Sym004 targets the extracellular domain of EGFR, which plays an important role in development and progression of mCRC and is considered relevant in other epithelial cancers, such as non-small-cell lung, head-and-neck, and brain cancers.
Sym004 induces rapid internalization and degradation of the EGFR that leads to down-modulation of EGFR and subsequent inhibition of cancer cell growth. The inhibition of EGFR with two antibodies contained in Sym004 results in a mechanism of action that is distinct from the more limited actions of single anti-EGFR antibodies.
Biomarker-defined patient selection in mCRC
In the current era of precision medicine, almost all mCRC patients are tested for the genetic biomarkers RAS and BRAF to guide targeted therapy. It is well-known, that mutations in these proteins involved in directing cell growth, cell division or tissue signaling are predictive of a very poor response to anti-EGFR mAb therapy. Approximately 10-20 percent of patients who receive initial treatment with an anti-EGFR mAb therapy respond to such treatment.
However, patients who initially respond ultimately progress while on therapy. Mutations in RAS and BRAF are associated with primary or acquired anti-EGFR resistance in mCRC. In addition, mutations in the extra-cellular domain of EGFR (EGFR-ECD) are believed to be associated with acquired resistance.
Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses
Compelling clinical data for Sym004 in mCRC
In September 2017, we reported data from a randomized Phase 2b trial of Sym004, which enrolled 254 patients with late-stage mCRC who had become refractory to prior anti-EGFR mAb therapies, including Erbitux® (cetuximab) and Vectibix® (panitumumab), thus suffering disease progression.
Data showed remarkable improvement in overall survival in well-defined patient populations and we believe, that Sym004 has the potential to become precision medicine for refractory mCRC patients that otherwise have very limited or no treatment options. Our press release from September 11, 2017 provides additional details about the trial, efficacy findings and adverse effect profile.
Colorectal cancer market facts
In 2017, an estimated 504,000 patients will be newly diagnosed with CRC in the United States, the five major EU countries (France, Germany, Italy, Spain, and the United Kingdom) and Japan. A further 271,000 patients will have been diagnosed in urban China.
50 percent of all patients with CRC will relapse and die due to metastatic disease within five years after being diagnosed.
The 2017 market for mCRC-targeted therapies was estimated at DKK 33 billion. The market is dominated by anti-VEGF compounds, primarily Avastin® (bevacizumab), with annual worldwide sales estimated at DKK 20 billion, and anti-EGFR mAbs, including Erbitux® (cetuximab) and Vectibix® (panitumumab), with annual worldwide sales estimated at DKK 11 billion.
Currently available therapies for patients who have undergone 2-3 previous medicine treatment regimes, and thus considered 3rd or 4th line mCRC patients, generally provide only marginal survival benefit or stabilization.