Discovery
Pre-clinical
Phase 1
Phase 2

Phase 3 ready. Further development subject to partnering

Overview

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.

Target
EGFR
Trial
Phase 3 ready
Patients
Sym004 has been studied in more than 400 cancer patients, of whom 350 were patients with mCRC

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.

Publication

Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses

Clara Montagut, MD, Guillem Argilés, MD, Fortunato Ciardiello, MD, Thomas T. Poulsen, PhD, Rodrigo Dienstmann, MD, Michael Kragh, PhD, Scott Kopetz, MD, Trine Lindsted, PhD, Cliff Ding, PhD, Joana Vidal, MD, Jenifer Clausell-Tormos, PhD, Giulia Siravegna, PhD, Francisco J. Sánchez-Martín, PhD, Klaus Koefoed, PhD, Mikkel W. Pedersen, PhD, Michael M. Grandal, PhD, Mikhail Dvorkin, MD, Lucjan Wyrwicz, MD, Ana Rovira, PhD, Antonio Cubillo, MD, Ramon Salazar, MD, Françoise Desseigne, MD, Cristina Nadal, MD, Joan Albanell, MD, Vittorina Zagonel, MD, Salvatore Siena, MD, Guglielmo Fumi, MD, Giuseppe Rospo, PhD, Paul Nadler, MD, Ivan D. Horak, MD, Alberto Bardelli, PhD, Josep Tabernero, MD
JAMA Oncol. Published online February 8, 2018. doi:10.1001/jamaoncol.2017.5245

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.

Trial design
The trial was an open-label, randomized, controlled, multi-center Phase 2b trial investigating two Sym004 doses versus investigator’s choice in 254 patients with mCRC and acquired resistance to anti-EGFR monoclonal antibodies.
End-points
The primary objective of the trial was to assess efficacy of the two different Sym004 dosing regimens compared with investigator’s choice in terms of overall survival.
Results
In the intent to treat population, the trial did not meet its primary endpoint of a three-month improvement of median overall survival compared to the control arm. In a secondary pre-specified analysis, a patient subset termed ‘triple-negative’ demonstrated a clinically relevant increase in median overall survival of 5.5 months over investigator choice.

Colorectal cancer market facts

Incidence
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.

Survival
50 percent of all patients with CRC will relapse and die due to metastatic disease within five years after being diagnosed.

Value
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.

Current treatment
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.

Publications

Read more about our mAb mixtures