Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy

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 (mBC), T-DM1 was dose-escalated with a fixed standard pertuzumab dose in a 3þ3 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-1b), 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 antitumor efficacy with T-DM1 and pertuzumab resulting from the unique antitumor activities of each agent. In patients with mBC 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 antitumor activity. In patients, this combination showed an encouraging safety and tolerability profile with preliminary evidence of efficacy. Clin Cancer Res; 20(2); 456-68. Ó2013 AACR.

The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers

“…Small differences were evident for the respective in vitro cytotoxicity in high-expressing HER2 (3þ) cell lines, and antitumor activity studies in vivo in high HER2-expressing breast cancer xenografts. For both ADCs, these data are in line with previous publications (12,(26)(27)(28), although this first head-tohead comparison presented here shows that SYD985, especially in vivo, is more active than T-DM1 in high HER2-expressing tumors.…”

One‐Step Method for Instant Generation of Advanced Allogeneic NK Cells

“…Tumor‐bearing NOD scid Gamma (NSG, NOD.Cg‐ Prkdc scid Il2rg tm1Wjl /SzJ) mice administered with 1 × 10 7 SE‐NK/T‐DM1 cells received ≈210 µg of T‐DM1, which is similar to the recommended dose found in the literature for mice models (7–10 mg kg −1 ) 25. In the HER2‐positive tumor model, SE‐NK/T‐DM1 cells exhibited the strongest anticancer efficacy through the combinatorial effects ( Figure 6 a).…”

Ado-trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: latest evidence and clinical potential

“…Understanding mechanisms of resistance to T-DM1 is crucial in designing future trials and combinations that could overcome this resistance. Recently, a novel and so far only mechanism of resistance to T-DM1 was reported through expression of the HER3 ligand, neuregulin β1 [Lewis Phillips et al 2014]. Binding of HER3 by neuregulin leads to heterodimerization of HER2 with HER3 thus strongly activating the PI3K pathway.…”

“…Lewis Phillips and colleagues showed that the presence of neuregulin can inhibit the cellular response to T-DM1. Interestingly, however, they also showed that combination of pertuzumab, an inhibitor of HER2-HER3 dimerization, with T-DM1 is not only synergistic in its antitumor activity but can specifically overcome the effects of neuregulin [Lewis Phillips et al 2014]. The clinical relevance of this interesting observation will be tested in trials of T-DM1 with pertuzumab (MARIANNE, KRISTINE, KAITLIN) compared with T-DM1 alone.…”