T-DXd: Updated Results from the DESTINY-Breast Studies and Practical Considerations for Followup


Drs McArthur and Telli discuss recent data updates from the DESTINY-Breast trials of T-DXd, including a pooled analysis, and share best practices for monitoring patients for lung complications.


Sara Hurvitz, MD: Along came this other study, DESTINY-Breast02, looking at T-DXd [trastuzumab deruxtecan] after T-DM1 [trastuzumab emtansine]. Can you talk to us about that study, Heather?

Heather McArthur, MD: Sure. DESTINY-Breast02, as you just said, was looking at trastuzumab deruxtecan vs physician’s choice chemotherapy in the later-line setting, with really impressive progression-free survival [PFS] and overall survival benefits in favor of the antibody-drug conjugate. The progression-free survival was 17.8 months vs 6.9 months in favor of trastuzumab deruxtecan, and the overall survival was 39.2 vs 26.5 months, so a really impressive benefit. When they interrogated all of the subsets, looking at age, hormone receptor status, etc, the benefits were consistent across all of those subsets.

We learned a lot from DESTINY-Breast01 [about] the interstitial lung disease [ILD] issue. In later DESTINY-Breast studies, [patients] had more frequent scans to identify potential interstitial lung disease early, because with asymptomatic interstitial lung disease, which can only be detected radiographically, you’re supposed to hold the drug. In grade 2 or beyond, you’re supposed to permanently discontinue the drug. So they were doing more frequent monitoring, and in DESTINY-Breast02, the interstitial lung disease rate was much lower at 0.5%.

I personally have been struggling with how to monitor my patients in my own clinical setting. I’d be interested to hear how you all have been navigating this. I can’t do scans every 6 weeks, which is what they’ve been doing in the later-line DESTINY-Breast studies. It’s a hardship for patients, and there are payer issues as well. So I’ve been doing my scans every 9 weeks, which is a bit more frequent than I do in my other standard of care setting, but I haven’t gone to the 6-week frequency that we’ve seen in these recent studies.

Sara Hurvitz, MD: There was a recent pooled analysis of all the phase 1 and 2 T-DXd trials, looking at factors that may be associated with the development of ILD: older age, renal impairment, Japanese origin, baseline interstitial lung disease to start with, pulmonary fibrosis, [and other] things like these. What was interesting to me was the time to first event of ILD, it seemed to even out around 12 to 18 months, that you didn’t get a whole bunch of patients having events later. It seemed to plateau around that time point. Melinda, what are you doing in your practice? Are you doing Q [every] 6- to 9-week scans, and then pulling back if they are on year 2 or 3, or are you sticking with the more frequent lung imaging?

Melinda L. Telli, MD: I talk to my patients about the risk of this toxicity and try to stress to them that if they do notice any changes at all, to definitely let us know. I’m like Heather, I struggle with it because I feel that every 6 weeks is very frequent. And for some of our patients who have been on first-line THP [docetaxel, trastuzumab, pertuzumab] and on HP [trastuzumab, pertuzumab] maintenance, and are not getting scans very frequently, they object to some degree about getting these really frequent scans. So I think I’m doing it a bit sooner than I would normally, but not at the every-6-week frequency.

Sara Hurvitz, MD: What about you Virginia? Are you pulling back after a certain period of time or sticking with it?

Virginia G. Kaklamani, MD, DSc: I stick with it, but I’ll do it every 3 cycles, so that 9 weeks that everybody’s talking about. I think it is a struggle to do scans earlier, but I also would like to catch pneumonitis as quickly as I could, because it can progress very quickly from grade 2 to grade 5.

Sara Hurvitz, MD: Absolutely. We must have our eye on the ball and tell our patients to notify us immediately of any symptoms. Melinda, there was a pooled analysis presented at ASCO [American Society of Clinical Oncology annual meeting] by Ian Krop, [MD, PhD,] of the DESTINY-Breast studies, looking at outcomes based on age. Can you review the highlights?

Melinda L. Telli, MD: Yes. We’ve seen a couple at this meeting of these types of analyses, specifically looking at older populations, and I think it’s useful data. For this analysis, it was pooled data from the DESTINY-Breast01, 02, and 03 studies. These studies overall had not that many patients who are age 65 or older. It was roughly around 20%, so we’re talking less than 200 patients. But they looked at efficacy and compared it between those who were 65 or older, or less than 65. Very reassuringly, everything looked great there in terms of response rates, PFS, overall survival outcomes.

There were some differences in terms of toxicity, with higher rates of grade 3 or higher toxicity, serious adverse events in the older population. Specifically when looking at the ILD question, about 1 in 4 patients 65 and older had any grade ILD compared to those who were younger, [where] it was only around 18% any grade. I think certainly that is something to look at. There were few patients in these trials who had a more advanced age, 75 and older, so there are limited data there. But there is an increase in any grade ILD in the greater than 65 population. Fortunately, no increase in deaths from ILD in that population, but certainly something we need to pay attention to and need more data on.

Sara Hurvitz, MD: Absolutely. I thought it was very interesting, the pooled analysis sort of reflected prior analyses looking at outcomes with T-DXd based on age. I think a recurring theme we’re seeing is older patients and patients with renal impairment are at higher risk for ILD. So maybe those would be the patients for whom we should be sticking to the Q [every] 9 week, real close follow-up, and checking in about how they’re doing and how they’re breathing is. Very interesting. At this point, it’s a very exciting time. It sounds like second line is T-DXd, so not a lot of us are going to be using it in the third line or beyond, unless our patients are already there right now.

Transcript edited for clarity.

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