An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer
Abstract Background Poly (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...
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doaj-73538d58c45c449bae948e795b13f1202021-03-11T12:09:34ZengBMCBreast Cancer Research1465-542X2021-03-0123111210.1186/s13058-021-01408-9An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancerErica M. Stringer-Reasor0Jori E. May1Eva Olariu2Valerie Caterinicchia3Yufeng Li4Dongquan Chen5Deborah L. Della Manna6Gabrielle B. Rocque7Christos Vaklavas8Carla I. Falkson9Lisle M. Nabell10Edward P. Acosta11Andres Forero-Torres12Eddy S. Yang13Department of Medicine, Division of Hematology Oncology, University of Alabama at BirminghamDepartment of Medicine, Division of Hematology Oncology, University of Alabama at BirminghamDepartment of Medicine, Brookwood Baptist HealthDepartment of Medicine, Division of Hematology Oncology, University of Alabama at BirminghamDepartment of Medicine, Division of Hematology Oncology, University of Alabama at BirminghamDepartment of Medicine, Division of Hematology Oncology, University of Alabama at BirminghamDepartment of Radiation Oncology, University of Alabama at BirminghamDepartment of Medicine, Division of Hematology Oncology, University of Alabama at BirminghamDepartment of Medicine, Division of Hematology Oncology, University of Alabama at BirminghamDepartment of Medicine, Division of Hematology Oncology, University of Alabama at BirminghamDepartment of Medicine, Division of Hematology Oncology, University of Alabama at BirminghamDepartment of Pharmacology/Toxicology, University of Alabama at BirminghamDepartment of Medicine, Division of Hematology Oncology, University of Alabama at BirminghamDepartment of Radiation Oncology, University of Alabama at BirminghamAbstract Background Poly (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. Methods A 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. Results Twenty 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. Conclusions Lapatinib 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 registration ClinicalTrials.gov , NCT02158507 . Registered on 12 September 2014https://doi.org/10.1186/s13058-021-01408-9PARP inhibitorsDNA repairSynthetic lethalityTargeted therapyTriple-negative breast cancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Erica M. Stringer-Reasor Jori E. May Eva Olariu Valerie Caterinicchia Yufeng Li Dongquan Chen Deborah L. Della Manna Gabrielle B. Rocque Christos Vaklavas Carla I. Falkson Lisle M. Nabell Edward P. Acosta Andres Forero-Torres Eddy S. Yang |
spellingShingle |
Erica M. Stringer-Reasor Jori E. May Eva Olariu Valerie Caterinicchia Yufeng Li Dongquan Chen Deborah L. Della Manna Gabrielle B. Rocque Christos Vaklavas Carla I. Falkson Lisle M. Nabell Edward P. Acosta Andres Forero-Torres Eddy S. Yang An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer Breast Cancer Research PARP inhibitors DNA repair Synthetic lethality Targeted therapy Triple-negative breast cancer |
author_facet |
Erica M. Stringer-Reasor Jori E. May Eva Olariu Valerie Caterinicchia Yufeng Li Dongquan Chen Deborah L. Della Manna Gabrielle B. Rocque Christos Vaklavas Carla I. Falkson Lisle M. Nabell Edward P. Acosta Andres Forero-Torres Eddy S. Yang |
author_sort |
Erica M. Stringer-Reasor |
title |
An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer |
title_short |
An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer |
title_full |
An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer |
title_fullStr |
An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer |
title_full_unstemmed |
An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer |
title_sort |
open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2021-03-01 |
description |
Abstract Background Poly (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. Methods A 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. Results Twenty 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. Conclusions Lapatinib 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 registration ClinicalTrials.gov , NCT02158507 . Registered on 12 September 2014 |
topic |
PARP inhibitors DNA repair Synthetic lethality Targeted therapy Triple-negative breast cancer |
url |
https://doi.org/10.1186/s13058-021-01408-9 |
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