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HER2 Positive mBC: New Options
Takeaways From a Large Educational Program on Available and Emerging Treatment Options for HER2-Positive mBC

Released: July 25, 2025

Shipra Gandhi
Shipra Gandhi, MD, MS
Laura Spring
Laura Spring, MD
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In this episode, listen to Laura M. Spring, MD; and Shipra Gandhi, MD, MS, share their takeaways from a large educational program on available and emerging first-line treatment options for patients with HER2-positive mBC:

  • Emerging new data from the phase IIII DESTINY-Breast09 trial of first-line treatment with trastuzumab deruxtecan ± pertuzumab vs THP for advanced HER2-positive breast cancer
  • Interactive decision support tool with recommendations from 5 experts for the treatment of HER2-positive breast cancer
  • Outcomes data from a live webinar on applying the latest data for first-line management of HER2-positive mBC, including analyzing the latest clinical results and developing tailored interventions to address challenges with novel ADCs

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

The DESTINY-Breast09 study was one of the major presentations at ASCO 2025. This was a global, randomized, three-arm phase III trial enrolling 1,157 patients with untreated HER2-positive, locally advanced or metastatic breast cancer.

There were three comparison arms. One was trastuzumab deruxtecan, T-DXd, plus pertuzumab, that enrolled 383 patients. That was one of the arms that was presented at ASCO. Another arm, the data was not yet reported is the T-DXd plus placebo arm, which enrolled 387 patients. The comparison was standard THP, so a standard taxane plus trastuzumab plus pertuzumab, enrolling 387 patients.

I think importantly, whenever we look at a study, it is important to think about the cohort characteristics. In this trial, about 50% of patients had de novo metastatic disease, and about 54% were hormone receptor-positive. Overall, nearly half of the patients had received treatment in the early-stage setting.

The key efficacy outcome for DB09 was progression-free survival. Overall, the median progression-free survival was 40.7 months with T-DXd plus pertuzumab versus 26.9 months with THP. This result was even more pronounced when you looked at the investigator-assessed PFS, 40.7 months versus 20.7 months for a hazard ratio of 0.49.

There are multiple other secondary endpoints as well. The 24-month PFS rates were 70% versus 52% favoring T-DXd plus pertuzumab. The objective response rate was 85.1% versus 78.6%, again, favoring T-DXd plus pertuzumab. In terms of complete response rate, 15.1% versus 8.5%, again, favoring T-DXd plus pertuzumab.

Overall survival data are immature at this point, with the trend favoring T-DXd plus pertuzumab.

Another important aspect to consider is safety. In terms of grade 3 or greater treatment-emergent AEs, it was pretty similar in the two groups. In terms of serious treatment-emergent AEs, that was 27% versus 25.1%. Again, fairly similar between the two groups.

Of course, a really important area of interest is interstitial lung disease. ILD occurred in about 12% of patients on T-DXd plus pertuzumab. This was mostly grade 1 to 2. About 0.5% of cases were grade 5. Overall, this 12% is compared with just 1% in the THP arm. Other side effects like nausea, vomiting, and constipation were more common in the T-DXd arm, but no new safety signals were identified.

Overall, this was a major study presented at ASCO and is creating a lot of buzz, of course, in the oncology community. T-DXd plus pertuzumab significantly increased the median PFS compared to the long-standing THP regimen, and represents the first major advancement in the first-line treatment of metastatic HER2-positive breast cancer in over a decade.

This does establish a potential new standard of care. There are a number of clinical questions, though, that come up with this study, as many people know. T-DXd compared to THP, there is a difference in tolerability. With the THP regimen, we often drop the taxane after several cycles, and patients can then continue on HP for a long, long time and experience a very good quality of life. That has, I think, been a major topic of discussion.

Dr. Gandhi: DESTINY-Breast09 presented remarkable results showing us that the first-line standard of care has likely now changed to T-DXd plus pertuzumab. We wanted to go over a clinical interactive decision tool for HER2-positive metastatic breast cancer.

In this tool, five experts in breast medical oncology were questioned about their preference for first-line management of metastatic breast cancer. Unanimously, everyone agreed on the CLEOPATRA regimen. That is the taxane plus trastuzumab and pertuzumab, which would be the standard of care in the first-line HER2-positive metastatic breast cancer setting.

A couple of experts also said that they would consider stopping the taxane after several cycles because of potential for cumulative toxicity, and then just continuing patients on trastuzumab and taxane.

At San Antonio last year, 2024, we also heard the data from the PATINA trial, which was a phase III randomized clinical trial that enrolled triple-positive metastatic breast cancer patients in the first-line setting, who had received induction with the CLEOPATRA regimen. That was taxane, trastuzumab, pertuzumab for six cycles. Those patients who had a complete response, partial response, or stable disease, they were then randomized to either continue the trastuzumab/pertuzumab with endocrine therapy, or the other arm was when palbociclib was added to this combination. It was trastuzumab, pertuzumab, endocrine therapy with palbociclib.

In this study, we saw that there was a remarkable improvement in progression-free survival from 29.1 months to 44.3 months, with a hazard ratio of 0.74, showing a 15-month improvement in progression-free survival. Based on this data presented from the PATINA trial, the experts were again questioned as to how their treatment recommendation would now change for metastatic triple-positive breast cancer patients. Unanimously, everyone agreed that they would still continue treating these patients with taxane, trastuzumab, and pertuzumab. But again, based on the PATINA trial, everyone favored dropping taxane after six to eight cycles or maximum response, and then considering continuing trastuzumab-pertuzumab with the addition of palbociclib and endocrine therapy as maintenance in patients who have achieved a good response or a stable disease after induction treatment.

Then at ASCO this year, as Dr. Spring had already presented the data from DESTINY-Breast09, all the five experts were again questioned as to how their treatment recommendation would now change for HER2-positive metastatic breast cancer patients?

I think the data from DESTINY-Breast09 was very encouraging, showing that T-DXd is not only effective in the second-line setting, which we already have seen data from DESTINY-Breast03. But now, based on DESTINY-Breast09, T-DXd with pertuzumab had a remarkable improvement in progression-free survival compared to the CLEOPATRA regimen. Everyone agreed to treat patients with T-DXd and pertuzumab in the first-line setting in metastatic HER2-positive breast cancer.

However, I think all the experts agreed that there has to be some kind of shared decision-making, because it is clear that T-DXd is a very effective agent, both in the second-line and in the first-line setting. But given the toxicities associated with T-DXd and the dose interruptions and dose reductions that were seen on the clinical trial, the question is that, would a first-line approach be more effective, or could this also be given in the second-line setting?

I think the sequencing question could not be very well addressed by the design of DESTINY-Breat09, because in the control arm, that was THP, only 10% patients had gotten T-DXd in the second-line setting. Although the PFS2 was higher in T-DXd plus pertuzumab, given the small number of patients who actually had the crossover and got T-DXd in the second-line setting, I think the question could not be fully addressed.

This brings us to the question of whether you would give T-DXd plus pertuzumab to all the patients, or would there be a subset of patients? I think all the experts agreed that they would give it. They would prefer it in the first-line setting, but there are some patient populations where we would definitely want to consider T-DXd plus pertuzumab. Those would be patients with brain metastases or patients with a significant amount of visceral disease, or those who have had recent progression after neoadjuvant or adjuvant HER2-targeted therapy.

On the DB09, the disease-free interval had to be more than six months. For this patient population, which is representing aggressive disease, where the recurrence is happening even six to 12 months after completion of anti-HER2 therapy, I think we would prefer the T-DXd plus pertuzumab regimen.

For the triple-positive metastatic breast cancer patients, I think the other question is, the PATINA trial looked so impressive, where addition of palbociclib to AI and trastuzumab plus pertuzumab prolonged progression-free survival. On DB09, T-DXd was continued until disease progression, so it is not clear as to what should be the duration of T-DXd. Do you really need it until disease progression? Or should we wait until maximum disease response and then potentially switch T-DXd to trastuzumab?

A lot of experts thought that we may also continue T-DXd until maximum disease response. For a triple-positive metastatic breast cancer patient, we could have a maintenance strategy where we are doing trastuzumab plus pertuzumab with the addition of palbociclib and AI.

Some of the experts also thought that there could be shared decision-making. For example, if a patient has a very slow-growing disease, de novo disease, and has a low volume of disease, a lot of comorbidities where we do not think we would want to treat these patients with T-DXd plus pertuzumab, we could potentially also consider the CLEOPATRA, taxane, trastuzumab and pertuzumab regimen for those patients.

Laura, now I would just turn it over to you. I would like to see what your thoughts are as to who are the patients you think the DB09 regimen would be applied in the first-line setting, and what are your thoughts on the duration of treatment with T-DXd.

Dr. Spring: These are great questions, and I agree with all your comments. I think it is tough because the patient population included patients who were treated in their early breast cancer setting. As you said, some recurred early, and that is definitely the group we are more concerned about. It also included patients with de novo disease.

Clearly, they benefited from T-DXd plus pertuzumab as well. But that is also a patient population that we know has done so well with THP, and then shifting to maintenance HP. I think we all can recall or have patients who have been on maintenance HP for years.

When I think about indefinite T-DXd, it is hard to think about that. It is a drug that, over time, not for all, but for many patients, can get harder. The fatigue impact is significant, of course. Nausea is common as well.

I am very interested in the idea of induction. I know that is being explored in some current studies and discussions about different study designs, I am sure, as well. How do you define that, I think, is one challenge. Or do you take the approach where it is a set number of cycles, like we do with the taxane? Sometimes people think about six to eight cycles. To individualize it would be most helpful, but I think we need some trial guidance on how to best do that.

As you said as well, the PATINA data, how do we think about that in the context of DB09, when those results were so impressive as well? We know for patients who also have hormone receptor-positive disease have this additional tool that we could use.

Dr. Gandhi: Yeah, I totally agree about your comment on the duration of treatment. I think it is unclear if we should do six to eight cycles, or should we do it until maximum disease response. Clearly, there are clinical trials that are being designed to answer this very question.

I think another discussant at ASCO had also mentioned that who are the patients where we really think the DB09 regimen would be preferred? Specifically for patients with brain metastases, recent disease progression, significant visceral disease, as well as those with the PIK3CA mutation. Because when we see the results from taxane, trastuzumab-pertuzumab, it is really these patients with the PIK3CA mutation who are not doing very well on that regimen.

When we saw the results from DB09, both PIK3CA mutation, I think there were 30% patients on DB09 with PIK3CA mutation. They had superior outcomes compared to the THP regimen. If we are trying to tease out particular subsets of patients who would benefit from T-DXd plus pertuzumab, I think we have to consider the clinical factors as well as certain biomarkers where we really think this regimen would be superior compared to THP.

Dr. Spring: I agree. I think that was a really interesting discussion point about the PIK3CA mutations. I think often we are not as focused on genomic testing for first-line HER2-positive MBC. This could change that.

Dr. Gandhi: I think it is so interesting that over the last six months, the treatment for first-line metastatic, HER2-positive breast cancer has significantly evolved from the taxane HP regimen. We see this data with the hormone receptor-positive, HER2-positive PATINA regimen and now with DB09. Now, we are actually trying to think how to incorporate the PATINA into the DB09 design, especially for our triple-positive metastatic breast cancer patients.

Dr. Spring: I think it is going to be really interesting to look at real-world data over time to see how folks do apply this. I imagine a few different approaches will happen where T-DXd is either, as we said, used until you reach a maximal response, or a plateaued response. Some may use it, as we said, for six to eight cycles. Probably more commonly, others may use it through shared decision-making and tolerability that it is decided to stop and transition, say, to HP. For those with HR-positive disease, I think that is where the PATINA regimen will come into play as well.

Dr. Gandhi: A survey for persistent educational needs was conducted to understand first-line treatment after adjuvant anti-HER2 therapy. Learners showed marked improvement in evaluating the latest data. There was a 25% increase and ability to tailor interventions for addressing safety profile challenges with antibody drug conjugate therapy. There was a 17% increase following CME education.

Most of the learners also indicated that the decision topics helped increase their awareness about these topics, and that they will be sharing or integrating this new information with their colleagues.

Dr. Spring: One of the situations was considering a patient with progression of six months or less on either neoadjuvant or adjuvant pertuzumab-containing regimen, and whether or not that patient would be a candidate for front-line T-DXd. On the pretest, 62% felt they would be a candidate. And then the post-test, there was an increase in understanding of the recommendations, and 84% felt that patient would be a candidate for T-DXd.

Of course with the DB09 data, this is all evolving, and there will be greater use of T-DXd in the early line settings.

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