Transcript:
Andrew Seidman, MD: Having an agent that now targets HER2 [human epidermal growth factor receptor 2]-low breast cancer, where do we go from here, Bill? What are the next steps, other ADCs [antibody-drug conjugates], other targets, other payloads? Are we starting to see the end of naked chemotherapy drugs?

William Gradishar, MD: I think chemotherapy won’t go away, but the hope is that we will have additional agents. We heard TROPiCS-02 data, looking at sacituzumab in a population that may in some ways be similar, if they were actually discriminating based on HER2 levels. I did want to make one point, picking up on the pathology piece. It was interesting, at a meeting a couple of days ago, [Giuseppe] Viale, [MD, FRCPath,] from Italy was there. He was saying that when we’re looking at pathology, until this point we would look at the slides, spend 10 seconds, 15 seconds, if it wasn’t anything other than 3+ [immunohistochemistry score], it was 0. A lot of pathologistsdidn’t spend a lot of time [figuring out if] it was 1+ or 2+. I think the point being that as we go forward, if you’re going to be utilizing archival samples, they may need to be reviewed. It also speaks to the need to get a newer sample if possible.

Andrew Seidman, MD: Yes, HER2 can evolve during the course of the disease, so we shouldn’t be satisfied with the pathologist report that says HER2-negative. We need more information.

William Gradishar, MD: Yes.

Andrew Seidman, MD: You have to go back to the pathologist and ask him to score it for you.

William Gradishar, MD: To your point, I think we will have available other drugs and other antibody-drug conjugates. Again, [this is] the same discussion we had earlier, the challenge will be how to optimally sequence them.

Andrew Seidman, MD: This term bystander effect has been applied a lot to the ability of the payload to permeate. What implication does this have in this trial, in the sacituzumab govitecan experience? Stephanie, do you have any thoughts on that?

Stephanie Graff, MD: The bystander effect, at simplicity, just means that once that antibody has bound to its target…. An antibody-drug conjugate is the antibody, what binds the target; the linker or the conjugate, which is either soluble or insoluble, or some gray scale between those two; and then the drug or the payload, which is actually the chemotherapy. The concept of bystander effect is how stable that linker is. In the most stable antibody-drug conjugate, the linker doesn’t go away until that ADC is absorbed intracellularly, and then there is no bystander effect. But that’s not what most of our antibody-drug conjugates do. Most of the time, once it’s bound to the receptor, that linker starts to dissolve, and you see the chemotherapy go into the microenvironment, and as we have seen from the wealth of information that we are learning in immunotherapy, that microenvironment plays a huge role in how our cancer and cancer treatment work together. We are getting huge effects with a big bystander effect with the delivery of these targets.

Andrew Seidman, MD: Some of those neighboring cells may be HER2-0. Tiffany, maybe you can speak to the 11% or so of patients in DESTINY-Breast04 who would by all other descriptions be called triple negative. What have we learned, if anything, from that subset?

Tiffany Traina, MD: As you alluded to, this was largely a hormone receptor-positive, HER2-low study. That 11% of patients who were hormone receptor-negative would have previously been classified as triple negative. I think we have always had some caution with that definition because it doesn’t actually define the driver, as VK was saying before. But this is an area where there has been huge unmet need. We have been fortunate to have sacituzumab, which works across the spectrum of HER2—0, 1+, 2+. We saw those data at ESMO Breast [European Society for Medical Oncology Breast Cancer annual meeting] as well. It’s wonderful to see a highly active drug in a population that was considered triple-negative breast cancer. If we looked at the hazard ratios for that small, maybe 60 patients, in DESTINY-Breast04, they were I think 0.46 for benefit, in both PFS [progression-free survival] and overall survival for hormone receptor-negative, HER2-low.

Vijayakrishna Gadi, MD, PhD: Tiffany, can I follow up on that?

Tiffany Traina, MD: Yes.

Vijayakrishna Gadi, MD, PhD: I don’t know if there is a plan to do this, but it would be interesting to know how many of these HER2-lows are actually luminal-type triple negatives with androgen receptor or some other expression pattern.

Tiffany Traina, MD: Exactly. [There are] a lot of ways to define the underlying biology there. Interestingly, we have also seen data for trastuzumab deruxtecan in HER2-0 from our colleagues in a much smaller study. the DAISY trial.

Andrew Seidman, MD: For the patient who has HER2-0, you’ve gone back and done a biopsy at progression after second chemotherapy, and now they are triple negative. Should we be driven by DESTINY-Breast04, or we should be driven by the ASCENT trial?

Tiffany Traina, MD: In that setting we have data from ASCENT, which is a dedicated triple-negative breast cancer trial, with activity in overall survival benefit from sacituzumab govitecan, superior to chemotherapy regardless of HER2-0, 1, or 2+. I think that would remain my option.

Transcript edited for clarity.