Data show clinically meaningful improvement in overall survival in a biomarker-defined patient population with late-stage metastatic colorectal cancer
COPENHAGEN, Denmark – Symphogen, an advanced clinical-stage antibody company focused on oncology, today announced detailed results from its randomized Phase 2 study with Sym004, a synergistic mAb mixture targeting epidermal growth factor receptor (EGFR), compared to investigator-choice chemotherapy or best-supportive-care, in patients with advanced metastatic colorectal cancer (mCRC) and acquired resistance to anti-EGFR monoclonal antibodies (mAbs).
Efficacy and safety data were announced today in an oral presentation at the ESMO 2017 Congress in Madrid, Spain. The study did not meet the primary end-point of a 3-month improvement of overall survival (OS) in the total population, however, treatment with Sym004 was associated with clinically meaningful improvement of overall survival in mCRC patients who were tested negative on selected biomarkers of acquired resistance to anti-EGFR therapy.
“A total of 254 patients were enrolled in the study and biomarker analysis performed on 193 patients proved that 131 patients were negative on three biomarkers associated with resistance to anti-EGFR treatment. These patients responded very well to treatment with Sym004 and the findings provide a clear rationale for prospective clinical validation,” said Josep Tabernero, principal investigator in the trial and Head of the Medical Oncology Department of Vall d’Hebron University Hospital. “Safety was manageable but more patients treated with Sym004 had treatment-emergent adverse events, especially dermatologic toxicity and infusion reactions. Despite not meeting the primary-endpoint, the study carries promise for patients with refractory metastatic colorectal cancer, who have very limited treatment options today.”
Martin Olin, Chief Executive Officer of Symphogen, commented: “The results presented suggest that a population of advanced metastatic colorectal cancer patients that can be identified based on circulating tumour DNA profiling may experience clinically meaningful survival benefit when treated with Sym004. To our knowledge, Sym004 is currently the only compound in late-stage clinical development targeting patients with acquired resistance to approved mAb EGFR-therapy, which gives us a great opportunity to offer a precision medicine approach to patients whose medical need is not met today,” Olin continued.
About the study
The study (ClinicalTrials.gov Identifier: NCT02083653) was a randomized Phase 2, open-label, three-arm trial of two Sym004 doses and a control group in subjects with metastatic colorectal cancer (mCRC) and acquired resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs). Sym004, a mixture of two anti-EGFR mAbs, was shown to be clinically active in a prior Phase 1/2 trial in refractory mCRC. Due to its unique mode of action, Sym004 was developed to overcome acquired resistance to anti-EGFR antibodies.
Method
A total of 254 patients were enrolled in the trial which compared two regimens (12 mg/kg (Arm A) or 9 mg/kg loading dose followed by 6 mg/kg (Arm B)) of weekly Sym004 versus investigator-choice of chemotherapy or best supportive care (Arm C). Patients had to be refractory to chemotherapy and have responded to, and progressed on, anti-EGFR mAb-based therapy. The study was designed to detect a 3-month improvement in overall survival (OS; 6 vs 9 months) between either Arm A or B and Arm C.
Results
The primary endpoint of the study was not met. The Sym004 adverse event (AE) profile was typical to approved anti-EGFR mAbs although frequency/severity of dermatologic AEs and hypomagnesemia was higher and gastrointestinal AEs appeared lower than with approved anti-EGFR mAbs. Arm B was better tolerated than Arm A, and was also associated with improved survival.
Comprehensive circulating tumour (ct) DNA profiling was performed at baseline to identify mutations common in mCRC patients including biomarkers of resistance to anti-EGFR therapy. Certain patients without these mutations at baseline, termed triple-negative (TN, N=131), demonstrated markedly prolonged survival with an increase in OS of 5.5 months over investigator choice or best-supportive-care (Median: 12.8 vs 7.3).
Key efficacy findings
| Population | Arm A (Sym004 12 mg/kg) |
Arm B (Sym004 9mg/kg followed by 6 mg/kg) |
Arm C (Investigator Choice or BSC) |
| Intention To Treat (N=254) Median OS (Range) |
7.9 (6.5, 9.9) N=83 |
10.3 (9.0, 12.9) N=86 |
9.6 (8.3, 12.2) N=85 |
| US&EU Biomarker Analysis (N=193) Median OS (Range) |
7.7 (5.5, 11.3) N=70 |
9.9 (7.1, 12.9) N=67 |
8.5 (6.4, 9.9) N=56 |
| US&EU with TNmCRC* (N=131) Median OS (Range) |
10.6 (6.8, 13.1) N=47 |
12.8 (9.7, 14.7) N=46 |
7.3 (6.3, 8.8) N=38 |
*no RAS mutant allele frequency >20% in ctDNA, no BRAF V600E and no EGFR extracellular domain mutation
Results support Symphogen’s mAb mixture approach
Symphogen believes that the results of this study of Sym004 support the company’s proprietary pipeline of mAb mixture product candidates, which also includes Sym013 and Sym015. These products, based on synergistic mAb mixtures in a single drug product, have the potential to become a new category of therapeutics.
Sym013 (Pan-HER) is a novel drug candidate currently in Phase 1 comprised of six different antibodies, targeting each of the EGFR, HER2 and HER3 receptors with synergistic antibody pairs. Administration of Sym013 is associated with rapid elimination of all three targets and consequently leads to a total horizontal blockade of HER family oncogenic signalling. The mechanism of action for Sym013 is associated with anti-tumour activities as evidenced in several preclinical models of epithelial tumours.
Sym015 (MET) is a combination of two antibodies against the MET receptor which induce receptor elimination. MET is a tyrosine kinase receptor regulating multiple cellular processes including cell proliferation, invasion and angiogenesis. Sym015 is currently in a Phase 1/2 trial in patients with MET amplified tumours.
About Sym004
Sym004 is comprised of two antibodies targeting non-overlapping epitopes on EGFR that are designed to block ligand induced receptor activation and also to elicit removal of EGFR from the cancer cell surface by inducing receptor internalization and degradation. Positive clinical efficacy findings for Sym004 in patients with metastatic colorectal cancer (mCRC) and with acquired resistance to anti-EGFR antibody was reported in the June 2015 issue of Cancer Discovery (Cancer Discovery 2015 Jun;5(6):598-609).
About Symphogen A/S
Symphogen is a private biopharmaceutical company leading the field of recombinant antibody mixtures for therapeutic use in oncology. Symphogen is dedicated to bringing truly innovative oncology products to the market, creating optimally selected antibody mixtures that address multiple oncology targets in a single drug product. The company has collaborations for the development of antibody therapeutics in the infectious disease area with Genentech, and in immuno-oncology with Shire. Symphogen has offices in Denmark and New Jersey, US and its investors include Essex Woodlands Health Ventures, Novo A/S, PKA, Sunstone Capital, Gilde Healthcare Partners, Danica Pension, Takeda Ventures, Inc., and Genentech. For more information, please see www.symphogen.com