A phase II trial evaluated lurbinectedin in patients with BRCA1/2-mutant and wild-type tumors.
Major finding: A phase II trial evaluated lurbinectedin in patients with BRCA1/2-mutant and wild-type tumors.
Clinical relevance: Lurbinectedin achieved a 41% response rate in metastatic breast cancer with germline BRCA1/2 mutation.
Impact: Lurbinectedin warrants further investigation for the treatment of patients with BRCA1/2 mutations.
Germline mutations in BRCA1 or BRCA2 occur in 3% to 5% of patients with metastatic breast cancer and impair homologous recombination repair (HRR) of double-strand breaks, thereby sensitizing tumor cells to the antitumor agent trabectedin. The trabectedin analogue lurbinectedin is a selective inhibitor of active transcription that promotes irreversible stalling of RNA polymerase II, resulting in recruitment of DNA repair factors and induction of double-strand breaks. HRR deficiency enhances these effects, suggesting that BRCA1/2-mutant tumors may be sensitive to lurbinectedin treatment. Cruz and colleagues evaluated the safety and efficacy of lurbinectedin in a phase II trial of patients with metastatic breast cancer. Patients were treated in two arms, with 54 patients with germline BRCA1/2 mutations treated in arm A and 35 patients with wild-type BRCA1/2 or unknown status treated in arm B. The primary endpoint was objective response rate, and resistance mechanisms were investigated via exome sequencing and in patient-derived xenografts. The overall response rate was 41% in arm A and 9% in arm B, indicating that lurbinectedin has antitumor activity in patients with germline BRCA1/2 mutations. In patients with BRCA2 mutations, the overall response rate was 61%, the median progression-free survival was 5.9 months, and median overall survival was 26.6 months. The safety profile of lurbinectedin was acceptable. Exome sequencing of five paired pre- and post-treatment samples identified multiple mutations in the nucleotide excision repair pathway in three patients, and these mutations were linked to resistance in patient-derived xenograft models. Taken together, the results of this phase II trial indicate that lurbinectedin has antitumor activity and warrants further investigation in patients with metastatic breast cancer with BRCA1/2 mutations.
Cruz C, Llop-Guevara A, Garber JE, Arun BK, Pérez Fidalgo JA, Lluch A, et al. Multicenter phase II study of lurbinectedin in BRCA-mutated and unselected metastatic advanced breast cancer and biomarker assessment substudy. J Clin Oncol 2018 Sep 21 [Epub ahead of print].
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