Abstract 4827: The therapeutic superiority of neratinib in combination with trastuzumab compared to pertuzumab plus trastuzumab in HER2-positivein vivobreast cancer models

Neoadjuvant clinical trials in HER2+ breast cancer showed that lapatinib (L) plus trastuzumab (T), combined with endocrine therapy for ER+ tumors, achieved meaningful complete pathologic response rates without chemotherapy. The irreversible pan-HER kinase inhibitor neratinib (N) has shown greater potency compared to L in the preclinical setting. However, the efficacy of N in combination with T (N+T) and how it compares to pertuzumab (P) +T (without chemotherapy) has not been well studied. We hypothesize that dual HER2 inhibition using N+T will be highly efficacious due to more complete blockade of the HER pathway, with comparable or better potency than P+T. Here, we evaluate the therapeutic efficacy and molecular mechanisms of N, P, and T, either alone or in combination, in cell- and patient-derived xenograft (PDX) models. Immunodeficient mice bearing BT474-AZ cell (ER+/HER2+), and BCM-3963 PDX tumors (ER-/HER2+, wild-type PIK3CA) were randomized to vehicle, N, T, P, N+T, or P+T, with simultaneous estrogen deprivation in BT474-AZ xenograft model. Study endpoints included: (i) treatment outcome - time to tumor regression (TTR) and progression (TTP) (tumor halving/doubling over baseline, respectively), and rate and time to complete response (CR and TCR, respectively); and (ii) biomarker analysis - immunohistochemistry (IHC) and western blot (WB) analysis of tumors harvested 2-4 days post-treatment to assess key biomarkers. In the BT474-AZ model, while tumor regression was observed in 100% of N, P, T, N+T, and P+T treated mice, the tumors treated with N+T regressed faster compared to P (p<0.001), T (p=0.004), and P+T (p=0.044). Further, N+T was superior to N (p=0.018), and T (p=0.007) alone in achieving accelerated CR. In the BCM-3963 model, which was refractory to T, P, or T+P, while CR was achieved in 100% of N and N+T treated mice, the combination of N+T accelerated the attainment of CR compared to N alone (p=0.026). IHC analysis of short-term treated tumors showed that Ki67, pAKT, and pMAPK levels were significantly inhibited by N and N+T, but not by T, P, or P+T. Compared to P+T, N and N+T more potently inhibited Ki67, suggesting the superiority of N-containing regimens in suppressing tumor cell proliferation. Likewise, WB analysis showed that N and N+T markedly inhibited pHER2 (Y1248), pEGFR (Y1068), pAKT (S473), pERK, and pS6 levels, compared to P+T, suggesting a more potent blockade of the HER pathway by N-containing regimens, especially after short-term treatment. In the BT474-AZ model, short-term N+T treatment yielded greater inhibition of pHER2 (Y1248) and survivin levels, compared to N alone. These preclinical findings establish the efficacy of combining N with T for HER2+ breast cancer and support further clinical testing to investigate the efficacy of N+T without chemotherapy in the neoadjuvant setting for patients with HER2+ breast cancer.Citation Format: Jamunarani Veeraraghavan, Vidyalakshmi Sethunath, Martin J. Shea, Tamika Mitchell, Resel Pereira, Lanfang Qin, Sarmistha Nanda, Carmine De Angelis, Kristina Goutsouliak, Irmina Diala, Alshad S. Lalani, Sepideh Mehravaran, Susan G. Hilsenbeck, Chandandeep Nagi, Carolina Gutierrez, Mothaffar F. Rimawi, C. Kent Osborne, Rachel Schiff. The therapeutic superiority of neratinib in combination with trastuzumab compared to pertuzumab plus trastuzumab in HER2-positive in vivo breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4827.