Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab

Critical role for neuregulin blockade in antitumor response to combination therapy

Gail D Lewis Phillips, Carter T. Fields, Guangmin Li, Donald Dowbenko, Gabriele Schaefer, Kathy Miller, Fabrice Andre, Howard A. Burris, Kathy S. Albain, Nadia Harbeck, Veronique Dieras, Diana Crivellari, Liang Fang, Ellie Guardino, Steven R. Olsen, Lisa M. Crocker, Mark X. Sliwkowski

Research output: Contribution to journalArticle

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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 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 HER3ligand, 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 enhancedantitumor 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 dosepertuzumab. 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 showedan encouraging safety and tolerability profile with preliminary evidence of efficacy. Clin Cancer Res; 20(2);456-68.

Original languageEnglish
Pages (from-to)456-468
Number of pages13
JournalClinical Cancer Research
Volume20
Issue number2
DOIs
StatePublished - Jan 15 2014

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Neuregulins
Neoplasms
Heterografts
Therapeutics
Breast Neoplasms
Neuregulin-1
Cultured Tumor Cells
Maximum Tolerated Dose
ado-trastuzumab emtansine
pertuzumab
Dimerization
Drug Combinations
Cell Death
Research Design
Cell Culture Techniques
Cell Proliferation
Safety
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab : Critical role for neuregulin blockade in antitumor response to combination therapy. / Phillips, Gail D Lewis; Fields, Carter T.; Li, Guangmin; Dowbenko, Donald; Schaefer, Gabriele; Miller, Kathy; Andre, Fabrice; Burris, Howard A.; Albain, Kathy S.; Harbeck, Nadia; Dieras, Veronique; Crivellari, Diana; Fang, Liang; Guardino, Ellie; Olsen, Steven R.; Crocker, Lisa M.; Sliwkowski, Mark X.

In: Clinical Cancer Research, Vol. 20, No. 2, 15.01.2014, p. 456-468.

Research output: Contribution to journalArticle

Phillips, GDL, Fields, CT, Li, G, Dowbenko, D, Schaefer, G, Miller, K, Andre, F, Burris, HA, Albain, KS, Harbeck, N, Dieras, V, Crivellari, D, Fang, L, Guardino, E, Olsen, SR, Crocker, LM & Sliwkowski, MX 2014, 'Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: Critical role for neuregulin blockade in antitumor response to combination therapy', Clinical Cancer Research, vol. 20, no. 2, pp. 456-468. https://doi.org/10.1158/1078-0432.CCR-13-0358
Phillips, Gail D Lewis ; Fields, Carter T. ; Li, Guangmin ; Dowbenko, Donald ; Schaefer, Gabriele ; Miller, Kathy ; Andre, Fabrice ; Burris, Howard A. ; Albain, Kathy S. ; Harbeck, Nadia ; Dieras, Veronique ; Crivellari, Diana ; Fang, Liang ; Guardino, Ellie ; Olsen, Steven R. ; Crocker, Lisa M. ; Sliwkowski, Mark X. / Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab : Critical role for neuregulin blockade in antitumor response to combination therapy. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 2. pp. 456-468.
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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 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 HER3ligand, 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 enhancedantitumor 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 dosepertuzumab. 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 showedan encouraging safety and tolerability profile with preliminary evidence of efficacy. Clin Cancer Res; 20(2);456-68.",
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AU - Li, Guangmin

AU - Dowbenko, Donald

AU - Schaefer, Gabriele

AU - Miller, Kathy

AU - Andre, Fabrice

AU - Burris, Howard A.

AU - Albain, Kathy S.

AU - Harbeck, Nadia

AU - Dieras, Veronique

AU - Crivellari, Diana

AU - Fang, Liang

AU - Guardino, Ellie

AU - Olsen, Steven R.

AU - Crocker, Lisa M.

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