Gastric/GEJ Cancer

HER2 2+ positive / FISH positive

MM-111, paclitaxel and trastuzumab-containing regimen

Based on the currently approved therapies for gastric cancer, most patients are tested for their HER2 status before defining a treatment path. There are two different ways to test HER2 status – one called uses an approach called immunohistochemistry (IHC) and the other uses something called fluorescence in situ hybridization (FISH). In the IHC test, you are given a ranking of HER2 1+, 2+ or 3+. In the FISH test, you are either positive or negative.

Patients who have what is considered very high levels of HER2 receptors (HER2 2+ or HER2 3+) and who also test positive on the FISH test, are often given treatment with one of the traditional HER2-targeted therapies such as trastuzumab. However, even in very high HER2-overexpressing tumors, HER3 has recently emerged as a key driver in cancer cell growth. Heregulin and betacellulin-induced signaling of HER3 activates pathways promoting the development, growth and progression of cancer. Compensatory activation of HER3 is believed to be a central mechanism by which cancer cells acquire resistance to targeted therapies as well as many chemotherapies (Schoeberl et al., 2010).

MM-111 is a bispecific antibody fusion protein that binds with both specificity and avidity to HER2 and HER3-expressing tumor cells. The HER3 arm, the therapeutic arm, is designed to block ligand-induced signaling while the HER2 arm is used for initial cell targeting and docking (McDonagh et al., 2012).

Taxanes are a class of chemotherapeutics commonly used to treat gastric cancer. They function by inhibiting the ability of rapidly proliferating cells to properly divide, causing stress and ultimately cell death. Despite this mechanism, cancer cells have the potential to adapt to overcome the toxic effect of taxanes and MM-111 may prevent this resistance. MM-111 is being tested clinically in combination with paclitaxel and trastuzumab in HER2-overexpressing gastric cancers.

The intent with this treatment is to deliver a cytotoxic agent (paclitaxel) while simultaneously inhibiting the addicted HER2-signaling (with trastuzumab) and adaptive HER3-signaling (with MM-111) pathways. Merrimack is performing the trial to find out whether, by using this combinatorial approach, HER2 signaling is effectively inhibited rendering the cell more susceptible to the toxic effects of paclitaxel and driving cancer cell death.

To attempt to correctly identify those patients likely to respond to regimens containing MM-111, Merrimack has created a diagnostic strategy to quantitatively determine the amount of HER2, HER3 and HRG present at an individual’s tumor cells. This ability, coupled with an understanding of how the levels of these proteins affect MM-111 function, provide an opportunity that may enable us to identify individual patients having a tumor composition likely to respond to treatment containing MM-111.

 

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