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 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

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

“…An open-label pilot study of the lapatinib and veliparib combination demonstrated the potential antitumor activity of this combination in patients with advanced TNBC without DLTs [ 648 ]. Gene expression analysis revealed an increase in the expression of genes involved in antigen presentation, immune cell infiltration, and cytokine and chemokine signaling.…”

The impact of race and ethnicity in breast cancer—disparities and implications for precision oncology

“…This lack of diversity in trials to test targeted therapies has important implications for breast cancer disparities given the marked variation in the prevalence of certain mutations of high-penetrance genes, such as BRCA1 and BRCA2 [ 13 ], and breast tumor subtypes across racial and ethnic populations [ 14 – 16 ]. For example, Black women have a lower frequency of PIK3A mutations than White women [ 17 ] and are therefore less likely to benefit from targeted therapies with PI3K inhibitors. Moreover, utilization of targeted therapies has been disproportionate across racial and ethnic minority populations and varies according to socioeconomic status [ 18 ].…”

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 .…”