Patients with HER2-positive metastatic breast cancer with both stable and active brain metastases treated with Enhertu (fam-trastuzumab deruxtecan-nxki) experienced improvements in intracranial responses vs comparator therapies, according to findings from a retrospective pooled analysis of the DESTINY-Breast trials presented at the 2023 European Society for Medical Oncology Congress (ESMO).
The pooled analysis included data from the phase 2 DESTINY-Breast01 trial, the phase 3 DESTINY-Breast02 trial and the phase 3 DESTINY-Breast03 trial.
Among a pooled population of patients with brain metastases treated with Enhertu, the intracranial (wthin the skull) objective response rate (ORR, patients whose disease responded to treatment)) was 45.2% in those with treated/stable brain metastases and 45.5% in those with untreated/active brain metastases. The median intracranial duration of response (DOR) in each respective group was 12.3 months and 17.5 months.
In the comparator treatment brain metastasis population, the intracranial ORR was 27.6% in patients with treated brain metastases and 12% in those with untreated brain metastases. Additionally, the intracranial DOR was 11 months in patients with treated brain metastases. The DOR data for the untreated brain metastases population were not available.
“Shrinkage of brain metastases in response to Enhertu seemed to be more prominent, whereas, in the comparator pool, brain metastases showed less of a response,” said Dr. Sara A. Hurvitz, senior vice president of the clinical research division at Fred Hutch Cancer Center and head of the division of hematology and oncology at the University of Washington department of medicine.
The median central nervous system (CNS) progression-free survival (the time a patient lives without their disease spreading or worsening) (CNS-PFS) was 12.3 months vs 8.7 months with Enhertu and comparator therapy, respectively, in patients with stable brain metastases. Among those with active brain metastases, the median CNS-PFS in each treatment population was 18.5 months vs four months, respectively.
Investigators of this exploratory pooled analysis aimed to describe the population of patients enrolled on the DESTINY-Breast trials with brain metastases at baseline and to assess the pooled efficacy and safety of Enhertu vs comparator treatment.
In the DESTINY-Breast01 trial, 253 eligible patients previously treated with Kadcyla (trastuzumab plus emtansine) were assigned to receive Enhertu, 184 of whom received treatment. Additionally, 608 patients in the DESTINY-Breast02 trial were randomly assigned 2:1 to receive Enhertu (406 patients) or Herceptin (trastuzumab) or lapatinib in combination with capecitabine (202 patients). Those enrolled on the DESTINY-Breast03 trial (524 patients) were randomly assigned 1:1 to receive Enhertu (61 patients) or T-DM1 (263 patients).
Overall, the pooled population included 851 patients treated with Enhertu, 148 of whom had brain metastases. The comparator pool consisted of 465 patients, which included 83 with brain metastases.
Patients with asymptomatic and stable brain metastases who received prior local treatment were eligible for enrollment on the DESTINY-Breast01 trial. Following protocol amendments, patients with treated, asymptomatic brain metastases could enroll on the DESTINY-Breast02 and DESTINY-Breast03 trials.
Across the pooled Enhertu and comparator populations with and without brain metastases, anywhere from 49.4% to 68.1% of patients had recurrent breast cancer. Additionally, anywhere from 70.9% to 96.6% of patients in each group had visceral disease.
“Overall, patients with brain metastases were heavily pretreated with a median of three prior systemic therapies in the metastatic setting,” Hurvitz said.
Most patients had extracranial (outside of the skull) sites of first disease progression. According to Hurvitz, rates of any progressive disease were similar in both brain metastasis pool populations.
Drug-related treatment-emergent side effects affected anywhere from 88.5% to 98.9% of the brain metastasis pool populations. Additionally, the incidence of grade 3 or higher side effects was comparable across all patient subgroups, and the frequency of side effects leading to treatment discontinuation or dose reductions was consistent in patients regardless of whether they had brain metastases.
“The safety profile of Enhertu in patients with brain metastases was acceptable, generally manageable, and similar to the safety profile in the overall population. Thus, Enhertu is an effective treatment option for patients with HER2-positive metastatic breast cancer with brain metastases,” Hurvitz concluded.
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