjuvant for another nine cycles, adjuvant pembrolizumab.

The trial had already reported an improvement in pathologic complete response with the addition of the immune checkpoint inhibitor, which has also been seen with other immune checkpoint inhibitors. But what was reported a few months ago, and then published early this year, was the impact on event-free survival. So, there was a statistically significant improvement in event-free survival with the addition of pembrolizumab, which, at that point, it's a highly clinically meaningful endpoint, there are now two highly clinically meaningful endpoints. Both of these were the primary endpoints of this study. And so, it has rapidly been adopted on that basis for use and we felt because of that it needed to be addressed in a rapid update for helping clinicians interpret the data and use them effectively.

Brittany Harvey: Understood, and I appreciate your work and the panel's work to rapidly interpret this data. So then, what should clinicians know as they implement this recommendation for the use of pembrolizumab?

Dr. Lisa Carey: I think the key elements are unlike the metastatic setting, there's really no role for PD-L1 testing in the early triple-negative setting because the pembrolizumab seemed to improve outcomes regardless of PD-L1 status, which is a big difference from what's true in the metastatic setting where all of these immune checkpoint inhibitors seem to only benefit patients that are PD-L1 positive. So, it's kind of regardless of PD-L1 status.

It's also true that in the KEYNOTE-522 study when they did do PD-L1 testing, most early triple negatives are PD-L1 positive. There really wasn't a subset of patients in the trial. And again, this is T2 or greater in tumor size or node-positive, who didn't seem to benefit from it.

So, it's a pretty broad recommendation. The 'however' is that, as we all know at this point, when you add immune-directed therapies, you have a different set of toxicities you have to be aware of, specifically what they call immune-related adverse events or irAEs, which are, of course, essentially autoimmune.

The thing that you have to remember is these can be permanent. These are frequently glandular disorders. Typically things like thyroid disease, which can be handled with replacement, but you can sometimes have colitis, myositis of different kinds, pneumonitis, and things like that. And some of these can be permanent.

So, they have to be monitored very carefully. And ASCO has a guideline for managing irAEs and patients treated with immune checkpoint inhibitors - because again, we use these in lots of tumor types - that gives a lot of detailed practice recommendations, that clinicians should really consult frequently, not just in triple-negative, but in other disease types that we use these drugs.

Brittany Harvey: Great. Thanks for explaining that aspect of the guideline. So then, you just mentioned that this recommendation is broadly applicable to many patients with early-stage triple-negative breast cancer. So, how will these guideline recommendations impact patients with early-stage triple-negative breast cancer?

Dr. Lisa Carey: Well, it means that it's a totally new game. So, as you are evaluating a patient, first off, virtually all of these are treated neoadjuvantly now, except for the T1N0s, and pembrolizumab and the addition of pembrolizumab should be considered in all of them.

Again, if they have, particularly organ-threatening autoimmune disorders themselves, they are a poor choice for these drugs, but otherwise, it should at least be considered. It's also true that there's been for many years a debate about the optimal chemotherapy to give in triple-negative breast cancer in the backbone that was used to which pembro was added had four drugs in it. And I think for that reason, that is considered the standard of care now.

I do think one of the challenges for us moving forward is to decide if we need all of those drugs or not. I think a challenge for us also is to figure out who actually benefits from, again, these are five drugs, you know, a lot of therapy, a fair amount of toxicity. And so, I think that's a challenge going forward.

Brittany Harvey: Thank you. And then finally, you just mentioned a couple of upcoming challenges, including the debate about the optimal chemotherapy regimen. But what are the outstanding questions regarding neoadjuvant therapy for patients with breast cancer?

Dr. Lisa Carey: I think the outstanding questions regarding neoadjuvant therapy are one thing. I think neoadjuvant therapy, there isn't a lot of outstanding questions that are medically related other than what's the right backbone and things like that, because I think the neoadjuvant paradigm, if you're just purely talking about whether you're giving drugs before or after surgery, the drugs themselves tend to be the same because the key endpoint for the medical oncologist and for the patient, of course, is their outcome from a relapse standpoint.

But it's also true that the neoadjuvant approach allows tailoring of the medical therapy. Like, in the past before we had immune checkpoint inhibitors, patients who received chemotherapy and had residual disease would get additional chemotherapy.

That wasn't allowed in the KEYNOTE study. So, I think many people, because patients with residual disease in KEYNOTE, still had pretty poor outcomes are incorporating additional chemotherapy, specifically adjuvant capecitabine with the pembrolizumab, but there's no data for that.

So, I think that's a challenge that we do have to address. I think the other challenge is simply surgical management: whether we can use these improved pathologic response and clinical response outcomes to minimize some of the local therapies, in addition to tailoring the medical therapies.

Brittany Harvey: Great! Well, we look forward to maybe tackling some of these challenges when we have more data in upcoming guidelines. I want to thank you so much for your time to rapidly update these guideline recommendations and for your time speaking with me today, Dr. Carey.

Dr. Lisa Carey: It's my pleasure. Thank you so much, Brittany.

Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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