Lurbinectedin Active in BRCA1/2-Mutated Advanced Breast Cancer

Patients with advanced breast cancer who carry germline mutations in BRCA1/2 genes are highly sensitive to DNA damage due to deficiencies in homologous recombination repair (HRR) mechanisms. Lurbinectedin, an analog of the DNA damaging agent trabectedin, is a selective inhibitor of the transcription of protein-coding genes that results in accumulation of double-strand DNA breaks. In preclinical studies, lurbinectedin demonstrated antitumor activity similar to trabectedin in HRR-deficient cell lines. A two-arm phase II trial evaluated the activity of lurbinectedin in patients with metastatic breast cancer, including both patients with germline BRCA1/2 mutations (arm A; n = 54) and BRCA unselected patients (arm B; n = 35).

In patients with BRCA1/2 mutations (arm A), lurbinectedin resulted in an overall response rate (ORR) of 41%, including 2 complete responses and 20 partial responses. The median progression-free survival (PFS) and overall survival (OS) were 4.6 months and 20.0 months, respectively. Best responses were seen in the subgroup of patients with BRCA2 mutations, where ORR was 61%, median PFS was 5.9 months, and median OS was 26.6 months. In patients with BRCA1 mutations, ORR was 26%, PFS was 3.0 months, and OS was 15.9 months. ORR increased in patients without prior poly (ADP-ribose) polymerase inhibitor (PARPi) therapy, especially in BRCA2 patients (ORR: 72% vs 30% in BRCA1). Responses were also higher in platinum-naïve patients (56%) than in platinum-pretreated patients (26%). Multivariate analysis of patients in arm A identified BRCA2 expression as the only variable predicting response. At initial futility analysis, lurbinectedin was not active in BRCA unselected patients (arm B), with an ORR of 9%, and thus this cohort was closed.

Lurbinectedin was initially given at a flat dose of 7 mg that was later adjusted to 3.5 mg/m2 due to toxicity. Dose adjustment resulted in notable reductions in rates of grade 4 hematologic abnormalities and febrile neutropenia. The most common all-grade nonhematologic adverse events in patients receiving the adjusted dose were nausea and fatigue (both 74%).

A parallel translational research study used whole exome sequencing on paired pre- and post-lurbinectedin biopsy samples to identify potential resistance mechanisms to lurbinectedin. Mutations in genes related to nucleotide excision repair were identified in 4 of 7 tumors with primary or acquired resistance and one patient with stable disease.

The investigators concluded that lurbinectedin has a unique mechanism of action and demonstrated promising activity in patients with advanced breast cancer with BRCA1/2 mutations, particularly in those patients with BRCA2 mutations. While this study was limited by a small sample size, it provides sufficient evidence for further exploration of this agent in BRCA2 mutated tumors.

J Clin Oncol. 2018 Sept 21. [Epub ahead of print.]
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