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.
Due to the financial requirements associated with a Phase 3 trial, management has decided to advance Sym004 through partnering only.
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 our randomized Phase 2b trial of Sym004 in patients with late-stage mCRC that have acquired resistance to anti-EGFR antibody therapies. Although the primary endpoint of the trial was not met, the trial confirmed published data on the negative predictive value of RAS and BRAF mutations associated with anti-EGFR antibody treatment (double negative).
Further, we discovered a third negative predictive factor being mutations in the extracellular domain of the EGFR (EGFR-ECD). Based on these findings, we identified two subpopulations who may benefit from treatment with Sym004, double and triple negative patients.
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.