Dual targeting of HER2-positive cancer with trastuzumab-emtansine (T-DM1) and pertuzumab: critical role for neuregulin blockade in anti-tumor response to combination therapy
Menée sur des lignées cellulaires et à l'aide de xénogreffes, puis sur 9 patientes atteintes d'un cancer métastatique du sein HER2+, cet essai de phase Ib/II évalue l'efficacité et la toxicité d'un traitement combinant le pertuzumab et le trastuzumab emtansine (T-DM1)
Purpose: Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-positive cancers. We investigated combining the HER2-directed antibody-drug conjugate trastuzumab emtansine (T-DM1) with the HER2 dimerization inhibitor pertuzumab (Perjeta™). Experimental Design: Drug combination studies with T-DM1 and pertuzumab were performed on cultured tumor cells and in mouse xenograft models of HER2-amplified cancer. In patients with HER2-positive locally advanced or metastatic breast cancer, T-DM1 was dose-escalated with a fixed standard pertuzumab dose in a 3+3 Phase Ib/II study design. Results: Treatment of HER2-overexpressing tumor cells in vitro with T-DM1 plus pertuzumab resulted in synergistic inhibition of cell proliferation and induction of apoptotic cell death. The presence of the HER3 ligand, heregulin (NRG-1β) reduced the cytotoxic activity of T-DM1 in a subset of breast cancer lines; this effect was reversed by the addition of pertuzumab. Results from mouse xenograft models showed enhanced anti-tumor efficacy with T-DM1 and pertuzumab resulting from the unique anti-tumor activities of each agent. In patients with metastatic breast cancer previously treated with trastuzumab, lapatinib, and chemotherapy, T-DM1 could be dosed at the maximum tolerated dose (MTD, 3.6 mg/kg every 3 weeks) with standard-dose pertuzumab. Adverse events were mostly Grade 1 and 2, with indications of clinical activity. Conclusions: Dual-targeting of HER2 with the combination of T-DM1 and pertuzumab in cell culture and mouse xenograft models resulted in enhanced anti-tumor activity. In patients, this combination showed an encouraging safety and tolerability profile with preliminary evidence of efficacy.