12 Oct Anti-Tumor Activity of PM01183 (lurbinectedin) in BRCA1/ 2-associated Metastatic Breast Cancer Patients
MedicalResearch.com Interview with:
Dr. Judith Balmaña
Judith Balmaña MD
Medical Oncology
Hospital Vall d’Hebron and
Vall d’Hebron Institute of Oncology
Barcelona, Spain
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Tumors with brca1 or brca2 mutations share homologous recombination repair deficiency, which confers sensitivity to different types of dna damaging agents. An understanding of the role of brca1 and brca2 in the repair of double-stranded dna damage opened a window of opportunity for treating brca mutation–associated cancers with targeted therapies.
Lurbinectedin is a trabectedin analog that specifically binds to cg-rich motifs with a selective mechanism of action: in living cells, lurbinectedin inhibits active transcription by degradation of elongating rna polymerase ii. This process occurs specifically on activated genes and is associated with the formation of double strand dna breaks and the collapse of replication forks. In addition, lurbinectedin exerts some antitumoral effect in the microenvironment by inhibiting the transcription of selected cytokines by tumor-associated macrophages, abrogating their protumoral properties. Observations that lurbinectedin was active against homologous-recombination-deficient cell lines led us to test it in patients with metastatic breast cancer having deleterious germline brca mutations.
This phase II trial enrolled patients with brca mutation positive, measurable metastatic breast cancer per recist 1.1, with performance status ≤ 1. Lurbinectedin was initially to be administered to all patients at 7 mg fixed dose by i.v. 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 by recist 1.1. Of 54 patients with evaluable data, the orr was 40.7% the best overall response with lurbinectedin included complete response in one (2%) patient, partial response in 21 (39%) patients, and stable disease in 23 (43%) patients. Just 9 (17%) patients with advanced metastatic breast cancer experienced progressive disease as the best response. The median duration of response was 6.7 months, progression-free survival was 4.1 months, and overall survival was 20 months. Platinum pre-treated patients demonstrated an ORR of 26% and patients not exposed to platinum achieved a 56% response rate. A higher ORR was observed in brca2 mutation carriers compared to brca1 carriers, 61% and 26% respectively; and responses were similar regardless of hormone status: 36% of tnbc and 48% of hr +.
MedicalResearch.com: What should readers take away from your report?
Response: We concluded that the trial met the primary endpoint with a confirmed overall response rate above 40%, with efficacy observed regardless of hormone status and prior platinum. Tolerance to lurbinectedin improved at the 3.5 mg/m2 dose without compromising efficacy.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: In the laboratory, we would like to keep investigating on the specific mechanism of action of lurbinectedin in transcription inhibition and the functions of brca1 and brca2 in this process in order to identify biomarkers of sensitivity. There is also the need to keep investigating on mechanisms of resistance and delineating the best sequential strategy of therapies that lack cross-resistance in this group of patient. A better knowledge of the mechanisms of cross-resistance and sensitivity to targeted therapies for patients with a brca mutation will be helpful to improve the most optimal therapeutic strategy. In the clinics, we would like to further develop lurbinectedin and compare its efficacy to standard treatment.
MedicalResearch.com: Is there anything else you would like to add?
Response: We believe that these results encourage further development of lurbinectedin in patients with brca mutation and metastatic breast cancer.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Citation:
Anti-tumor activity of PM01183 (lurbinectedin) in BRCA1/ 2-associated metastatic breast cancer patients: results of a single-agent phase II trial J. Balmaña1, C. Cruz1, B.K. Arun2, M. Telli3, J. Garber4, S. Domchek5, C. M. Fernandez6, C. Kahatt6, S. Szyldergemajn6, A. Soto-Matos6, A. Perez de la Haza6, J.A. Perez Fidalgo7, A. Lluch-Hernandez7, S. Antolin8, N.M. Tung9, L. T. Vahdat10, R. Lopez11, S.J.J. Isakoff12 1 Medical Oncology, Hospital Vall d’Hebron and Vall d’Hebron Institute of Oncology, Barcelona, Spain, 2 Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA, 3 Medical Oncology, Stanford University Medical Center, Stanford, CA, USA, 4 Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA, 5 Medical Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA, 6 Clinical Development, PharmaMar SA, Colmenar Viejo, Spain, 7 Medical Oncology, Hospital Clinico Universitario de Valencia, Valencia, Spain, 8 Medical Oncology, Complejo Universitario Hospitalario La Coruña, A Coruna, Spain, 9 Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA, 10Medical Oncology, Weill Cornell Medicine, New York, NY, USA, 11Medical Oncology, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago De Compostela, Spain, 12Medical Oncology, Massachusetts General Hospital, Boston, MA, USA
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Last Updated on October 12, 2016 by Marie Benz MD FAAD