Cruz C, et al. - In patients with metastatic breast cancer, researchers assessed lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, this multicenter phase 2 trial. In addition, a unicenter translational substudy evaluated possible mechanisms of lurbinectedin resistance. In patients with BRCA1/2 mutations, lurbinectedin displayed notable activity. In patients with BRCA2 mutations, response and survival was also noteworthy. The most common severe hematologic adverse event was neutropenia. Nausea and fatigue were the most common nonhematologic adverse events, seen at 3.5 mg/m².

Methods

• For this investigation, two arms were assessed according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n=54) and unselected (BRCA1/2 wild-type or unknown status; arm B; n=35).
• In arm A, lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m².
• Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) was the primary end point.
• The translational substudy of resistance mechanisms involved exome sequencing (n=13) and in vivo experiments with patient-derived xenografts (n=11) from BRCA1/2-mutated tumors.

Results

• According to the findings obtained, ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B.
• It was observed that 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) in arm A.
• An ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months was seen in patients with BRCA2 mutations.
• With lurbinectedin dose adjustment to body surface area, the safety profile improved.
• Nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%) were the most common nonhematologic adverse events seen at 3.5 mg/m².
• The most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%) was neutropenia.
• Exome sequencing displayed mutations in genes related to the nucleotide excision repair pathway in 4 of 7 tumors at primary or acquired resistance and in 1 subject with short-term stable disease.
• The present data indicated that sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts in vivo.