• Cristina Cruz, Alba Llop-Guevara, Judy E Garber, Banu K Arun, José A Pérez Fidalgo, Ana Lluch, Melinda L Telli, Cristian Fernández, Carmen Kahatt, Carlos M Galmarini, Arturo Soto-Matos, Vicente Alfaro, Aitor Pérez de la Haza, Susan M Domchek, Silvia Antolin, Linda Vahdat, Nadine M Tung, Rafael Lopez, Joaquín Arribas, Ana Vivancos, José Baselga, Violeta Serra, Judith Balmaña, and Steven J Isakoff.
• Cristina Cruz and Judith Balmaña, Vall d'Hebron Hospital; Cristina Cruz, Alba Llop-Guevara, Joaquín Arribas, Ana Vivancos, Violeta Serra, and Judith Balmaña, Vall d'Hebron Institute of Oncology; José A. Pérez Fidalgo, Ana Lluch, Joaquín Arribas, and Violeta Serra, Centro de Investigación Biomédica en Red; Joaquín Arribas, Institució Catalana de Recerca i Estudis Avançats, Barcelona; José A. Pérez Fidalgo and Ana Lluch, Hospital Clínico de Valencia, Valencia; Cristian Fernández, Carmen Kahatt, Carlos M. Galmarini, Arturo Soto-Matos, Vicente Alfaro, and Aitor Pérez de la Haza, PharmaMar, Madrid; Silvia Antolin, Complejo Universitario Hospitalario La Coruña, La Coruña; Rafael Lopez, Complejo Hospitalario Universitario Santiago de Compostela, Santiago de Compostela, Spain; Judy E. Garber, Dana Farber Cancer Institute; Nadine M. Tung, Beth Israel Deaconess Medical Center; José Baselga and Steven J. Isakoff, Massachusetts General Hospital Cancer Center, Boston, MA; Banu K. Arun, MD Anderson Cancer Center, Houston, TX; Melinda L. Telli, Stanford University School of Medicine, Stanford, CA; Susan M. Domchek, University of Pennsylvania, Philadelphia, PA; and Linda Vahdat, Weill Cornell Medicine, New York, NY.
• J. Clin. Oncol. 2018 Nov 1; 36 (31): 3134-3143.

PurposeThis multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance.Patients And MethodsTwo arms were evaluated 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). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was 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.ResultsORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, 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). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The 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%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts.ConclusionLurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

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