HER2+ mBC: Practical Selection and Sequencing of Therapy


Comprehensive discussion on how oncologists may practically select and sequence novel treatment approaches in HER2+ metastatic breast cancer.


Andrew Seidman, MD: This may be a good time to try to address the unknown, and Bill is always the best person to do that with. Bill, in the second and beyond-line setting, so someone has had CLEOPATRA therapy, and now based on DESTINY-Breast03 that patient most likely would have trastuzumab deruxtecan [T-DXd], where do we go next? What’s third line look like, and do we have more than one option? How do we think about this?

William Gradishar, MD: We have lot of options as you know. I know you were making reference to your favorite reading material earlier, and as you know on that guideline, there are number of different options…. But the question could be better posed as, do we have evidence that one sequence is better than another? And therein lies the lack of data. I think as you framed the question, people are getting CLEOPATRA, they may have gotten T-DXd as their second line, and then what comes next? You have to remember that the tucatinib trial was a randomized phase 3 trial with a survival benefit. It didn’t look at patients who had gotten T-DXd before, but I would view that as a pretty strong piece of evidence that that would be a reasonable approach. Are there other options? Of course. You could switch out chemotherapy, continue trastuzumab with a variety of agents, you could give neratinib, which we talked about earlier. These would not be my first choices. I would tend to use the HER2CLIMB regimen preferentially before then, but the caveat is not everybody can tolerate the HER2CLIMB regimen either, and it’s complicated with 3 drugs.

Andrew Seidman, MD: VK, if that patient progressed on T-DXd as her second-line regimen after having had CLEOPATRA therapy in the first line, and at the time of progression, you had some vague suspicions she might have CNS [central nervous system] disease, and you happened to grab an MRI and she had 2 subcentimeter lesions, and it’s not even sure they were causing her symptoms, are you’re going to send her for stereotactic radiation [SRS]? Are you going to try the HER2CLIMB [regimen] and see if you get a CNS response in that asymptomatic oligometastatic patient? Or are you going to give T-DM1 [trastuzumab emtansine]?

Vijayakrishna Gadi, MD, PhD: That’s a good question. There are 2 scenarios here. Say she is controlled below the neck, in which case I want to retain the previous agent and maybe target those few CNS metastases with stereotactic radiosurgery. The other scenario of course is she is progressing below the neck and above the neck, and that’s frightening because below the neck progression is strongly correlated with additional brain metastases as well. So, yes, maybe target the CNS directly with stereotactic surgery and radiosurgery, and then move on to the HER2CLIMB regimen for that patient. Or even better, if we have a clinical trial, explore some combinations in that setting. I might do both.

Andrew Seidman, MD: Stephanie, once upon a time there was a study called LANDSCAPE, where a group of very brave or foolish European investigators gave capecitabine and lapatinib to patients with brain metastases before radiating them, just to see if it worked. There was some evidence of efficacy, and many of those patients needed to be radiated. I guess it’s the same case, is there anybody here who would consider not radiating the 5mm asymptomatic brain metastasis because we have enough faith in CNS penetration and efficacy?

Stephanie Graff, MD: I think it’s important to have data like LANDSCAPE that you can hold in your pocket because of course every once in a while you have a brain metastasis that simply is not amenable to radiation, or patient who outright refuses it. Knowing that you have agents that penetrate the CNS, that there are some data that you can rest your decision-making on is valuable. But in short, no. I would want to offer SRS to that little brain lesion, or use one of the newer agents like tucatinib, where we have overall survival and brain control data. With our newer agents that have stronger CNS data I’d be more comfortable than with some of the older agents where the data weren’t quite as strong.

Andrew Seidman, MD: Tiffany, in the absence of randomized data comparing T-DM1 to the HER2CLIMB regimen, is there a patient characteristic that might steer you in one direction or the other? And not to lead the witness, but a patient with inflammatory bowel disease or irritable bowel syndrome, the patient who has preexisting neuropathy from her prior taxane. Are there other characteristics that might influence your choice?

Tiffany Traina, MD: I think you raised a point that reflects how we approach oncology and caring for our patients overall, and it’s very personalized. Everybody comes to the table with a unique set of comorbidities and individual priorities. We know GI [gastrointestinal] toxicity is a concern with the oral TKI [tyrosine kinase inhibitor] in the HER2CLIMB regimen, and yet we have ways to use prophylaxis and manage that, but I think these are discussions to have with our patients. I might be more inclined to lean toward T-DM1 in the setting of somebody who has tremendous difficulty with GI toxicity and diarrhea. In contrast, somebody who has preexisting neuropathy, LFT [liver function test] abnormalities, difficulty with blood counts and thrombocytopenia, I may be more inclined to think about the HER2CLIMB regimen.

Andrew Seidman, MD: Stephanie, considering other therapies that we use in later lines, where if ever, do you fit in agents like neratinib, lapatinib, margetuximab, and other FDA-approved agents?

Stephanie Graff, MD: Great question. I think that they all have a place. In the current landscape, I still don’t know if I really know what that is. The approved therapies of trastuzumab deruxtecan and tucatinib keep fighting to move [to earlier lines]. I am lucky to practice in an environment where I have those agents on trials earlier. I think that we’re seeing patients stay on trastuzumab deruxtecan and tucatinib longer. That also begs the question about what we’re doing with T-DM1 now because if I am moving trastuzumab deruxtecan earlier in my portfolio of treatment or sequence of treatment, when am I putting T-DM1 back in the sequence?

I do think that HER2-positive disease, because of the pattern of metastasis—visceral metastasis, brain metastasis—it’s hard to know if patients are going to get fifth-, sixth-, seventh-line therapy, especially after heavy pretreatment, and long durations of therapy with these very effective HER2 antibody-drug conjugates. [These are] very effective third-generation HER2-targeted therapies. [It’s hard to know if] I am going to get to pick between neratinib, lapatinib, and margetuximab in that next line of therapy. But the answer is, somewhere in there, and I am probably, at that point, choosing based on the medications we are using them in combination with and the toxicity profile relative to the patient I am looking at and their constellation of adverse effects.

Andrew Seidman, MD: And sometimes when you’re at the fourth, fifth, and sixth line in a regimen, there may be cytotoxic partners for trastuzumab that you haven’t explored that are mechanistically different.

Stephanie Graff, MD: Correct.

Andrew Seidman, MD: It is, I don’t want to say an embarrassment of riches, but we have lots of options.

Transcript edited for clarity.

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