Options in Overcoming Resistance to HER2-Targeted Therapy


Mark D. Pegram, MD, discusses proposed mechanisms of resistance to HER2-targeted therapies.

Mark D. Pegram, MD

There are several proposed mechanisms of resistance being studied in the quest to overcome resistance to HER2-targeted therapy. 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 Miami Breast Cancer Conference®.

The recent phase III SOPHIA trial holds promise for overcoming ADCC resistance via the combination of chemotherapy with 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, in multiple tumor types, in a previous phase I study.

In his presentation, Overcoming Resistance to HER2-Targeted Therapy, Pegram, director of the Breast Cancer Oncology program at Stanford Comprehensive Cancer Institute, outlined proposed mechanisms of resistance to HER2-targeted therapies. He touched on anatomical mechanisms, signal transduction perturbation, parallel pathway activation, and ADCC. In an interview withTargeted Oncology, Pegram discussed his presentation.

TARGETED ONCOLOGY:What are some of the key aspects of these proposed mechanisms of resistance?


In signal-transduction perturbation, mutations of the PI3 kinase gene and PTEN have been shown to be important mediators of resistance in trastuzumab (Herceptin) and lapatinib (Tykerb). We recently published data showing that T-DM1 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 compares 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 will also discuss parallel pathway activation like epidermal growth factor receptor 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 Fc-gamma 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 mono-clonal 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.

TARGETED ONCOLOGY:What new data are particularly exciting?


The data from N9831 and BCIRG-006 were used to interrogate the question of polymorphisms of the Fc-receptors in adjuvant cohorts. Both of those were negative studies including one that was done in my laboratory, and I was co-author on the NCCTG-N9831 paper. But, the reason those trials failed to demonstrate the correlation, which was discussed in my paper, is that we simply did not have enough events because the most active subsets based on a particular polymorphism, for example, only occur in 15% of human populations. So, we did not really have the statistical power that you need in an adjuvant setting to be able to show a correlation between Fc-receptor interactions and ADCC.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, with longer follow-up, did have enough events to demonstrate significant difference in outcome based on the Fc-gamma receptor genotype. The same association has been shown previously in metastatic cohorts—that the high-affinity polymorphism patients respond better to trastuzumab plus chemotherapy in the adjuvant setting in B-31. So, this finally corners a conundrum that’s bothered the field for the past 10 years or so regarding the adjuvant data.

TARGETED ONCOLOGY:Which of these proposed mechanisms of resistance could potentially have a bigger clinical impact in this field?


I think that potentiation of ADCC has legs and that the ongoing phase III SOPHIA trial will test that hypothesis. In addition, our phase I study here at Stanford with CD137 antibodies is just about to start, but it’s still early for that approach, so that will take longer to demonstrate. I think the checkpoint combinations with HER2 antibodies may well be able to overcome the signal transduction mechanisms of resistance, and that’s potentially very exciting. I would predict that those trials have a high probability of success—but not without significant toxicities that we might have to worry about as well.

We are already able to overcome the signal perturbation mechanisms, at least to some degree, with antibody drug conjugates. Also, there are more antibody drug conjugates targeting HER2 in various pipelines, so, during my presentation, I’ll probably touch on the fact that these already overcome PI3 kinase pathway mutations.

TARGETED ONCOLOGY:Are there significant toxicities that are cause for concern?


In the case of the checkpoint inhibition approach, there are autoimmune phenomena ranging from pneumonitis to myocarditis to encephalitis to enteritis to dermatitis. The checkpoint antibodies are all associated, potentially, with autoimmune toxicities that we have to be mindful of and closely monitor for.


Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791. http://www.nejm.org/doi/ full/10.1056/NEJMoa1209124#t=article. Accessed February 13, 2017.

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