Lurbinectedin activity shown in metastatic breast cancer
medwireNews: Lurbinectedin, a selective inhibitor of active transcription of protein-coding genes, has promising activity in patients with BRCA1/2-mutated metastatic breast cancer, phase II study data show.
The efficacy was particularly good in women with BRCA2 mutations suggesting that “[a]dditional clinical development in this subset of patients […] is warranted,” Judith Balamaña (Vall d’Hebron Institute of Oncology, Barcelona, Spain) and co-investigators remark.
The researchers found that the objective response rate (ORR) to lurbinectedin (7 mg flat dose or 3.5 mg/m2) was 41% in the 54 women they studied. This included two complete responses and 20 partial responses, with a median response duration of 6.1 months.
The disease control rate was 83%, while the median progression-free survival (PFS) and overall survival (OS) times were 4.6 and 20.0 months, respectively.
When the researchers separated the patients by BRCA mutation type, they found that the ORR was 61% among women with BRCA2 mutations (n=23). This increased to 72% and 71% without prior PARP inhibitor and platinum therapy, respectively.
Median PFS and OS durations among the women with BRCA2 mutations were 5.9 and 26.6 months, respectively.
By comparison, women with BRCA1 mutations had an ORR of 26%, a median PFS of 3.0 months, and a median OS of 15.9 months.
Balamaña et al say: “The reasons for the different efficacy of lurbinectedin in BRCA2 versus BRCA1 disease are under investigation.”
A separate analysis of 35 unselected patients with BRCA1/2 wild-type or unknown status, who all received lurbinectedin at the flat dose of 7 mg, showed reduced efficacy in this group. The ORR was 9.0%, while PFS and OS were a median of 2.5 and 12.5 months, respectively.
All 89 patients were evaluated for safety, and the most commonly reported nonhematologic adverse events were fatigue and nausea, each experienced by between 57% and 91% of patients.
Neutropenia and thrombocytopenia were the most common hematologic adverse events, but the researchers note that the rate of grade 4 events in each of these classes fell substantially when lurbinectedin was adjusted from the 7 mg fixed-dose to 3.5 mg/m2. Specifically, the rate of grade 4 neutropenia fell from 51% to 10%, while grade 4 thrombocytopenia fell from 26% to 0%.
Balamaña and team also carried out a translational substudy to assess the potential mechanisms of lurbinectedin resistance.
In this analysis, whole exome sequencing showed “no secondary BRCA1/2 mutations in either primary or acquired resistance,” but identified mutations in genes involved in the nucleotide excision repair pathway in tumors from four of seven patients with primary or acquired resistance and in one patient with short-term stable disease.
The study findings are published in the Journal of Clinical Oncology.
By Laura Cowen
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