 I think as you look at the future of HER2+ breast cancer, I would say the future appears to be very exciting. Even if you look in the past few years at the number of agents that have become available to us in the treatment of these individuals, there has been multiple new options that have been added to what we have already been able to offer to individuals. I think areas of interest are still looking at brain metastases; it’s very exciting that we have drugs now that are available that have somewhat more reliable response in brain metastases, but we do still see patients. I have seen patients who continue to progress intracranially and even when they’re responding well outside of the brain, and so I do still think that there needs to be further advances in drugs, or combinations of agents, which are able to deliver more consistent responses in the brain. When I look at some of these patients, I’ve had several individuals through the years, who have completed adjuvant or neoadjuvant therapies and then subsequently relapse in the brain. The question of how do we utilize some of these new agents earlier in their treatment can perhaps [be answered] in the adjuvant or neoadjuvant setting as a way to prevent relapses in the brain because those are oftentimes the more challenging ones to manage. It allows you to see when you see someone who relapses in the brain alone, you have that feeling that your systemic therapy that you had given before probably did a pretty good job at clearing cells from the rest of the body, but not so in the brain. I think looking at how to sequence these agents where we have activity in the brain earlier in their treatment will be helpful.

For the DESTINY-Breast03 trial, just to talk a little more specifically about the patients who were enrolled that did have brain metastases, when you look at median progression-free survival for those individuals when compared to T-DM1, their medium progression-free survival was 15 months versus 3 months; a substantial improvement there. Also, when you look at them as far as overall responses, it was 67% versus 20% for those individuals. The median duration of response was 12.9 months for individuals with T-DXd versus 7.2 months for those with T-DM1. There were also intracranial responses seen. The overall response to intracranial disease to T-DXd was 63.8% versus 33.3% for T-DM1. There were complete responses intracranially with both drugs, but that was seen in 27.8% in individuals with T-DXd versus just 2.8% with T-DM1. When I look at that data, when I give consideration to someone who presents with brain metastases early on and I'm in that second-line setting, again based on this data it gives you further assurance if you're giving consideration to T-DXd versus T-DM1 that in particular with that patient with brain metastases, it gives you some reassurance of that potential for intracranial responses are there. Also, even if it's someone who you need to treat their brain metastases upfront, it does give us a good signal of intracranial activity for that drug.

A good use of endocrine therapy is something that does not get a lot of use in women who have HER2+ breast cancer in part because the HER2 overexpression tends to be the bigger driver in those tumors. However, there have been small studies looking at use of drugs like fulvestrant in combination with trastuzumab, and seeing unique options for combinations of endocrine therapy along with the HER2-targeted agents as well.

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Closing out her discussion on HER2+ metastatic breast cancer, Cynthia Lynch, MD, shares her excitement for treatment strategies in the setting of brain metastases. 

Treating Brain Metastases and the future of HER2+ mBC

 When I'm looking at a patient with HER2+ metastatic breast cancer, the way I would consider usage of drugs and how I might sequence them is as follows. For someone who is in the first-line, I think that's pretty clear: the NCCN [National Comprehensive Cancer Network] guidelines recommend the use of pertuzumab, trastuzumab, and a taxane. Again, that can be docetaxel or paclitaxel in combination with that. In general, those agents are continued until disease progression with the exception of the cytotoxic agent, which is typically dropped off after 6 cycles as long as patient is responding well. In the second-line setting, based on the DESTINY trial, the use of trastuzumab deruxtecan has moved up to the preferred drug for second-line therapy. Again, that is based on both efficacy and noting that it overall has a very good safety profile. Previously, I had mentioned that there are a few adverse drug effects that need to be managed well and that oncologists need to be aware of. I would say that is the risk of nausea, vomiting as well as the risk of pneumonitis in the interstitial lung disease, but with close monitoring of patients that can be administered very safely. Trastuzumab emtansine or T-DM1 also, which had previously been the preferred second-line agent, still is an option in the second-line therapy, but for many oncologists that is probably moving more down into the third-line of therapy beyond trastuzumab deruxtecan with trastuzumab deruxtecan as well. We've seen it with all different types of combinations, but I think both of those drugs have demonstrated ability to show a response for intracranial metastases. Then when I look beyond that, I'm usually giving consideration to sequencing trastuzumab or margetuximab in combination with different chemotherapy agents. Usually, I'm partnering it with all of the similar agents that we use for women who don't have HER2+ breast cancer, but that's drugs like gemcitabine, vinorelbine, eribulin looking at those in combination with the trastuzumab. Basing that on those women at that point have had several prior lines of chemotherapy and so giving consideration to what things are important to them as far as side effects, maybe looking at prior side effects that are still persistent like neuropathy and those types of things would help me choose what drugs I would be considering for further lines of therapy.

In the context of recently approved novel regimens, expert Cynthia Lynch, MD, revisits the optimal sequencing of therapy for patients with HER2+ metastatic breast cancer.

HER2+ mBC: Sequencing Novel Treatment Regimens

 Other agents that have recently come available based on trials is used of tucatinib and oral tyrosine kinase in combination with trastuzumab and capecitabine. That was based on the HER2Climb trial; it was a randomized double-blind trial in individuals with metastatic HER2+ breast cancer who had previously progressed on prior therapies including trastuzumab and taxane-based therapy as well as T-DM1. This was unique at that time because it did allow patients who had brain metastases that were untreated as long as they were clinically stable and did not require urgent treatment to be enrolled on that clinical trial. What they found was individuals who received tucatinib, again, this was trastuzumab capecitabine+/-tucatinib, the risk of progression or death was reduced by 46%, the risk of death was reduced by 34%, and the risk of progression or death in patients with brain metastases was reduced by 52%. The progression-free survival at 1 year was higher with the use of tucatinib at 20% and overall survival at 2 years was higher at 18%. The main side effects when you think of adverse drug effects associated with the tucatinib arm were similar to the ones that you would see in individuals who are receiving capecitabine; diarrhea, hand-foot syndrome, nausea, and fatigue. The next trial I was going to mention is the NALA trial which was a randomized phase 3 trial evaluating the use of neratinib, a tyrosine kinase inhibitor, in combination with capecitabine versus lapatinib in combination with capecitabine in patients who had HER2+ metastatic breast cancer. What that trial demonstrated was that there was a significant improvement in progression-free survival, and that was when you looked at 6 and 12 months progression-free survival, the rates were 47% versus 37%, and in the 12 months was 28% versus 14%. Also, there was a trend towards overall survival. At 6 months, that was 90% versus 87% and at 12 months, that was 72% versus 66%. The next trial I'm going to talk about is the SOPHIA trial, which is a phase 3 trial that looked at the combination of margetuximab in combination with chemotherapy versus trastuzumab in combination with chemotherapy. The chemotherapy that was utilized was based on the selection of the oncologist. There were several options: eribulin, gemcitabine, vinorelbine, and capecitabine were options for combination for those. With that, the patients were required to have at least 2 prior lines of anti-HER2-directed therapy for that clinical trial. The results of that trial showed that was patients who received a combination of margetuximab in combination with chemotherapy did show improvement in progression-free survival; when you looked at the safety of that use of that monoclonal antibody was comparable to trastuzumab.

Data from the HER2CLIMB, NALA, and SOPHIA trials that led to the FDA approval of respective agents in the setting of HER2+ metastatic breast cancer.

Recently Approved Regimens for HER2+ Metastatic Breast Cancer 

 I would say for the DESTINY-Breast03 trial, the results have been very exciting in looking at the substantial improvement and progression-free survival as well as looking at the overall risk in reduction of progression of disease. Based on that, when you look at these 2 drugs, both being compared in the second-line setting, to say what should be our consideration when someone is progressing on trastuzumab and a taxane or had a recurrent metastatic event less than 6 months out from having received trastuzumab and a taxane type combination. Based on this data, the T-DXd has moved up into the preferable drug in the second-line setting. I will say personally, I do have a conversation; I always think it's so important to involve patients in the conversations about looking at efficacy of drugs, but also the side effects and safety of the drug as well. In discussing this study and the potential side effects of the 2 different agents, I do feel that efficacy-wise, T-DXd is preferable for second-line therapy, but there are sometimes patients who have had difficulties with GI side effects. I would say the nausea is one that requires a little more oversight and treatment, whereas for T-DM1, nausea is not typically much of a problem to manage. I do have some patients who might choose if they've had a difficult time with nausea before they might be a little bit leerier of use of that drug. I think it's important to make them aware also of the risk of interstitial lung disease in pneumonitis with this drug. There have been deaths associated with that, and so I think it's important for patients to understand the severity of the potential risks. Thankfully this trial has shown us that 10% rate for that when they're being watched very closely for signs of development; I think as guidelines have come out to better inform medical oncologists on how to address the drug-induced pneumonitis, that has been very helpful. That idea that from the time we see it, we put that drug on hold and there's very clear guidelines as how to address that. That was reflective in this trial, that there were no grade 4/5 events associated with that. I think that's because of us being better informed, but those are discussions that I have with patients as I'm looking at those. Thankfully patients who have HER2+ metastatic breast cancer, often live many years and so choosing 1 agent in the second-line setting doesn't necessarily mean you can't use the other agent in the next line. Most of these individuals would anticipate to go on and receive another line of therapy. I do think based on efficacy and the ability to manage the side effects, T-DXd would be my preferred second-line agent.

Since the DESTINY-Breast03 trial data has come out, that has impacted guidelines. The NCCN [National Comprehensive Cancer Network] guidelines now lists trastuzumab deruxtecan [T-DXd] as the preferred regimen. That gives an NCCN category of evidence of a level 1. Also, T-DM1 trastuzumab emtansine is still listed as a potential second-line option, but it's listed as the other recommended regimen with the level of data being 2A. Trastuzumab deruxtecan does have FDA [Food and Drug Administration] approval. Originally it received its approval beyond after 2 prior lines of therapy but then based on the most recent trial data, it has also received approval for second-line therapy as well.

Focusing on real-world treatment selection, Cynthia Lynch, MD, considers how the DESTINY-Breast03 trial impacted her practice and broader treatment guidelines.

Impact of DESTINY-Breast03 on Real-World Management of HER2+ mBC

 When you look at the total percentage of adverse drug events, about 98% of patients in the T-DXd group had drug-associated adverse event compared to 86.6% in the T-DM1 group. Of those, when you look at grade 3/4 adverse events, that occurred in about 45% of individuals with T-DXd versus 39.8% in those with T-DM1. An adverse event of special interest is the interstitial lung disease, or pneumonitis, associated with T-DXd. This was an adverse event that was known from the prior studies, and so this was of special interest. That did occur in approximately 10.5% of patients in the T-DXd group versus 1.9% in the T-DM1 group. When you look at the grade of those, the majority of those were a grade 2. Thankfully there were no grade 4/5 adverse events. It felt that perhaps it was because of being aware of this as the potential adverse event; medical oncologists were more aware of how to respond to that. Also, there was a lot of direction from the trial itself in how to address the appearance of drug-induced pneumonitis or interstitial lung disease. The median time to onset for interstitial lung disease was 168 days. It did result in discontinuation of therapy in about 8% of patients with T-DXd versus 1% in patients with T-DM1. The most common side effects associated with the T-DXd would be nausea, fatigue, vomiting, some alopecia as well, that was at 36%. There was some neutropenia and thrombocytopenia as well. Looking at always a concern of oncologists in individuals who are on trastuzumab type-directed therapies is looking at reductions in ejection fraction and that occurred in about 2.3% of individuals on the T-DXd versus 0.4% on the T-DM1 group.

In clinical practice, the most common side effects that I see associated with trastuzumab deruxtecan are the GI side effects of nausea. Typically, when I’m utilizing that drug, I do treat it as a highly emetogenic type regimen where I would be giving consideration for a drug such as palonosetron as well as Emend [aprepitant] along with the steroid. I have found that with the use of that combination of agents, patients typically do very well with that as long as they have as-needed rescue medicines too. I have had a few patients that have been a little more challenging, sometimes requiring dose reductions to address that, but I do think if oncologists are ready and understanding that it is a drug that can have a little bit higher level of nausea associated with it, it is something that can be very manageable. Fatigue, that’s so common with so many agents. I wouldn’t say this one necessarily causes more fatigue than others but that’s present. There can be some hair loss associated with it, that’s important for patients to be aware of. I will say overall when you look at cell counts, when you look for neutropenia, thrombocytopenia, and anemia, those are all fairly low occurrences that we would see associated with this drug. In fact, I’ve been impressed at how high the hemoglobins tend to run in patients who are receiving that agent.

With the drug trastuzumab deruxtecan, I’ll just emphasize that there is that risk of pneumonitis and interstitial lung disease. There have been deaths associated with that, so it is very important to be aware of that as a potential side effect to be sure to educate your patients about signs and symptoms of pneumonitis so that they can report that early. Also, to be aware, to be very quick to place that drug on hold if there is evidence on imaging of the development of pneumonitis there. I think that’s one of the things that really can help to protect patients who are receiving that agent; just being that heightened awareness of the risk of pneumonitis and jumping on treatment for it or holding drug at the first signs of its development.

Insight on the safety events observed in the DESTINY-Breast03 trial and how this translates to real-world adverse event management in HER2+ metastatic breast cancer.

HER2+ mBC: Safety Outcomes From the DESTINY-Breast03 Trial

 DESTINY-Breast03 trial was a phase 3 randomized trial that was comparing trastuzumab deruxtecan [T-DXd] to trastuzumab emtansine [T-DM1] in the second-line setting, following the use of trastuzumab containing regimen and a taxane. That trial looked to ask that question of, ‘What should be the second-line therapies? What should we be considering as a second-line therapy after patients have progressed on a trastuzumab-containing regimen and a taxane?’ That did include individuals who were metastatic and were progressing on that combination. It also included individuals who had had a metastatic recurrence or unresectable recurrence within 6 months of having completed their neoadjuvant or their adjuvant chemotherapy. As I mentioned previously, the background to that was that previously through the AMELIA trial, that is where T-DM1 had gotten its approval for usage and became the standard second-line therapy. How they differ is, T-DXd is one of the drug antibody conjugates, so it has trastuzumab with a linker molecule attached to a cytotoxic agent. In the case of trastuzumab deruxtecan, it is a topoisonorase1 inhibitor. It’s a little bit different from T-DM1; what we term the payload, how much chemotherapy is packed on there, that ratio is higher with T-DXd than what we have with T-DM1. How that drug works is, sometimes people use the term a smart bomb; it uses the antibody to deliver the chemotherapy directly to those HER2 overexpressing cells. Then there also is some dispersion amongst the cells, even in that region as well that can have cytotoxic effects too. Just to talk a little bit more about the trial design itself; when you look at the randomization, the patient characteristics, and demographics of individuals in each of the two groups, it was well balanced. About a little under ½ of patients on both arms of the trial had received prior chemotherapy in the metastatic setting; about 60% of patients in each of the arms of the trial had received prior pertuzumab. Patients who had brain metastases were allowed to enter the trial, however they had to have stable asymptomatic disease or been previously treated. The percentages for that on each of the group is about 23.8% of patients on the T-DXd group had brain metastases whereas 19.8% on the T-DM1 arm had brain metastases. The overall results showed a 72% reduction in risk of progression compared to looking at that of T-DM1. At 12 months, when you look at the progression-free survival at that point, that was 75.8% with T-DXd versus 34% with T-DM1; a substantial improvement in those percentage of patients who were alive and without progression at 12 months between those 2 arms. As far as investigator-assessed median progression-free survival, it was 25.1 months with T-DXd versus 7 months with T-DM1. Again, a substantial statistically significant improvement in the investigator-assessed progression-free survival. Also, when you look at overall responses seen for T-DXd, it was 79.7% versus 34.2%. There were complete responses seen with around 16% for the T-DXd group versus 8%, so almost a doubling of the complete responses seen with T-DXd. When you look at brain metastases, the median progression-free survival of individuals who had brain metastases was 15 months for T-DXd versus 3 months for T-DM1. If you look at overall response rates, it was 67% versus 20% in favor of T-DXd, and then also they assessed for intracranial responses to therapy where there was an overall 63.8% intracranial response versus 33.3% intracranial response for T-DM1. Again, very significant responses in brain metastases. There were complete responses seen in the brain as well, that was 27.8% versus 2.8% again, in favor of T-DXd.

Expert perspectives on the DESTINY-Breast03 trial, which compared T-DXd to T-DM1 in the setting of relapsed/refractory HER2+ metastatic breast cancer.

DESTINY-Breast03: T-DXd in HER2+ Metastatic Breast Cancer 

 My name is Dr Cynthia Lynch, and I’m a medical oncologist specializing in breast cancer with Cancer Treatment Centers of America, which is now a part of City of Hope. I'm going to talk a little bit about HER2+ metastatic breast cancer, and some of the treatments that are currently available.

For the current standard for individuals who have metastatic HER2+ breast cancer in the frontline setting, we would typically think of HER2-directed therapies in combination with a taxane. That would entail the use of trastuzumab and pertuzumab along with either docetaxel or paclitaxel. There is some data out there that supports the use of using HER2 targeted agents in combination with an endocrine therapy in patients who have hormone receptor-positive disease. However, in general I would typically favor the use of combining the antibodies along with a taxane, then subsequently if a patient is doing well on their taxane therapy, once they have completed several [6] cycles and they're doing well, then we would typically drop off the taxane, the cytotoxic agent, and continue the antibodies. At that point if someone is hormone receptor-positive, then we would add back in an endocrine therapy.

For many years now, for second-line metastatic HER2+ breast cancer trastuzumab emtansine [T-DM1] was considered the standard of care. That was based on a prior trial called the AMELIA trial that showed progression-free arrival of around 6-7 months. That was the basis of that becoming the standard of care after an individual has progressed on trastuzumab containing regimen and taxane, from there we would then we would be stepping to T-DM1. There are other drugs that are also can be utilized; the landscape has changed quite a bit over the past 2 years for HER2+ breast cancer. We do now have data looking at use of tucatinib in combination with trastuzumab and the oral chemotherapy capecitabine. One of the drugs I'll be talking a little bit more about today would be trastuzumab deruxtecan, or T-DXd, as well. I will say that prior to these drugs coming on the scene, previously we would be looking at doing combinations of trastuzumab with various chemotherapies, and there was also data for capecitabine and lapatinib.

Expert perspectives on novel management of HER2+ metastatic breast cancer in the context of recent clinical trials and FDA approvals.  

Cynthia Lynch, MD

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