TY - JOUR
T1 - Multicenter phase II study of lurbinectedin in BRCAMutated and unselected metastatic advanced breast cancer and biomarker assessment substudy
AU - Cruz, Cristina
AU - Llop-Guevara, Alba
AU - Garber, Judy E.
AU - Arun, Banu K.
AU - Perez Fidalgo, Joe A.
AU - Lluch, Ana
AU - Telli, Melinda L.
AU - Ferńandez, Cristian
AU - Kahatt, Carmen
AU - Galmarini, Carlos M.
AU - Soto-Matos, Arturo
AU - Alfaro, Vicente
AU - De La Haza, Aitor Perez
AU - Domchek, Susan M.
AU - Antolin, Silvia
AU - Vahdat, Linda
AU - Tung, Nadine M.
AU - Lopez, Rafael
AU - Arribas, Joaqúin
AU - Vivancos, Ana
AU - Baselga, Joe
AU - Serra, Violeta
AU - Balmaña, Judith
AU - Isakoff, Steven J.
N1 - Publisher Copyright:
© 2018 by American Society of Clinical Oncology.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - Purpose This 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 Methods Two 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 patientderived xenografts (n = 11) from BRCA1/2-mutated tumors. Results ORR 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) patientderived xenografts. Conclusion Lurbinectedin 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.
AB - Purpose This 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 Methods Two 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 patientderived xenografts (n = 11) from BRCA1/2-mutated tumors. Results ORR 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) patientderived xenografts. Conclusion Lurbinectedin 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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U2 - 10.1200/JCO.2018.78.6558
DO - 10.1200/JCO.2018.78.6558
M3 - Article
C2 - 30240327
AN - SCOPUS:85055798726
SN - 0732-183X
VL - 36
SP - 3134
EP - 3143
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 31
ER -