Other Trials with Trastuzumab Deruxtecan in Breast Cancer


Breast cancer experts, Drs. Sara Tolaney and Mark Pegram discuss ongoing and noteworthy trials with trastuzumab deruxtecan in mBC.


Sara Tolaney, MD: We’ve seen updated data now from DESTINY-Breast01, which was the single-arm study of trastuzumab deruxtecan [T-DXd] in pretreated patients. We have now seen not only is the progression-free survival holding up of around 19.4 months, but in fact, we also saw that overall survival was about 29 months. Which is really incredible considering that this population has had a median of 6 prior lines of therapy. I think seeing this is very impressive. Certainly now we know that trastuzumab deruxtecan has a role even in earlier lines of therapy based on DESTINY-Breast03 [DB03] and so I think it will become a standard for us in the second-line setting. It also begs a question of where do we go from here with trastuzumab deruxtecan? Seeing that there is such robust efficacy and in fact, also a very high complete response rate. We want to be able to move this agent even earlier. Seeing the data that we’ve seen from DESTINY-Breast03 with such prolonged progression-free survival, with the median not even reached, does make one wonder if it will beat the CLEOPATRA regimen. Because, again, it does look like it’s performing better than what we’ve seen from CLEOPATRA in a first-line population. I think there’s certainly lots of open-ended questions though, because if we also are seeing such a high, complete response rate in the second-line setting, it makes you wonder what that will be in the first line. Will we potentially be able to cure some of our metastatic HER2 [human epidermal growth factor receptor 2]-positive patients? Additionally, seeing the toxicity from DB03, with the lack of grade 4 or 5 ILD [interstitial lung disease] and a lower rate of overall ILD it actually makes us much more comfortable to move this agent up into the early disease setting, seeing if we can cure more of our early-stage HER2-positive patients. There is an ongoing study looking at trastuzumab deruxtecan in patients who have residual disease comparing it to T-DM1 [trastuzumab emtansine]. Going up against the KATHERINE regimen for those patients who have residual disease after preoperative HER2-directed therapy. But I think again, it makes you want more and also wants us to think about using it in the preoperative setting as well. I think we’re going to see a lot more to come from T-DXd given the very robust data that we’ve now seen from Destiny-Breast03.

Mark Pegram, MD: The brain metastasis subset of both DESTINY-Breast01 and now DESTINY-Breast03, are very interesting. It demands prospective new trials for patients with HER-positive breast cancer brain metastasis. To that end, we now have the TUXEDO trial which is a phase II study of HER2-positive metastatic breast cancer with newly diagnosed or progressive brain metastasis who will be treated with trastuzumab deruxtecan in standard dosing schedule. The primary end point will be CNS [central nervous system] response. We’ll get a really clear picture from TUXEDO as to the activity of trastuzumab deruxtecan in the central nervous system. The DESTINY-Breast12 trial is an open label phase 3b/4 multicenter, multinational 2 cohort study for patients with or without brain metastasis in pretreated HER2-positive metastatic breast cancer that are tucatinib naive. Brain metastasis in DESTINY-Breast12 can be new, untreated, not needing immediate local treatment or stable treated or even active progressing brain metastasis are allowed in that study. The primary end point is objective response rate in the cohort 1, patients without breast cancer brain metastasis, and progression free survival in cohort 2 in the brain metastasis cohort. This is a nice study because of the two different parallel cohorts, there’ll be some opportunity to compare the cohorts in terms of outcomes with and without breast cancer brain metastasis. We’ll really get a good chance to look at not only the stable treated brain metastasis subset but also other groups, such as new or active brain metastasis as well in DESTINY-Breast12.

Transcript edited for clarity.

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