Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models

Abstract

Lapatinib (L) plus trastuzumab (T), with endocrine therapy for estrogen receptor (ER)+ tumors, but without chemotherapy, yielded meaningful response in HER2+ breast cancer (BC) neoadjuvant trials. The irreversible/pan-HER inhibitor neratinib (N) has proven more potent than L. However, the efficacy of N+T in comparison to pertuzumab (P)\u2009+\u2009T or L\u2009+\u2009T (without chemotherapy) remains less studied. To address this, mice bearing HER2+ BT474-AZ (ER+) cell and BCM-3963 patient-derived BC xenografts were randomized to vehicle, N, T, P, N+T, or P+T, with simultaneous estrogen deprivation for BT474-AZ. Time to tumor regression/progression and incidence/time to complete response (CR) were determined. Changes in key HER pathway and proliferative markers were assessed by immunohistochemistry and western blot of short-term-treated tumors. In the BT474-AZ model, while all N, P, T, N\u2009+\u2009T, and P\u2009+\u2009T treated tumors regressed, N\u2009+\u2009T-treated tumors regressed faster than P, T, and P\u2009+\u2009T. Further, N\u2009+\u2009T was superior to N and T alone in accelerating CR. In the BCM-3963 model, which was refractory to T, P, and P\u2009+\u2009T, while N and N\u2009+\u2009T yielded 100% CR, N\u2009+\u2009T accelerated the CR compared to N. Ki67, phosphorylated (p) AKT, pS6, and pERK levels were largely inhibited by N and N\u2009+\u2009T, but not by T, P, or P\u2009+\u2009T. Phosphorylated HER receptor levels were also markedly inhibited by N and N\u2009+\u2009T, but not by P\u2009+\u2009T or L\u2009+\u2009T. Our findings establish the efficacy of combining N with T and support clinical testing to investigate the efficacy of N\u2009+\u2009T with or without chemotherapy in the neoadjuvant setting for HER2+ BC.