T-DXd Benefit in Metastatic Breast Cancer Extends to Older Patients

Older patients with HER2-positive metastatic breast cancer tend to have worse efficacy and safety outcomes, regardless of treatment. At the American Society of Clinical Oncology (ASCO) annual meeting, researchers reported age-specific (<65 vs ≥65 years) efficacy and pooled safety analyses of trastuzumab deruxtecan (T-DXd, Enhertu) from DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03.

In this exclusive MedPage Today video, trial investigator Ian Krop, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut, explained the data and offered his take-home message.

Following is a transcript of his remarks:

Multiple studies have demonstrated that older patients with HER2-positive metastatic breast cancer tend to have inferior efficacy outcomes and worse adverse events compared to younger patients, regardless of what treatment they receive. And unfortunately, our attempts to try to understand what’s causing this discrepancy are limited by the fact that older patients are generally underrepresented in our clinical trials.

We are particularly interested in a drug called trastuzumab deruxtecan, or T-DXd, which is one of the newer HER2 directed antibody-drug conjugates that’s shown very good efficacy in multiple clinical trials. It’s now FDA-approved and widely used in HER2-positive disease. But we really don’t have detailed information on how T-DXd performs in older populations in terms of efficacy and toxicity.

So, to kind of address that, we conducted this pooled analysis to try to generate enough patients, using all three of the large studies of T-DXd in patients with HER2-positive metastatic breast cancer. What we found was a total of 851 patients; 80% roughly were younger than 65, and about 20% were 65 and older. And we had a small population of patients who were 75 and older.

What we found was that amongst the older population — overall, they’re relatively healthy because they had to meet the eligibility criteria of these registrational trials — but their performance status was slightly lower than the younger population in terms of the percent that was performed at zero in the two groups differed modestly. And while overall comorbidity rates were relatively low, again because of the entrance criteria of the trials, there were substantially higher rates of hypertension, vascular disease, and mild-to-moderate renal impairment in the 65 and older population compared to the younger population.

But despite this modest difference in health status of the older patients, when we looked at efficacy, it was essentially exactly identical in the 65 and older population compared to the younger population. So, in terms of median progression-free survival, landmark analysis of overall survival, and objective response rate, very similar between the younger population and the 65 and older population, which was certainly reassuring and encouraging.

When looking at adverse events, the total degree of adverse events in any grade was actually very similar between the two groups, and that was true essentially across all of the specific adverse event categories. There were, however, a modest increase in the rate of grade three and higher adverse events in the 65 and older population. There was a modestly higher rate of drug discontinuation because of adverse events. And the percentage of fatal adverse events, so grade five adverse events, was slightly higher in the older population, but the absolute rate was very low fortunately, in both, across all ages. Rate of dose reductions actually were very similar between the older and younger population.

One key adverse event that we pay attention to with trastuzumab deruxtecan is interstitial lung disease because that is a important and potentially serious adverse event. In this population, there were a greater rate of ILD overall in the 65 and over population compared to younger patients, but this was virtually all due to low-grade events. And the grade four and five adverse events was very low in both groups and very similar.

So, overall, we found that the 65 and older population had essentially exactly the same efficacy with T-DXd as the younger population. The adverse event profile was similar and acceptable. There were albeit a modestly increased rate of grade three or higher adverse events in the older population.

Going forward, I think we do need to appreciate the fact that the patients who volunteer to go on trials don’t necessarily reflect the entire global population of patients with metastatic breast cancer. So there is a need for more real-world types of data sets to ask this question in more detail, but certainly the data we have so far is very encouraging. The efficacy is very similar across all age groups, and toxicity is only modestly increased in the 65 and older population.

So, I think our take-home message is that T-DXd is a very effective option and safe option across all age groups.