ESMO 2016: Antitumor Activity Demonstrated With Lurbinectedin in Patients With Metastatic Breast Cancer and BRCA Mutations
Lurbinectedin showed promising clinical benefit in pretreated patients with metastatic breast cancer and BRCA1 or BRCA2 mutations, including patients previously treated with platinum, according to phase II trial results presented by Balmaña et al at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen (Abstract 223O).
Lurbinectedin (PM01183) blocks transactivated transcription by binding to the minor groove of DNA. Activity has been demonstrated in patients with diverse tumor types, and in those that are resistant to platinum-based chemotherapy. Observations that lurbinectedin was active against homologous recombination–deficient cell lines led investigators to test it in patients with metastatic breast cancer having deleterious germline BRCA mutations, said lead investigator Judith Balmaña, MD, PhD, of the Department of Medical Oncology, Hospital Vall d’Hebron and Vall d’Hebron Institute of Oncology in Barcelona.
Trial Details
This phase II trial enrolled patients with BRCA mutation–positive, measurable metastatic breast cancer per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, with performance status ≤ 1. Patients were required to have adequate major organ function. L
urbinectedin was initially to be administered to all patients at a 7-mg fixed dose intravenously every 3 weeks, but the dose was changed by protocol amendment to 3.5 mg/m2 for improved safety. In all, 35 patients received 7 mg of lurbinectedin, and 19 patients were treated with 3.5 mg/m2. The primary endpoint of the trial was confirmed overall response rate (ORR) by RECIST v1.1.
The patients’ median age was 43 years. Thirty patients had performance status 0, and 33 patients had more than 2 metastatic sites. The patients had a median of one prior chemotherapy treatment for advanced disease. Additionally, 45 patients had received prior anthracyclines, 47 received taxanes, 27 received platinum, and 9 had been treated with PARP inhibitors. BRCA1 mutations were documented in 30 patients, and 31 patients had triple-negative breast cancer.
Primary Endpoint Met
Lurbinectedin had been administered to 54 patients as of May 2016, with patients receiving a median of 6 (range: 1–24) treatment cycles.
Of 54 patients with evaluable data, the ORR was 39% (95% confidence interval [CI] = 26%–54%) in patients receiving the fixed dose and 44% in patients dosed at 3.5 mg/m2, with an overall response rate of 40.7% (95% CI = 27%–55%). The best overall response with lurbinectedin included complete response in 1 patient (2%), partial response in 21 (39%), and stable disease in 23 (43%). Just 9 patients (17%) with advanced metastatic breast cancer experienced progressive disease. The median duration of response was 6.7 months (95% CI = 3.0–11.3), and progression-free survival was 4.1+ months (95% CI = 2.8–5.9).
Platinum-pretreated patients demonstrated an ORR of 26% (95% CI = 11%–26%).
In patients receiving the fixed dose of lurbinectedin, the most commonly reported grades 3/4 adverse events included neutropenia in 71% of patients and grade 4 neutropenia, which was seen in 51%. Febrile neutropenia occurred in 29%; thrombocytopenia and transaminase increase were each seen in 26% of patients. Grade 4 throbocytopenia, and transaminase increase occured in 20% and 3% of patients, respectively. Grade 3 fatigue and nausea occurred in 17% and 9% of patients, respectively.
Conclusions
At the reduced dose, adverse events included neutropenia in 50% of patients, febrile neutropenia and thrombocytopenia in 6% each, transaminase increase occurred in 11%, and grade 3 fatigue and nausea occurred in 17% and 6%, respectively. Grade 4 neutropenia was seen in 5% of patients but no other grade 4 adverse events occurred in this cohort.
The investigators concluded that the trial met the primary endpoint and lurbinectedin showed activity in primary BRCA–positive metastatic breast cancer, including patients who had previously received platinum therapy.
They noted that tolerance to lurbinectedin improved at the 3.5 mg/m2 dose without compromising efficacy.
Based on these results and on predefined criteria of 17 or more confirmed responses in the cohort of evaluable patients, the investigators concluded that further development of lurbinectedin in patients with BRCA mutation and metastatic breast cancer is warranted.
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