Optimizing Treatment for HR+/HER2- Metastatic Breast Cancer - Episode 6

Considering HER2-Directed Therapy in HER2-Low Metastatic Breast Cancer

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Centering discussion on HER2-targeted trastuzumab deruxtecan, experts reflect on the presence of HER2-low metastatic breast cancer and optimal treatment strategies.


Jules Cohen, MD: What do you think about HER2-low disease? There was a debate yesterday about whether it exists. Where do you stand with all your experience with HER2 disease?

Dennis J. Slamon, MD, PhD: It clearly exists. There is a spectrum of HER2-low disease. One of the best studies done was by Tim Cook, a Scottish investigator, who quantitated the amount of HER2 receptor on malignant and normal tissues. It turns out that, using…analysis and radiolabeling, so a pretty robust way of looking, they quantitated that normal tissues express between 15,000 and 50,000 receptors on the cell, of normal tissue. Malignant breast cancers take that up a notch. They start at about 150,000 and go up to 250,000, but those that are amplified go up by almost a log. There’s a big gap. That is what gave us the therapeutic window for trastuzumab and trastuzumab-chemotherapy combinations because those really super levels of expression are what allow that to happen. Now that you have an ADC [antibody-drug conjugate] that’s going to recognize those lower levels and internalize that toxic combination into the cell where the payload is going to get released, you are seeing responses in these lower levels. Again, normal tissues express those same low levels. It’s real. I don’t know that it’s a separate disease. It’s simply nonamplified, -expressing disease that is in the spectrum of what you see in those malignant tumors that don’t have the amplicon.

Jules Cohen, MD:Can you talk a little bit about using trastuzumab deruxtecan [T-DXd]? I think there is a “fam” before the name.

Joanne Mortimer, MD, FACP, FASCO: T-DXd, this antibody-drug conjugate to HER2, was first approved in patients with metastatic HER2-positive breast cancer. It’s an incredibly active drug. The forest plot for the DESTINY-01 trial with 168 patients showed only 4 didn’t respond to therapy. It’s an amazingly effective agent. As Dennis said, in this continuum of HER2 expression in breast cancer, the 1-plus and 2-plus [HER2 testing score] patients have also been tested with T-DXd, and this therapy is almost equally effective. It’s been used as a second-line plus therapy. We know that in patients who are 1- and 2-plus HER2-low, there is a response to them.

I think one of the important things, and why I’m glad we’re having this discussion, is that T-DXd is such an incredibly active drug and has a long duration of efficacy too, that people are tempted in the patient with liver metastases to forge on and use immediately T-DXd, which is sort of the shiny object that we have right now. T-DXd is important in this group of patients we’re focused on today, but…hormone therapy is still the appropriate first-line therapy. We should use it until the patient is hormone-resistant, before they head on to chemotherapy, even when you have this incredibly active drug like T-DXd.

Jules Cohen, MD:I think that’s a good point. ER-positive patients can get between 2 and 3 lines of antiestrogen-based therapy in combination with CDK, with alpelisib, if they’re PI3 kinase mutated, and then everolimus and exemestane before they are candidates for T-DXd. Technically, don’t they have to have an actual line of chemotherapy before getting T-DXd?

Joanne Mortimer, MD, FACP, FASCO: Yes, it’s second-line plus. I think the median was 5 lines of chemotherapy for the DESTINY-04 trial.

Jules Cohen, MD:Still, the progression-free survival was over a year, right? It was astronomical.

Joanne Mortimer, MD, FACP, FASCO: That’s why it’s such an exciting drug. These are heavily pretreated patients you’re seeing phenomenal responses in.

Jules Cohen, MD: Also, in DESTINY-04, I believe 90% of the patients were ER-positive. So that’s kind of why we think of HER2-low as an ER-positive phenomenon. Now, technically you can treat an ER-negative patient who is HER2-low with T-DXd, and it’s approved for that. But again, it was a relatively small percentage of the overall study.

Transcript edited for clarity.