Dr. Shanu Modi on DESTINY-Breast04 and how a BCRF grant helped her career

This year’s American Society of Clinical Oncology (ASCO) annual meeting was one of the most exciting in recent years—especially in metastatic breast cancer news. The practice-changing DESTINY-Breast04 trial results garnered rapturous applause for demonstrating that a subset of breast cancer tumors with low levels of HER2 could be targeted with a drug called trastuzumab deruxtecan (T-DXd/Enhertu®).

Dr. Shanu Modi of Memorial Sloan Kettering Cancer Center presented these exciting results at ASCO. In addition to treating patients as a breast medical oncologist, she is also involved in developing new targeted therapies for breast cancer, with a focus on HER2-positive disease, as a clinical researcher. In 2009, Dr. Modi received the Advanced Clinical Research Award (ACRA) in Breast Cancer, which BCRF supports in partnership with Conquer Cancer, the ASCO Foundation.

BCRF invited Dr. Modi to join our video series, Behind the Breakthroughs, to discuss DESTINY-Breast04’s results and what they mean for patients, plus what that BCRF–Conquer Cancer grant enabled her to do.

Watch the full video above or read an edited version of the conversation below.

Tell us about DESTINY-Breast04’s findings and why they are so notable.

It was quite a thrilling ASCO and to be able to present this important and groundbreaking study for our field. Just as a small bit of background: In breast cancer, we have traditionally defined HER2 status in a very binary fashion. Either the tumor is HER2-positive or HER2-negative. HER2-positive cancers are breast cancers that are really driven by the HER2 oncogene, and they respond to our available HER2-targeted therapies. Everything else we call HER2-negative, and that's like 80 percent of breast cancers, so a large group of patients. But we know this is really an oversimplification. Even within this HER2-negative population, there are tumors that express low levels of the HER2 protein, which we have called HER2-low breast cancer. And we define that as tumors who would have IHC scores of 1+ or 2+ without gene amplification. And this is a group for which our currently available HER2-targeted therapies are also not effective, even though they have low levels of this target. So we've been grouping these patients within this HER2-negative population and treating them that way. But we know there is this exciting new generation of HER2-targeted antibody-drug conjugates, and they are now showing potential to target even this low level of HER2 expression.

That was really the basis and the rationale for the DESTINY-Breast04 trial, which was the first randomized study to ever look at using this antibody-drug conjugate, trastuzumab deruxtecan, which we call T-DXd for short, and testing T-DXd versus standard therapy for these patients, which is single agent chemotherapy. And so this was a real test of whether this drug could be effective for these patients who have this low level of HER2 expression. This was a very positive trial, and it showed very clearly that patients who got the trastuzumab deruxtecan therapy had a doubling of their disease control or prolongation of progression-free survival. On average, it went from five months with chemotherapy up to approximately 10 months with T-DXd therapy, which is very significant. And it also improved overall survival. It prolonged survival. On average, patients had a gain of about six months of survival with T-DXd.

I know for some people that may or may not sound dramatic enough, and I think we feel that way too. But I have to also put into context that this is a setting [advanced breast cancer] where for many of the new drugs we introduce, we don't see any survival advantage. We see quality of life benefits. And so that six months is actually a very profound result for this group of patients. These are really, really phenomenal data, and I think that's partly why they garnered that standing ovation. The audience was thrilled to see such positive forward progress for this group of patients. And, of course, there were many other reasons. We were all there together [at ASCO] for the first time after the pandemic. There was a lot of emotion running through that audience that day.

This was also a unique study population, because the trial enrolled both patients with hormone receptor (HR)–positive breast cancer and HR-negative, the latter group of which might include triple-negative patients. Can you put that in context for us?

The HER2-low population is a very heterogeneous population. That’s a real key thing. And we're starting to understand the features of this population more. And there have recently been a lot of studies looking back in time into big trials and experiences at people's institutions, to ask: What is this HER2-low population comprised of? And it's predominantly patients who also have hormone receptor–positive breast cancer. And there's a smaller group that has hormone receptor–negative HER2-low breast cancer. The ratio is almost eight-to-one, so it's a very heavy hormone-positive HER2-low population. But that group of patients that's hormone receptor–negative HER2-low, we can also call that group triple-negative. We know this is historically a group that has a very aggressive subtype of breast cancer, and for which there is an unmet need for effective therapies. That was one of the motivations when we designed this trial.

Initially, knowing that this is largely a hormone-positive population, DESTINY-Breast04 was intended to be a hormone positive, HER2-low population. But given that we know there is a small group of triple-negative patients that also are part of this group, that they really need more effective therapies, and that this drug’s the mechanism of action shouldn't discriminate between hormone-positive and hormone-negative, we decided to include that population of patients as well. And I'm so pleased we did, because we saw just as impressive results for those triple-negative patients as we saw for the hormone-positive patients. I think this offers a small subset of the triple-negative population of patients with an exciting therapy that prolongs survival.

T-DXd is an antibody-drug conjugate. How is it different from T-DM1 (Kadcyla®), an antibody-drug conjugate for HER2-positive breast cancer?

As clinicians, we were used to this type of therapy because we've been using T-DM1. This is for HER2-positive breast cancer, but the concept is the same. Antibody-drug conjugates are very unique drugs. They combine tumor specificities of targeted therapy. But they combine it with what we say is a really cytotoxic chemotherapy payload. These are usually comprised of an antibody, and attached to it via special linkers, is a chemo payload. And it's often a very potent chemo payload.

T-DM1 has been extremely effective for HER2-positive breast cancer. But what's different about T-DXd as a new generation of ADCs is, first and foremost, foremost, the chemotherapy is very unique. The chemotherapy payload in T-DXd is a topoisomerase 1 inhibitor. This is a kind of chemotherapy we don't really use very often in breast cancer, so it's very novel. Most of the patients will not have been previously exposed to this kind of a chemotherapy drug before. There's also twice as many molecules of chemo attached to each antibody in T-DXd versus T-DM1. If we put three or four chemo molecules on a T-DM1 antibody, we attach eight with T-DXd, so we're taking a lot more of this very potent chemotherapy to the cancer cells.

Then perhaps the last—and key—feature that makes T-DXd different is the linker. T-DXd unlike T-DM1 has a cleavable linker. When the chemo is lopped off from the antibody, it leaves the chemotherapy in a membrane-permeable state. So now when the chemotherapy is released in the cancer cell, it can kill that HER2-positive cancer cell. And that's where most ADCs would stop. That's where T-DM1 would stop. But now this chemotherapy can pass through the cell membrane and can enter the microenvironment and neighboring cells and kill those cells as well. And that can include cells that have variable levels of HER2 expression—even HER2-low cells. That’s the tremendous advantage of T-DXd, not only over T-DM1, frankly, but over all of our currently available HER2-targeted therapies. Itt works in a broad range of HER2-expressing cancers.

That’s really amazing—just to think about the utility of this for breast cancer, but for other cancers, as well.

That hits upon something that I say a lot: This is an important study. We've opened up a new targetable population of patients within breast cancer, and we can design targeted therapies for them. There are more therapies besides T-DXd that are on the horizon. This is really exciting. But in some ways, this is more than just about this drug and more than just about breast cancer. It's about a huge advancement in cancer therapy in general. What this trial has shown us is that there is untapped potential in this new generation of antibody-drug conjugates by virtue of their unique mechanism of action. And for the first time, I think we've seen that we can now target proteins that have very low levels of expression on cancer cells. This is something we couldn't do before. And T-DXd has shown us we can do that. This can open up the door to targeting low level proteins that we've never targeted before—even in other cancer types. It’s a real revolution in cancer therapy.

How has this changed your daily clinical practice? What are you advising your patients?

We’re fortunate that the medical community has moved quickly on this data. Our National Comprehensive Cancer Network (NCCN) guidelines committees have already incorporated T-DXd into our American guideline paradigm, which is very helpful as we try and get this therapy available for our patients today. As we know, there’s a stepwise process to get any therapy FDA approved. We've submitted these data to the FDA, and we will likely hear from them sometime before the fall. Obviously, we’re expecting that this is going to be viewed favorably, but in the meantime, we have the potential to access this therapy for patients today through the fact that it's now part of our guidelines. We’re already starting to offer it to the appropriate patients—and that’s a large population of our metastatic breast cancer patients. Patients are coming to us knowing about this drug. One of the things I’m telling patients and colleagues even is that it's important to start to focus on the precise level of HER2 expression—and not think of it in this binary way. So it's important to know if someone’s tumor has 1+ and 2+ [IHC scores], which we didn't pay a lot of attention to before. But now we need to pay attention to the actual level of HER2 expression because it has real clinical meaning for our patients.

You received an Advanced Clinical Research Award from Conquer Cancer, supported by BCRF, in 2009. What impact did that research grant, at that time, have on your career?

Thank you for asking that. I was so honored, and it was such a prestigious award for me to receive. I was just starting off as a junior investigator at that time. So that award really came at a very crucial moment in my career, and in many ways, it allowed me to dedicate myself to performing clinical research—and as you can see, that has really been the foundation of my work even today. It had a real impact in my life. We all know that good research requires not just bright ideas, but there is practically a need for support on many different levels. I'm very thankful that I work in a field where there are a lot of smart and dedicated researchers. And for me, the ACRA award came at just the right time and allowed me a platform to put forth my ideas and have the backing for them.

Read more of BCRF’s coverage of this year’s ASCO meeting here.

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