Convenient therapy selection and sequencing


Andrew Seidman, MD: It might be a good time to try to approach the unknown, and Bill is always the best person to do it with. Bill, in the second frame and beyond the line, so someone had CLEOPATRA treatment, and now based on DESTINY-Breast03, this patient would most likely have trastuzumab deruxtecan [T-DXd], where do we go next? What does the third line look like and do we have more than one option? How do we think about this?

William Gradishar, MD: We have many options as you know. I know you were referring to your favorite reading material earlier, and as you know on this guideline there are a number of different options…. But the question could be better posed: do we have proof that one sequence is better than another? And therein lies the lack of data. I think when you phrased the question, people get CLEOPATRA, maybe they got T-DXd as the second line, and then what happens? You have to remember that the tucatinib trial was a randomized phase 3 trial with a survival advantage. It didn’t take into account patients who had previously received T-DXd, but I would consider that to be pretty strong evidence that this would be a reasonable approach. Are there other options? Sure. You can give up chemotherapy, continue trastuzumab with a variety of agents, you can give neratinib, which we talked about earlier. They wouldn’t be my first choices. I would tend to use the HER2CLIMB regimen preferably before that, but the caveat is that not everyone can tolerate the HER2CLIMB regimen either, and that’s complicated with 3 drugs.

Andrew Seidman, MD: VK, if this patient progressed on T-DXd as a second-line therapy after receiving first-line CLEOPATRA therapy, and at the time of progression you had vague suspicions that she might have CNS [central nervous system] disease, and you had an MRI and she had 2 subcentimeter lesions, and it’s not even sure they were causing her symptoms, are you 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 this asymptomatic oligometastatic patient? Or will you give T-DM1 [trastuzumab emtansine]?

Vijayakrishna Gadi, MD, PhD: It’s a good question. There are 2 scenarios here. Let’s say it’s controlled below the neck, in which case I want to keep the previous agent and maybe target those few CNS metastases with stereotactic radiosurgery. The other scenario is of course that it progresses below the neck and above the neck, and that’s scary because below the neck progression is also highly correlated with additional brain metastases. So yes, maybe target the CNS directly with stereotactic surgery and radiosurgery and then switch to the HER2CLIMB regimen for that patient. Or better yet, if we have a clinical trial, explore some combinations in that context. I could do both.

Andrew Seidman, MD: Stephanie, once upon a time there was a study called LANDSCAPE, where a group of very brave or insane European researchers gave capecitabine and lapatinib to patients with brain metastases before irradiating them, just to see if it worked. There was evidence of effectiveness, and many of these patients needed irradiation. I assume this is the same case, is there anyone here who would consider not irradiating the asymptomatic 5mm brain metastasis because we have enough confidence in CNS penetration and efficacy?

Stephanie Graff, MD: I think it’s important to have data like LANDSCAPE that you can keep in your pocket, because of course every once in a while you have a brain metastasis that just isn’t amenable to radiation, or a patient that categorically refuses it. Knowing that you have agents entering the CNS, that there is data that you can rely on to make your decision is invaluable. But in short, no. I would offer SRS to this little brain injury, or use one of the newer agents like tucatinib, where we have overall survival and brain control data. With our newer agents who have stronger CNS data, I would be more comfortable than with some of the older agents where the data wasn’t as strong.

Andrew Seidman, MD: Tiffany, in the absence of randomized data comparing T-DM1 to the HER2CLIMB regimen, is there any patient characteristic that might point you in one direction or the other? And not to direct the witness, but a patient with inflammatory bowel disease or irritable bowel syndrome, the patient who has pre-existing neuropathy from his previous taxane. Are there any other features that might influence your choice?

Tiffany Traina, MD: I think you brought up a point that reflects how we approach oncology and the care of our patients in general, and that’s very personalized. Everyone comes to the table with a unique set of individual comorbidities and priorities. We know the GI [gastrointestinal] toxicity is a concern with oral TKI [tyrosine kinase inhibitor] in the HER2CLIMB regimen, and yet we have ways of using prophylaxis and managing that, but I think those are discussions to be had with our patients. I might be more inclined to lean towards T-DM1 as part of someone who has tremendous difficulty with gastrointestinal toxicity and diarrhea. In contrast, someone who has a pre-existing neuropathy, LFT [liver function test] abnormal, difficulty with blood counts and thrombocytopenia, I might be more inclined to think about the HER2CLIMB diet.

Andrew Seidman, MD: Stephanie, given the other therapies we’re using in later lines, where, if ever, do you fit with agents like neratinib, lapatinib, margintuximab, and other FDA-approved agents?

Stephanie Graff, MD: Excellent question. I think they all have their place. In the current landscape, I still don’t know if I really know what it is. Approved therapies of trastuzumab deruxtecan and tucatinib continue to fight to move [to earlier lines]. I am fortunate to practice in an environment where I had these agents on trial earlier. I think we’re seeing patients stay longer on trastuzumab deruxtecan and tucatinib. It also raises the question of what we do now with T-DM1, because if I move trastuzumab deruxtecan earlier in my treatment portfolio or my treatment sequence, when do I put T-DM1 back in the sequence ?

I think HER2-positive disease, because of the pattern of metastases – visceral metastases, brain metastases – it’s unclear whether patients are going to receive fifth, sixth or seventh line treatment, especially after heavy pretreatment and long treatment times with these highly effective HER2 antibody-drug conjugates. [These are] highly effective third-generation therapies targeting HER2. [It’s hard to know if] I will have to choose between neratinib, lapatinib, and margetuximab in this next line of treatment. But the answer is, somewhere in there, and I’m probably, at this point, choosing based on the drugs we use them in combination with and the toxicity profile relative to the patient I’m looking at and their constellation of adverse effects.

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

Stephanie Graff, MD: To correct.

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

Transcript edited for clarity.

Martin E. Berry