Triple-Negative Breast Cancer: Expert Perspectives On Recent Advances - Episode 15
Joyce A. O’Shaughnessy, MD: Let’s spend a little time on toxicities in terms of hints for us all about how we manage toxicities. What do we have to lookout for, and how do we manage them? Sara Tolaney, could you say a few words about that?
Sara Tolaney, MD, MPH: Sacituzumab is given on days 1 and 8 of a 21-day cycle. What we’ve seen is that the most frequent toxicity is really neutropenia. About 60% of patients do end up getting grade 3 or 4 neutropenia. Because of this, we did see in the ASCENT trial that almost 50% of people ended up using growth factor support. I very commonly will add on growth factor support when giving it. If they come in and their neutrophil counts are a little low, then I realize that they can’t really tolerate treatment at this dose unless they get a growth factor. I definitely introduce that early with any signs of neutropenia.
The other adverse effect to keep in mind is diarrhea, although I will say it is mostly low-grade diarrhea. The rate of grade 3/4 diarrhea is very low, and it was about 10% in the ASCENT trial. Most of my patients have intermittent loose stool, so maybe every once in a while they may need to take loperamide. I counsel them on that when starting the sacituzumab, but it’s not that they need prophylactic loperamide or anything like that for the majority of our patients. I also let people know that they will lose their hair. All my patients generally do lose their hair. Obviously, at this point in time many patients are going to go into it without hair if it’s in the later-line setting. For those with hair, it’s important to let them know.
I also generally premedicate patients, so on the day of treatment I usually give a Zofran and a Decadron prior to treatment. I have use Zofran at home as needed if they want. Some people will use something like Aloxi instead of Zofran, but either way, generally that’s what’s used. I don’t really have much trouble though with nausea. Honestly, most of my patients actually do pretty well with it outside the neutropenia and intermittent loose stool and fatigue. Those are the major things that we deal with.
Joyce A. O’Shaughnessy, MD: It was interesting to think about. One of the reasons sacituzumab had a big impact in survival—those curves are very impressive: They really pull apart immediately and quite strongly continuing to pull apart; it’s an amazing set of curves—is that it really is possible to continue the therapy. It is something that we don’t usually have to stop. You don’t get into treatment limiting toxicity. I want to get Adam’s take on this because you and your practice have are very good stewards of resources. As Sara just said, about half the patients in ASCENT who are on sacituzumab end up getting growth factors.
On the 1 hand, you say, if they’re not having diarrhea or other toxicities and they just can’t get their day 8 on time, maybe we should just do a dose or 2 of filgrastim to make sure that they can get their day 8. The survival advantage started with the 10 mg/kg, so maybe we want to get the initial cycles and keep it up there. On the other hand, I forget what percentage of patients did require dose reduction, but there are of course always are patients who require dose reduction, yet you still see this very nice survival advantage in spite of the fact that some patients got a dose reduction. I have been going down to 7.5 mg/kg in patients who can’t get their day 8 and I want them to. I don’t want them to be missing day 8, so I’ve been going down.
On the other hand, 50% did get growth factors in this. That’s where we saw the survival. I know we don’t really know the answer about whether we just dose reduce without growth factors, because a lot of our guidelines suggest that unless there is definite, known impact on dose intensity in the metastatic setting, the dose reduction should be considered. What’s your take on that, Adam?
Adam M. Brufsky, MD, PhD: You just mentioned it, Joyce. Twenty-two percent of the patients had a dose reduction in the sacituzumab govitecan arm, so we have no idea what their PFS [progression-free survival] and OS [overall survival] were. That needs to be presented. The problem is that the company was bought by Gilead Sciences, Inc, and who knows what their priorities are going to be, but that data will probably need to be presented somewhere. That’s the first thing. The second thing is that 50% did require growth factors. Normally in a non-OS setting, we would try to avoid them, but maybe we need to rethink that.
Traditionally, the approach for my colleagues here and me has always been single palliative chemotherapy. You reduce the dose, and you don’t use growth factors, but I think I’m changing that. I’ve found as we do more of this, we’re using more growth factors. Initially we didn’t in a clinical trial. I use a little more dose reduction, but I’m starting to use growth factors more with this.
Joyce A. O’Shaughnessy, MD: I must say, this is a remarkably non-cross-resistant agent. I’ve had a number of patients who really were quite primary refractory from the get-go and very symptomatic who have had responses. It does make me want to think more about what you just said about this has a survival impact here. At least in the beginning, I have to really try to keep the dose intensity up for these patients. I’m going to really rethink that.
I want to also mention the bystander effect about sacituzumab. Even if some cells don’t have Trop-2, maybe the expression is a little heterogeneous, when the SN-38 is cleaved—it’s a cleavable linker; it’s such a high concentration of the SN-38 on the antibody—you get diffusion to the other cells, and it can kill the cells even though they don’t have Trop-2. This really nice bystander effect probably helps play a role in the effectiveness of this agent. It’s a remarkable drug, and we’re going to see a lot of it in other cancers and it will be moved up into the curative setting very quickly.
Transcript Edited for Clarity