Phase II Trial Evaluating Lurbinectedin Shows Notable Efficacy in BRCA 1 and 2

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Patients with BRCA1 or BRCA2-mutated metastatic breast cancer may benefit from treatment with lurbinectedin (PM1183 | Zepsyre®; PharmaMar), a selective inhibitor of active transcription of protein-coding genes.

This is the outcome from a Phase II study. The results of this study were published in The Lancet Oncology and the Journal of Clinical Oncology and present noteworthy clinical activity in patients with metastatic breast cancer that have mutations in the BRCA 1 and/or BRCA 2 genes. [1]


This phase II trial showed a notable efficacy in patients with metastatic breast cancer and a germline BRCA1/2 mutation


Lurbinectedin is a synthetic tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one alkaloid analogue which covalently binds to residues lying in the minor groove of DNA, and may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death.

Multiple trial
The anticancer efficacy of lurbinectedin is being investigated in various types of solid tumors, including a Phase III study for platinum-resistant ovarian cancer, a Phase III study for small cell lung cancer, and has completed a Phase II study for BRCA 1 and BRCA 2-associated metastatic breast cancer (MBC).

Photo 1.0: Judith Balmaña Gelpi, MD, PhD, a medical oncologist at the Clinical Cancer Genetics/Breast Cancer Unit Medical Oncology Vall d’Hebron University Hospital, Barcelona, Spain. In 2015 Dr Balmaña was awarded with the Prize to Biomedical Research Excellence by the Col.legi Oficial de Metges de Barcelona. She teaches at the School of Medicine of Universitat Autònoma de Barcelona (UAB) and Universitat Internacional de Catalunya (UIC), and is the clinical coordinator of the cancer genetics module in the Master Program in Genetic Counselling (IDEC/ Universitat Pompeu Fabra).

Trial design
In this trial, two arms were evaluated according to germline BRCA1/2 status. The first arm included BRCA1/2 mutated (arm A; n = 54). The second arm included unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35).

Eligible patients were between 18 and 75 years of age with a histologically proven diagnosis of metastatic breast cancer. These patients had received no more than three prior chemotherapy-containing regimens in the advanced setting, including at least one prior trastuzumab-containing regimen in patients with known HER2-overexpressing tumors. Finally, eligible patients had measurable disease per Response Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status ≤ 1, and adequate major organ function.

The starting dose of the investigational drug was a 7-mg flat dose and later, 3.5 mg/m2 in arm A.

The primary end point was an Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors.

Trial results
In arm A, the ORR was 41% (95% CI, 28% to 55%). 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 patients with BRCA2 mutations, the confirmed Overall Response Rate (ORR) was 61%, the median progression-free survival (PFS) was observed to be 5.9 months and the median Overall Survival (OS) was observed to be 26.6 months.

In arm B the ORR was 9% (95% CI, 2% to 24%).

In the prior, untreated PARP population, the confirmed Objective Response Rate (ORR) was 72%, this being the highest reported figure in this tumor setting so far. However, this trial intended to assess the clinical activity of lurbinectedin in patients affected by metastatic breast cancer in BRCA 1 and/or BRCA 2 gene mutations.

The 54 breast cancer patients with mutations in the BRCA 1 and/or BRCA 2 genes included in the trial were recruited from 11 research centers in the United States and Spain.

Adverse events
The study results showed an improved safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). The most common severe hematologic adverse event was Neutropenia (grade 3, 47%; grade 4, 10%).

“Lurbinectedin is a selective inhibitor of active transcription of protein-coding genes,” explained Judith Balmaña Gelpi, MD, Ph.D, an oncologists at Vall d’Hebron Institute of Oncology, in The Lancet Oncology. “In this phase II trial, it showed a notable efficacy in patients with metastatic breast cancer and a germline BRCA1/2 mutation.”

Clinical trial
A Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer – NCT01525589

References
[1] Gourd E. Lurbinectedin for BRCA-mutated advanced breast cancer. Lancet Oncol. 2018 Sep 27. pii: S1470-2045(18)30737-X. doi: 10.1016/S1470-2045(18)30737-X. [Epub ahead of print]
[2] Cruz C, Llop-Guevara A, Garber JE, Arun BK, Pérez Fidalgo JA, Lluch A, Telli ML, Fernández C, et al.Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy. J Clin Oncol. 2018 Sep 21:JCO2018786558. doi: 10.1200/JCO.2018.78.6558. [Epub ahead of print]


Last Editorial Review: November 8, 2018

Featured Image: Mother and daughter expressing intergenerational breast cancer awareness. Courtesy: © 2018 Fotolia. Used with permission. Photo 1.0: Judith Balmaña Gelpi, MD, PhD, a medical oncologust at the Clinical Cancer Genetics/Breast Cancer Unit Medical Oncology Vall d’Hebron University Hospital, Barcelona, Spain. Courtesy: © 2018: Fundación Bancaria Caixa d’Estalvis i Pensions de Barcelona, “la Caixa”. Used with permission.

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