Komal Jhaveri, MD, FACP: Before we talk about the DESTINY-04 [DB04] trial, we used to think about HER2 [human epidermal growth factor receptor 2] as either HER2-positive or HER2-negative. It was a binary way of thinking about HER2. Then we’d tie HER2 therapies for the HER2+ patients, which is IHC [immunohistochemistry] 3+ or 2+ that’s FISH [fluorescence in situ hybridization] amplified. What we’re learning with these novel antibody-drug conjugates—a good example is T-DXd [trastuzumab deruxtecan]—is that there’s a bystander effect. That kills neighboring cancer cells that might have some HER2 but aren’t necessarily overexpressing HER2. Because of that bystander effect, we’re thinking about what we define as HER2-low. This is IHC 1+ or IHC 2+ that’s not FISH amplified. Certainly, we saw a hint of activity in a phase 1 study when we saw an overall response rate of 37%, which led to this registrational trial, presented by Shanu Modi at the ASCO [American Society of Clinical Oncology] Plenary Series. Let me walk through that data quickly, and we can talk about the implications.

These were HER2-low centrally tested patients who had then been randomized to T-DXd [trastuzumab deruxtecan]. This is 2:1 randomization vs physician choice. This is capecitabine eribulin, gemcitabine, paclitaxel. A taxane, not paclitaxel or paclitaxel allowed. The progression-free survival [PFS] in the hormone receptor [HR]–positive group was the primary end point. There was hierarchical testing and then [the study] looked at progression-free survival in all HER2-low patients. Then it looked at overall survival [OS] in the hormone receptor–positive patients. As a reminder, when we think about HER2-low, the prevalence is about 55%, and the natural prevalence is more so. It’s about 60% or more in the hormone receptor–positive patient population and about 40% in the hormone receptor–negative patient population. This is why the trial looked at enrolling 480 hormone receptor–positive and about 60 hormone receptor–negative patients. When we think about what disease characteristics these patients had, these patients had 3 lines of therapy in the metastatic setting. No more than 1 line, [with a] median of 1 line of chemotherapy, yet no more than 2 were allowed on the study. About 70% of these patients had progressed on a prior CDK4/6 inhibitor.

Here are the results for progression-free survival and overall survival in all patients. These are physician choice in gray, where the median PFS is 5.1 months and T-DXd [trastuzumab deruxtecan] is about 10 months. This is a median difference of about 5 months favoring the T-DXd [trastuzumab deruxtecan]. In overall survival, there was a 6.6-month improvement favoring T-DXd [trastuzumab deruxtecan]. Improvement from 16.8 months in overall survival to a median OS of 23.4 months. We saw similar results in the primary end points subgroup, which was your HR-positive subgroup.

Looking at 60 HR-negative [patients], this was an exploratory end point but an important 1 in this patient population. This is such a difficult disease. Here we also see a 5.6-month improvement in median progression-free survival, which improved from 2.9 months in the control arm to 8.5 months in the T-DXd [trastuzumab deruxtecan] arm. Median overall survival improved by 10 months, from 8.3 months in the control arm to 18.2 months in the control arm. Adam, what do you think about these data for your HR-positive and HR-negative [patients]? How have you thought about utilizing this in clinic for your patients?

Adam Brufsky, MD, PhD: These are dramatic data. About 60% of the patients who are hormone receptor–positive turn out to be HER2 1+ or 2+. It’s interesting. I’ll talk briefly about the hormone receptor–negative subgroup. Although this is an exploratory subgroup, the data are pretty dramatic. I didn’t realize this—I thought it was 15% to 20% were 1+ or 2+—but it turns out to be about 50% of hormone receptor–positive or hormone receptor–negative patients are 1+ or 2+. These are exploratory data. Although they’re exploratory, a lot of us are going to use T-DXd [trastuzumab deruxtecan] in this population until we get a larger trial. We all have 5 or 6 or 10 or 15 patients who we’ve lined up waiting for the DB04. In fact, I’ve put already 2 or 3 people on it. I put 1 or 2 today in clinic on T-DXd [trastuzumab deruxtecan]. It has the opportunity to change everything. The big issue with these is that pathologists were not used to differentiating 0 for 1+ because there’s no reason to. We’re in an era in which we’re going to have to do a lot more detailed analyses of these tumors to differentiate 0 from 1+.

Obviously, the first thing as we talked about is that you’re going to have to do IHC. RNA-based assays probably aren’t going to cut it because you need the protein expression on the surface. The other thing is Pat LoRusso [DO] talked about the stuff that Dave Rimm is doing at Yale [MD, PhD at the School of Medicine], where they’re looking at quantitative immunohistochemistry and immunofluorescence. It shows that when you do that more sensitive assay, only 80% of the patients have HER2 or HER2 expression. I believe this is something that will be used widely. We have to be careful of ILD [interstitial lung disease], as we have said in DESTINY-Breast03. Short of that, this has the opportunity to make a dent in the natural history of this disease. These are really exciting data.

Komal Jhaveri, MD, FACP: Absolutely. The discordance between HER2 0 and HER2 1+ among pathologists is about 25%, 26%. Because HER2 was not designed to look at the differences between HER2 0 and HER2 1+. It was designed to identify your amplified or overexpressing patients from your negative patients when we started thinking about anti-HER2 therapies. But now we’re going back to IHC 1+ and 2+. For sites that are only now doing FISH, that’s a problem. They’ll have to go back to the IHC until we have a better biomarker, which we really need. Efforts are already underway.

Transcript edited for clarity.