Antitumor Activity of PM01183 in BRCA-Associated Metastatic Breast Cancer
PM01183 (lurbinectedin) is an investigational anticancer drug that blocks transactivated transcription, induces DNA double-strand breaks, and modulates the tumor microenvironment. Its activity has been observed in several different tumor types, and in patients who are resistant to platinum-based chemotherapy. Due to PM01183âs observed activity in homologous recombination-deficient cell lines, this phase 2 trial was initiated in patients with metastatic breast cancer and germline BRCA mutations (BRCAmut). In highlighting an unmet need in this population of patients, Dr Judith BalmaÃ±a of Barcelona, Spain, who was affiliated with this study, said, âThere are no approved therapies specifically for breast cancer patients with a BRCA1/2 mutation, and these patients are being treated mainly according to their hormone receptor and HER2 [human epidermal growth factor receptor 2] status.â
BRCAmut patients with metastatic breast cancer who had had fewer than 3 chemotherapy regimens in the advanced/metastatic setting were eligible for inclusion in this study. Additionally, included patients had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines, minimal disease-related symptoms (performance status â¤1), and adequate major organ function. Patients received PM01183 intravenously once every 3 weeks. Planned dosing was adjusted during the course of the trial from an initial fixed dose of 7 mg to 3.5 mg/m2 to improve safety. The primary end point of this trial was overall response rate (ORR) by RECIST v1.1.
As of May 2016, 54 eligible patients (median age, 43 years; median, 1 prior advanced chemotherapy treatment) had been treated. A total of 35 patients had received the 7-mg fixed dose; 19 patients had received the 3.5-mg/m2 dosing). Of the 51 evaluable patients, ORR was 39% (95% confidence interval [CI], 26-54), with 43% of patients having stable disease, 37% having partial response, 18% having progressive disease, and 2% having complete response. The median duration of response was 4.6 months (95% CI, 3.4-11.3), and the median progression-free survival was â¥4.1 months (95% CI, 2.6-6.0). Of the 22 responding patients, 5 had ongoing response at the time of data cut-off for this report. For patients having received prior treatments with platinum-based chemotherapies, ORR was 23% (95% CI, 9-44).
The most common grade 3-4 related adverse events by dose (7-mg fixed dose/3.5 mg/m2) were neutropenia 71%/50% (grade 4: 51%/6%); febrile neutropenia 29%/6%; thrombocytopenia 26%/6% (grade 4: 20%/0%); grade 3 fatigue 17%/17%; transaminase increase 26%/11% (grade 4: 3%/0%); and grade 3 nausea 9%/6%.
These results confirm that PM01183 is an active drug in BRCAmut patients with metastatic breast cancer, including in those who have received prior platinum-based treatments. Efficacy was maintained at the adjusted 3.5-mg/m2 dosage, while tolerance was notably improved. Further development of this therapy is currently underway with the planning of a phase 3 trial.
BalmaÃ±a J, et al. ESMO 2016. Abstract 223O.