SABCS 2021: Combination Strategies Under Investigation for R/R HER2+ mBC

Vijayakrishna Gadi, MD, PhD: Let’s go to the exciting new stuff and frame it in terms of this patient. Michelle, I’m going to start with you. Maybe highlight a couple of San Antonio Breast Cancer Symposium abstracts or things that caught your eye, and we can use that as a launching point.

Michelle Melisko, MD: In terms of what was presented in San Antonio, a review of things presented at previous meetings, DESTINY-Breast03 was the most powerful presentation. It was interesting. Maybe it’s not so interesting for this community-based audience, because we’re in the United States. But the number of presentations on other tyrosine kinase inhibitors, like ceritinib, got a plenary or was in 1 of the main general sessions, because it’s being developed in China. It’s interesting that 1 of the speakers mentioned, why is this relevant? This drug is being tested in a space where we have many other options in the United States. I thought it was amazing that these drugs that we take for granted—like trastuzumab deruxtecan, or Kadcyla, or even pertuzumab—are not routinely available for people in most of the world. That’s not necessarily the question you asked, but it’s important for us to recognize that we have an embarrassment of riches in the United States with our care.

In terms of other agents that are interesting, no other antibody-drug conjugate [ADC] stood out as being so remarkable, that had me jumping up and down to use it instead. In HER2 [human epidermal growth factor receptor 2], there were data on other combinations. As Nancy mentioned, we’re wondering how we’re going to be combining Kadcyla with tucatinib, trastuzumab deruxtecan with tucatinib—all these combinations of what we have are where we’re moving forward.

Another session I thought was very interesting in San Antonio was the triple positive. We’ve been largely talking about this patient who has ER [estrogen receptor]–negative, HER2-positive disease, but some of the more challenging questions are how do we make changes in treatment in a patient who’s ER+, HER2+? We have to understand the phenotype of those patients and recognize, are they more HER2 driven or ER driven? That’s not necessarily the case that we’re talking about, but that stood out as questions that folks have in the community.

Another thing about this case is that this patient has progression in the bone. Let’s say that they did this single isolated new lung metastasis. What’s the role of stereotactic radiation, stereotactic body radiation, or isolated radiation to a single site to allow patients to remain on that same second-line therapy? Unfortunately, I can’t say I was jumping up and down about any other agent. I’m curious if I missed something. The questions about the management of this patient come down to how can we maximize, keeping everything we have going and stretching as long as possible?

Vijayakrishna Gadi, MD, PhD: Thank you. Chuck, I’ll go to you. There are new molecules that Michelle just mentioned. Anything stick out for you from San Antonio in terms of first in class?

Charles Geyer, MD, FACP: We’re clearly seeing ADCs revolutionizing in a way we’re treating patients. It’s interesting because we’re getting into seeing more of the heterogeneity and how we’re going to deal with heterogeneity. Then T-DXd [trastuzumab deruxtecan] drops in, and maybe we don’t have to worry as much about the heterogeneity. It’s so active in all these subtypes. That’s a particularly disruptive drug in terms of trying to predict the best way to use it. It’s going to be interesting to sort it out, but even with all the great information on T-DXd [trastuzumab deruxtecan], there are still patients progressing and failing. Now it’s what you do post-antibodies, post T-DXd [trastuzumab deruxtecan], post-tucatinib.

Now we’re talking about a fourth line, so you’re getting into whether it’s lot of heterogeneity. But there were a couple of types of drugs. It looks like there are bispecific antibodies that bind to 2 parts of a single antibody, binding to 2 different points on the extracellular domain of HER2. There were some early studies—in particular, KN026 from a Chinese company Jiangsu Alphamab Biopharmaceuticals—developing this, but they were looking at heavily pretreated patients. They did a quick phase 1/2 study reporting on activity of this antibody on 57 patients in this heavily pretreated population. They had an overall response rate of 28%. The neat thing is they also prospectively planned on looking at the subset where there was coamplification of CDK12. I had to read about this. When I saw those, I thought, “I don’t know what that is. I’ve got to go look.” Apparently this is 1 of the CDK family that is frequently coamplified with HER2 and appears to be a resistance mechanism. So when they looked at that subset, it was a response rate of 50%, so maybe there will be subsets. That seemed to be well tolerated, so I found that to be an interesting abstract.

There was another bispecific antibody that took the next step, giving it with chemotherapy. The name—you have to hear it said a couple of times—is zanidatamab. I love it. It was dealer’s choice with chemotherapy for 20 patients, but they had overall response rate of 38% clinical benefit. It’s remarkable when you get into those patient populations whose tumors have been under so much pressure for many active drugs for many years, but they’re still vulnerable. These are interesting things to keep an eye on and conceptually think about. There are ADCs. There are also antibodies. People are turning to the partner HER3 [human epidermal growth factor receptor 3]. What about monoclonal antibodies and ADCs linked to HER3. To me those are what to look for behind ADCs that might see the light of day. Maybe will be some bispecifics or ADCs targeting the HER3. The studies look that way, but we’re years from the clinic.

Vijayakrishna Gadi, MD, PhD: I agree. What’s interesting is that these new bispecifics are being combined with chemotherapy. We’re getting those safety data. I can see these slotting in much earlier lines of therapy, eventually being able to challenge a classic combination like THP [docetaxel, trastuzumab, pertuzumab] with zanidatamab. With a drug like that with combination chemotherapy, you can see that you haven’t enrolled down the road.

Transcript edited for clarity.