Lani
10-08-2013, 05:35 PM
not yet ready for prime time...but getting closer ie, cell line, xenograft model and phase II/IIb trials results below
Clin Cancer Res. 2013 Oct 4.
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.
Lewis Phillips GD, Fields CT, Li G, Dowbenko D, Schaefer G, Miller KD, Andre F, Burris HA 3rd, Albain KS, Harbeck N, Dieras V, Crivellari D, Fang L, Guardino E, Olsen SR, Crocker LM, Sliwkowski MX.
Source
Research Oncology, Genentech.
Abstract
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.
PMID: 24097864
Clin Cancer Res. 2013 Oct 4.
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.
Lewis Phillips GD, Fields CT, Li G, Dowbenko D, Schaefer G, Miller KD, Andre F, Burris HA 3rd, Albain KS, Harbeck N, Dieras V, Crivellari D, Fang L, Guardino E, Olsen SR, Crocker LM, Sliwkowski MX.
Source
Research Oncology, Genentech.
Abstract
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.
PMID: 24097864