Evolving Treatment Landscape of HER2+ Metastatic Breast Cancer

Closing out their discussion on novel therapies for HER2+ metastatic breast cancer, experts share excitement for future clinical trials and strategies.

Vijayakrishna Gadi, MD, PhD: We’re getting close on the end of time, and before we say farewell, maybe I can hear some final thoughts of big takeaways and what we should look for at SABCS [San Antonio Breast Cancer Symposium] 2022 or ASCO [American Society of Clinical Oncology] 2022. Michelle, I’ll start with you.

Michelle Melisko, MD: Oh wow, that’s tough. I’m hopeful, there are a couple more studies, the DESTINY-BREAST12 and other studies, looking at the value of trastuzumab deruxtecan [T-DXd] in patients with stable or progressing brain mets [metastases]. I don’t think we’re going to see that data at San Antonio 2022, but I think there will be a number of other smaller studies showing hopefully the value of trastuzumab deruxtecan in CNS [central nervous system] disease, whether these are community-based retrospective trials, or smaller phase 2 studies. There was a very small study that was in abstract form that basically gave no data, a lot of trials in progress kind of things. In the HER2-positive space, there’s this tension I believe in the neoadjuvant setting. De-escalation is a popular strategy, particularly in the ER [estrogen receptor]-positive, HER2-positive patients. And there’s increasing awareness that it’s pathologic complete response [path CR] that likely drives outcome, so no matter how you get there, if we can do less in the neoadjuvant setting and get a patient to a path CR, then maybe they don’t need to get so much. In my particular patient population, those who are reading these studies and want to avoid chemotherapy, I think they’ll be very interested in the idea of, for the triple positive, the hormone receptor-positive plus antibodies or plus antibody-drug conjugate. I think that’s what I’m looking forward to, seeing some changes in the neoadjuvant setting. We’ve essentially almost always eliminated anthracyclines in the neoadjuvant setting, can we do more? Do patients need to get 6 cycles of TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] in order to get where we want to be? That’s where I think we’re headed, and that’s what I’m going to be excited about next year.

Vijayakrishna Gadi, MD, PhD: Nancy, how about you?

Nancy Lin, MD: I would agree that I think we’ll see more data for T-DXd in the CNS. We saw some data at San Antonio. There are some phase 2 trials where we saw initial results of some of the cohorts but not all of the cohorts, and I think there‘s definitely something there. All of the studies consistently reported very impressive CNS response rates, so I think that’s going to be something to look out for, and presumably we’ll see some updated data from the CNS subset of DB3. I think that there’s the potential for a pretty significant shake-up in ER-positive, HER2-negative metastatic breast cancer and how we treat it in 2022 because we’re waiting for results of multiple phase 3 trials. We have T-DXd versus standard of care in HER2-low patients, we have sacituzumab versus treatment of provider choice in ER-positive, HER2-negative patients, and there are a number of phase 3 SERD [selective estrogen receptor degrader] trials that we’re waiting on the reporting of. I think there’s the potential that by the end of 2022, our treatment algorithm for ER-positive, HER2-negative disease is going to undergo a major shake-up, and that would be really exciting to see.

Vijayakrishna Gadi, MD, PhD: Chuck?

Charles Geyer, MD, FACP: Now I have to say something after all of that?

Vijayakrishna Gadi, MD, PhD: Yes, good luck.

Charles Geyer, MD, FACP: Gee, thanks. I guess stepping back a little bigger picture, I honestly do believe that we are going to soon be at a point where patients who come to us with early HER2-positive breast cancer, or even oligometastatic disease, can be pretty much assured that we’re going to be able to take care of this disease. We’re getting close to the cure. My concern is that as we’re doing that, you already are hearing, and we’ve run into this a little with the NRG-BR004 trial, like, “Oh those patients do so well with standard therapy, why do we need to do trials?” We get a little pushback there, and I think there clearly are going to continue to be that subset of patients who present with metastatic disease. With everything we’ve got, we really do need to seriously think in terms of, we need to cure these people too. We have enough tools, and I think that’s going to be the real challenge for us, a research community and resourcing. We’ve had some sites tell us, “We’re not activating BR004 because we don’t see enough of those patients anymore.” This is reality, and I think it would be a real tragedy if we get stuck in the palliative mode for patients with metastatic disease, with all that’s available, that we can’t find a path forward to clear their disease as well. That’s the bigger picture.

Michelle Melisko, MD: Circling back, that brought up a thought that I have about this idea of curing HER2-positive disease. I think this is for the community audience, a huge question presenting now that we do more scans, we identify more patients with de novo metastatic diseases is what is the role of surgery? And that’s not what we’re talking about here, but it is an incredibly common consult question because with all of the randomized trials, the surgeons will say there’s no benefit from surgery, there’s no role for surgery. But we have these young women in front of us who present with a very large tumor, a HER2-positive tumor often, that melts away, and their oligometastatic disease has melted away, it’s no longer hypermetabolic. So then what is the role of surgery? I think this is a challenge, especially with all the data that were presented at San Antonio about de-escalation of axillary resections, fewer axillary node dissections.

I personally have had a number of patients like this who present with HER2-positive de novo metastatic disease where they have a fantastic response, and then the first thing that grows back is the disease in the breast when it’s not removed. Their liver metastasis stays quiet, their bone metastases don’t become active again, but their breast mass becomes active, or their axillary node. Even though the question, Seema Khan MD, did a trial looking at this. There are studies, ex-United States, that have tried to address this question, but I feel like this is a subset, the HER2-positive de novo disease, where we really need to do a better job, whether it’s through a registry or a randomized clinical trial. It’s not that sexy of a question in terms of the pharmaceutical companies, but from a standpoint of the patient and the questions that we get, I think it’s critically important. For someone who has a fantastic response, do you just do a lumpectomy and radiation to the breast? Do you do an axillary node dissection? It’s kind of off topic for here, but it’s a huge clinical question in this space about curing patients with HER2-positive disease.

Vijayakrishna Gadi, MD, PhD: I’ll step in here and share my perspective as well on this because this is really exciting and about what I hope to happen. When I think about the early stage setting, Chuck, I agree, we’re doing a great job here, getting a lot of these women to be indefinitely disease free. Then it’s incumbent on us to identify the good-acting cancers from the bad-acting cancers and to see how we can pare down, and based on the responses we’re seeing, modify our approach so that we do less surgery, or maybe do less axillary investigation, or maybe even fewer agents. You look at the really long-term data now from the trastuzumab taxane trial and the small node-negative cancers. They’re still hanging out at 98%, 99%, and so the idea of escalating therapies in those patients makes no sense to me, right? But at the other end of the spectrum there are probably other patients who fall into that category, we just have not had a way to find them. What I hope for in the near future is something that helps us define a deep molecular remission the way we have in leukemias. In CML [chronic myeloid leukemia] at 5 logs below zero, if you can’t find the CML transcript, that patient’s probably cured. We just need technologies like that for breast cancer, whether it’s HER2 or other kinds of cancers.

One of the other things that struck me at San Antonio is how much we have moved toward these antibody-drug conjugates and these small molecules, and really stopped talking about the immunology of these cancers, at least for the HER2. I know there were some abstracts and posters, but we didn’t see mention of cell therapy for this particular patient group, and not a lot with regard to the checkpoint inhibitors, and so forth. I think the data are percolating. But it’s interesting that those technologies, which even just 2 or 3 years ago, to Chuck’s point, there was a lot of enthusiasm about folding them in, and now we’re having a hard time finding patients because the patients are doing well. It raises the question, is escalating here for the broad overall group the right move, or is this something where we really need to look at and find those patients who are most likely to benefit and not just treat them in a palliative setting?

All that’s to say, I’m going to mirror something that a colleague, an advocate who works closely with us, in 2019 said to me when we were in the meeting before it all went virtual. She turned to me as these data were being presented and said, “Gosh, I have HER2 envy,” because she didn’t have HER2-positive disease. We’d love for that envy to be available for all these types of patients. But certainly for HER2, we’ve done such a tremendous job as a community of investigators narrowing the patients, identifying them, getting them right therapies, and hopefully we’ll continue to see the gains for that group and not more harms.

With that, thank you so much. This has been extremely stimulating, there were a lot of small bits of data that I think continue to add to the story. It was hard to say there were blockbuster new things that came out of San Antonio this year, but it makes us all better doctors. So with that, thank you guys.

Transcript edited for clarity.

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