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 (g BRCA1/2 ) 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 previously showed an induced synthetic lethality with combined EGFR inhibition and PARPi. 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 and taxane therapy. Patients with g BRCA1/2 mutations were excluded. Results: Twenty patients were enrolled of which 17 were evaluable for response. 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. Gene expression analysis suggest 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.

Neoadjuvant study of niraparib in patients with HER2-negative, BRCA-mutated, resectable breast cancer

“…All statistical analyses were performed using SAS statistical software v.9.3 or later unless otherwise noted; data distribution was assumed to be normal, but this was not formally tested. No statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those reported in previous publications 17 . Data collection and analysis were not performed blind to the conditions of the experiments.…”

Identification of a novel pathogenic variant in PALB2 and BARD1 genes by a multigene sequencing panel in triple negative breast cancer in Morocco

“…The role of PARP inhibitors in the setting of non-BRCA associated cancers has been limited. Recently, Lapatinib plus Veliparib therapy have a manageable safety profile and promising antitumor activity in advanced TNBC [34].…”

Immunotherapy in triple-negative breast cancer: Insights into tumor immune landscape and therapeutic opportunities

“…Veliparib and niraparib are PARP-1 and PARP-2 inhibitors that are under clinical investigation for the treatment of TNBC (Geenen et al, 2018). Velaparib demonstrated efficacy when used in combination with EGFRinhibitor lapatinib (Stringer-Reasor et al, 2021) or cisplatin (Sharma et al, 2020) but did not improve pCR when added to a standard neoadjuvant plus carboplatin regimen (Loibl et al, 2018). Niraparib's clinical activity was evaluated in a phase II trial in combination with pembrolizumab immune checkpoint inhibitor (Vinayak et al, 2019) and a phase III trial as monotherapy against standard chemotherapy (Turner et al, 2021).…”