Tukysa Makes Waves as Firstline Maintenance in HER2+ Breast Cancer

Wrapping up what she described as a “blockbuster year” for advancements in breast cancer treatment research, Dr. Erika Hamilton sat down for an interview with CURE to discuss key findings from throughout 2025 — including her own work on the HER2CLIMB05 clinical trial evaluating Tukysa (tucatinib) in combination with Herceptin (trastuzumab) and Perjeta (pertuzumab) in patients with HER2-positive metastatic breast cancer that were presented at the 2025 San Antonio Breast Cancer Symposium (SABCS).

Hamilton is the Chief Development Officer, Late Phase, as well as Director, Breast Cancer Research, at the Sarah Cannon Research Institute (SCRI). She spoke with CURE’s editor-in-chief, Dr. Joshua K. Sabari, an Assistant Professor in the Department of Medicine at NYU Grossman School of Medicine and Director of High Reliability Organization Initiatives at NYU Langone’s Perlmutter Cancer Center.

To watch Hamilton and Sabari’s full conversation, be sure to visit CURE’s YouTube channel.

Your study, HER2CLIMB-05, is very exciting. Let’s discuss [Tukysa], a HER2 tyrosine kinase inhibitor, really an exciting therapy. Can you tell us about that data and how it impacts patients care.

[Tukysa] is an FDA-approved drug that was based on the initial HER2CLIMB study. This was later-line capecitabine and Herceptin (trastuzumab) versus capecitabine and [Herceptin] with [Tukysa], which improved progression-free survival (PFS), improved overall survival (OS), improved central nervous system (CNS) outcomes and CNS PFS in patients that had brain metastases. So, this is already an approved drug.

And what this trial, HER2CLIMB-05, asked is the benefit of moving it up into an earlier setting. So not second line, which is where the current FDA approval is, but in the first line maintenance strategy. Now this idea of maintenance in the first line is honestly a little bit new to us. Our first data we got about a maintenance was from the PATINA study, which was actually San Antonio Breast Cancer Symposium 2024. It is still not FDA approved. … But that showed the addition of [Ibrance (palbociclib)] for patients that are HER2-positive and ER-positive to endocrine therapy plus [Herceptin] and [Perjeta], once the chemo taxane was dropped out, was beneficial. So that really introduced this whole idea of maintenance, because sometimes patients can be on this three, four, five years. I have a patient that's continuing to get [Herceptin] that has been on it for six years now.

So, this looked at not only ER-positive, but also ER-negative disease — with, of course, everyone having HER2-positive disease — and asked that same question: After four to eight cycles of taxane, induction therapy, when you drop your taxane out, does adding [Tukysa], with or without endocrine therapy if they're ER positive, benefit? And we found that it did.

The hazard ratio was 0.725, the benefit was almost nine months in PFS, so 16 months up to over 24 months. I think this is meaningful for patients. It was nice because it included both patients who were ER-positive and ER-negative. And so, I think that's at the FDA looking for approval too, but we're likely to have two maintenance strategies where patients conceivably can drop out their cytotoxic chemo and be on targeted therapy only in this first line setting, which I think is very patient friendly.

That's exciting. Hazard ratios of 0.7 are quite impressive. That's about a 27% reduction in the rate of progression or death with the use of [Tukysa] in the maintenance setting. Dr. Hamilton, what are the side effects of the drug? We know that all therapies, whether they're chemotherapy or targeted therapy, have some side effects.

With tyrosine kinase inhibitors, we immediately think of rash and diarrhea. What's special about [Tukysa] is it's HER2 specific. It's not a general, so it doesn't block HER1 or EGFR, and so we don't get as much rash, we don't get as much diarrhea, but historically, we do get some diarrhea with [Tukysa], and particularly because we've been giving it with capecitabine, which causes diarrhea. So, we did see diarrhea. Dose reductions due to diarrhea was in 6% of patients receiving [Tukysa]. So honestly, not that much. And in fact, 3% of the patients reduced placebo that weren't actually receiving [Tukysa]. So small actual numbers of patients were actually needing a dose reduction. In terms of discontinuation, exceedingly rare, 1.5%, so this really was able to be given frequently.

What we did see was the most common reason for a hold was actually due to hepatic elevations. This was 7.7% of patients had to discontinue due to elevated liver function. This is predominantly AST, ALT, we saw that in HER2CLIMB, the original study. So, you’re definitely going to have to monitor the liver function enzymes, definitely going to have to make sure patients know about strategies for diarrhea, but it tends to really be pretty tolerable there, and we don't see rash with this.

So if you're a patient or a family member getting this medicine and your liver numbers are mildly elevated, how do you counsel patients?

That's a great question. So for very mild elevations, we really don't need to do much. We'll see what the FDA label ultimately says. I imagine it'll mirror HER2CLIMB in the later setting, where we really kind of hold and discontinue with grade 3 (severe elevations). A lot of our patients do have a liver metastases, and so they're even allowed to start this drug at 2.5 times the upper limit of normal, etc. So we don't need to worry about these more mild ones. It's really the ones where we're bumping a little bit higher than that that we need to worry about.

We know that small molecules tend to have decent blood-brain barrier penetration, meaning that the drug gets into the brain, and we see activity in the brain. Any data for the activity of [Tukysa] in patients with breast cancer who have brain metastases?

Absolutely, that was one of the primary outcomes in the original HER2CLIMB study, we actually had almost half of patients that entered that study had brain metastases, because there was mandatory brain screening when patients entered. It significantly improved CNS PFS, improved OS for those patients. We looked at it in HER2CLIMB-05. Now this is first line, HER2-positive metastatic disease. So brain metastases are much more rare in that setting than they are in later line. So we didn't see a difference yet, but there was an exploratory analysis for those patients that came on with known brain metastases and the PFS was about double, 4.4 up to 8.5 months, not large enough to be statistically significant, not enough patients, but certainly a signal looking like those patients with brain metastases definitely did much better if they had [Tukysa], that this is a drug that we know crosses the blood-brain barrier.

Transcript has been edited for clarity and conciseness.

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