PMID- 36037567 OWN - NLM STAT- MEDLINE DCOM- 20221024 LR - 20221103 IS - 2059-7029 (Electronic) IS - 2059-7029 (Linking) VI - 7 IP - 5 DP - 2022 Oct TI - Lurbinectedin, a selective inhibitor of oncogenic transcription, in patients with pretreated germline BRCA1/2 metastatic breast cancer: results from a phase II basket study. PG - 100571 LID - S2059-7029(22)00201-0 [pii] LID - 10.1016/j.esmoop.2022.100571 [doi] LID - 100571 AB - BACKGROUND: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer. PATIENTS AND METHODS: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m(2) 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Confirmed partial response (PR) was observed in six patients [ORR = 28.6%; 95% confidence interval (CI) 11.3% to 52.2%] who had received a median of two prior advanced chemotherapy lines. Lurbinectedin was active in both BRCA mutations: four PRs in 11 patients (36.4%) with BRCA2 and two PRs in 10 patients (20.0%) with BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in 10 patients (47.6%), including 3 with unconfirmed response in a subsequent tumor assessment [ORR unconfirmed = 42.9% (95% CI 21.8% to 66.0%)]. Clinical benefit rate (PR + SD >/= 4 months) was 76.2% (95% CI 52.8% to 91.8%). No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors. The most common treatment-related adverse events (AEs) were nausea (61.9%), fatigue (38.1%) and vomiting (23.8%). These AEs were mostly grade 1/2. The most common grade 3/4 toxicity was neutropenia (42.9%: grade 4, 23.8%: with no febrile neutropenia). CONCLUSIONS: This phase II study met its primary endpoint and showed activity of lurbinectedin in germline BRCA1/2 breast cancer. Lurbinectedin showed a predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II studies, further development of lurbinectedin in this indication is warranted. CI - Copyright (c) 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Boni, V AU - Boni V AD - START Madrid-CIOCC, Centro Integral Oncologico Clara Campal, Madrid, Spain. FAU - Pistilli, B AU - Pistilli B AD - Gustave Roussy, Villejuif, France. FAU - Brana, I AU - Brana I AD - Hospital Universitario Vall D'Hebron (VHIO), Barcelona, Spain. FAU - Shapiro, G I AU - Shapiro GI AD - Dana-Farber Cancer Institute, Boston, USA. FAU - Trigo, J AU - Trigo J AD - Hospital Universitario Virgen De La Victoria, IBIMA, Malaga, Spain. FAU - Moreno, V AU - Moreno V AD - START Madrid-FJD, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain. FAU - Castellano, D AU - Castellano D AD - Hospital Universitario 12 de Octubre, Madrid, Spain. FAU - Fernandez, C AU - Fernandez C AD - PharmaMar, Colmenar Viejo, Madrid, Spain. FAU - Kahatt, C AU - Kahatt C AD - PharmaMar, Colmenar Viejo, Madrid, Spain. FAU - Alfaro, V AU - Alfaro V AD - PharmaMar, Colmenar Viejo, Madrid, Spain. FAU - Siguero, M AU - Siguero M AD - PharmaMar, Colmenar Viejo, Madrid, Spain. FAU - Zeaiter, A AU - Zeaiter A AD - PharmaMar, Colmenar Viejo, Madrid, Spain. FAU - Longo, F AU - Longo F AD - Hospital Universitario Ramon y Cajal, Madrid, Spain. FAU - Zaman, K AU - Zaman K AD - University Hospital CHUV, Lausanne, Switzerland. FAU - Anton, A AU - Anton A AD - Hospital Universitario Miguel Servet, Zaragoza, Spain. FAU - Paredes, A AU - Paredes A AD - Hospital Universitario Donostia, Donostia-San Sebastian, Spain. FAU - Huidobro, G AU - Huidobro G AD - Hospital Universitario de Vigo Alvaro Cunqueiro, Pontevedra, Spain. FAU - Subbiah, V AU - Subbiah V AD - The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: vsubbiah@mdanderson.org. LA - eng SI - ClinicalTrials.gov/NCT02454972 GR - R01 CA242845/CA/NCI NIH HHS/United States GR - U01 CA180964/CA/NCI NIH HHS/United States GR - UL1 TR000371/TR/NCATS NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220828 PL - England TA - ESMO Open JT - ESMO open JID - 101690685 RN - 0 (PM 01183) RN - 681HV46001 (Ribose) RN - 0 (Poly(ADP-ribose) Polymerase Inhibitors) RN - 0 (Hormones) RN - 61D2G4IYVH (Adenosine Diphosphate) RN - 0 (BRCA1 protein, human) RN - 0 (BRCA1 Protein) SB - IM MH - Humans MH - Female MH - *Breast Neoplasms/drug therapy/genetics/pathology MH - Genes, BRCA2 MH - Genes, BRCA1 MH - Ribose/therapeutic use MH - Germ-Line Mutation MH - Poly(ADP-ribose) Polymerase Inhibitors/pharmacology/therapeutic use MH - Germ Cells/pathology MH - *Neutropenia/drug therapy MH - Hormones/therapeutic use MH - Adenosine Diphosphate/therapeutic use MH - BRCA1 Protein/genetics PMC - PMC9588879 OTO - NOTNLM OT - BRCA1 OT - BRCA2 OT - breast cancer OT - lurbinectedin OT - phase II OT - response rate COIS- Disclosure VB received grants as consultant or advisory role from Puma Biotechnology, Ideaya Biosciences, Loxo Therapeutics, CytomX Therapeutics, Guidepoint, Oncoart; honoraria as speaker from Eli Lilly; and institutional financial support for clinical trials from AbbVie, ACEO, Adaptaimmune, Amcure, AMGEN, AstraZeneca, BMS Cytomx, GSK, Genentech/Roche, H3, Incyte, Janssen, Kura, Lilly, Loxo, Nektar, Macrogenics, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, PUMA, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Takeda, Incyte, Innovio, MSD, PsiOxus, Seattle Genetics, Mersana, GSK, Daiichi, Nektar, Astellas, ORCA, Boston Therapeutics, Dynavax, DebioPharm, Boehringer Ingelheim, Regeneron, Millennium, Synthon, Spectrum, Rigontec, and Zenith. BP received consulting fees from AstraZeneca and Pfizer for her institution and from Myriad and Pierre Fabre for herself; payment or honoraria for lectures, presentations, speakers bureaus or educational events from Daiichi-Sankyo, Novartis and Puma; support for attending meetings and/or travel from AstraZeneca, Pierre Fabre and MSD; and participation on a Data Safety Monitoring Board or Advisory Board from Novartis, Astra Zeneca and Daiichi-Sankyo. VM received grants or contracts as principal investigator or institutional funding from AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM,Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics and Upshersmith; consulting fees from Roche, Bayer, BMS, and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Bayer, BMS; and participation on a Data Safety Monitoring Board or Advisory Board from Basilea. CF, CK, VA, MS and AZ have personal fees for salary as full time employees from PharmaMar S.A. CF, CK, VA and AZ are stock ownership of PharmaMar S.A. FL received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and support for attending meetings and/or travel, and participation on a Data Safety Monitoring Board or Advisory Board from Roche, Merck, Amgen, Lilly, Servier, MSD, BMS and Sanofi. AA received consulting fees from Gilead, Lilly and Seagen; payment for expert testimony from Pfizer; and leadership or fiduciary role in ECO Foundation. VS received grants from PharmaMar, Eli Lilly/LOXO Oncology, Blueprint Medicines Corporation, Turning Point Therapeutics and Boston Pharmaceuticals; and grants from Helsinn Pharmaceuticals during the conduct of the study; in addition, VS received a grant and advisory board/consultant position with Eli Lilly/Loxo Oncology during the conduct of the study; research grants from Roche/Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, PharmaMar and Medimmune; an advisory board/consultant position with Helsinn, Incyte, QED Pharma, Daiichi-Sankyo, Signant Health, Novartis, Relay therapeutics, Roche and Medimmune; travel funds from PharmaMar, Incyte, ASCO, ESMO; and other support from Medscape, all outside the submitted work. All other authors have declared no conflicts of interest. Data Sharing Individual participant data are not publicly available since this requirement was not anticipated in the study protocol considering that this trial started patient enrollment in 2015. Clinical trial summary results were placed in the European Clinical Trials Database (EudraCT; https://eudract.ema.europa.eu; study 2014-003773-42) and ClinicalTrials.gov (identifier: NCT02454972). EDAT- 2022/08/30 06:00 MHDA- 2022/10/25 06:00 PMCR- 2022/08/28 CRDT- 2022/08/29 18:15 PHST- 2022/05/13 00:00 [received] PHST- 2022/07/21 00:00 [revised] PHST- 2022/07/27 00:00 [accepted] PHST- 2022/08/30 06:00 [pubmed] PHST- 2022/10/25 06:00 [medline] PHST- 2022/08/29 18:15 [entrez] PHST- 2022/08/28 00:00 [pmc-release] AID - S2059-7029(22)00201-0 [pii] AID - 100571 [pii] AID - 10.1016/j.esmoop.2022.100571 [doi] PST - ppublish SO - ESMO Open. 2022 Oct;7(5):100571. doi: 10.1016/j.esmoop.2022.100571. Epub 2022 Aug 28.