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Highlights From the 2023 San Antonio Breast Cancer Symposium With Jason Mouabbi, MD

At the recent San Antonio Breast Cancer Symposium (SABCS), numerous updates were presented which have the potential to improve treatment outcomes for patients with breast cancer. After returning from the meeting, Dr. Jason Mouabbi, Assistant Professor of Breast Medical Oncology at MD Anderson Cancer Center and Editorial Board Member of Oncology Data Advisor, sat down to highlight some of the most exciting research presented, including the HER2CLIMB-02, MONARCH 3, and INAVO trials.  

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, I am joined by Dr. Jason Mouabbi, who is one of our Editorial Board members. Dr. Mouabbi recently returned from the 2023 San Antonio Breast Cancer Symposium, and today, he's here to talk about some of the highlights from the conference. Thank you so much for coming on the show today.

Jason Mouabbi: Thank you for having me. It's always a pleasure to be here. We just came from a very interesting San Antonio Breast Cancer Symposium. A lot of new stuff and a lot of exciting research is happening in the field of breast medical oncology. Today, we're going to highlight some of the new advances for medical oncologists.

During the meeting, there was a lot of basic science happening, a lot of research pertaining to radiation oncology, and a lot of research pertaining to surgical oncology. Here, we're going to focus on the perspective of the medical oncologist. What's new? What's exciting? What's coming to practice in the near future? Again, I'm Jason Mouabbi. I'm an Assistant Professor in the Department of Breast Medical Oncology at MD Anderson, and I'm part of the Editorial Board of Oncology Data Advisor. I'm also the Chair of the Scientific Advisory Board of the Lobular Breast Cancer Alliance.

As an outline, we're going to talk about three things. We're going to talk about HER2CLIMB-02, we're going to talk about updates of the MONARCH 3 trial, and we're going to talk about this new drug that was thrown to us. The press release happened that Tuesday, and the organizers were scrambling to add it to the meeting. They finally added it on Friday, the last day of the meeting. This is the INAVO120 study. It's very exciting stuff.

Let's first start with HER2CLIMB-02. This was the primary analysis of a randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine, also known as T-DM1, for previously treated HER2-positive metastatic breast cancer. It was presented by Dr. Sara Hurvitz. Let's do a little bit of perspective for why this study is important. If you look at the approach to therapy for human epidermal growth factor receptor (HER2)–positive breast cancer, first-line therapy is still the CLEOPATRA regimen, which is a taxane in combination with dual HER2 blockade, trastuzumab and pertuzumab. Second line has changed in recent years with the emergence of DESTINY-BreastO3, where the second line now is trastuzumab deruxtecan.

The HER2CLIMB-01 study is investigating a third-line regimen. This is tucatinib plus capecitabine plus trastuzumab. Some physicians are using it as second-line therapy, especially in patients with brain metastases (mets), which is very relevant for HER2-positive breast cancer because 50% of metastatic HER2-positive breast cancers will have involvement of the central nervous system (CNS). At fourth line plus, here we have single-agent chemotherapy plus HER2-directed therapy, either trastuzumab or margetuximab. As you can see from this landscape, T-DM1 has been lost. If you remember a few years ago, trastuzumab emtansine was the second-line therapy for patients with metastatic HER2-positive breast cancer. However, with the immersion of trastuzumab deruxtecan and tucatinib, it has lost its weight. Nowadays, we really don't know where to put it in our algorithm. Where does it fit? We're going to see now.

This is the HER2CLIMB-02 study. It was for HER2-positive, locally advanced or metastatic breast cancer that progressed on a prior taxane in combination with HER2-directed therapy. The study did allow for patients with brain mets. They were randomized 1:1 to receive either T-DM1 plus tucatinib or T-DM1 plus placebo. The primary outcome they were looking for was progression-free survival. If you look at the demographic and baseline characteristic of the patients enrolled, you can see that about two-thirds of them were also hormone-positive, which really represents this population very well. If you look at whether they had brain mets, about 50% did. Out of those, 20% had active brain mets.

Now, let's focus on prior lines of systemic therapy. The median prior lines of therapy was one. If you look at those patients, most of them received prior pertuzumab, and a small minority of them received a prior anti-HER2 tyrosine kinase inhibitor (TKI). The primary end point was progression-free survival (PFS). We can see here that the addition of tucatinib to T-DM1 improved the progression-free survival from 7.4 months to 9.5 months, with a hazard ratio of 0.76. That was statistically significant. If you look at those patients of special interest, the patients with brain mets, you can see that the addition of tucatinib improved the PFS from 5.7 months to 7.8 months, with a hazard ratio of 0.64.

When looking at the common adverse events, nothing out of the norm was seen here. We already are experienced with tucatinib, remember, from the HER2CLIMB-01 study in combination with capecitabine and trastuzumab. We are well-versed about using tucatinib, and we did see what's expected from tucatinib. This is an increased incidence of diarrhea and elevation of liver function enzymes.

If we look at, again, at the landscape of how we treat HER2-positive advanced breast cancer, so where I truly believe the HER2CLIMB regimen is going to come into place is going to be as a replacement for tucatinib plus capecitabine plus trastuzumab, where here you can use tucatinib plus T-DM1 instead of that regimen. It's not going to change much of the landscape of the current treatment, but I'm happy to see one of those drugs, which for the longest time has been one of the best medications we had for HER2-positive breast cancer, make a resurgence in combination with tucatinib.

Now, let's shift gear to the MONARCH 3 trial. The MONARCH 3 trial, as we're going to discuss in a little bit, already met its primary end point of improving progression-free survival. However, we still did not have the final overall survival results. At San Antonio, they finally showed us the final overall survival results of the addition of abemaciclib, which is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, plus a nonsteroidal aromatase inhibitor, which is considered an endocrine therapy or an anti-hormone therapy, as first-line therapy for hormone-positive HER2-negative advanced breast cancer. This was presented by Dr. Matthew Goetz.

Just a little bit of a refresher—when we look at CDK 4/6 inhibitors, initially we thought that maybe all of them are equivalent. But recently, we started getting more and more data that maybe they are not. Maybe each one has special characteristics. Here I'm going to highlight, for example, two of them. The one in blue is abemaciclib. This is the one on the top. The one on the bottom is palbociclib. You can see that their targets are a little bit different. All of them target CDK4/6, but you can see that abemaciclib has more targets, so it targets other CDKs. You can see here the targets of CDK7 and CDK 2, whereas palbociclib is more specific to CDK4/6.

This is a busy slide, but here I'm trying to summarize all the different studies that look at CDK4/6 inhibitors in hormone-positive breast cancer. The PALOMA studies are with palbociclib the MONALEESA studies are with ribociclib, and the MONARCH studies are with abemaciclib. Now, let's focus first on the MONALEESA studies. All three studies have shown to statistically significantly improve progression-free survival and overall survival (OS). If we focus on the PALOMA studies, yes, all three of those studies did improve progression-free survival. However, none of them improved overall survival. If you look at MONARCH, the MONARCH 2 study did statistically improve the PFS and OS. However, MONARCH 3 did improve PFS, but we didn't know if it improved OS. That was the study.

Again, this is just a refresher about the PFS result of MONARCH 3 that led to the global approval. Here you can see that it improved the progression-free survival from 14.8 months to 28.2 months, with an impressive hazard ratio of 0.54 that was statistically significant. This is the overall survival, and that was the highlight slide of this whole presentation. Here you can see that it did numerically improve the overall survival from 53.7 months to 66.8 months. However, unfortunately, that was not statistically significant.

Looking back at the three drugs we have now—palbociclib, ribociclib, and abemaciclib—the only drug that has statistically significantly improved PFS and OS in every single study that it undergone is ribociclib. That led to the National Comprehensive Cancer Network (NCCN) putting this regimen of aromatase inhibitor plus ribociclib as the Category 1 recommendation in their guidelines, whereas abemaciclib and palbociclib are not categorized as Category 1.

All right, let's shift gears to the third study. This is a new drug called inavolisib, which is a PIK3CA inhibitor. Here, the study looked at inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer. The study was called INAVO120 study. That was presented by Dr. Komal Jhaveri.

Again, let's put it into context with a little bit of background. Let's look at the landscape or the algorithm of how we treat hormone–positive, advanced or metastatic breast cancer. The first-line therapy is a doublet, usually a combination of endocrine therapy, either an aromatase inhibitor or fulvestrant in combination with CDK4/6 inhibition. Then for the second line or third line, if the patient is still considered endocrine-sensitive, we try to change the endocrine therapy to something else and add another targeted therapy, something like everolimus or alpelisib. For patients with PIK3CA mutations or patients with ESR1 mutations, we tend to do a different endocrine therapy called elacestrant, which is known also as an oral selective estrogen receptor degrader (SERD).

If a patient has an alteration in the PTEN/ PI3K/AKT pathway, we can also give them a targeted therapy called capivasertib, which is newly FDA-approved. In this line of therapy, if patients do have a pathogenic BRCA1 or BRCA2 mutation, we can consider giving them a poly-ADP ribose polymerase (PARP) inhibitor like olaparib or talazoparib. Now, once patients become endocrine-refractory on either the third-line or fourth-line therapy, here we can do single-agent sequential chemotherapy. It's very important; we often forget that if patients have high tumor mutational burden (TMB) or are microsatellite instability (MSI)–high, regardless of tumor type, they qualify for pembrolizumab, even breast cancer patients. So, keep that in mind. If patient do belong to the HER2-low category, they can qualify for a drug like trastuzumab deruxtecan, and patients who are HER2 0 can receive sacituzumab govitecan, or in the near future, datopotamab deruxtecan.

But the question here is, can we give first-line patients a triplet therapy? Can we move precision oncology more to the early setting? To understand what we're going to talk about is very important to understand the estrogen receptor pathway. Yes, this is a busy slide, but we're going to try to digest it together. The hallmark of the estrogen pathway is estradiol. Estradiol goes freely into the cytoplasm of breast cancer cells and bind to the estrogen receptor, which leads to a cascade and leads to cell division. Historically, the way we target that pathway is by inhibiting the production of estrogen or estradiol. Here, we use an aromatase inhibitor to do that. However, you can also block it the other way around. Instead of blocking the estrogen, you can block the estrogen receptor (ER). You can do that either by a selective estrogen receptor modulator like tamoxifen, or you can do it with a degrader of estrogen receptor or a down-regulator of the estrogen receptor like fulvestrant.

Parallel to that pathway that happens at the same time—and often it's the culprit for the resistance to the therapy that targets the estrogen receptor—is the PI3K-AKT-mTOR pathway. This is usually activated by something like insulin-like growth factor. When it binds to the insulin-like growth factor receptor 1, it activates a phosphorylation cascade that leads to the activation of the PI3K, which in turn will activate the AKT. That will lead to unleashing mTOR. Now, both those pathways eventually emerge into the cyclin D1 pathway, which is at the nucleus of the cell, and here it binds to the CDK4/6 proteins. Together, they will allow the cell to go from the G1 phase to the S phase and allow for cell division and propagation of the cancer.

So, we need more effective treatments for patient with PI3K mutation that are also hormone–positive, HER-2 negative. Historically, this has been a very attractive pathway. However, it's been very hard to target due to the challenges of tolerability and safety of those drugs that target that pathway. Now, this new drug, inavolisib, is a highly potent, selective PI3K alpha inhibitor that also promotes the degradation of mutant P110 alpha, which may improve the therapeutic window. In preclinical data, we found that there is synergy between inhibiting PI3K and CDK4/6 in models that had a PIK3CA mutation.

This was a first-line study of hormone-positive, HER2-negative advanced or metastatic breast cancer. They looked at the cohort that did have a PIK3CA mutation. Patients needed to have measurable disease. They also specifically chose patients with either primary or secondary endocrine resistance. These are tumors that have progressed within 12 months of finishing adjuvant endocrine therapy. Either from the early setting or while they were receiving adjuvant endocrine therapy, the cancer recurred. They were randomized 1:1 to receive inavolisib plus palbociclib, which is one of the CDK4/6 inhibitors, plus fulvestrant, which is considered endocrine therapy, versus placebo plus palbociclib plus fulvestrant.

The primary end point of the study was progression-free survival. If we look at the demographic and baseline disease characteristics, as you can see here, over 30% of patients were premenopausal. Those patients received ovarian function suppression to suppress their ovaries. There was very little bone-only disease, and I really commend them for not only including bone-only disease. I mean, those are truly, truly high-risk patients, because remember, in hormone-positive breast cancer, a lot of patients have bone-only disease. But of these patients, very, very few of them were bone-only; 82% of them had visceral metastatic disease. If you look at what the patients received prior to receiving that line of therapy, most of them received chemotherapy in the early setting. If you look at prior endocrine therapy, 50% of those patients received tamoxifen.

That's one of the weaknesses, I would say, of the study, because the majority of high-risk patients, in the US at least, will receive an aromatase inhibitor. But here, 50% received tamoxifen and went straight on to receive fulvestrant in this study. They missed a very important line of therapy, which is an aromatase inhibitor. The other weakness of the study is that not a lot of patients received prior adjuvant CDK4/6 inhibitors—three patients in inavolisib arm and one patient in the placebo arm, which is also not what we see currently nowadays. Nowadays, most patients that are high-risk will have already received adjuvant CDK4/6 inhibition.

This is the primary end point of progression-free survival, and here we can see that the median progression-free survival improved from 7.3 months to 15 months. It more than doubled, which is very impressive, with an impressive hazard ratio of 0.43. When we have a hazard ratio of 0.43, that means about 60% of patients that received inavolisib had a lower chance of progression by receiving that therapy compared with placebo. If you look at the subgroup analysis, all of them seem to benefit. I do want to caution you—these were small numbers, so that's why I take them with great caution—that some subgroups of patients did not benefit. Just keep in mind, there were very small numbers of patients in those groups. But in general, everybody seems to benefit across the board from INAVO.

Overall survival is not met yet. However, it's good to see that the separation of the curves has occurred and that those curves are still separated. This is reassuring. If you look at the overall response rate, it has improved by 33% by the addition of inavolisib. If you look at the clinical benefit rate, it also has improved by around 30%. Now, let's put it in perspective. This is the first time we see a target to the PI3K-ATK-mTOR pathway in the first-line setting. Here you can see that it's hard to really compare it to other drugs in term of efficacy because all the other drugs that target that pathway were mainly focusing on the second line and beyond. But here you can see a little bit of comparison of PFS for those different agents compared with placebo.

However, safety is what we really need to focus on. Although these drugs are exciting and this is a very attractive pathway that we need to use, inavolisib does not come without its own fair share of adverse event. I really want to highlight the diarrhea. Almost half of patients will experience diarrhea, and about 5% will have grade ≥3 diarrhea. One out of four patients will experience rash on this drug. About two-thirds of patients will experience hyperglycemia, and 6% will have grade 3 hyperglycemia and become diabetic. Stomatitis, which is ulcers in the mouth, was experienced by half of the patients, and 6% had severe stomatitis.

So yes, these are exciting drugs, but they come at a huge cost. It's really important to give them to the right patients, not just everybody. Again, the side effect profile is comparable to what was seen with other drugs that target that pathway. However, if you compare it to alpelisib, these side effects tend to be more manageable. Case in point, if you look at the discontinuation rate, it was way less with Inavolisib compared to alpelisib—7% within inavolisib and 25% with alpelisib. So, if we look at the landscape of hormone-positive advanced breast cancer, we can see that in the first line, we're soon going to get a new triplet therapy of fulvestrant plus palbociclib plus inavolisib in patients with PIK3CA mutations.

Thank you.

About Dr. Mouabbi

Jason Mouabbi, MD, is in Assistant Professor in the Department of General Oncology and the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, where he specializes in lobular breast cancers. His research focuses on the management of breast cancer subtypes and their impact on treatment. Dr. Mouabbi has been the recipient of multiple honors and awards, including the Guiding Researchers and Advocates to Scientific Partnerships (GRASP) Advocate Choice Award in 2022 and the Lester & Sue Smith Breast Cancer Award of Excellence in 2021.

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor. 

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