At the 2023 ASCO Annual Meeting, Ian Krop, MD, PhD, Yale Cancer Center, New Haven, Connecticut, presented on age-specific pooled efficacy and safety analyses of trastuzumab deruxtecan from the DESTINY-Breast01, -02, and -03 trials.

In this report, the outcomes of older patients with HER2-positive metastatic breast cancer, who tend to have worse efficacy and safety outcomes, were examined. Dr Krop concluded, “Our take home message was that the efficacy of trastuzumab deruxtecan is preserved across all age groups and, with an acceptable safety profile, this drug can certainly be used, again, across all the age groups.”

What was the rationale for this analysis?

There are a number of studies that demonstrated that older patients with HER2-positive metastatic breast cancer tend to have the worst efficacy and toxicity outcomes when treated with virtually any current therapy compared to younger patients. Unfortunately, our attempts to try to understand why these discrepancies occur are limited by the fact that, in general, older patients are underrepresented in clinical trials.

Trastuzumab deruxtecan, or T-DXd, is a HER2-directed therapy that has shown very significant efficacy in HER2-positive breast cancer. It is approved in that setting and is widely used. But unfortunately, we don't really have detailed data on the outcomes and adverse events with trastuzumab deruxtecan in older patients. In this analysis, we pool data from all 3 of the large, randomized trials and single-arm studies in patients with HER2-positive breast cancer to look at both efficacy and safety profile.
 

What trials were included in this analysis? What were the characteristics of the overall patient population?

This included the DESTINY-Breast01 trial, which was a phase 2, single-arm study, as well as DESTINY-Breast02 and DESTINY-Breast03, which were randomized trials. Altogether, there were 851 patients treated with trastuzumab deruxtecan in this analysis. About 80% of the patients had ages under 65, and about 21% were 65 and older. We also had a small population, about 4% of patients, who were 75 or older.

Looking at the patient population, overall, the characteristics were pretty similar in terms of the tumor characteristics. Comorbidities also were relatively low, reflecting the fact that all these patients had to be eligible for the registration trials. But there were higher rates of hypertension, vascular disease, and mild to moderate renal impairment in the older population compared to the younger population. Also, there tended to be a greater percentage of patients with an ECOG performance status 0 in the younger patients compared to the older patients.
 

What were the results of this analysis?

Despite those differences in comorbidities and performance data, when we look at the efficacy analysis comparing the 65 and over population to the under 65 population, it actually was virtually identical. That was true both for median progression-free survival, overall survival as a landmark analysis, and objective response rate. So, very similar efficacy between the under 65 and 65 and older populations.

When we looked at the adverse event profile, in general, the adverse events in terms of all-grade events were very similar between the under 65 and 65 and older population. However, in the 65 and over population, there were modestly greater levels of grade 3 and higher adverse events, drug discontinuation because of adverse events, and grade 4 or fatal adverse events, where the absolute number was very low in the both under 65 and 65 and older population. Interestingly, those reductions were pretty similar between the different age groups.
 

Did this analysis reveal anything about the rate of interstitial lung disease within this population?

The one serious potential adverse event we see with trastuzumab deruxtecan is interstitial lung disease (ILD) or pneumonitis. We also looked at that in the younger and older age population. There were a greater rate of interstitial lunge disease as adjudicated by a central committee in the 65 and older population compared to the younger patients, but that was virtually all due to low-grade events. In the actual grade 4 adverse events or fatal adverse events as indicated with ILD, fortunately were very low in both groups.
 

What were the conclusions of this analysis?

In conclusion, what we have gathered from this analysis was that the efficacy of trastuzumab deruxtecan is remarkably similar between the younger patients and the 65 and older population, which was reassuring and encouraging. Adverse events were felt to be acceptable in the 65 and older population, albeit there was a greater rate of grade 3 or higher adverse events.

Clearly, these data need to be further explored. We know that the older population that goes on a clinical trial may not be representative of the overall population of elderly patients, so real world evidence types of studies would certainly be helpful to look at this question in more detail. But I think our take home message was that the efficacy of trastuzumab deruxtecan is preserved across all age groups and, with an acceptable safety profile, this drug can certainly be used, again, across all the age groups.
 

Source:

Krop IE, Wildiers H, Hurvitz SA, et al. An age-specific pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) from DESTINY-Breast01, -02, and -03. Presented at 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL.