An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer

Breast Cancer Research

Eva Olariu¹  Carla I. Falkson²  Valerie Caterinicchia²  Gabrielle B. Rocque²  Jori E. May²  Christos Vaklavas²  Erica M. Stringer-Reasor²  Andres Forero-Torres²  Dongquan Chen²  Lisle M. Nabell²  Yufeng Li²  Edward P. Acosta³  Deborah L. Della Manna⁴  Eddy S. Yang⁵ 

[1] Department of Medicine, Brookwood Baptist Health, Birmingham, AL, USA;Department of Medicine, Division of Hematology Oncology, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Pharmacology/Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA;O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, 1700 6th Avenue South, HSROC Suite 2232 (176F), 35249, Birmingham, AL, USA;

关键词: PARP inhibitors;    DNA repair;    Synthetic lethality;    Targeted therapy;    Triple-negative breast cancer;   

DOI  :  10.1186/s13058-021-01408-9

来源: Springer

【 摘 要 】

BackgroundPoly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC.MethodsA first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded.ResultsTwenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0–2). Fifty percent of patients were Caucasian, 45% African–American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug–drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders.ConclusionsLapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed.Trial registrationClinicalTrials.gov, NCT02158507. Registered on 12 September 2014

【 授权许可】

CC BY