Abstract P6-17-12: Neratinib in combination with trastuzumab is superior to each alone and to pertuzumab plus trastuzumab in HER2-positive in vivo breast cancer models
Authors: Veeraraghavan J , Sethunath V , Qin L , Shea MJ , Mitchell T , De Angelis C , Nanda S , Diala I , Lalani AS , Hilsenbeck SG , Rimawi MF , Osborne CK , Schiff R 
Published: May 2019

Background: Lapatinib (L) plus trastuzumab (T) alone or with endocrine therapy for HER2+/ER+ tumors but without chemotherapy, yielded complete tumor eradication in xenograft models. In neoadjuvant trials (NCT00548184, 00999804, 01973660), a substantial number of patients achieved pathologic complete response with this same strategy. The irreversible pan-HER inhibitor neratinib (N) has been recently approved by the FDA for early stage HER2+ breast cancer and has shown greater potency compared to L in the preclinical setting. However, the therapeutic 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 and more effective than P+T due to more complete blockade of the HER pathway. Here, we evaluate the therapeutic efficacy of N, P, and T, either alone or in combination, with a primary focus on comparing N+T vs. P+T in established cell line- and patient-derived xenograft (PDX) models.

Methods: Athymic nude and SCID/Beige mice bearing BT474-AZ cell line (ER+/HER2+), and BCM-3963 PDX tumors (ER-/HER2+, wild-type PIK3CA), respectively were randomized to vehicle, N (20mg/kg, 5 days/week), T (10mg/kg, twice a week), P (6mg/kg, once a week), N+T, or P+T, with simultaneous estrogen (E2) deprivation (ED) in BT474-AZ model. Treatment response was assessed by biweekly tumor measurements. Study endpoints included time to tumor regression (TTR) and progression (TTP) (tumor halving/doubling over baseline, respectively), and the rate and time of complete response (CR and TCR, respectively). Results were analyzed using survival analysis (Kaplan-Meier estimates) and generalized Wilcoxon tests.

Results: In the BT474-AZ model, mice treated with E2+vehicle and ED+vehicle showed steady tumor growth, with a median TTP of 8 and 25 days, respectively. While tumor regression was observed in 100% of mice treated with N, P, T, N+T, and P+T, tumors treated with N+T regressed faster compared to P (p&lt;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, tumors treated with vehicle, T, P, and P+T continued to grow with a median TTP of 11, 16, 19, and 17 days, respectively. In contrast, CR was achieved in 100% of N and N+T treated mice. Importantly, combining N with T accelerated the attainment of CR compared to N alone (p=0.026). Molecular and pathologic analysis of short-term treated tumors in both models to evaluate alterations in HER signaling, cell proliferation, and apoptosis is ongoing.

Model/TreatmentN of miceMedian TTP (Days)Median TTR (Days)Median TCR (Days)CR (%)BT474-AZ     E2+Vehicle98--0ED+Vehicle1025--0ED+N13-214100ED+T12-519100ED+P12-185492ED+N+T13-210100ED+P+T14-414100BCM-3963     Vehicle1511--0N15-417100T1416--0P1319--0N+T19-614100P+T1617--0

Conclusions: Our findings establish the preclinical efficacy of combining N with T for HER2+ breast cancer and warrant further clinical testing to investigate the efficacy of N+T without chemotherapy in the neoadjuvant setting for patients with HER2+ breast cancer.

Citation Format: Veeraraghavan J, Sethunath V, Qin L, Shea MJ, Mitchell T, De Angelis C, Nanda S, Diala I, Lalani AS, Hilsenbeck SG, Rimawi MF, Osborne CK, Schiff R. Neratinib in combination with trastuzumab is superior to each alone and to pertuzumab plus trastuzumab in HER2-positive in vivo breast cancer models [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-12.