HER2+ Horizons: Debates and Decisions in Metastatic Breast Cancer: Episode 1

First-Line Therapy—Has the Standard of Care Shifted for Good?

In this episode, Dr. Sara Tolaney, of Dana-Farber Cancer Institute, discusses how DESTINY-Breast09 is redefining first-line treatment in HER2-positive metastatic breast cancer. She explores whether T-DXd plus pertuzumab should replace the long-standing THP regimen, the future role of induction-maintenance strategies, and open questions on optimal therapy duration.

Transcript

Dr. Tolaney: My name is Sara Tolaney. I’m a breast medical oncologist at Dana-Farber Cancer Institute and chief of our breast oncology program here. And today we’re going to be covering approaches for treating first-line metastatic, HER2-positive breast cancer. Our paradigm for treating metastatic HER2-positive disease has really dramatically evolved over the last several years. We’ve had a standard though in the first-line setting for now over a decade.

So the standard for first-line treatment of metastatic HER2-positive breast cancer was really established by the CLEOPATRA trial, where patients had been randomized to get a taxane with trastuzumab, with or without pertuzumab. And this study really demonstrated that that taxane-trastuzumab-pertuzumab combination, or THP, led to substantial benefits in both progression-free survival and overall survival when compared to a taxane with trastuzumab. And so we saw patients hitting a median progression-free survival of a little under 19 months and a median overall survival of around 57 months.

And so this was really an extraordinary change compared to our prior first-line standard of care, just Taxol-Herceptin. However, it has not changed in over a decade. So again, it has really been the tried-and-true treatment. And what we’ve seen is there are some patients who have extraordinary long-term outcomes on THP, where in fact, if you look at around eight years of follow-up on patients who got first-line THP on CLEOPATRA, about 16% of them remain free of progression or death all the way out at eight years. And it does make you wonder if maybe there are some patients who could even be cured from metastatic HER2-positive disease.

And so I think, again, it has been extraordinary. But a few years ago we saw the introduction of an antibody drug conjugate called T-DXd, or trastuzumab deruxtecan. And this was a game changer in pre-treated metastatic HER2-positive disease, where we really saw unprecedented outcomes. And in the second-line setting, T-DXd was associated with almost a 29-month PFS. And we’ve never seen a PFS this long in any line of therapy for metastatic HER2-positive disease prior to the data that we saw from DESTINY-Breast03.

And so because there was such extraordinary outcomes with T-DXd and because the PFS was 29 months, which is longer than what we saw in CLEOPATRA, which again, remember was a little under 19 months, it made us think that T-DXd could replace the CLEOPATRA regimen as a potential new first-line standard of care. And so a few years ago, DESTINY-BreastO9 was designed to really try to address the optimal first-line standard of care for patients. And back when DBO9 was designed, we actually didn’t have the data from DB03, so we didn’t actually know that T-DXd had a 29-month PFS in the second-line setting.

In fact, we started designing DB09 after we saw data from DB01. And so this trial looked at patients who had a median of six prior lines of systemic therapy in the metastatic setting and showed almost a 19-month PFS. And so when we saw that back in 2019, we knew it was a game-changer because we never saw patients have such prolonged disease control in pre-treated disease. And so back then we started thinking about how to move T-DXd into the upfront setting, but we weren’t so sure that T-DXd would beat CLEOPATRA because we didn’t, again, have data where it was used in earlier line settings. So we also were trying to think about whether or not combination therapy could be beneficial.

And we had some pre-clinical data that showed that T-DXd and pertuzumab, in fact, could be synergistic, where we saw that there was better internalization of T-DXd when you gave it with pertuzumab, and we saw better suppression of HER2 signaling when given in combination. And so we thought, well, maybe this would be a good combination to look at in that upfront setting. And so in DESTINY-Breast09, we not just looked at T-DXd monotherapy but also had an arm looking at T-DXd plus pertuzumab, and each of these arms was compared to THP, the first-line standard of care.

And so far we’ve only seen data from DESTINY-Breast09 that was from an interim analysis, because at the time of the interim analysis, the combination of T-DXd and pertuzumab met the very stringent criteria that was set for superiority at this early time point, where you in fact had to have a P value that was less than 0.00043. So it was very stringent criteria, and that, again, combination arm was successful, whereas the T-DXd monotherapy arm did not meet those stringent criteria for success.

And so we’ve seen data now from the combination data where we saw that T-DXd and pertuzumab was associated with a PFS of about 40.7 months upfront compared to 26.9 months for THP. So almost doubling progression-free survival in that first-line setting. And so seeing the data from DESTINY-Breast09 certainly suggests that the combination of T-DXd and pertuzumab could become a new first-line standard of care. Again, because we’re seeing such a dramatic improvement in progression-free survival, we don’t have mature overall survival data at the time of this interim analysis, there was a slight trend favoring T-DXd and pertuzumab with a hazard ratio of 0.84. But again, the data are just not mature right now for overall survival. There’s only 16% of survival events that had occurred at that time point.

The trial did look at what we call PFS2. So from the time of randomization to progression on second-line therapy and at that time of this analysis, we saw that PFS2 was significantly longer with T-DXd and pertuzumab compared to THP. But I think a lot of people are wondering, do you really have to give everyone T-DXd and pertuzumab upfront? We know that T-DXd alone has benefit in the second-line setting where we’ve seen, again, unprecedented PFS and OS for a pre-treated population. And so again, the question is a now-versus-later question. Do you have to give T-DXd first-line or can you give it second-line? We don’t have, again, mature OS data from first-line exposure. And so some people have argued that if you don’t see OS first-line, maybe you could reserve it for second-line.

I would, however, think of this cautiously, because not all patients who get first-line HER2-directed therapy are actually able to go on to receive a second-line of treatment. We know that from multiple registration trials, somewhere between 20 to 30% of patients after getting first-line treatment are not able to go on to get a second-line of therapy either due to deterioration in health or death. And so I think, for the most part, we have tried to use our most efficacious therapies upfront because we don’t know and can’t guarantee what’s going to happen over time.

We also know that the complete response rate with T-DXd and pertuzumab is almost double that seen with THP. And so it does make us wonder with longer-term follow-up, will we see potentially more patients have durable long-term outcomes and potentially even cure more patients with the T-DXd-pertuzumab combination? And so reserving treatment for subsequent lines could potentially have impact on this potential long-term benefit.

I think one other caveat with using T-DXd and pertuzumab upfront though is that the approach is different than the approach we take with THP. So when we use the CLEOPATRA regimen, we usually give, on average, somewhere between six to eight cycles of taxane therapy and then shift patients to trastuzumab and pertuzumab maintenance. And so people are only getting cytotoxic therapy for somewhere around six or nine months or so. They’re not getting years of cytotoxic treatment. However, on the DESTINY-Breast09 trial, T-DXd was given until time of disease progression or until development of toxicity.

And so if someone developed a significant toxicity for which they had to discontinue T-DXd, then trastuzumab could be added. And so patients were either on trastuzumab alone if they were on the T-DXd monotherapy arm or trastuzumab and pertuzumab if they were on the T-DXd pertuzumab arm. But that was a very small proportion of patients in DESTINY-Breast09. Again, the vast majority of patients were treated until time of disease progression. And so if you know the median PFS is over 40 months, that means that people are on cytotoxic therapy obviously way over three years on average. And that is a long time. And in truth, the median is not even so precise at this point in time because it’s just from an interim.

So one could imagine it will be even longer with longer term follow-up, again suggesting that people would be getting cytotoxic therapy for long duration periods of time. So I think there are some, again, who argue is it worth it to keep people on cytotoxic therapy this long and is it really necessary? Is it potentially possible to use an induction strategy with T-DXd or T-DXd pertuzumab upfront and then turn to a maintenance strategy and potentially still achieve these extraordinary outcomes? We’ve seen some hint that optimal maintenance can really improve long-term outcomes from the PATINA trial, where they had looked at upfront THP therapy and then shifted people to get herceptin pertuzumab maintenance therapy with endocrine therapy with or without palbociclib in patients who had hormone receptor positive disease. And we saw a 44-month progression-free survival for maintenance treatment with palbociclib endocrine therapy and dual HER2-directed treatment.

And so again, there are some patients who can have extraordinary long-term outcomes without getting perpetual cytotoxic treatment. But I will say there are caveats to this approach, because for example, in PATINA where they looked at this maintenance strategy, you had to get through induction therapy and not have disease progression and then go on to maintenance. So this was not the average HER2-positive patient. You also had to have hormone receptor positive disease. And we know that in DESTINY-Breast09, for example, on the THP arm, 12% of patients had already progressed on THP within the first six months. And so not everyone is getting through induction strategies.

And so I think one thing that is needed in this first-line setting is a potential biomarker that could really help us understand if there are patients who potentially could get away with induction maintenance strategies versus patients who may need more prolonged cytotoxic therapy exposure and even to help us select patients who may not need any cytotoxic therapy. And we’ve seen some first-line trials that have looked at strategies of endocrine therapy, CDK4/6 inhibition in HER2-directed therapy, and also seen very nice long-term outcomes. But we just don’t know who those patients are and how we can select patients who don’t need any cytotoxic therapy.

So I think what DESTINY-Breast09, in essence, has opened the door to is trying to figure out the optimal way to treat first-line patients. Again, our first-line treatment for many years has been CLEOPATRA with THP. I think the data from DESTINY-Breast09 has shifted the needle towards a T-DXd-based approach upfront. But I think ways to refine this are needed, and there is work ongoing to do this, including studies like the DEMETHER trial, which are looking at optimal induction followed by maintenance. So the patients get six cycles of T-DXd followed by maintenance therapy with herceptin pertuzumab. It’s a single-arm study and would give us a sense of how induction followed by maintenance works with T-DXd.

There are also trials ongoing looking at what the optimal maintenance strategy should be. We’ve obviously seen the data with palbociclib as a potential option for patients with hormone receptor-positive HER2-positive disease. But what about looking at tyrosine kinase inhibitors like tucatinib that’s being explored in the HER2CLIMB-05 trial. There’s also oral SERDs being looked in the heredERA study looking at giredestrant with HP. And then for those patients who have PI3 kinase mutations with HER2-positive disease, there’s the ongoing INAVO122 study looking at introducing an abemaciclib with HP treatment as maintenance.

So you can see there are lots of ways to think about first-line therapy. And again, I think this space will continue to evolve. We’ll also need to wait to see the final data from DESTINY-Breast09, because we also don’t know how T-DXd monotherapy will perform. And it’s not clear if everyone will need to get pertuzumab with T-DXd upfront. So you can see there are many unanswered questions. What’s the optimal duration of T-DXd? Do people really need pertuzumab? Could we do an induction maintenance strategy upfront? What should optimal maintenance be post-T-DXd?

So clearly an evolving space, but I think also a really exciting time where we’re really seeing patients with metastatic HER2-positive disease have a significant improvement in their long-term outcomes. And I think we hope that some of these patients may even have the potential to be cured. So again, I think really remarkable the shift in outcomes for these patients. Thank you so much.