Case 2: DESTINY-Breast03 and T-DXd in HER2+ Metastatic BC


Shared insight on the DESTINY-Breast03 trial, which analyzed trastuzumab deruxtecan therapy in patients with HER2+ metastatic breast cancer.


Sara A. Hurvitz, MD: I thought we could go through the DESTINY-Breast03 study a bit because these data were quite stunning in my opinion. The first randomized clinical trial looking at T-DXd [trastuzumab deruxtecan] against a standard of care, and in this setting, it was T-DM1 [trastuzumab emtansine]. Sara [Tolaney], do you want to take us through the highlights of this study, its primary results?

Sara M. Tolaney, MD, MPH: Yes, I totally agree with you. I think these data were unprecedented that we’ve seen now for metastatic HER2-positive disease, and is establishing a new level of outcomes for patients, which is really exciting. Just as you said, this was a trial that took patients who had metastatic HER2-positive disease who had progressed on a taxane and trastuzumab. They weren’t required to have had prior pertuzumab, but about 60% of patients in the study had prior pertuzumab. It compared the T-DXd to T-DM1; I’ll say I was pretty blown away with the results, where you could see that the median progression-free survival [PFS] was not reached in the T-DXd arm. By investigator assessment, it was about 25 months; that’s compared to 6.8 months in the T-DM1 arm, dramatically different. With a hazard ratio I don’t think I’ve ever seen before in a phase 3 study in breast cancer at 0.28, and with a P value that again, it would’ve been interesting if someone presented the number of 0s here, because it was 7.8 x 10-22. Again, it’s a different level of significance than we ever see, a dramatic difference really. With a PFS that again has never even been achieved in metastatic breast cancer. If you look at CLEOPATRA, the PFS was 18 months. This is longer in a pretreated population with T-DXd than we’re even seeing in first-line data. It is a dramatic difference, and benefits across all the subgroups. I don’t know if you want to comment because you presented the data in patients who had a history of stable treated brain metastases, I thought those were very interesting data.

Sara A. Hurvitz, MD: Yes. The subgroup analyses were compelling, that forest plot with all of the dots,far to the left of the null point, including those patients who had a history of brain metastases, of which there were about 20%. Then patients who had baseline brain metastases by independent review, 15% in each arm. It was interesting to see that they not only benefited from T-DXd compared to T-DM1, but when looking at the objective response rate in the brain, almost 64% of patients had some type of shrinkage or disappearance of brain metastases in the T-DXd arm. That compared favorably to T-DM1, where it was about 33% or 34%. I think those data are very interesting and compelling because they’re changing our assumptions about bulky antibody-drug conjugates and the activity they may have in the brain. I know we’ll be talking about brain metastases in a bit, but it is changing our fundamental assumptions about what types of systemic therapies might work in the brain. The overall survival data weren’t mature at the time of reporting but certainly are looking exciting, with a hazard ratio of 0.56 and a P value that didn’t meet the statistical significance yet, however, very interesting with very few events being reported.

Bill, I’m wondering here, based on these data, if you had a patient who had been treated in the adjuvant setting with THP [docetaxel, trastuzumab, pertuzumab] or TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] and completed their maintenance therapy HP [trastuzumab, pertuzumab] 9 months ago, where is your cutoff where you would say, “OK, they are metastatic now, it has been 6, 9, 12 months since their HP, let’s pull the trigger and use T-DXd.” How do you think through that? Because now a lot of us are using T-DXd in the pretreated setting.

William J. Gradishar, MD: I’d have to be persuaded pretty vehemently not to use T-DXd. I’m making this up, but if somebody was 4 or 5 years out from having had THP, maybe then I would come back to it. But I think the shorter the interval, the data that you just described are so compelling, that one would be hard-pressed to ignore it. I would be preferentially using T-DXd in most patients.

Transcript edited for clarity.

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