Andrew D. Seidman, MD: This discussion did answer a few of the audience questions that came in that were about specific patients with brain mets [metastases]. They had SRS [stereotactic radiosurgery]. Hopefully we addressed some of those questions because there were a lot on that theme.

One of the questions was do you think we’ll routinely adopt subcutaneous trastuzumab on a regular basis in the future in the metastatic setting? I guess you could extend that to the combination of subcutaneous trastuzumab and pertuzumab. Any thoughts on that? Do patients prefer this, or do they like spending more time in your infusion room chatting with the nurses?

Mark Pegram, MD:We did it, particularly in the COVID-19 era. We did it deliberately. We strongly encouraged the shorter infusion time of the subcutaneous route of administration for antibodies.

Andrew D. Seidman, MD: Do you all routinely use endocrine therapy in patients on antibody-drug conjugates [ADCs] when you have triple-positive metastatic breast cancer, ie, trastuzumab emtansine [T-DM1] or trastuzumab deruxtecan [T-DXd]? Are there scenarios in your practice where you would find the occasion to give endocrine therapy at the same time as an ADC? Aditya, do you want to lead with that?

Aditya Bardia, MD, MPH:It’s a good question about a patient with hormone receptor-positive, HER2-positive disease who’s either getting T-DM1 or trastuzumab deruxtecan, be it DESTINY-Breast03 or 01, and in EMILIA as well. Theoretically, there was some concern that if you combine chemo [chemotherapy] with endocrine therapy, it could impact the efficacy of chemotherapy, and ADCs have a cytotoxic payload, but the evidence is not that strong. At least in the adjuvant setting, the ATTEMPT trial did allow T-DM1 plus endocrine therapy. It’s an unknown question currently. We’ve not seen evidence to suggest that if you combine endocrine plus ADC the outcomes are going to be better than ADC alone. If a patient is doing well on an ADC, I would not rock the boat. I would just continue the ADC. The situation where I would consider endocrine therapy would be in a patient who’s getting trastuzumab and pertuzumab as maintenance therapy in the first-line setting. There I would feel comfortable adding endocrine therapy, but with an ADC, until we have more evidence I’m not compelled to add endocrine therapy.

Andrew D. Seidman, MD: Here’s an interesting question. Ruta, I’ll let you lead with this one. In what setting does the faculty still use lapatinib or neratinib? If you say you don’t, that’s OK too, but where is the niche for the first and second HER2 TKIs [tyrosine kinase inhibitors]?

Ruta Rao, MD:In the metastatic setting, I’ll be honest, I have not used lapatinib since I don’t remember when. Neratinib, based on the NALA trial that we covered, certainly does have a role. I would consider it in later lines of therapy when patients have been through the CLEOPATRA regimen and both of the ADCs that we’ve discussed, the HER2CLIMB regimen. It may be something we want to do at that point. I’d be curious to see what the others have to say.

Andrew D. Seidman, MD: I would just say that occasionally you’ll have a patient who’s on her ninth regimen. When you’ve been through your usual NCCN [National Comprehensive Cancer Network] algorithm through the first 3 or 4 lines, you’ve got people who aren’t in visceral crisis. Some of us get creative, and we may want to recycle agents or similar agents that we used in earlier lines later. So I might occasionally find a patient where I would think about using neratinib or lapatinib, perhaps who had prior tucatinib, but those situations haven’t come up much. Mark, Aditya, any use of those older TKIs in your practice currently?

Mark Pegram, MD:I would put such a patient on a clinical trial at our center all day long and twice on Sundays instead of either one of those choices. Neratinib is a difficult drug to take. It has a low therapeutic index. Remember, this is a palliative disease setting with metastatic HER2+ breast cancer. None of these patients except maybe some of the de novo oligometastatic cases, and maybe the rare exceptional responders, none of the rest have curable disease. You don’t want make people feel sicker with their treatment than they would from the underlying disease itself, and neratinib drops to the bottom of that list, especially when combined with a fluoropyrimidine. All bets are off in terms of diarrhea with that combination. I don’t have any enthusiasm for recycling TKIs. I’d rather see a patient on a good clinical trial.

Andrew D. Seidman, MD: Before we go to the next polling question, there have been several questions relating to interstitial lung disease [ILD]. We heard about a patient who’s a smoker, but her PFT [pulmonary function test] was still preserved, and the therapeutic option was to choose trastuzumab deruxtecan. Do you guys ever think about performing PFTs in patients where you have some concern about pulmonary reserve? Do you get pulmonary consultations? Is there a PFT parameter that might influence your choice of therapy? Aditya, do you want to lead with that?

Aditya Bardia, MD, MPH:I would say all of the above. If there’s a patient I’m concerned about, and we do this in clinical trial as well, it’s reasonable to get the PFT, and particularly looking at the diffusing capacity because that is what can be impacted by T-DXd, or trastuzumab deruxtecan, and getting pulmonary consult is very reasonable. The key in someone who has some problem with the lung or who you’re worried about, is close monitoring. We see clearly that in DESTINY-Breast01 where the team was not that accustomed to looking for ILD, as opposed to DESTINY-Breast03 where this was an adverse effect that was closely monitored, you can see a difference in terms of incidence of grade 4, grade 5 toxicity. In a patient who’s on trastuzumab deruxtecan, when they get their restating scans, you’re not just looking at disease control, but you’re also looking at early signs of interstitial lung disease. If present, you can intervene early.

Andrew D. Seidman, MD: That’s a great way to transition to our final polling question, and then we’re going to kind of wrap up with a high-level view from each of you about sequencing, and then perhaps a discussion about supportive care, quality of life, and toxicity management. The fifth polling question is somewhat ideological perhaps, and it certainly can be evidence-based. When do you use the most active regimen in your patients? Do you choose to go strong and go early, so up front as early as indicated? If you have a differentiation between regimens, are you inclined to start with the most active regimen, or are you more inclined to save it for a later line? It’s an interesting question, not just for breast cancer, but in the approach to other malignancies as well. Some of you might have algorithmic thinking in terms of clinical trial data that have emerged. Some might think about this more based on tumor kinetics, but so far, we have unanimity here as the responses come in. There’s always going to be somebody brave who doesn’t agree with the first 21 users, so you don’t all have to jump on the bandwagon. So far we’ve got a strong preference to lead with your best foot, using your most active regimen as early as possible. Ruta, why don’t you lead with that? Is this your approach in HER2+ breast cancer? You want to lead with your most active regimen, and then maybe the second batter in the lineup should also have an excellent batting average? How do you think about this?

Ruta Rao, MD:Yes, absolutely. I would also choose A, to lead with the most active regimen up front. I think we’ve seen both from the CLEOPATRA trial with the significant improvement in overall survival, and even in the DESTINY trial now with a significant improvement in progression-free survival, that these patients can do really well for a long time, especially when we give them our most active regimens first.

Andrew D. Seidman, MD: Does anybody disagree with the 100%, or can we move on?

Mark Pegram, MD:The other point to make Andy is that if you look at data on what fraction of patients move from first line to second line to third line, etc, in an academic center, there’s about a 10% drop line by line, where patients drop out and no longer have ability to take further treatment. In the community, it’s probably double that based on claims data. If you’re going to save your best drug for a rainy day, that rainy day may never come because the patient may get too sick from their underlying disease to ever have the opportunity to take the best treatment available. That’s another reason why it’s wise to use your best drugs first.

Transcript edited for clarity.