Sara Tolaney, MD, MPH: Thank you. This next case is an example of things to look out for in terms of adverse effects and to foster some discussion about optimal management of toxicity. This is a 43-year-old woman who presented with de novo metastatic disease. She presented with a palpable breast mass that got biopsied with noted adenopathy and then had staging scans, and was found to have metastasis predominantly to bone and lymph nodes, and was ER [estrogen receptor]-negative, HER2-positive. She got upfront weekly paclitaxel with trastuzumab and pertuzumab, was on that for 6 or 7 cycles, had a tremendous response with not much disease left except her bone metastases. She was on HP [trastuzumab, pertuzumab] maintenance therapy then, but after about 18 months of treatment, she did develop progressive disease and moved on to T-DM1 [trastuzumab emtansine]. Then she was on that for 5 or so months, but then progressed and went on to get T-DXd [trastuzumab deruxtecan]. When she was on T-DXd, she did very well with it. We continued prophylactic antiemetics, which worked well, and then some Zofran [ondansetron] as needed, and that was great to control her nausea.

We also tend to do restaging scans every 6 weeks as had been done and DESTINY-Breast01 and DESTINY-Breast03. On her second set of restaging scans, now at 12 weeks, we didn’t see ground glass changes. She was totally asymptomatic, and had grade 1 ILD [interstitial lung disease]. We did hold the T-DXd, and I always find this challenging with asymptomatic changes, but I want them to resolve, and I thought, I’ll just give the steroids. While you don’t have to give the steroids, she is asymptomatic, I thought I will give them and see if we can get things to improve on her imaging. We rescanned her in 3 weeks hoping to get her back on, but her CT was not improved, and I will be honest, I have not had ground glass changes improve that fast in general. It’s pretty hard to get them to go away in 3 to 4 weeks, but we continue to monitor her. And finally, around the 6- to 7-week mark her ground glass did resolve, and she did restart with a dose reduction. But I will say that this case goes back to your case where you had to hold, although in a much more challenging situation.

It’s hard to hold therapy in these situations, when someone is having benefit and otherwise totally asymptomatic, not having any issues. But to withhold treatment is tough, and it gets really nerve-racking when you don’t see things improve and can’t restart. It’s a reminder though that this is a guideline for grade 1 ILD, that you do need to be mindful, and while maybe these guidelines are very conservative, we need more information given that there have been deaths with this drug, and so we follow these very conservative guidelines.

Shanu Modi, MD: I agree with you. Sometimes it worries me because we count on patient reporting of respiratory symptoms. And I know there are patients who are like, “But that cough is because I was around my nephew who…” That’s the scenario I dread, attributing important symptoms to something maybe less important. You are right, I don’t think we know enough yet about this drug to take those chances. And those are hard scenarios when someone is finally doing well on something and you have to stop it for what seems like an unnecessary reason, because they feel fine. Having said that, do you start these patients on steroids typically early?

Sara Tolaney, MD, MPH: I’ve only had a few cases of grade 1 ILD, but I have been doing it just because I want it to go away and I think maybe it will help things resolve sooner. The guidance is strict because they want it to go away so fast, to resume the same dose. But I will be honest, to get it down in 28 days is not, again, I have never had ground glass completely go away that fast on imaging. It is usually quite delayed, so that is tough. I remember back when we did DESTINY-Breast01 before they changed the protocol, and you got kicked off at 28 days. I had a patient get kicked off. I had tried the steroids and I was like, “I’ve got to get this back so she can keep on the study,” and we couldn’t. It’s hard.

Shanu Modi, MD: I have had the same experience as you in that sense, that it has taken longer than I expected for the ground glass changes to resolve. I do tend to jump on steroids soon as well. Do most of your patients accept getting a CT scan every 6 weeks? That’s incredible that you are able to do that.

Sara Tolaney, MD, MPH: There are some patients who love it because there are some who like getting information back on a regular basis, and it’s comforting, particularly with this drug, when people do so well in general. But on the flip side of it, sometimes insurance doesn’t like this. That is a problem when you sometimes can’t do it if that becomes an issue. And then again, there are people who do get very anxious, understandably, with restaging, and that’s hard. The whole anticipation around restaging is difficult for many patients, so I will say it’s tough. When people are on it for a little while, I then start to go to 9 weeks, I start extending, but at the beginning I generally have been doing every 6 weeks. What is your group typically doing for intervals of scans?

Shanu Modi, MD: For most of us, we are counseling patients about the respiratory symptoms. We are a big group, I can’t speak for everyone, but in general, most of us are trying to do standard of care intervals, so a little less frequently than 6 weeks, closer to 10 to 12 weeks. I will say, I pick and choose sometimes patients for whom I am more concerned that they may have exams or respiratory symptoms at baseline that may make it challenging to follow them that way, clinically. Then I will do CT scans. I have had a couple of patients ask me if they could have a CT scan at 6 weeks; it’s a very savvy audience sometimes. I don’t have one standard approach, but the default is to use more standard of care, sort of 10 to 12 weeks. I hope we will have better tools or additional tools in the future besides just CT scans for monitoring these patients. It would be a great investment as we develop these drugs to figure out how to best select patients who are not going to run into lung toxicity.

Transcript edited for clarity.