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1L HER2-Positive mBC
Oncologist On-Call: Thoughts on the Current Treatment Landscape for First-line Management of HER2-Positive mBC

Released: March 25, 2025

Stephanie L. Graff
Stephanie L. Graff, MD, FACP, FASCO
Laura Spring
Laura Spring, MD
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In this episode, listen to Stephanie L. Graff, MD, FACP, FASCO; and Laura M. Spring, MD, share their clinical insights and takeaways regarding the current treatment landscape for first-line treatment of patients with HER2-positive metastatic breast cancer including:

  • Data from multicenter, single-arm, phase IIIb/IV DESTINY-Breast12 evaluating trastuzumab deruxtecan (T-DXd) in patients with advanced HER2-positive metastatic breast cancer and 2 or fewer previous therapies
  • Treatment sequencing and preferred treatment options in patients with brain metastases
  • Results from phase III PATINA trial of trastuzumab, pertuzumab, plus endocrine therapy with or without palbociclib in hormone-receptor positive/HER2-positive metastatic breast cancer
  • Thoughts on the use of T-DXd earlier in the treatment paradigm in light of recent results from the PATINA trial and highly anticipated results from the DESTINY-Breast09 trial

This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.

Dr. Laura Spring (Massachusetts General Hospital): My name is Dr. Laura Spring. I am a breast medical oncologist at Massachusetts General Hospital in Boston and at Harvard Medical School.

Dr. Stephanie Graff (Brown University Legorreta Cancer Center): I am Dr. Stephanie Graff. I am a breast medical oncologist at Brown University Legorreta Cancer Center in Providence, Rhode Island. We are honored to be here together today with Clinical Care Options, talking about Advanced Precision Care and Shared Decision-making and First-Line HER2+ Metastatic Breast Cancer Management.

Dr. Spring and I are going to be covering a lot of ground. Laura, I think we agreed we are just going to be Laura and Stephanie today while we are talking. Right?

Dr. Spring: Yes, that sounds good.

Dr. Graff: I think one of the exciting things that came out through 2024 was really looking into the role of trastuzumab-deruxtecan for patients with HER2+ breast cancer.

Dr. Nancy Lin presented the results of DESTINY-Breast12 at San Antonio.

Dr. Graff: DESTINY-Breast12 was a multicenter, single-arm, two-cohort study that accrued patients who had HER2+ metastatic breast cancer that had previously received two or fewer prior lines of therapy. Patients were eligible if they had brain metastasis. It also did include a cohort of patients who had no brain metastasis for comparison, but it was nonrandomized, and all patients received trastuzumab-deruxtecan at 5.4 milligrams per kilogram IV every three weeks.

The primary endpoint in the brain metastasis cohort was progression-free survival, and the primary endpoint in the no brain metastasis cohort was objective response rate. Secondary endpoints did include things like central nervous system, PFS, and overall survival. Lots of interesting data was presented.

At San Antonio, we saw the results of the overall progression-free survival in the group that both had and did not have brain metastasis at baseline. We saw that progression-free survival was similar to what we have seen with other trials looking at trastuzumab-deruxtecan for patients with HER2+ metastatic breast cancer, with a 12-month PFS of 61.6%. The PFS in the brain metastasis cohort was similar at 58.9%, which was reassuring.

The overall survival and the objective response rate in patients without brain metastasis at 12 months was 90.3%, which was wonderful. Really high objective response rate, 62.7%. Then when they got into the details of how patients with brain metastasis responded, we did also see that there was a really great response in the CNS. I think that seeing that CNS response really offered me a lot of confidence in a clinical setting that for my patients with brain metastasis, trastuzumab-deruxtecan is a very effective therapy that likely crosses the blood-brain barrier and offers good clinical control for those patients.

I think before we had seen this splitting in big national guidelines, whether it was asthma or NCCN or for patients with brain metastasis based on HER2CLIMB, there was some discussion about perhaps going to tucatinib in that patient population in that second-line setting.

Now I think that given the body of evidence for HER2+ metastatic breast cancer, even in the setting of brain metastasis, I feel very comfortable utilizing trastuzumab-deruxtecan. Unless, of course, there is another indication, perhaps interstitial lung disease that would drive me toward choosing tucatinib-based therapy. How has your practice been shaping up, Laura?

Dr. Spring: Yes, I completely agree. I think seeing the similar PFS in the group with and without brain metastases was very reassuring. That algorithm was always one of debate, which way to go. I think with how impressive this drug has been for response rate overall, this was very helpful data and helps support its use in the earlier lines.

Dr. Graff: Yes. Then I think another thing that is interesting is, of course, Dr. Lin did get a question from the audience about the risk of radionecrosis with radiation relative with trastuzumab-deruxtecan ADCs have been associated with that. She had said in her practice that traditionally they have been waiting three to four weeks after radiation prior to starting or try to create that space.  

That is what we have been doing as well. Of course, if we have a small or clinically asymptomatic brain metastasis, I do think it is okay to omit radiation or do surveillance with brain imaging, but some patients prefer still to do stereotactic radiosurgery. Obviously, we have got fantastic radiation oncology techniques, that often, patients are amenable to both options. Combination therapy. How have you guys been approaching that?

Dr. Spring: We have been doing something very similar. Not doing the drug concurrently with radiation. I think we have more published data with T-DM1 showing the radiation necrosis risk as well. I think there is a concern that we would see the same here. I think that there is some debate on exactly how long to wait. Obviously, there is a drug with a long half-life. We have had some situations and more urgent cases where there has been some debate, systemic therapy first versus can we do radiation first? Which is what we traditionally would do.

There I think we sometimes debate doing a little shorter afterwards, but I think especially if you were to treat with T-DXd with someone receiving it in advance, with the long half-life, it is trickier because it would be on board unless you wait a bit before doing the radiation.

Dr. Graff: I think all of this complexity about how to approach particularly oligo metastatic brain metastasis lends itself well to interdisciplinary teams. I know we are going to have a case coming up that our audience hopefully will join us and participate in online. Check that out, and you can participate in our case and share with us how you would answer questions like these.

Dr. Graff: What do you think the role of tucatinib is? Do you think that tucatinib is just now our standard third-line therapy?

Dr. Spring: That is, I think, a difficult question as we think about if T-DXd moves to the first line.

Dr. Graff: Right now, we will say we are still CLEOPATRA / T-DXd.

Dr. Spring: Right now, I think I view it [tucatinib] as a more solid third line. I think the combination with capecitabine and trastuzumab obviously it is tricky with two oral drugs and IV. Capecitabine does have some CNS activity as well. I think also maybe generation of real-world data on the efficacy of the HER2CLIMB regimen after T-DXd. I think there is some initial data in that space available, but it would be interesting to see that.

In my own experience, I have overall just gotten more mileage out of T-DXd even with CNS disease, than I have with the HER2CLIMB regimen. I have also had patients who have tolerated the HER2CLIMB regimen much better than T-DXd. When we talk about biomarkers, also, more predictive biomarkers regarding things like ILD and tolerability

Dr. Spring: Another study I would really like to discuss with you today is the PATINA study. This was another really interesting presentation at San Antonio. This was a open-label phase III trial that looked at the addition of palbociclib to anti-HER2 therapy, plus endocrine therapy versus standard anti-HER2 therapy plus endocrine therapy in those with hormone receptor-positive/HER2+ metastatic breast cancer.

These are patients who are essentially in the first-line with the exception that they got their initial induction chemotherapy. Typically, 6 to 8 cycles of trastuzumab plus/minus pertuzumab with a chemotherapy partner, typically a taxane. Then, typically in standard of care, we drop the taxane or the chemotherapy backbone and then continue on with HP indefinitely until progression or changes in goals of care or side effects.

In this interesting study, with the endocrine therapy portion, the CDK4/6 inhibitor palbociclib was added at standard dosing 125 milligrams daily days one through 21 followed by a week off, and they continued on this until progressive disease or toxicity.

The primary endpoint was progression-free survival by investigator.

We saw overall a significant improvement in the median progression-free survival, I believe, over 15 months, favoring the addition of palbociclib. Stephanie, when you heard this result, were you surprised? What was your first impressions?

Dr. Graff: Yeah, I really loved Dr. Hurwitz's, I started to say editorial. She was the discussant after Dr. Metzger presented this and pointed out appropriately that these patients were already selected in that they had not progressed on the triplet of chemo plus HER2-directed therapy and had been able to de-escalate, for lack of a better word, to the HER2 therapy alone, which already was telling you that these are patients that were performing well.

Most of them had a clinical response and so that point that you are able to say, "Okay, we can drop off the chemo, you are doing great. You have already selected a good group of patients." This really, really good endpoint may be in part related to that, but I loved seeing these numbers come out of a metastatic breast cancer trial.

My immediate reaction was that this is immediately practice changing. I started running a list in my head of patients I would want to reach out to when I got back to clinic after San Antonio.  

It was exciting to see because it was a trial that actually was difficult to accrue to, nationally. It is a good moment for all of us to reflect on how valuable this cooperative group research is and the role that studies like these play in helping us advance the standard of care in our field.

Dr. Spring: I agree completely. I think it is really nice results to see but as you point out, this is a population of patients who often will do very well for years, which is great. Can be on HP for several years. I guess I wonder a bit and hope there will be some maybe follow-up analyses trying to really pick out what are the patients that benefit the most from this strategy.

On the other hand, it is a pretty well-tolerated drug. I think we all find that, and obviously, there is the opportunity for dose reductions when needed as well, but I assume they have some interesting translational analyses planned, so maybe we will learn more from some sub-studies in the future.

Dr. Graff: Yeah, and I did see also in the aftermath of the presentation I saw on social media some patients and some clinicians were asking about other CDK4/6 inhibitors. I would just say, "No, not yet." Of course, the other CDK4/6 inhibitors outside of palbociclib do have some unique cardiotoxicity that outside of the context of a clinical trial actually have black box labels from regulatory agencies that they should not be combined. Drug-drug interactions are a real problem in our field that we have to consider carefully.

Dr. Graff: Yeah. Laura, one of my questions in the context of PATINA, building on that for you is: I think PATINA has such to me again, immediate impact.

How are you thinking about moving T-DXd to the first line?

Dr. Spring: Yeah, I feel like I give it [T-DXd] like candy, but it is not candy. I wonder if we are going to see folks do their own induction strategy like a CLEOPATRA model of 6 to 8 cycles because even I have a group of patients who tolerate it very well. As you said, after time it just gets tough. These people who have been on this agent [T-DXd] a couple of years, it really just gets so hard. These are some of my most enjoyable appointments-- Sometimes our patients on HP for years.

I do not think we as a breast oncology community can really imagine giving it [T-DXd] indefinitely. Maybe there will be enough push. I would love to maybe see a trial using it in that induction setting. I am sure maybe they will want more than six cycles, maybe a little bit more, and then actually doing a PATINA type approach like to see that in sequence.

I know another case that we will be talking about at our upcoming webinar is specifically asking about some drug-drug interactions. Again, just a little teaser for everybody to check out our upcoming webinar on first-line HER2+ metastatic breast cancer to think through some of these issues with us. Considering both what the patient takes for their standard of care drugs and how our cancer therapies interact with each other is always an important part of what we do in the art of oncology. I hope we will see you at that webinar.

Dr. Spring: Yes. Please remember to tune in for the webinar on discussion of First-Line Therapy in HER2+ MBC.

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