123P - Genotyping circulating tumor DNA identifies metastatic colorectal cancer (mCRC) patients highly sensitive to Sym004

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Cancer in Adolescents
Biomarkers
Colon Cancer
Rectal Cancer
Translational Research
Presenter Clara Montagut Viladot
Citation Annals of Oncology (2017) 28 (suppl_5): v22-v42. 10.1093/annonc/mdx363
Authors C. Montagut Viladot1, A. Bardelli2, T. Tuxen Poulsen3, R. Dienstmann4, M. Kragh5, S. Kopetz6, K. Koefoed3, F. Ciardiello7, C. Ding8, J. Vidal1, J. Clausell-Tormos3, G. Siravegna2, T. Lindsted3, M.W. Pedersen3, G. Rospo2, G. Argilés Martinez9, P. Nadler3, I.D. Horak3, J. Tabernero10
  • 1Medical Oncology, Hospital del Mar, 08003 - Barcelona/ES
  • 2Dept Of Oncology, IRCCs University of Torino School of Medicine, 10060 - Candiolo/IT
  • 3-, Symphogen, Ballerup/DK
  • 4Oncology Data Science (odyssey) Group, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 5-, Symphogen, -/DK
  • 6Gi Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston/US
  • 7U.o.c. Di Oncologia Medica E Di Ematologia, Università degli Studi della Campania "Luigi Vanvitelli", 80131 - naples/IT
  • 8-, Symphogen, Somerville, New Jersey/US
  • 9Medical Oncology, Vall d’Hebrón Institut d’Oncologia (VHIO),, 08035 - Barcelona/ES
  • 10Medical Oncology, Vall d'Hebron University Hospital, 08035 - Barcelona/ES

Abstract

Background

Acquired resistance of mCRC patients (pts) to anti-EGFR monoclonal antibodies (mAbs) is frequently due to mutations in RAS/BRAF and EGFR extracellular domain (ECD), and amplifications in MET/ERBB2. Studies suggest that some anti-EGFR mAb refractory pts retain tumor EGFR-dependency potentially targetable by more efficacious agents such as Sym004 – a mixture of two non-overlapping mAb targeting EGFR for degradation. A Phase 2b trial of Sym004 in 254 mCRC pts tissue RAS wt that relapsed on anti-EGFR blockade was recently completed.

Methods

Baseline circulating tumor (ct)DNA profiles (Guardant360, Guardant Health, N = 193 pts) were obtained from blood samples collected from pts in the Sym004 Phase2b trial. Serial blood samples during treatment were analyzed for EGFR-ECD mutation dynamics.

Results

High mutant allele frequency (MAF >20%) of KRAS/NRAS was found in 5% of pts and BRAF V600E and EGFR-ECD mutations in 6.7% and 25% of pts, respectively. At least 1 of these mechanisms of resistance was identified in 32% of the pts. Mutations in KRAS, NRAS, and BRAF V600E, and amplifications of ERBB2 and MET were more likely to co-occur with EGFR-ECD mutations, demonstrating genomic complexity developed as a result of EGFR blockade. Comparative analysis of MAFs of driver genes indicated that EGFR-ECD mutations are subclonal events. The absence of any EGFR-ECD/BRAF/high RAS MAF mutation at baseline was associated with a significantly improved OS in the Sym004 treated pts as compared to control arm with investigator’s choice chemotherapy. Sym004 has previously been demonstrated to retain in vitro efficacy in EGFR-ECD mutated cancer cells, and ctDNA monitoring demonstrated decrease in EGFR-ECD in Sym004 treated pts. This suggests that EGFR-ECD mutated cells are targeted by Sym004, but this activity does not translate into clinically meaningful OS benefit, likely due to other co-occuring resistance mechanisms.

Conclusions

Comprehensive liquid biomarker profiling of 193 mCRC pts captured high intrapatient heterogeneity following anti-EGFR therapy, and identified a highly Sym004 sensitive mCRC pts subset with a RAS/RAF/EGFR-ECD wild type profile. Our data indicates heterogeneous responses of different subclones to targeted agents in mCRC.

Clinical trial identification

Legal entity responsible for the study

Medical Oncology Department, Hospital del Mar, Barcelona, Spain

Funding

Funded by Symphogen

Disclosure

C. Montagut Viladot: Advisory Board for Amgen, Bayer, Merck Serono, Sanofi, Symphogen. T. Tuxen Poulsen, M. Kragh, K. Koefoed, C. Ding, J. Clausell-Tormos, T. Lindsted, M.W. Pedersen, P. Nadler, I.D. Horak: Full time employee at Symphogen. S. Kopetz: Advisory boards for Amgen, Merrimack, Bayer, Sanofi, Array BioPharma, Genentech, MolecularMatch, Symphogen, Guardant Health, EMD Serono, Merck. J. Tabernero: Advisory boards for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda. All other authors have declared no conflicts of interest.