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Changing the Paradigm in HER2-Positive Early Breast Cancer

Dr. Shanu Modi (Memorial Sloan Kettering Cancer Center): Hi, my name is Shanu Modi. I am a breast medical oncologist at New York City in Memorial Sloan Kettering. I am joined today by Dr. Sara Hurvitz, who is also a breast medical oncologist and director of the Clinical Research Division at the Fred Hutchinson Cancer Center in Seattle, amongst the many other hats she wears.

Welcome, Sara.

Dr. Sara Hurvitz (Fred Hutchinson Cancer Center): Great to be here. Thank you.

Dr. Modi: We are here together to discuss updates in early‑stage HER2‑positive breast cancer. To me, that means we need to discuss the two big trials from last year, which are DESTINY‑Breast11 and DESTINY‑Breast05.

You and I have been involved with HER2‑positive clinical research for a good part of both of our careers. I would say it has been a fairly predictable field. It is very algorithm‑driven. We have a lot of consensus. It is a pretty easy conversation in oncology. I feel like that predictability has been upended this past year with these two trials. It has really opened things up, and now we have new options, but also potentially less uniformity in our approaches. It makes it more interesting and obviously allows us to tailor therapy. It is a great conversation, I think, that we are going to have.

Maybe before we launch into DESTINY‑Breast11 data, why don't I ask you to walk us through how have you been sequencing therapy in the neoadjuvant/adjuvant setting for early‑stage disease before these trials? What is the standard?

Dr. Hurvitz: It certainly has become increasingly tricky and long consultations and discussions now, whereas before, we had a standard way to manage early‑stage breast cancer that was HER2‑positive and frontline metastatic, and now we will talk about options and the embarrassment of riches.

Prior to the readout of DESTINY‑Breast11 and DESTINY‑Breast05, my standard of care for somebody with stage II to III non‑metastatic breast cancer that was HER2‑positive was for a healthy patient to offer the TCHP regimen. In the past, AC‑TH was also a standard. It was the original standard. However, we have seen a lot of evidence mounting showing that omission of the anthracycline is safer, does not appear to have worse outcomes to omit the anthracycline and use the TCHP regimen. In some cases, numerically, the pathologic complete response rate or longer‑term outcome may even be better.

I think maybe five years ago, NCCN guidelines shifted to moving AC‑TH‑based therapy to another regimen, whereas the TCHP has been the regimen. For a patient with a smaller T1 HER2‑positive breast cancer that was node negative, many of us grappled with whether we would start with APT‑type regimen or THP in the neoadjuvant setting, and then choosing what to do, especially if they are T1c based on the pathologic response.

In the very small T1a/T1b setting, waiting for the adjuvant setting was perfectly appropriate. Many of us adopted single‑agent paclitaxel‑trastuzumab based on the APT trial.

Dr. Modi: We are pretty aligned in that. This has been a real standard way of treating HER2‑positive early‑stage breast cancer. DESTINY‑Breast11 was a really important study; the first trial to bring T‑DXd, or trastuzumab deruxtecan, to early‑stage HER2‑positive breast cancer. It is also really the first time we are seeing a new regimen in a phase III trial show superiority over a standard‑of‑care treatment for early‑stage HER2‑positive disease, not just equivalence, as you were saying.

Just to briefly remind the audience, DESTINY‑Breast11 was a randomized global phase III study. It was for patients who had high‑risk HER2‑positive breast cancer, and they were randomized to one of three neoadjuvant therapies. The standard of care arm, which was dose‑dense AC‑THP, a monotherapy T‑DXd arm of eight cycles, or a sequence T‑DXd arm; so, four cycles of T‑DXd followed by four cycles of THP. The primary endpoint, of course, was to look at pathologic complete response. As we all heard, the monotherapy arm surprisingly was closed early due to a low pathologic complete response rate.

In the end, DESTINY‑Breast11 is really a study comparing two arms, the standard of care and the sequence T‑DXd, THP. Great data. Of course, we saw very impressive statistically significant improvement in pathologic complete response rate in favor of the T‑DXd arm, 56% pathologic complete response rate with AC‑THP moving up to 67% with the T‑DXd sequence arm. A gain of 11% in pathologic complete response rate. We saw this advantage in the hormone‑positive patients, we saw it in the hormone receptor‑negative patients, and at this early point, even a trend for event‑free survival.

What was the most important corollary to all of this was the safety. What we saw was safety profile also favored the T‑DXd arm, which was a little bit surprising but reassuring to see. In many ways, I saw this as a win‑win trial for patients. My question to you is, what were your impressions of the data and key takeaways?

Dr. Hurvitz: Yes, I agree it is a very unique study and the first of its kind to demonstrate an ADC can replace a component of chemotherapy in the neoadjuvant setting. The KRISTINE trial that tried that, obviously with T‑DM1 + pertuzumab, did not meet that level of evidence. The pathologic complete response rate was significantly inferior to a TCHP regimen. This is historic in many ways.

I thought the data were very interesting. Many of us in the US criticized it for not using the TCP arm as the comparison arm. However, that said, as I said earlier, TCHP and AC‑THP seem to have similar outcomes. I would call out that this was a high‑risk patient population. The majority of patients, almost three‑quarters, had estrogen receptor co‑expression of their tumors. It was also very uncommon to have node‑negative. Under 10% had node‑negative disease. I would not necessarily apply these data to patients with N0 breast cancer, but the improvement in pathologic complete response was certainly notable, statistically significant for both ER‑positive and ER‑negative. EFS was not different. It was not powered for EFS. People talk about the trend being in that direction. There are really only seven events that span the two arms that differ between the two arms. I am not ready to say that those are long‑term outcomes in support of the use of it in the neoadjuvant setting. If it were the only thing presented at ESMO, it would have been like a standalone change in the practice of care. It was presented the same day as the DESTINY‑Breast05 data were presented. That almost got overshadowed, in my opinion, by DESTINY‑Breast05.

Dr. Modi: That is interesting. You raised so many good points there. First of all, the DESTINY‑Breast11 really was a very high‑risk population. They were careful in choosing those patients given the risk‑benefit. Appropriately done, I would say. Were you surprised by the FDA giving that broad approval for all stage II and all stage III patients? It sounds like you are not really going to use it in that fashion. I mean, really limit it to your higher risk population.

Dr. Hurvitz: Yes. It is interesting that FDA seems to be giving broader approvals, giving clinicians the freedom to practice the art of medicine within the confines, but not perfectly matching the trial population and the eligibility criteria. I do not think that is the incorrect thing. I think it is really incumbent upon us to interpret the data and look at the patient sitting before us, as well as their comorbidities and how likely they are to tolerate a given therapy while making an appropriate decision.

Dr. Modi: Yes. Totally agree. That was a welcome decision in many ways. It does allow us to individualize treatment, as you said. What did you think about the ILD rates? Those were really reassuring, I thought. Four cycles, we saw about 4% in both arms of the trial. Very reassuring. How are you planning to monitor patients if you are going to use this approach?

Dr. Hurvitz: Very reassuring indeed. Keeping in mind patients only received four doses of T‑DXd in the arm that actually was superior. Was a bit surprising to see ILD in AC‑THP arm when we do not really see that clinically. Because they are being monitored every six weeks, you are going to pick up that asymptomatic ILD, and perhaps our focus and attention on ILD is biasing or making us call it more than we would have in the past 10 years ago when a lot of these other trials were being done. Very reassuring.

I still think patients should be monitored intensively. It is a curative setting. To lose a patient to ILD because there are grade 5 events that occur would be a tragedy in the curative setting like this. I think it would be tough to get every six‑week scans ordered and scheduled and approved by insurance, but I would try to do it every eight weeks, at least.

Dr. Modi: Yes. They did do those scans even in the control arm, the Q6 weeks. We saw ILD rates that we did not know about even with AC‑THP. It was very illuminating.

Let us jump for a moment to DESTINY‑Breast05.Another important global phase III trial, as you said, both were presented at the same time, and you could not give either one their due. This was once again a very carefully curated population of high‑risk, HER2‑positive patients with residual disease, in spite of standard neoadjuvant treatment. Then randomized to either T‑DM1 for 14 cycles or T‑DXd modelled right after the KATHERINE trial.

The primary endpoint was met. We saw a very impressive, statistically significant improvement in invasive disease‑free survival in favor of T‑DXd with a hazard ratio of 0.47. More than a 50% decrease in the risk of recurrence on the T‑DXd arm. When we look at the three‑year iDFS rates, 84% with T‑DM1 and 92% with T‑DXd. That is a delta of almost 9%. It is even more impressive when you consider that these were the highest‑risk residual disease patients. For me, I think this was one of the most exciting results from last year in that ESMO meeting.

The FDA again gave DESTINY‑Breast05 that really broad label. We have the option to use this, based on discretion for patients who have done at least some neoadjuvant taxane, trastuzumab‑based therapy and have residual invasive disease. Not the strict DESTINY‑Breast05 population.

Now come the really hard questions. You have a high‑risk patient sitting in front of you in the clinic tomorrow, and you have got both of these trials, a lot of options. A lot of flexibility now. How are you going to select the choice of therapy for this person? Is it pathologic complete response? Is that the critical endpoint for you, or are you more in line with the idea we can reserve escalation for a selected population, and that is your preferred strategy?

Dr. Hurvitz: I try to echo the eligibility criteria of a trial as much as possible when I am applying data. I do appreciate the freedom that the FDA has given us to select therapy and use the factors we have associated with the patient before us to make the right decision for them.

A 29‑year‑old with high‑risk disease is different from somebody who has got a lot of comorbidities and competing issues, for example. There are a lot of clinical features we have to digest as we are making our recommendations.

That said, for a very high‑risk patient, as you said, patients to get on this study had to have inoperable disease at diagnosis or lymph node metastases at the time of surgery. It was not just a little bit in the breast, unless they were inoperable from the get‑go. For my highest‑risk patients, I would rather give them the treatment that you can give longer, 14 cycles, and that is associated with a clear invasive‑free survival benefit. I trust that, ultimately, we will see survival benefit because the data are as compelling as KATHERINE were when they were presented. I would prefer to use that after proving that the patient needs it, because there are some patients who appear very high‑risk at the get‑go when you have the diagnosis, but you give them TCHP, for example, and the disease melts, and it is all gone at the time of surgery. Really, they probably do not need T‑DXd. My bias is to use it that way.

That said, if there is a patient who I start on THP or maybe even TCHP, and I go three or four cycles ‑ and I always do image midway ‑ and it is really not responding, there is clearly going to be residual disease. The NCCN guidelines allow us to reverse the orders. Maybe then that is when I switched to T‑DXd and give that to try and get that pathologic complete response. Pathologic complete response is important, but long‑term, it is the iDFS that is compelling.

The final thing I would say is we see in the metastatic setting, as you well know, CNS benefit with T‑DXd over and over again. For the very high‑risk patients, having the opportunity to use it in the adjuvant setting for 14 cycles makes me feel like we are doing more to protect the brain.

Dr. Modi: Yes. This keeps coming up. There was some indication, although it is pretty early right now in these trials to definitively say anything, but a hint that we may be seeing some benefits from T‑DXd in the CNS space as well in early‑stage disease.

Are there any scenarios where you might use T‑DXd in the neoadjuvant setting and then follow it up with more T‑DXd in the adjuvant setting, sequencing almost DESTINY‑Breast11 and DESTINY‑Breast05, if you will?

Dr. Hurvitz: Yes, that is a great question. I have actually been discussing this with colleagues at conferences and at my institution as well, because the FDA was clear that it is an either/or, not a both, but NCCN guidelines are more permissive. I think that I might. I might do that because what do you do in a patient who has had what you think is a clinical response to neoadjuvant T‑DXd for four cycles, but there is residual disease in the nodes? Especially knowing that T‑DM1 requires high homogeneous levels of HER2 expression for activity. T‑DXd may be selecting out and killing those HER2 overexpressing cancer cells. In that situation, it might be better to continue the T‑DXd. I think I would. What about you?

Dr. Modi: Yes, it is a really difficult question, because it comes down to the point: what does that residual disease represent? Is it resistant disease, or is it just insufficient therapy? We do not really know how many cycles of T‑DXd we really should be giving. Is it four? Is it 14? I will say this one thing we have never done before is give more cycles of the same drug when we have residual disease. We do not give more THP when we have residual disease. We traditionally have moved to an alternate therapy.

It was interesting when we looked at the monotherapy T‑DXd arm of eight cycles. We did not really see an impressive pathologic complete response there. It was higher to switch out to use four and four of something else. It is a question, like you said, it keeps rearing its head because nobody really knows what to do after T‑DXd. What is really going to work? We are concerned about the potential lowering of the HER2 levels and how well does T‑DM1 perform there. Then, of course, how many cycles do you give? Do you commit to 14, and then ILD becomes a real risk again. A lot of unanswered questions. The reality is most of these patients will be hormone‑positive patients as well. We have great endocrine therapy to offer, and there is more ADC therapy. What they really need.

There are so many factors to consider in that decision. I don't think we are going to have one single easy answer for all of the scenarios really. It is a data‑free zone. At the end of the day, I view it as we have a lot of standard of care options. Even potentially giving more AC chemotherapy for high residual burden. This is probably a great place for a clinical trial. I think this is something we are going to have to, at some point, address, looking at the residual disease and the biology and figuring out what is really the right thing to do for these patients.

Dr. Hurvitz: Yes. To your point about endocrine therapy, the data that came out of San Antonio, indicating that we really do need to treat aggressively with endocrine therapy, even in HER2‑positive disease, was a little bit paradigm‑changing, because we were thinking it is all about the driver amplification, and it is important. I do think that should be taken into consideration when we are dealing with residual disease.

Dr. Modi: Absolutely. I am going to switch us for a moment now just to touch upon metastatic setting.

The first‑line metastatic setting, because the other really big trial that came out just recently was the DESTINY‑Breast09 ‑ it feels like a long time ago now ‑ which was a first‑line study. Again, it was a big practice‑changing trial in the field where we have the option now to use T‑DXd + pertuzumab as first‑line therapy, really displaced CLEOPATRA after more than a decade. First combination to do that too.

Has that become your new first line? Is that what you are using standardly?

Dr. Hurvitz: I know, just like we started in the beginning, it has become super complicated. It was so simple for like 10 years. So simple. I would not say I am doing that for everyone, but it is certainly enters the discussion. We do not yet have the single‑agent T‑DXd data from that study, which may change things. We do not have survival yet. There was not crossover built in, so we do not know how much the patients are losing by waiting until the second line or if they are losing anything. There are unanswered questions.

However, for somebody with very symptomatic visceral metastases, liver dysfunction, previous exposure to taxane and trastuzumab, maybe ER‑negative disease where your maintenance options may be a little less, I definitely discuss it with patients. The PFS data are super compelling, but it is not just a simple knee‑jerk reaction.

Dr. Modi: One of those scenarios where we are potentially seeing a divergence in practice is that hormone‑positive, HER2‑positive patient population again, with the PATINA data. Always do it cautiously. However, the cross‑trial comparisons, really impressive numbers. We are in the same ballpark potentially. Adding a CDK4/6 inhibitor was very, very impressive. Following right along that was the HER2CLIMB-05, as you said, and compelling for a lot of reasons to the brain met potential and specifically for those hormone receptor‑negative patients. A lot of things happening in this space.

Coming back to the early‑stage setting, as we are going to now use T‑DXd for our early‑stage patients, how will this affect that first‑line metastatic setting? Thankfully, we are probably not seeing them today, but it will not be a lot of patients, I hope, but there will be some patients who are going to relapse from early‑stage T‑DXd.

What is your first‑line approach looking in that scenario?

Dr. Hurvitz: It is going to depend on whether or not there are CNS metastases. How long it was, the disease‑free interval from receipt of last T‑DXd. What agents are available at that time. There is a lot in discovery now for patients exposed to prior T‑DXd. We may have something like zanidatamab, zongertinib, evorpacept. We just do not know how it is going to look by the time we start seeing these patients.

What about you?

Dr. Modi: I think you hit on the key point. For me as well is, what does that disease‑free interval look like from the prior T‑DXd? That has been a pattern of practice, whether it is right or wrong, but that 12‑month magic number, we have used that a lot. The longer the interval, the more likely I am to go back to something like T‑DXd as a first‑line option. In those rapid relapsers, that is going to be a very challenging patient population to treat. We may even think about going back to something like THP potentially. Biology is going to have to really guide us as to what works for those patients. Still so much more work left to do. Two steps forward and still many, many more to go.

I think we covered so much territory, and we certainly made it through some of the key paradigm‑shifting HER2‑positive trials of last year. Thank you, Sara, for sharing your insights. It is always a pleasure to talk to you about science, medicine, and HER2‑positive breast cancer.

Dr. Hurvitz: Thanks so much, Shanu.

Dr. Modi: I also want to mention that I will be working on a CME‑certified video module and an interactive example patient case that will be posted on the Decera Clinical Education website elaborating on this data and best practices for neoadjuvant treatment.

Thank you, everyone, for listening with us. Until next time.