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

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, 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

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.

Keywords: DNA repair; PARP inhibitors; Synthetic lethality; Targeted therapy; Triple-negative breast cancer.

Conflict of interest statement

E. Yang: consultant for AstraZeneca; advisory board for Clovis Oncology, Strata Oncology, Bayer, and Lilly; research funding from Tesaro/Janssen.

E. Stringer-Reasor: involved in clinical trials with money paid directly to UAB from Seattle Genetics, Pfizer, Novartis, TESARO, and GSK; on advisory boards for Mylan Institutional and Lilly; grants provided by Susan G. Komen and Victory Foundation.

C. Falkson: advisory boards for Agendia, Biotheranostics, and Oncotype Dx.

G. Rocque: grants from Genetech, Pfizer, and Carevive; consult for Pfizer.

C. Vaklavas: consulting/advisory role: Daiichi-Sankyo (one time); research funding paid to my institution: Seattle Genetics, Genentech, Roche, Pfizer, Incyte, Pharmacyclics, Novartis, TRACON Pharmaceuticals, Innocrin Pharmaceuticals, Zymeworks, and H3 Biomedicine; other relationships: Puma Biotechnology, Takeda, Daiichi Sankyo; uncompensated relationship: Genentech (unpaid thought leader).

E. Acosta, L, Yufeng, L. Nabell, J. May, E. Olariu, D. Della Manna, and V. Caterinicchia have no conflicts to disclose.

Figures

Fig. 1
Fig. 1
Consort diagram
Fig. 2
Fig. 2
Summary of best overall response by RECIST criteria. Abbreviations: PR, partial response; SD, stable disease; PD, progressive disease
Fig. 3
Fig. 3
Response in UAB009: a pre-treatment and post-treatment at b 2 weeks, c 2 months, and d 5 months
Fig. 4
Fig. 4
Pre-treatment immune pathway scores in patients with partial response (PR) and progressive disease (PD). a Antigen presentation score. b Cytokine and chemokine signaling score. c Immune infiltration score

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