Selecting and Sequencing Therapy for HER2+ Breast Cancer


Shared insight on the optimal sequencing of therapeutic agents for patients undergoing treatment for HER2+ metastatic breast cancer.


Neil Iyengar, MD: I’d like to turn it over to Dr Dolezal and ask her to speak a bit about how the guidelines for treating metastatic breast cancer in the HER2-positive space have recently changed.

Milana Dolezal, MD, MSci: Thank you so much, Neil. I appreciate that nice overview of the landscape. You outlined nicely all the different ways we can target the HER2 family, both from outside of the cell, in terms of the monoclonal antibodies and the antibody-drug conjugates. I like to think of those sort of as a magic bullet where you’re bringing chemotherapy directly into those HER2-positve or HER2-low, which is a whole different discussion, types of cancer cells, as opposed to the tyrosine kinases that work from more the inside of the cell on that signaling pathway. They do have what we call blood-brain barrier penetration. That’ll be relevant for the cases that we discuss today.

In terms of the guidelines, the pandemic has shown an explosion of some new agents in the HER2 space that have offered a lot more options in the third, fourth, fifth line of treatment of metastatic HER2-positive breast cancer. You talked about neratinib, which we have used in the extended adjuvant setting, but that was also approved in the metastatic setting in combination with Xeloda [capecitabine]. You mentioned tucatinib, which is another tyrosine kinase inhibitor that was also approved during this pandemic, in April of 2020. Even though everybody was at home, the FDA was still busy looking at these drug approvals.

In terms of the landscape that’s changed, we’ve had a lot of updates in these lines of therapy. Typically we’ve done the first line with CLEOPATRA, which has been a combination of chemotherapy Taxotere [docetaxel]with pertuzumab, which is a HER dimerization inhibitor, in addition to Herceptin [trastuzumab]. That overall survival continues to be impressive in terms of patients living past 4 to 5 years. In the second-line setting, typically we had done T-DM1 [trastuzumab emtansine], and that’s another different type of antibody-drug conjugate. That’s a HER2 antibody with a Herceptin-like backbone, but it is linked by a cleavable linker to a type of chemotherapy called maytansine that gets into those cancer cells. It has a smaller antibody-to-drug ratio. Typically we’ve done that in the second-line setting.

Then in the third-line setting, there have been different approvals, including a different antibody-drug conjugate. In the second and third-line settings there is also a tyrosine kinase inhibitor option. Really when you look at the guidelines, it’s the patient selection and personalized care depending on where their disease is. I like to think of it like we’re not just cooks anymore. We’re sort of a chef in terms of how we personalize our treatments based on where a patient’s disease is and how much disease they have. That’s relevant when we talk about this second-line setting, now with more recent data, and third-line settings in terms of patients who have what we call visceral metastases.

What that means is patients who have HER2-positive breast cancer that’s gone to either their liver or their lungs, and maybe it hasn’t hit the brain yet. In those kinds of patients, they might present with pain, they might present with difficulty breathing, they might present with abnormal liver enzymes, or other types of adverse effects of their cancers affecting those areas. In that case, we might choose one therapy over another because we want to shrink those tumors quickly, we want the patient to feel better. Maybe their performance status, which is a measure of how well they’re doing, how much time are they spending in bed? Are they able to do their activities of daily living? That is a factor that we think about when we treat patients. Then the other side of that is, has this cancer gone to their brain yet? We know that HER2-positive breast cancer has a proclivity for going into the brain, and that hasn’t been something that we’ve been able to tackle very well with the larger monoclonal antibodies. Certainly, radiation therapy, gamma knife stereotactic, and even whole brain radiation has been an option.

The guidelines are evolving in terms of this first-line, second-line, third-line setting. In the second- and third-line setting, tucatinib, which is a tyrosine kinase inhibitor that’s HER2 specific, as opposed to lapatinib and even neratinib, which you had mentioned before, that are more pan-HER family and they have a different adverse effect profiles, specifically hitting the EGFR/HER1, where you have more diarrhea. Tucatinib is now approved in the second and greater line metastatic advanced HER2-positive space. That is in combination with oral chemotherapy Xeloda, in addition to Herceptin IV [intravenous]. That is based on the HER2CLIMB study. We’ll talk a little more about that and the population in that study. That study did include different buckets of patients, but it included patients who had asymptomatic brain metastases. About 26% of the patients in that clinical trial had a baseline brain MRI as part of their staging and screening for the clinical trial. That’s how the brain metastases were discovered. We’ll dig a little deeper into that clinical trial and what patient population we would use that agent in. It’s a great new option that’s available.

In terms of other agents out there, there are different antibody-drug conjugates than T-DM1 that I had mentioned, which typically we use in the second-line setting after progression on a CLEOPATRA-type regimen. The one agent I’m talking about is in HER2, and that’s an antibody-drug conjugate, but it is linked to a different cytotoxic chemotherapy in the class of irinotecan and is an agent that patients with breast cancer haven’t seen much in their treatment trajectory. We have used it very frequently in gastrointestinal malignancies. Irinotecan has been a core agent there. This is one of the metabolites of irinotecan, but because it’s actually bound to the HER2 backbone antibody, the chemotherapy portion is only getting released into the cancer cells, and so by default, there’s not as much systemic throughout the body toxicity and less diarrhea and some of the adverse effects that we expect with that agent. That’s an exciting newer agent that’s also been available in the third-line space, typically in terms of the original FDA approval, and that was based on a phase 2 study with very impressive overall response rates. What that means is that the tumors are shrinking, and we can see that on scans.

More recently, that agent has shown very impressive results in a clinical trial that looked at HER2 in addition to T-DM1 in a head-to-head in the second-line HER2-positve setting. That was originally presented at ESMO [European Society for Medical Oncology annual meeting]. The data have continued to be very impressive in terms of the progression-free survival and a P value that I don’t think I’ve ever seen of 10 to the minus 22, which is pretty amazing when you start having data like that, especially given that the comparator arm was also a very active regimen per the EMELIA trial in the second-line setting, and overall survival hasn’t yet to be reached. The hazard ratios were so impressive that there was almost a 70% improvement in progression-free survival, and also very impressive response rates.

That gives you a bit of meat on the bones. This has even been incorporated into our NCCN [National Comprehensive Cancer Network] guidelines in terms of the first line, second line, and third line. That’s where the patient selection comes in as to where is the disease, is there disease in the liver and the lungs, is there disease in the brain in terms of needing to protect the brain and treat brain metastases, and how do we do that? We’ll talk a bit about some of the adverse effects I alluded to, like diarrhea. The other one that is important to call out in HER2 is interstitial lung disease. That’s something that can manifest as a cough or shortness of breath. Fortunately, during COVID-19, we’ve been very astute at picking up any sort of respiratory symptoms. But even for asymptomatic patients, there are guidelines in terms of how to monitor those patients, and when we use steroids and discontinuation of that particular agent. I know I spoke a lot about the landscape and the changing guidelines, and I think it’s really exciting to have all of these new options available for patients who are living much longer with this disease, including with brain metastases.

Transcript edited for clarity.

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