Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy

被引：46

作者：

Cruz, Cristina ^{[1
,2
]}

Llop-Guevara, Alba ^{[2
]}

Garber, Judy E. ^{[9
]}

Arun, Banu K. ^{[12
]}

Perez Fidalgo, Jose A. ^{[3
,5
]}

Lluch, Ana ^{[3
,5
]}

Telli, Melinda L. ^{[13
]}

Fernandez, Cristian ^{[6
]}

Kahatt, Carmen ^{[6
]}

Galmarini, Carlos M. ^{[6
]}

Soto-Matos, Arturo ^{[6
]}

Alfaro, Vicente ^{[6
]}

Perez de la Haza, Aitor ^{[6
]}

Domchek, Susan M. ^{[14
]}

Antolin, Silvia ^{[7
]}

Vahdat, Linda ^{[15
]}

Tung, Nadine M. ^{[10
]}

Lopez, Rafael ^{[8
]}

Arribas, Joaquin ^{[2
,3
,4
]}

Vivancos, Ana ^{[2
]}

Baselga, Jose ^{[11
]}

Serra, Violeta ^{[2
,3
]}

Balmana, Judith ^{[1
,2
]}

Isakoff, Steven J. ^{[11
]}

机构：

[1] Vall dHebron Hosp, Barcelona, Spain

[2] Vall dHebron Inst Oncol, Paseo Vall dHebron 119-129, Barcelona 08035, Spain

[3] Ctr Invest Biomed Red, Barcelona, Spain

[4] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain

[5] Hosp Clin Valencia, Valencia, Spain

[6] PharmaMar, Madrid, Spain

[7] Complejo Univ Hosp La Coruna, La Coruna, Spain

[8] Complejo Hosp Univ Santiago de Compostela, Santiago De Compostela, Spain

[9] Dana Farber Canc Inst, Boston, MA 02115 USA

[10] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

[11] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

[12] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[13] Stanford Univ, Sch Med, Stanford, CA 94305 USA

[14] Univ Penn, Philadelphia, PA 19104 USA

[15] Weill Cornell Med, New York, NY USA

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2018年 / 36卷 / 31期

关键词：

PM01183; DNA; TRABECTEDIN;

D O I：

10.1200/JCO.2018.78.6558

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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/m(2) 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/m(2) 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.

引用

页码：3134 / +

页数：21

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