pm-01183 and Breast-Neoplasms

Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer.. Confirmed partial response (PR) was observed in six patients [ORR = 28.6%; 95% confidence interval (CI) 11.3% to 52.2%] who had received a median of two prior advanced chemotherapy lines. Lurbinectedin was active in both BRCA mutations: four PRs in 11 patients (36.4%) with BRCA2 and two PRs in 10 patients (20.0%) with BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in 10 patients (47.6%), including 3 with unconfirmed response in a subsequent tumor assessment [ORR unconfirmed = 42.9% (95% CI 21.8% to 66.0%)]. Clinical benefit rate (PR + SD ≥ 4 months) was 76.2% (95% CI 52.8% to 91.8%). No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors. The most common treatment-related adverse events (AEs) were nausea (61.9%), fatigue (38.1%) and vomiting (23.8%). These AEs were mostly grade 1/2. The most common grade 3/4 toxicity was neutropenia (42.9%: grade 4, 23.8%: with no febrile neutropenia).. This phase II study met its primary endpoint and showed activity of lurbinectedin in germline BRCA1/2 breast cancer. Lurbinectedin showed a predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II studies, further development of lurbinectedin in this indication is warranted.

Topics: Adenosine Diphosphate; BRCA1 Protein; Breast Neoplasms; Female; Genes, BRCA1; Genes, BRCA2; Germ Cells; Germ-Line Mutation; Hormones; Humans; Neutropenia; Poly(ADP-ribose) Polymerase Inhibitors; Ribose

This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance.. ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m. Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

Topics: Adult; Aged; Animals; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Carbolines; Dose-Response Relationship, Drug; Female; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Heterocyclic Compounds, 4 or More Rings; Humans; Mice; Middle Aged; Progression-Free Survival; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Biomarkers, Tumor; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Carbolines; Clinical Trials, Phase II as Topic; Female; Genetic Predisposition to Disease; Heterocyclic Compounds, 4 or More Rings; Humans; Multicenter Studies as Topic; Mutation; Phenotype; Progression-Free Survival