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.
Original language | English |
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Article number | 30 |
Journal | Breast Cancer Research |
Volume | 23 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2021 |
Bibliographical note
Publisher Copyright:© 2021, The Author(s).
Funding
E. Yang is supported by AACR-Triple Negative Breast Cancer Foundation Research Fellowship Grant #15-20-43-Yang.
Funders | Funder number |
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Triple Negative Breast Cancer Foundation | 15-20-43-Yang |
Triple Negative Breast Cancer Foundation |
Keywords
- DNA repair
- PARP inhibitors
- Synthetic lethality
- Targeted therapy
- Triple-negative breast cancer
ASJC Scopus subject areas
- Oncology
- Cancer Research