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Overcoming Resistance to HER2-Targeted Therapy in Breast Cancer

Angelica Welch
Published: Wednesday, Mar 29, 2017

Mark D. Pegram, MD

Mark D. Pegram, MD

There are several proposed mechanisms of resistance being studied in the quest to overcome resistance to HER2-targeted therapy in breast cancer. The strengthening of antibody dependent cell-mediated cytotoxicity (ADCC) shows promise in clinical trials, but there also is potential benefit in exploring other avenues, such as mutations of the PI3-kinase gene and PTEN, parallel pathway activation, antibody-drug conjugates, and the combination of checkpoint inhibitors with HER2 antibodies, according to Mark D. Pegram, MD, who gave a presentation on the subject at the 2017 Miami Breast Cancer Conference (MBCC).

The recent phase III SOPHIA trial holds promise for overcoming ADCC resistance via the combination of chemotherapy with the Fc-modified monoclonal antibody margetuximab. In the ongoing trial, researchers are comparing margetuximab plus chemotherapy with trastuzumab (Herceptin) plus chemotherapy. Margetuximab, which binds to the same epitope as trastuzumab, demonstrated impressive single-agent activity in heavily pretreated HER2-positive tumors across multiple tumor types in a previous phase I study.

In an interview with OncLive, Pegram summarized the highlights of his MBCC presentation.

OncLive: What are some of the key aspects of these proposed mechanisms of resistance that you discussed?

Pegram: In signal-transduction perturbation, mutations of the PI3 kinase gene and PTEN have been shown to be important mediators of resistance in trastuzumab and lapatinib (Tykerb). We recently published data showing that T-DM1 (Kadcyla) can overcome this resistance mechanism because of the cytotoxic payload—a potent microtubule inhibitor—that appears to be agnostic to PIK3CA mutational status. That data is a subset analysis of the EMILIA pivotal trial of T-DM1, which compared a lapatinib-based chemo combination with T-DM1. Jose Baselga, MD, PhD, and collaborators, and I did a PI3 kinase gene mutational analysis in that cohort which showed that there were mutations that led to resistance of lapatinib but not T-DM1.

I also discussed parallel pathway activation like EGFR activation, IGF-1R activation, and MET receptors. Those mechanisms have been proposed based on laboratory experimental models, but still largely defy validation in clinical cohorts. Also, any attempt to treat all the HER2-positive comers with IGF-1R antibody, for example, probably won’t overcome an IGF-1R parallel receptor activation except in a subset of patients who have such activation. It will take much more nuanced and niche therapeutic trials to address these issues. In addition, being able to identify which patients have activation of which receptors that are bypassing the HER2 receptor will require companion diagnostic assays.

ADCC is another proposed mechanism of HER2 antibodies. The Fc-receptor knockout mouse data that Raphael Clynes published some years ago shows that if you knock out ADCC in the mouse, then these antibodies don’t work as well. In the data on Fc-gamma receptor polymorphisms in response to trastuzumab in metastatic breast cancer, the patients who inherit high-affinity Fcgamma receptor genotypes respond better to trastuzumab than those with lower-affinity genotypes, as least in metastatic disease. CD137 agonist antibodies can also potentiate ADCC reactions, and it’s been shown in vitro and in vivo laboratory models that adding a CD137 antibody to trastuzumab will increase preclinical efficacy in vivo in the mouse, for example. Trials involving CD137 agonist antibodies are just getting underway in human subjects, and we’ll see if that might be another way to augment ADCC to overcome resistance by lack of ADCC activity.

The speculation of T-cell activation by HER2 monoclonal antibodies has been previously reported in a scanty way in the literature. An ongoing set of trials that are exciting will combine checkpoint inhibitors with HER2 antibodies, including a trial with T-DM1 with checkpoint inhibitors that is forthcoming. Another way to overcome resistance is by exploiting the immunologic mechanisms of HER2 antibodies beyond ADCC to include cytotoxic T cells in the future, and maybe that will also be agnostic with regard to receptor bypass, or signal perturbation, or the other mechanisms of resistance described in the lecture.

What new data are particularly exciting?

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