HER2CLIMB: Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer


Focusing on the HER2CLIMB trial in HER2+ metastatic breast cancer, expert oncologists consider the value of a tucatinib-based regimen in this setting.


Komal Jhaveri, MD, FACP: I’m going to move on in the interest of time to HER2CLIMB and then talk about both of these together. HER2CLIMB [NCT02614794] was a large, randomized phase 2 trial for HER2-positive metastatic patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine]. Active brain metastases that do not require local therapy were allowed but not required. That’s very important to understand— [there are] active brain metastases but these are less than 2-cm tumors. These are not patients who are symptomatic, these are not large tumors with edema or a seizure or blurry vision and headaches. These are patients who are found to have say, new metastases or small progression despite prior local therapy that were permitted in the study. And which [I would give] kudos to the team because this is not something that we commonly see and I’m so glad was done in this trial. No prior TKI [tyrosine kinase inhibitor] was permitted on the study. And patients were then randomized 2:1, to receiving tucatinib with capecitabine and trastuzumab vs capecitabine with placebo and trastuzumab. And the primary end point, here again, was PFS [progression-free survival] by blinded independent central review, and secondary end points were PFS by blinded independent review for patients with baseline brain metastases. And overall survival among other end points. And here are the results for progression-free survival, on your left, where you can see that for the entire population.

[Concerning] your intention-to-treat population there was a statistically significant improvement from 5.6 to 7.8 months favoring the tucatinib combination. And when you look at the landmark analyses, you see that 33%vof the patients for progression-free [survival] in the tucatinib arm compared with 12% in the placebo arm. And on your right, you see the overall response rates [ORRs] where you see that the ORR was 41% in the tucatinib arm and 23% in the control arm. What about overall survival [OS]? Like how we’ve been fortunate with other molecules for HER2-positive metastatic disease, we did see OS here, which was statistically significant. OS in the placebo arm was 17.4 months, which improved to 22 months nearly in the tucatinib arm, the hazard ratio [HR] of 0.66 with a significant P value of .05. Again, when you see a larger proportion of patients were alive at the 24-month point in the tucatinib arm compared with the control arm. What about those patients with brain metastases? [That was] a key important secondary end point for our patients in this trial. And here, these are combined brain metastases so this could have been stable treated brain metastases patients or patients with active brain metastases. Meaning newly diagnosed untreated brain metastases that are not symptomatic or those that had prior radiation but now have some progression that could still be eligible for this study.

And again, similar to what we saw in the intention-to-treat, there was a statistically significant improvement from 5.4 to 7.6 favoring the tucatinib arm with the HR of 0.48. But really what I want to highlight here is the landmark analyses which was really impressive. A quarter of these patients were progression-free in the tucatinib arm at the 12-month point and we really have zero patients in the control arm at the 12-month time point. Really, the therapy works and it’s very reassuring that it works very well for our HER2CLIMB patients with brain metastases. Let’s take a moment here, Adam. And now that we’ve reviewed these data, if you are now utilizing say one agent over the other, we kind of spoke about a little bit about when you would think about T-DXd [trastuzumab deruxtecan] in the second-line [therapy setting] based on the DB03 [DESTINY-Breast03 trial; NCT03529110]. When are you thinking about HER2CLIMB say in the second-line setting? What are you doing with these patients’ progress and had T-DXd in the second line?

Adam Brufsky, MD, PhD: Then, I would give them the triplet. I think everyone’s going to get both. I think people live long enough now with HER2-positive breast cancer; they’re going to get both. And I think that there’s clear survival benefits in both of them. I think most of the survival benefit in HER2CLIMB, in my opinion, has more to do with the treatment of the untreated brain metastases. As you know, about a quarter of the patients on the trial had untreated brain metastases, which is pretty bold— it was a really bold idea at the time. Still, it is bold to take a woman and not give her radiation therapy. But nonetheless, I think that that’s where the survival benefit came from. I think the survival benefit in T-DXd came more from all disease, systemic disease more than anything, below the neck disease. I don’t have a problem. I think we’re still going to get the survival benefit with both. Fifty percent of women are going to get brain metastases and HER2-positive disease. I think that’s going to be the limiting factor at the end of the day. Thus, they’re going to get both. I think they’re going to need a TKI at some point, they’re going to need T-DXd at some point. We have a combined trial of them, a phase two where there was a lot of diarrhea, so it had to be adjusted. It’s a 70-patient phase 2 trial, I think there’s about 30 patients accrued on it so far. Thus, we’re going to answer the question, they’re going to get both but I’m going to favor DXd for the time being only because of the systemic benefit. Obviously, if they have brain metastases, as I said before, I probably would favor the triplet. That’s how I usually do it.

Komal Jhaveri, MD, FACP: I completely agree. I think when we think about the DB03 data and we talked about those curves, this is the complete response rate was about 16 percent. And if you think about even the CLEOPATRA study [NCT00567190], the complete response rate was about 5.5% in the first-line setting. And thus, we can think about maybe a potential proportion of patients who might be really cured, if I can use that word, in the metastatic setting. And we would love to have that scenario. And now, I think there are trials trying to evaluate T-DXd with pertuzumab, and maybe even with IO [immunooncology] in the first-line settings. [DESTINY-Breast09; NCT04784715] is ongoing with that combination and we’ll see how those results pan out. But I completely agree with you with the brain metastases patient population, specifically your active brain metastases, that does not require local therapy. And [if] a patient is interested in auto regimen, which many patients are, I think that the tucatinib capecitabine [is what] I would use specifically for that patient population assuming the systemic disease burden is really not taking over the disease at that point.

Transcript edited for clarity.

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