Novel Therapies on the Horizon in HER2+ Breast Cancer

Erika P. Hamilton, MD: Let’s wrap up with a bit of a conversation on the future. Are there new drugs you’re excited about? Are there new combinations you’re excited about? Where do you think we’re headed from here?

Stephanie Graff, MD, FACP: Yes, we’ve got a lot of new and exciting medicines, such as trastuzumab deruxtecan and tucatinib in the metastatic space. I’m excited to see those move forward down the pipeline. We still have a lot of questions about sequencing now that we have a celebration of riches. We’ve got so many agents now, and it is challenging trying to figure out whom to sequence, particularly given the unique trial design of tucatinib for patients with brain metastases.

One of the questions most of us have is, should we be prioritizing tucatinib over other HER2-directed therapy for patients specifically with brain disease? It’s not to say that the other agents don’t work for patients with brain metastases, but with such clear data in the tucatinib space, it’s hard to ignore that. That sequencing is 1 of the big future directions.

Looking at continued attempts to combine HER2-directed therapy to eliminate the chemotherapy backbone is also exciting. One of the trials that both of us are involved in is looking at T-DM1 [trastuzumab emtansine] in combination with some of these newer agents—tucatinib specifically, which would eliminate the role of capecitabine in combination with tucatinib, combining it with an antibody-drug conjugate. That might be a nice option with a more favorable toxicity profile for patients.

Erika P. Hamilton, MD: Absolutely, I completely echo that. Another question I have about tucatinib is whether we could prevent some brain metastases if we use it early. Instead of being reactionary, be a little forward thinking. With up to 50% of patients with metastatic disease eventually getting brain metastases, that’s a really important question to ask as well. Trastuzumab deruxtecan will very likely be moved up into the earlier settings as well.

As far as new agents, I have the privilege of working within our phase 1 unit, so I get to see some of the new things that are coming across the table as well. I’m pretty interested in the bispecifics. Bispecifics come in a couple of different flavors. We certainly have the bispecifics that bind not only to the trastuzumab binding site but also the pertuzumab binding site; or even a novel binding site on HER2 [human epidermal growth factor receptor 2]. Packaging that all in 1 is an attractive strategy. We also have bispecifics that are antibody-drug conjugates, so adding another little layer to it. Finally, we have bispecifics that bind HER2 on 1 side and then have an antibody that engages the immune system on another. Really, it’s a different way to think about so-called immunotherapy or how can we bring the immune system in to engage with these HER2-positive cells. For a new class of agents, those are some things that are coming.

For these patients who have HER2-positive metastatic cancer and are very HER2 driven, they live for a very long time and get benefit out of each HER2 agent that we give to them. As we see some of these agents that are very effective, such as T-DM1 [trastuzumab emtansine], such as pertuzumab being moved into the earlier setting, it really does open the stage to the fact that we still need new therapies for metastatic disease as well.

Stephanie Graff, MD, FACP: Yes. In regard to other future directions, we’re now seeing early endeavors using CAR T [chimeric antigen receptor T-cell therapy] in HER2-positive disease, which is exciting for those patients. We’ve been focusing on the traditional definition of HER2 positivity, but we’ve got drugs like MCLA-128 that are expanding the definition. We have trials looking at that HER2-low population—somebody who is HER2 1+ but not FISH [fluorescence in situ hybridization] amplified, HER2 2+ and not FISH amplified—to figure out if there are some patients who respond to these targeted approaches although they don’t meet the traditional definitions of HER2 positivity. That’s another direction to continue to explore.

Erika P. Hamilton, MD: Absolutely. We’ve seen good data on trastuzumab deruxtecan in that space. With it being an antibody-drug conjugate and having a bystander effect, the response rates in the HER2-low patients were really quite impressive. If we think about the small percentage of patients who are truly HER2 amplified, the percentage of patients who would be classified as HER2 low is even broader. We could potentially impact a large amount of people there. Is there anything else you want to say as we wrap up this discussion? Any last words of wisdom or things to think about?

Stephanie Graff, MD, FACP: My closing sentence would be what my closing sentence often is: Everything we just talked about, all the advances we’ve made, were because patients enrolled in clinical trials. That means we, as clinicians, have to be considering these for our patients, referring and recruiting them to clinical trials as much as possible, so we can continue to celebrate these 11%, 18-month improvements that we’re talking about, which is really exciting. Even more, all these advances were made because patients volunteered to participate. I can’t celebrate the contribution that patients make in advancing science enough. They are the unsung heroes of everything we’ve ever achieved, and I’m thankful for them.

Erika P. Hamilton, MD: Yes, absolutely. I completely echo that. I’m always amazed by our patients and what they’re willing to do. We have a responsibility on that end as well, to make sure that we offer patients clinical trials. And also, that we start looking critically at some of these clinical trials and how to broaden eligibility criteria. We certainly want therapies to be safe for our patients, and we want the right patients to be going on the right trials, but sometimes these are a little artificially restrictive. I think broadening those…

The HER2CLIMB trial with tucatinib was a great first step. We saw inclusion of a population of patients who typically would not have been allowed on a clinical trial there. They were patients who had brain metastases who were not only stable and treated. Rather, there were 2 other categories: Patients who had asymptomatic untreated brain metastases and patients who had treated and subsequently progressive brain metastases. Things like that. Things like, maybe, creatinine clearance, or baseline blood counts, etc, for drugs that we don’t really think affect those. You know, chronic infections like HIV, hepatitis C and hepatitis B, etc, are some of the opportunities we can really broaden to allow more people to participate on trials.

Stephanie Graff, MD, FACP: Yes.

Erika P. Hamilton, MD: Thank you so much for having this conversation. I’ve really enjoyed it. Thanks to our audience for watching this Targeted Oncology™ presentation on precision medicine. We hope you found this discussion to be useful and informative. We certainly enjoyed it. Thank you.

Stephanie Graff, MD, FACP: Thanks.

Transcript edited for clarity.

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