Dr. Carey Anders:
Welcome everyone to The ASCO Post Roundtable Series on updates on HER2-positive breast cancer. I'm Carey Anders, I'm the Medical Director of the Duke Center for Brain and Spine Metastasis, the Interim Division Chief at the Duke Cancer Institute, and a breast medical oncologist. I'm really pleased to have joining me today, two of my colleagues. I'll let Dr. Erika Hamilton introduce herself, followed by Dr. Sara Hurvitz.
Dr. Erika Hamilton:
Thanks so much. I'm Erika Hamilton I too am a medical oncologist and I direct the Breast Cancer Research Program at Sarah Cannon Research Institute in Tennessee Oncology in Nashville. Happy to be here with you today.
Dr. Sara Hurvitz:
Hi there. I'm Sara Hurvitz from the David Geffen School of Medicine at the UCLA Johnson Comprehensive Cancer Center. I am a medical oncologist as well and direct the Breast Cancer Clinical Trials Program. Really happy to be here with you too.
Dr. Anders:
Excellent. Today we're going to be discussing recent updates in HER2-positive breast cancer and the integration of new developments into four patient case studies. We're going to start with our first installment focusing on metastatic HER2-positive breast cancer. As I said, this will be case-based, and I'll be introducing the cases and then we'll have discussion about our management of them.
Case number one is a 46-year-old female with a history of de novo estrogen progesterone receptor negative, HER2-positive breast cancer that's metastatic to the liver at initial diagnosis and biopsy proven. She received THP (docetaxel, trastuzumab, and pertuzumab) for six cycles with resolution of symptomatic hepatomegaly and improvement in her liver metastasis radiographically. She was then transitioned to dual antibody therapy with trastuzumab and pertuzumab for approximately a year and a half with very good quality of life. She's the mother of two very active school-aged children, runs a nonprofit, and is also very artistic. On routine restaging scans, she's found to have progression in her liver and several new pulmonary nodules so we're really thinking here about second-line therapy for a patient who's received our first-line CLEOPATRA regimen. And I'd first like to turn over to Dr. Hurvitz to talk about what her approach might be to this patient's case.
Dr. Hurvitz:
Thank you so much, Carey. This is a pretty typical case. As we know from the CLEOPATRA study, the median progression-free survival (PFS) for patients treated with frontline THP was around 18 months and this patient had something just over that; somewhere around 2 years if you account for the THP induction regimen she received. Unfortunately, she's had progression in the liver, and this of course is a serious progression because it is of involving a viscera. If you look at our standard of care from 2013 to 2021, it would've been trastuzumab emtansine, based on the EMILIA clinical trial. This study showed that T-DM1 (trastuzumab emtansine) was better than lapatinib capecitabine in terms of both progression-free survival and overall survival.
But in fall of 2021, we had the very compelling results of the DESTINY-Breast03 study presented. This trial evaluated trastuzumab deruxtecan (T-DXd), an antibody drug conjugate that's novel in its high drug antibody ratio and the membrane permeability of the cytotoxic payload. The payload is a topoisomerase 1 inhibitor. This drug showed really promising efficacy in heavily pretreated patients with metastatic breast cancer in DESTINY-Breast01. That was a single arm study that led to the FDA accelerated approval of this agent back in 2019.
DESTINY-Breast03 is the first randomized study to evaluate T-DXd vs our current standard. And in this study, it was randomized against T-DM1. This was a large phase 3 clinical trial. Patients were randomly assigned one-to-one to T-DM1 or T-DXd. There were over 500 patients enrolled in this clinical trial and the only requirement was, in terms of past therapy, the patients had to have had prior trastuzumab and a taxane. It didn't require patients to be exactly second line. In fact, only about half of patients were in the second-line setting. The rest of them were in the later line setting.
And what the results showed in terms of progression free survival by blinded independent review, was nothing short of stunning. The Kaplan–Meier curve is something that I have not seen in the past actually. There is an early and dramatic separation of curves in favor of T-DXd, the median PFS for T-DXd was not reached and it was 6.8 months for patients treated with T-DM1. The hazard ratio was 0.28 with a p-value I've never seen that many zeros for a p-value in my career in breast cancer. Given it was already FDA-approved by accelerated approval in 2019, many of us saw this data and quickly adopted this as our standard second-line regimen. The objective response rate was around 80% in this study. Overall survival is not yet mature but very, very suggestive that there is a trend toward improvement. The guidelines quickly adopted this as the second-line regimen very, very quickly in the Fall and most recently, the FDA this year has actually given full regulatory approval in this setting. That would be my choice.
Dr. Anders:
Absolutely beautiful summary of really fantastic data. I think we have all been extraordinarily impressed by this data and I think we're seeing this data come to fruition in our own clinics, in our patients right in front of us. I would say that this would also be our standard of care second-line choice here at my institution. Dr. Hamilton. I'm curious if you would also agree.
Dr. Hamilton:
Absolutely. I think it's very hard to argue that we're not seeing dramatic benefits with trastuzumab deruxtecan in this space. Yes, in my practice, this is kind of firmly cemented as the second-line therapy at this point.
Dr. Anders:
Absolutely. And I think this is very much in line with the updated HER2-positive metastatic breast cancer guidelines that were recently reported through ASCO. Importantly, this very astute patient, who has a lot going on in her life outside of her metastatic breast cancer, as you're discussing this data with her, would importantly ask about what side effects to consider.
I think, we've all been very blessed by very few side effects for the majority of our patients on dual antibody therapy, particularly once the taxane component is dropped out from the CLEOPATRA regimen. From a quality-of-life perspective, Dr. Hurvitz, I wonder if you could discuss sort of what you would describe to her in the clinic about how her life would be impacted from a side effect perspective, how this might impact her life as a parent and someone running a nonprofit and what would monitoring of those side effects look like for her?
Dr. Hurvitz:
There are really important questions when we're in the palliative setting. We want to make sure that we are balancing efficacy with quality of life parameters. Our goal is to have patients feel as well as possible and to be functional in their life while we are controlling disease. So, T-DXd is a fairly well-tolerated drug. It's given every three weeks so patients aren't coming into the infusion room all the time but it does cause significant nausea in my experience. And that's what's been shown in the clinical trials, certainly more than we see with T-DM1. It tends to be a very early effect. I am using IV antiemetics for drugs that have high emetogenic potential. I am also arming patients with PRN (pro re nata) medications to have at home and spending a lot of time discussing how to manage the nausea because nausea really can interfere with the way one feels day-to-day and the way one functions day-to-day.
Another side effect that patients need to be made aware of is alopecia. While I have never seen patients have full hair loss, significant hair thinning is experienced by most patients and we don't know yet whether or not mechanisms such as scalp cooling are beneficial. And then there's a side effect that's not as common but can be life threatening and that is interstitial lung disease (ILD) or pneumonitis. This occurred in this clinical trial in around 10% or 11% of patients of all grades. There were no grade four or five events, which is good. However, in the DESTINY-Breast01 study, there were death events. In fact, 2.7% of patients died of ILD. It's really critical that patients be monitored closely for symptoms of interstitial lung disease, cough, shortness of breath, and fever, symptoms which actually could mimic a COVID infection in fact.
We also have to keep an eye on scans. This is a situation on a drug where I would not see a patient have a response and then send them off to do scans in four to six months. I am sticking with a fairly close scanning regimen to survey not only for disease response but also for early evidence of ILD in the lungs. In the trials, it was every six weeks. I think that's a lot for patients to do if they're doing really well on therapy but I am staying close to that, somewhere around every six to eight weeks because if a patient develops ground glass opacities, we really do need to hold therapy and wait for it to resolve.
Dr. Anders:
Absolutely agree with all that you've said. And I would love to just hear Dr. Hamilton's perspective, having presented this data beautifully at ASCO this year, the longer term safety follow up of the phase 3 data for DESTINY-Breast03 and any pearls that you may have Dr. Hamilton for how you also just as Dr. Hurvitz described, help mitigate some of these side effects, which I agree are harder to manage than our traditional T-DM1 side effect profile.
Dr. Hamilton:
I think Dr. Hurvitz really covered it quite well. I think one important point is that initially in DESTINY-Breast03, there were no mandated antiemetic prophylaxis recommended as part of the trial. So now, even as part of the label, we do recommend a multi-drug regimen. At least in my practice, and I think a lot of practices, this is a three-drug regimen. It's a 5-HT3, dexamethasone steroid as well as an NK1, and I think it's really important to have that on board from the start to really kind of control symptoms before they happen. I think what's interesting when we look at nausea and vomiting, is that it peaks very early in initial cycles. It's not a cumulative toxicity. It doesn't get worse over time but then it really persists throughout treatment.
It's quite likely that we need to keep these antiemetics on for our patients to make sure that they can tolerate this better. And I think we're doing a little bit better job of this now that all patients are getting multi-drug antiemetics up front. The fatigue really looked quite similar between the arms and also to Dr. Hurvitz's point, I think we were really reassured by the ILD pneumonitis. The big concern was there were fatal cases in DESTINY-Breast01. With increased awareness and increased recommendations about drug holding and treatment in DESTINY-Breast03, we've been able to eliminate that. There were no grade four or grade five cases, and in fact, grade three cases are less than 1%. I think this really has given us a lot of reassurance about bringing it into earlier-line patients and that with increased vigilance and monitoring, we can control this side effect.
Dr. Anders:
Absolutely. And I think being proactive from day one really helps, just as we're describing the patient's experience. I really like your point, Dr. Hamilton, about starting with the triple-drug regimen for antiemetics up front. One thing that I've been struck by in my own practice is that traditionally with most therapeutics, we see nausea sort of decline at about 72 hours, but I've seen more delayed nausea with trastuzumab deruxtecan. Just as you were saying, Dr. Hurvitz, I've really armed patients, not just for the first three days but even five and sometimes out to seven days. I've been a bit interested to see that in my own practice and really keeping those PRNs available and educating patients about how to take the antiemetics to improve their experience.
We'll keep moving on with this case. This is a highly educated patient who's very involved with metastatic breast cancer forums. She's very interested in clinical trial participation, both for her own benefit but for also altruistic reasons and helping us really move the dial forward in drug development for advanced breast cancer. She asks in the clinic, and Dr. Hamilton, I'll ask you what you might describe to her about what's on the horizon? What should she be excited about? And what should she be thinking about for next steps if her malignancy does develop resistance to trastuzumab deruxtecan?
Dr. Hamilton:
I think that's a really good point. I think the best option for a patient is always clinical trials if that patient can qualify. Certainly this patient does have a lot of standard of care options left for her to try. She's not seen capecitabine trastuzumab tucatinib. Now with us kind of taking trastuzumab deruxtecan into second line, we still have T-DM1 in our arsenal, as well as other drugs like lapatinib, neratinib, or chemotherapy in combination with trastuzumab. Certainly this patient does have a lot of options. There are new HER2 agents in development in clinical trials, a variety of different types of HER2 agents, novel antibody drug conjugate, bispecifics where we might be hitting HER2 and then also maybe even hitting something for the immune system, as well as just antibodies.
There was another abstract presented at ASCO where the minority of patients had HER2 positive disease, but I think maybe worthwhile talking about here, it's a very similar construct and so this is the HER3-DXd (patritumab deruxtecan). This is a very similar drug to trastuzumab deruxtecan, except instead of targeting HER2, now we're targeting HER3. The same HER3 antibody with a cleavable linker attached to a topoisomerase exatecan payload.
So, you can see here that the activity really looked quite encouraging across the board, whether we're looking at patients that we traditionally consider as triple-negative, hormone receptor-positive or the minority of patients that had HER2-positive disease.
I think one of the big questions moving forward is now that we seem to be in an ADC era, which personally I'm quite excited about, is what activity are ADCs going to have after each other? Or how should we be sequencing these? Theoretically you could imagine that perhaps there's cross-resistance with the payload but on the other hand, if we're targeting a different clone in the cancer and with bystander effect, that really may not be a large worry. I think we're going to have to get more data about antibody drug conjugate activity after an antibody drug conjugate but it’s certainly an area that we're looking into more.
Dr. Anders:
I think that's a fantastic point and sort of one of the key questions that we have, particularly given that many of the ADC payloads are topoisomerase inhibitors. How much is the resistance related to resistance to topoisomerase inhibition vs down regulation of the receptor on the extracellular domain? And could you envision strategies where we bring in a tyrosine kinase inhibitor along with an ADC in the next line of therapy to overcome that resistance. But I think that's where a lot of our translational studies will be fantastic to help us understand what are the true mechanisms to our ADC? That's going to be a really exciting space to learn more about.
This has been a fantastic discussion. Just to wrap up this case, I really appreciate all of the wisdom from this team, but I think some of the key points for us to take away. One, we want to keep a very close eye on our patients with metastatic HER2-positive breast cancer following dual antibody therapy, not only to monitor their disease status but also to monitor for the toxicities that we're seeing that are specific to the ADCs. We are seeing trastuzumab deruxtecan emerge as a highly effective second-line agent and I think we're all really excited to see what this compound in combination with other strategies might look like in the future with clinical trials. We are seeing additional ADCs just as the team described, in development targeting in this particular case, HER3, and also some immunotherapy strategies in the future.
This does bring us to the end of the case and please see the other segments for further discussion about the latest data in breast cancer and visit us on ASCOPost.com. Thank you.
