T-DXd Demonstrates Efficacy in HER2+ Metastatic Breast Cancer With Stable or Active Brain Metastases

Nancy Lin, MD

Findings from the phase 3b/4 DESTINY-Breast12 trial (NCT04739761) helped further define the potential role for fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in the treatment of patients with HER2-positive breast cancer with active or stable brain metastases, according to Nancy U. Lin, MD.

“For patients with brain metastases—even those with active brain metastases—we now have a good level evidence that T-DXd can be effective,” Lin said in an interview with OncLive^®.

Findings from DESTINY-Breast12 presented at the 2024 ESMO Congress showed that patients with baseline brain metastases (n = 263) experienced a 12-month progression-free survival (PFS) rate of 61.6% (95% CI, 54.9%-67.6%) and a median PFS of 17.3 months (95% CI, 13.7-22.1). In patients with stable (n = 157) or active (n = 106) brain metastases, the 12-month PFS rates were 62.9% (95% CI, 54.0%-70.5%) and 59.6% (95% CI, 49.0%-68.7%), respectively.

In the interview, Lin expanded on the key findings from DESTINY-Breast12, emphasized the importance of evaluating T-DXd in a larger population of patients with brain metastases, and explained the potential implications of these data.

Lin serves as director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

OncLive: What findings were previously reported regarding the intracranial activity of T-DXd?

Lin: What we've seen so far is a mix of studies. We've seen small, prospective studies. We've seen retrospective analyses of larger phase 3 trials, which mostly included patients with stable brain metastases; the prospective trials included more patients with active brain metastases. The intracranial overall response rates [IC-ORRs] in these studies ranged between approximately 44% to 73%; however, they were either small, prospective studies, or they were larger studies with retrospective analyses. The missing piece was prospective data in [a larger population of] patients with active brain metastases.

DESTINY-Breast12 was designed to provide a little closer of a real-world experience in a large, international setting for the use of T-DXd in patients with and without brain metastases. This was a way to a provide access [to treatment] as regulatory agencies were making decisions. [Another goal was] to gather important information about subsets of patients, like those with [active] brain metastases, who were not as well included in the registration trials [for T-DXd].

What was the design of DESTINY-Breast12?

This was a nonrandomized trial that enrolled two cohorts. The first cohort included patients with brain metastases; the second cohort was for patients without brain metastases. All patients had to have 0 to 2 prior lines of therapy in the metastatic setting. They had to have at least 1 line of HER2-directed therapy either in the adjuvant or metastatic setting and an [ECOG] performance status of 0 to 1. [Patients who received] prior tucatinib [Tukysa] were excluded.

Patients could either have stable brain metastases or active brain metastases. [Active brain metastases] were defined as either newly diagnosed, untreated disease, or previously treated disease that was progressing when patients entered the trial.

What were key efficacy findings that have been reported across the 2 cohorts of DESTINY-Breast12?

In the brain metastases cohort, the estimated 12-month PFS rate was 61.6%, and the median PFS was 17.3 months. The IC-ORR was 71.7% [among all patients with brain metastases]; it was 79.2% in patients with stable brain metastases, and it was 62.3% in patients with active brain metastases.

[Diving deeper into] the patients with active brain metastases, for previously untreated patients, the IC-ORR was 82.6%. In patients with previously treated brain metastases, [the IC-ORR] was 50.0%. All of these numbers have somewhat wide confidence intervals because the subsets get smaller.

In the non–brain metastases cohort, we saw an ORR that was in line with other phase 3 T-DXd trials. Approximately two-thirds of [responders] were still on protocol therapy at the time of data cutoff, and the median duration of response was not reached.

How did safety data from DESTINY-Breast12 compare with the known safety profile of T-DXd?

[Regarding the] adverse effect [AE] profile, we saw that nausea and fatigue were quite common, and we know that [these are AEs are common] from other T-DXd trials. The cohorts were not formally, statistically compared, but the AE profiles qualitatively look very similar [irrespective of the absence or presence] of brain metastases. There were no special safety signals in the brain metastases population.

The AEs of special interest were interstitial lung disease [ILD] and cardiac dysfunction. Cardiac dysfunction was very uncommon, and there were no cases of grade 4 or 5 [left ventricular ejection fraction (LVEF) decrease]. There were 2 cases of grade 3 [LVEF decrease], but they were reversible.

For the ILD, we did see a signal. There were 6 cases of grade 5 ILD in the brain metastases cohort, and there were 3 grade 5 cases in the non–brain metastases cohort. Notably, of the 6 [grade 5 ILD] cases in the brain metastases cohort, 4 of those patients had coexisting operative infections, including 3 cases of pneumocystis pneumonia and 1 case of aspergillosis. It is unclear whether T-DXd was associated with ILD on top of the opportunistic infection, or if these instances of ILD were related to the opportunistic infections; however, these data raise the importance of PCP prophylaxis in these patients.

What are the clinical implications of these findings?

These findings solidify the use of T-DXd in the second-line setting in patients [with advanced HER2-positive breast cancer] without brain metastases, and that has been our standard of care. [For patients with brain metastases] it can produce a very high IC-ORR, a respectable median PFS, and a respectable 12-month PFS [rate].

Reference

Lin NU, Ciruelos E, Jerusalem G, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) with or without brain metastases (BM): DESTINY-Breast12 primary results. Ann Oncol. 2024;35(suppl 2):S1211-S1212. doi:10.1016/j.annonc.2024.08.2256