Targeted Therapy in Early-Stage HER2+ Breast Cancer - Episode 5

Treating Early HER2+ Breast Cancer: KATHERINE

Targeted Oncology

Stephanie Graff, MD, FACP: OK, it’s gone on too long. You’re going to have to talk about KATHERINE now, because that’s the perfect segue.

Erika P. Hamilton, MD: Absolutely. We’ve talked about T-DM1 [trastuzumab emtansine] already, and the fact that it’s an antibody-drug conjugate. KATHERINE had a very beautiful trial design. It was beautiful because it asked the question about high-risk disease and defined a high-risk patient population in a way that was different than before. Before, we were always defining patients as high risk based on how big their tumors were, or whether they were node positive.

KATHERINE asked that question a little bit differently. Instead of worrying about how much disease they had to begin with, they focused their design on patients who had residual disease at the time of surgery. So regardless of whether they were lymph node-positive or lymph node-negative to begin with, if the patient had residual disease in the breast or the lymph nodes after neoadjuvant therapy, they were eligible to go on to the KATHERINE trial. By defining a high-risk population that didn’t respond the way we wanted it to, to good therapy, we were able to capture this true high-risk population. We’ve discussed and alluded to before that even patients with big tumors that may be lymph node-positive often get pathologic complete responses in HER2-positive disease. So those were probably diluting the effects and the magnitude of benefit from some other studies.

KATHERINE randomized women to either receive standard therapy, which was interesting because it was right around that pertuzumab time, but most often that was trastuzumab in the adjuvant setting, or T-DM1. That was for a continuation of a full year of therapy just like we would have given for trastuzumab. We saw a very impressive benefit in disease-free survival of over 10% there—it was 11%—and increased disease-free survival from 77% up to 88% with the addition of T-DM1 therapy. I think it’s not often, in this decade at least, that we get the gasps when we see the data. A lot of times that’s because it’s published online ahead of the presentation. But these were really impressive data, and I think it surprised a lot of people. Firstly, maybe how poor our patients who didn’t have a pathologic complete response did. But also, when we often measure our benefits in the 2% or 3% or 4% range these days, to see that magnitude of benefit of 11%.

Stephanie Graff, MD, FACP: Yes. And again, patient selection is everything. We knew that was a high-risk population, so choosing and designing the trial that way was very smart, very relevant, and then, honestly, at the end of the day, practice-changing, because of such a significant approach.

Clinically, I follow that KATHERINE thinking for anyone I treated neoadjuvantly regardless of what chemotherapy, regardless of what HER2 regimen they received, regardless of their clinical staging prior to surgery. If they did not achieve a pathologic complete response, I offer T-DM1 in the adjuvant setting. The KATHERINE trial did do 14 doses of T-DM1 in the adjuvant setting, and they used it concurrently with radiation. This is a question that comes up a lot, so I want to draw the listeners’ attention to that.

Erika P. Hamilton, MD: Additionally, you also can start your endocrine therapy during that period. I agree. I think 2 frequent questions that are found in the appendix are that radiation and endocrine therapy can be concurrent for those patients that’s appropriate for.

Tell me about the optimal patient selection for the KATHERINE regimen. How do you explain that risk/benefit ratio? How do you explain the adverse effects? What does that conversation look like in your clinic?

Stephanie Graff, MD, FACP: From the very beginning, when we’re starting neoadjuvant chemotherapy, I prepare patients and explain that one of the reasons to choose a neoadjuvant approach is that it gives us—I call it the pivot—an opportunity to pivot. If they don’t have a pathologic complete response, we can say, “Oh, we’ve got this other road we can go down.”

Compared to trastuzumab alone, does T-DM1 have some different adverse effects? Absolutely. But I think that with an 11% benefit seen, most patients are willing to accept those different adverse effects. We’ve already alluded a little bit to the T-DM1 adverse effects—a bit more liver function abnormality, a bit more thrombocytopenia. Although patients will get hair growth on T-DM1, I do find it happens a bit slower than it does for patients who are just on trastuzumab. Again, I’ve seen patients have some acceleration of their peripheral neuropathy when they’re on T-DM1 in the adjuvant setting.

So I look at the depth of their pathologic response. I’ve had a handful of patients who maybe have 2 mm of residual disease. And in that 2 mm, there’s only 10% cellularity. Is that really a pathologic complete response? No. But is the benefit of KATHERINE for that patient maybe a bit more nuanced? Absolutely. There’s still art to oncology, obviously. For some of those very good but not quite pathologic complete response patients, we have a more detailed discussion. But most of my patients know that pivot is coming and are ready for it, and do great on the medicine.

Erika P. Hamilton, MD: Yes, absolutely. Were you able to see the updated data from 2020 here, breaking out if there was a population that didn’t benefit from the KATHERINE regimen?

Stephanie Graff, MD, FACP: Yes, and that presentation reminded me so much of the subset analysis that we saw on who benefits from CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors. With every slide, it’s, “Well, what about this group? And what about this group?” The answer is, “No, give it, give it, give it.”

Erika P. Hamilton, MD: Right.

Stephanie Graff, MD, FACP: They looked at does tumor size, lymph node status, patient age, hormone receptor status impact the benefit of KATHERINE? The answer was that everyone seems to benefit. Perhaps most interestingly, they also did some repeat HER2 expression testing, and even patients who had a diminished HER2 expression still benefitted. I really think that it’s a worthwhile conversation for any patient who did not have a pathologic complete response.

Transcript edited for clarity.