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For nearly half of all breast cancer patients – those with low levels of the HER2 protein – targeted treatment options have always been limited. Palliative chemo has been the standard of care in stage 4 metastatic patients – until now. In this episode, Dr. Diane Reidy-Lagunes talks with Dr. Shanu Modi, the lead researcher of a groundbreaking trial that proved a drug that combines an antibody with a chemotherapy – trastuzumab deruxtecan (T-DXd) – can control cancer cells and extend survival in stage 4 HER2-low breast cancer patients. With a fresh FDA approval, T-DXd is now being tested on other cancers and changing the way oncologists treat their patients.
Cancer Straight Talk from MSK is a podcast that brings together patients and experts, to have straightforward evidence-based conversations. Memorial Sloan Kettering’s Dr. Diane Reidy-Lagunes hosts, with a mission to educate and empower patients and their family members.
If you have questions, feedback, or topic ideas for upcoming episodes, please email us at: [email protected]
Episode Highlights
It’s estimated that there are more than 168,000 people living with stage 4 breast cancer in the United States. T-DXd is a recently FDA-approved medication that improves outcomes and extends survival to this population of patients.
Dr. Shanu Modi, medical oncologist and principal investigator of the MSK-led DESTINY-Breast04 trial, received a standing ovation at ASCO, the national cancer meeting, after presenting her groundbreaking results on this new treatment.
What does HER2 status mean in relation to breast cancer?
HER2-positive means that the cancer has a lot of this protein on the surface of its cells, which makes the cancer behave more aggressively. We have wonderful, targeted therapies that are extremely active against HER2-driven cancers.
HER2-negative cancers make up a large variety of cancers, and a lot of them actually have low levels of the HER2 protein, so we call them HER2-low. It’s been a frustration that all the excellent targeted therapies have not been effective at targeting HER2-low breast cancers, so we’ve always treated them as if they were completely HER2-negative, meaning with chemotherapies that don’t have a lot of targeted therapy options.
HER2-low is expressed on almost half of all breast cancers, so it’s a large population of patients who have the potential to benefit from T-DXd.
How is T-DXd different than other cancer drugs?
Trastuzumab deruxtecan, or T-DXd, can bind to very small amounts of HER2 expression on cancer cells. It’s composed of an antibody, trastuzumab or Herceptin (brand name), and its job is to find HER2 and attach to it on the surface of the cell. The trastuzumab antibody is linked with six or seven or eight molecules of a very potent chemotherapy drug, deruxtecan.
When trastuzumab or Herceptin binds to its HER2 target on the cells, the whole complex including the deruxtecan gets internalized. It dumps the chemo right inside the breast cancer cell.
T-DXd can target and combine successfully with cancer cells with even the lowest levels of HER2. This is the first HER2-targeted therapy that’s active for HER2-low breast cancer.
When you tested T-DXd on patients, what did the DESTINY-Breast04 trial show?
In this study, we enrolled patients who had HER2-low advanced stage breast cancer. The standard of care, single agent palliative chemotherapy, formed the control arm of the trial, and the experimental arm was the trastuzumab deruxtecan.
The trial showed a very statistically significant, and very clinically meaningful, doubling of the control of the cancer with trastuzumab deruxtecan.
The trial also showed a one-third prolongation in the duration of time that people lived taking this therapy versus standard of care therapies. It’s not that common to see a survival advantage in late-stage metastatic breast cancer, so this was very exciting to see.
Can T-DXd benefit other cancer patients, as well as those with metastatic breast cancer?
Subsets of stomach (gastric), lung, colorectal, and other cancers are known to express HER2 as well, and T-DXd is already approved for a subset of patients with advanced gastric cancer and is under testing for its benefits in other tumor types to treat people who have HER2-expressing or HER2-altered tumors.
This drug has the potential to significantly improve treatment outcomes for a large population of patients with cancer.It opens up a whole new avenue of research. This is good news for all cancer patients.
What are the side effects of T-DXd therapy?
Nausea is the most common side effect with T-DXd, but it’s a very controllable kind of nausea. The other main side effect is the lowering of blood counts, which is something oncologists are very familiar with managing. An uncommon but important side effect to mention is lung toxicity. There are different degrees of the lung toxicity that patients can have, and most patients will have a low-grade, mild lung toxicity, if they have it at all. Lung toxicity is reversible for the vast majority of patients.
The key to managing your side effects is education and awareness, and for your doctor to hold this therapy. If you are aware of the potential risk, you can intervene early.
T-DXd received FDA approval in August 2022. Will T-DXd become the new standard of care?
The NCCN guidelines reacted almost instantaneously to the data and incorporated trastuzumab deruxtecan as an option in the International American Guidelines within two weeks of the release of the trial results.
T-DXd is now widely available in the United States. The next step is to make it available to patients around the world.
Show transcript
Dr. Diane Reidy Lagunes:
It's estimated that there are more than 168,000 people living with stage 4 breast cancer in the United States, and although they can often live for many years with the disease, we need every tool to keep it controlled for as long as possible. And now, clinical trial results will open the door for new treatment options for patients with metastatic breast cancer. A recently FDA-approved T-DXd is a medication that improves outcomes and extends survival to a new population of patients, and we're gonna talk about it right now.
Hello, I'm Dr. Diane Reidy-Lagunes from Memorial Sloan Kettering Cancer Center, and welcome to Cancer Straight Talk. We're bringing together national experts and patients fighting these diseases to have evidence-based conversations. Our mission is to educate and empower you and your family members to make the right decisions and live happier and healthier lives. For more information on the topics discussed here, or to send us your questions, please visit us at mskcc.org/podcasts.
Our guest today received a standing ovation at a national medical meeting after presenting the groundbreaking results of the DESTINY-Breast04 trial. Dr. Shanu Modi, medical oncologist and the principal investigator of this MSK-led trial, is here today to discuss the results and tell us what it means. Dr. Modi, welcome to the show.
Dr. Shanu Modi:
Thank you. Thank you, Diane. It's really my pleasure to be here.
Dr. Diane Reidy Lagunes:
We're so thrilled to have you. So before we get to the heart of this study, can you just share with us a little bit about what HER2 status really is in regards to breast cancer, and why for this particular drug it's so important, and why this drug may be a little different?
Dr. Shanu Modi:
Yeah, happy to do that. The background is actually really critical, I think, to understanding this new trial. So in breast cancer, we have generally defined the HER2 status of cancers in a very binary way. So you're either positive for this protein or you're negative, meaning the cancer is positive or negative. What it means to be HER2-positive is that this cancer has a lot of this protein on the surface of the cells. And that makes that cancer behave more aggressively. It is a driver, we say, of that cancer. And on the other side, we have wonderful targeted therapies that are extremely active against these HER2-driven cancers. So we call those HER2-positive breast cancers. Everything else we call HER2-negative.
So you can imagine that the HER2-negative group is a really mixed group of breast cancers actually. And the one thing that we've always known is it's an oversimplification to say these are all HER2-negative cancers, because actually many of those cancers do also have low levels of that HER2 protein present. But it's been a frustration that all of our really excellent HER2-targeted therapies have not been effective at targeting these HER2-low breast cancers. And so we've always treated patients with this type of breast cancer – HER2-low breast cancer – as if they are HER2-negative, and they are typically treated with chemotherapies and they don't have a lot of targeted therapy options. And then comes along trastuzumab deruxtecan, also called T-DXd for short, which is this new generation of HER2-targeted antibody drug conjugates. And it's just changed the whole field based on the DESTINY-Breast04 trial.
Dr. Diane Reidy Lagunes:
So essentially this drug is able to bind those small amounts of HER2 expression in this patient population?
Dr. Shanu Modi:
Exactly. So it is what we call a HER2 antibody drug conjugate, which means it's composed of an antibody, which is actually trastuzumab, or Herceptin is the other name. A lot of our breast cancer patients will be familiar with that. It's been a groundbreaking drug since it was approved 20 plus years ago. And it's an antibody therapy, right? So its job is to find HER2 and attach to it on the surface of the cell. But what's happened is, they've linked this trastuzumab antibody using a very special linker with six to seven, eight molecules of a very, very potent chemotherapy drug that's deruxtecan. So now when trastuzumab or Herceptin binds its HER2 target on the cells, the whole complex gets internalized and it really just dumps the chemo right inside the breast cancer cell. And even these little low levels of HER2 now, we're finding this antibody drug conjugate combine to and target successfully, and this is the first HER2-targeted therapy that's active for HER2-low breast cancer.
Dr. Diane Reidy Lagunes:
Amazing. So again, just to reiterate what you said, I like to tell my patients it's like a lock and a key, right? There's some locks on this cell. There's not a lot of them, but they're there. And now when this key binds to that lock, the key also has a little tiny bit of chemotherapy attached and is able to dump that chemotherapy, as you said, so perfectly right into where it matters, right into the breast cancer cell. So it's truly miraculous. Can you tell us, what did the study actually show?
Dr. Shanu Modi:
Right. This was a big randomized global phase three trial. It was opened and across three continents. In this study, we enrolled patients who had HER2-low advanced stage breast cancer. And so these are patients who had had at least one, but not more than two lines of chemotherapy. And if they were also hormone positive, HER2-low, they'd had to exhaust all the active endocrine lines of therapy as well. And standardly what we would offer these patients would be single agent palliative chemotherapy. So that formed the control arm of the trial: the typical standard chemo drugs these patients would normally get. And then the experimental arm was the trastuzumab deruxtecan. And it was a randomized trial. There was actually a two to one randomization, so there was two out of three chances to get onto the T-DXd arm. And we followed these patients to see how long we could control their cancers with either therapy.
And what we ended up showing was that there was a very statistically significant, and also I would say a very clinically meaningful, doubling basically of the control of the cancer with the trastuzumab deruxtecan. So it was really impressive data. And I think that was our primary endpoint, we say, of this trial. That was the main purpose of the study. But we had multiple secondary endpoints, you know, other things we were interested in. And one of the key secondary endpoints was overall survival. Did we just control the cancer, or did we also have an impact on the long-term survival of patients? And it's not that common to see a survival advantage in sort of a late-line metastatic breast cancer setting, and we saw that as well at this early timepoint in follow-up. We saw that there was a one-third prolongation also in the duration of time that people lived, taking this therapy versus just standard of care therapies. So it was very exciting to see that.
Dr. Diane Reidy Lagunes:
So, as you said, the alternative standard to this therapy was palliative chemo. So most of these patients have exhausted all therapies for the treatment of this disease. So I'd like to hear from Alison, an attorney from New York who has been benefiting from T-DXd for more than a year, and the impact it's had on her.
Alison:
Hi, I'm Alison. I'm a lawyer living in New York City with my Chihuahua mix named Daisy. I was diagnosed with stage 4 breast cancer nine years ago, and it's been a roller coaster for me being on different treatments over time. I was fortunate a year and a half ago to start taking T-DXd, which has been a real game-changer. For me, it's been wonderful to be on the same drug for that long, to feel hopeful, to have more time to live, to work, to spend time with family and friends and do the things that are important to me, and to do it all with mild side effects. I'm just really grateful to be on this drug and to be feeling really good. I hope it'll be made available to many other cancer patients.
Dr. Diane Reidy Lagunes:
Amazing. So Shanu, you've been saying that this was clearly a practice-changing study, and Alison's an example of that. Anything else to add on why this may be so important, not only for metastatic breast cancer patients, but potentially for even other patients?
Dr. Shanu Modi:
Yeah, I think you just hit the nail on the head there. This trial is positive, but it's also more about progress in cancer therapy. I think what we've shown is, for the first time we can actually target low-level proteins on cancer cells. This is something we haven't been able to do very successfully in the past, certainly not in breast cancer. And so I think this kind of sets a new paradigm. Right now, we have the ability to maybe target other proteins, enzymes on cancer cells that we haven't been able to do before. So this opens up, I think, a whole avenue of cancer research. And this is important not just in breast cancer, but all different types of cancers also.
Dr. Diane Reidy Lagunes:
Yeah, absolutely. I care for, for example, colorectal cancer, which has this expression too, and there's certainly potential there to use a similar type of approach in these patients that have HER2. But just again, not a lot of locks on the cell, if you will, but now you're able to identify them and go after them to be able to get this treatment right to the cancer cell. What are the side effects of this particular therapy? Anything additional or anything we need to know about this particular drug?
Dr. Shanu Modi:
That's an important question. Most of the side effects from this therapy really do probably come from that targeted chemo component. The most common types of side effects are generally either of a gastrointestinal nature or bone marrow suppression, meaning nausea was the most common side effect we've seen with this drug, but it's a very controllable kind of nausea. The other main sort of day-to-day toxicity is the lowering of the blood counts. Again, this is something as oncologists we're really familiar with managing. There is one side effect that's really important to mention. It's not a common side effect, thankfully, but it's an important one because it can be serious in some patients, and that's lung toxicity. We've seen that in almost every trial with this particular drug. There are different degrees of the lung toxicity that patients can have. Thankfully, most patients will have a low-grade, mild lung toxicity if they have it in the range of, you know, 10 to 12%. And that's reversible for the vast majority of patients. Unfortunately for some patients, it can be a more severe toxicity. And I think what we've learned with this drug and all the trials we've done, the key is education and awareness. Because if you are aware of this potential risk, you can intervene early. The key is for your doctor to hold this therapy. So I'm optimistic as people get more and more familiar with using this therapy, we're going to continue to see a decline in those high-grade lung toxicity events, as we've already started to see.
Dr. Diane Reidy Lagunes:
And as you know, the drug did receive FDA approval in early August. So what are the real-world implications? Do you think this will be considered standard practice, not only at MSK but beyond?
Dr. Shanu Modi:
So yeah, it was very exciting to see. I have to say it's probably the fastest response I've seen to a new drug. I want to credit that standing ovation a little bit for that. It really put a fire under people's feet. I think we saw the NCCN guidelines actually react almost instantaneously to the data, and they incorporated trastuzumab deruxtecan as an option in our International American Guidelines within two weeks of the release of the results. So this is now a drug that should be available widely in the United States. And now the next step is to get it available to patients around the world, frankly.
Dr. Diane Reidy Lagunes:
Absolutely. So Shanu, many of our patients with stage 4 disease know that ultimately they're going to succumb to the disease because we haven't figured out how to cure it yet when it spreads. What do medications like this mean? And how many patients are we really affecting by adding this drug into the toolkit, if you will?
Dr. Shanu Modi:
So HER2-low is expressed on almost half of all breast cancers, so we really are talking about a large population of patients who have the potential to benefit. And it's really important because, as you said, we recognize that curing stage 4 breast cancer has still alluded us, but this is one step closer to that. That's always our goal. Every new therapy, we hope, is going to push the needle further and prolong survival. But ultimately, our hope is that one day we can eradicate this stage of disease.
Dr. Diane Reidy Lagunes:
Absolutely. I don't want our patients with stage 4 disease to ever forget that. This isn't good enough. We're not content here. We're always saying we're trying to run faster than the bear for new therapies to come up and be able to ensure that our patients are living longer until we get the new next therapy FDA approved.
Dr. Shanu Modi:
We are trying to move away from the one-size-fits-all and really try to personalize therapy for patients, and this is one, I think, step towards that. I'm always optimistic that there's something great just around the corner. It's just our job to find it.
Dr. Diane Reidy Lagunes:
Amen. Dr. Shanu Modi, thank you so much for all that you do, for really doing very heavy lifting to make sure that this drug actually got into the clinic for our patients, and for sharing your insights with us today.
Dr. Shanu Modi:
It's really my pleasure. Thank you, Diane.
Dr. Diane Reidy Lagunes:
Thank you for listening to Cancer Straight Talk from Memorial Sloan Kettering Cancer Center. For more information or to send us any questions you may have, please visit us at mskcc.org/podcast. Help others find this helpful resource by rating and reviewing this podcast at Apple Podcasts or wherever you listen to your podcasts. Any products mentioned on this podcast are not official endorsements by Memorial Sloan Kettering. These episodes are for you but are not intended to be a medical substitute. Please remember to consult your doctor with any questions you have regarding medical conditions. I'm Dr. Diane Reidy-Lagunes. Onward and upward.