Joyce A. O’Shaughnessy, MD: Just to finish up our conversation today, I would love to get your practical application of sacituzumab and trastuzumab deruxtecan in the HR [hormone receptor]-positive, HER2-negative patient. When do you use it? When do you use them? And do you ever sequence them, as well? And what kind of toxicities are you particularly watching out for? Is there any kind of surveillance that you do? So let’s start with Pedram first, and then we hear from Komal.

Pedram Razavi, MD, PhD: So, unfortunately, we don’t have a biomarker to guide us on which ADC [antibody-drug conjugate]. And these are the first 2 that entered our clinical practice, and soon we’re going to have more. So far, we have been competing with naked chemotherapies with these ADCs. Overall, these are big drugs, much efficacy. And when we compare them with naked chemotherapy, regardless of the amount of expression, often they have efficacy. But if you look at, for example, the [phase 3] ASCENT trial [NCT02574455]…they looked at some different thresholds. That’s what you showed in the ASCENT index. It was 200, 100 cut points. But there was a clear association between the expression of Trop-2 and the response and the non–progression-free survival on sacituzumab. In every single expression level, sacituzumab was better than naked chemotherapy. But at the end of the day, when you look at it, there was a trend with the amount of expression of Trop-2 and response to sacituzumab. Going back to this analysis, they use just 100 with 50% of patients, more or less. I think there is a threshold, and we have to look more closely into the data that we have. What are the Trop-2 expression thresholds that dictate response to sacituzumab or predict response to sacituzumab? Overall, I agree, at this point, we don’t have a biomarker that [indicates] we should give it to all the patients. The same thing with HER2. There are HER2 0 patients, based on [the phase 2] DAISY [trial; NCT04132960], [who are] responding. Again highlighting the fact that the current IHCs [immunohistochemistries] that we have are not good for assessment of low expression of HER2, at low levels.… And you show a HER20 to one pathologist and another pathologist sitting next door, one of them says HER2 1+, one of them says HER2 0. And there [are] now multiple studies showing the same thing. Even now after T-DXd [fam-trastuzumab deruxtecan-nxki], when they look at [this] blindly—[Dr] David Rimm presented data—I think there is a need for us to better understand the expression profile of these markers and these anchors antigens over the cancer cell surface. At this point, I look at multiple factors and, again, [it’s] hard to decide. And if they’re comparing the clinical trials, yes, hazard ratio was better in DB-04 [the phase 3 DESTINY-Breast04 trial; NCT03734029] compared to [the phase 3] TROPiCS-02 [trial; NCT03901339]. But at the end of the day, the patient population was different.I don’t know if that hazard ratio of 0.5 or 0.6 are significantly different ... And, hopefully, we get some data on comparison of these. I’m not sure when we get them, but hopefully, we get some data. But until we get that, I take into account a lot of factors. For example, a patient has brain meds; we have good amount of data that T-DXd has a good brain penetration, a lot of activity... The DESTINY-Breast12 is ongoing to tell us how good T-DXd is in controlling the brain disease. But I have more tendency, for the patients who have brain disease, to offer them T-DXd over sacituzumab and the amount of expression of HER2 for the patients with HER2 0 one time, HER2 1+ next. But overall, it’s very low levels of HER2. I might actually go for sacituzumab at first and then go for T-DXd. And then, as you just mentioned and highlighted very nicely, the [adverse] effect profile of these drugs are very different. And I offer them to the patient and the patients often decides this one has much more alopecia compared to the other one. And that’s a no-brainer for the patient. I don’t want alopecia in my practice. I know that in clinical trial it was about 50%, but sacituzumab very often results in a significant alopecia. So I offer this to the patients, and they often decide which one they want. But that’s a point that we don’t have good data to guide us [about] which one of these we should offer the patients first.

Joyce A. O’Shaughnessy, MD: There’s no head-to-head data. There’s going to be some interesting sequencing studies being done too. That’s going to be helpful as well, to see if there’s a sequence that…[patients] potentially benefit from both, which would be awesome. And, Komal, how do you think through the choice of these, and any caveats around toxicity?

Komal Jhaveri, MD, FACP: I think Pedram quite summarized the thought process about this. Given the compelling efficacy data that we’ve seen with trastuzumab deruxtecan across tumor types now, I certainly discuss the toxicity profile. I kind of highlight that ILD [interstitial lung disease] pneumonitis…but it’s [an adverse] effect that can be detrimental, and one [a provider] has to really…[be] cognizant about. You mentioned pneumonitis existing in a patient. If a patient had a remote or a past history from a drug-induced pneumonitis, we see that with checkpoint inhibitors. If that has resolved in the baseline prior to initiating T-DXd, I obviously am nervous…but I still offer T-DXd in that case to that patient and obviously highlight this toxicity as a very important one and definitely do HRCTs [high-resolution CTs] every 6 weeks in that particular patient. If their baseline is clear, I do offer it. But if the baseline still shows some remote pneumonitis, I would probably not offer [it]. Short of that, for a HER2-low patient, I do tend to recommend trastuzumab deruxtecan, and I certainly am very vigilant about how to identify this grade 1 asymptomatic ILD, then image them often. Scans were done every 6 weeks on trial—that’s a little too frequent for standard-of-care coverage by insurance and payers. So I think about 9 weeks is my sweet spot. So I don’t wait the entire 12 weeks.… And particularly in those patients, when I’m worried about past history of pneumonitis as a potential mechanism, I think about doing high-resolution CT scans every 6 weeks. And then I could do PET scans every 12 weeks otherwise for the body. So that’s how I think about them. But I do think about HER2-low at T-DXd first. If I have baseline ILD pneumonitis or a HER2 0 in every sample that I have, it could be primary, it could be metastatic, as long as none of the samples have any HER2 low, I’m very comfortable offering them sacituzumab, until we have more data from the [phase 3] DESTINY-06 trial [NCT04494425] that has completed its accrual. We have 150 patients in that study, as we all know, that are HER2 ultra-low, which is what we think potentially could be a reason why DAISY had that cohort of 30% overall response rate. Maybe there were some HER2 ultra-lows, and their IHC [immunohistochemistry] is not perfect. Pedram pointed out we need [more] quantitative biomarkers. Or if I were to be provocative, do we need a biomarker? Maybe. We might be in a stage where DESTINY-06 and HER2 ultra-low and a majority of our patients will have some benefit. And maybe, unless we really don’t expect this patient to benefit, maybe we should offer it. We do that with sacituzumab. And I think the field is going to get a little more complicated… because we’re going to get data from the [phase 3] TROPION-01 trial [NCT04656652], which is another Trop-2 ADC. So we have datopotamab, which is exactly the same patient population of DESTINY-04. And so we’re going to have a biomarker average group for DESTINY-04, a non-biomarker selected data set from datopotamab. And then we have sacituzumab. We also have [phase 3] ASCENT-07 [NCT05840211], which is a counter-trial similar to what we have with DESTINY-06 and first-line chemotherapy. But in this case with ASCENT-07, it’s first-line sacituzumab versus first-line chemotherapy. So we’re going to, over the years, have more and more data. I think what we really are trying, and we might not necessarily get those answers, but what we’re definitely trying is to see [if there is] a better way of knowing how [to] sequence these agents? And you pointed out we have the trade DFD file, which is looking at trastuzumab deruxtecan or datopotamab deruxtecan. So both [are] deruxtecan payloads. And we’re trying to see if one sequence is better than the other. We start with T-DXd and go to datopotamab or vice versa. Is that a better strategy? We might have a registry to look at or real-world data set to look at sacituzumab and T-DXd to see what that [might] do. At ASCO [the American Society of Clinical Oncology Annual Meeting], we heard from the MGH group, a very small data set of 30 patients, where they looked at T-DXd and sacituzumab sequence and vice versa. And the second payload, there was some cross-resistance. I mean, the PFSs were 3 to 4 months. It’s a very small data set, but I guess those 3 to 4 months are better than single-agent chemotherapy, which is what we otherwise would offer. So is that bad? Potentially not. So I think we are going [try] to understand whether there is resistance of the target. Is there resistance to the payload? With chemotherapies, we were never able to solve that mystery. We could not identify all the mechanisms of resistance. We use different mechanisms for chemotherapy drugs, and we use a taxane and anthracycline, a 5-fluorouracil–based therapy, and different mechanisms. And I think we might end up being in that stage. But the good news is, I think ADCs are here to stay. There are many novel agents in development, whether it’s newer linkers, newer payloads, bispecific antibodies, biparatopic antibodies, radionuclide antibodies. And, hopefully, we’ll be in a world where we use ADC after ADC, and our outcomes are going to be better. Both of these ADCs have overall survival, and I think they’re very excited about that fact.

Transcript is AI-generated and edited for clarity and readability.