Sym004, a mixture of 2 anti-EGFR monoclonal antibodies (mAbs), was shown to be active in a prior P1/2 trial in refractory mCRC. Due to its unique mode of action, Sym004 was developed for overcoming of acquired resistance to anti-EGFR antibodies.
254 patients (pts) were entered to an open label, multinational, 3-arm (1:1:1) RP2S comparing 2 regimens (12 mg/kg [A] or 9 mg/kg loading dose followed by 6 mg/kg [9/6; B]) of weekly Sym004 vs investigator choice (IC) of 5-FU, capecitabine, or best supportive care [C]. Standard eligibility criteria were used; pts were to be refractory to chemotherapy and have responded to, and progressed on anti-EGFR mAb-based therapy; RAS exon 2 wild type in tumour archival sample. The study was designed to detect a 3-month (M) improvement in overall survival (OS) (6 vs 9 M) between either Arm A or B and Arm C.
Demographic and baseline parameters were well balanced. The Sym004 adverse event (AE) profile was typical although frequency/severity of dermatologic AEs and hypomagnesemia was higher and GI AEs appeared lower than with approved anti-EGFR mAbs. Arm B was better tolerated than Arm A. OS in the ITT population and exploratory subgroups are presented. The primary outcome of the study was negative due to unexpected outcomes of Arm C. Arm B (9/6 mg dose) was not only better tolerated over 12/6 mg (Arm A), but also was associated with improved survival. Biomarker-specific analyses evaluating pts with double-negative (DN) (no RAS mutant allele frequency >20% in circulating tumor [ct]DNA; no BRAF V600E) or triple-negative (TN) (DN + no EGFR extracellular domain mutation in ctDNA) mCRC demonstrated markedly prolonged survival and established the 9/6 regimen as well-tolerated and active in DNmCRC (OS increased 3.5 M) and TNmCRC (OS increased 5.5 M).Table: 478O
|Population||Arm A||Arm B||Arm C|
|ITT N = 254||7.9a (6.5, 9.9)b N = 83||10.3 (9.0, 12.9) N = 86||9.6 (8.3, 12.2) N = 85|
|US&EUc N = 224||7.7 (6.1, 11.3) N = 75||9.9 (8.0, 12.8) N = 74||8.5 (6.8, 10.2) N = 75|
|US&EU with biomarker data N = 193||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 DNmCRC N = 170 (88%)d||8.9 (6.2, 12.4) N = 62||11.9 (9.7, 13.8) N = 57||8.4 (6.4, 10.0) N = 51|
|US&EU with TNmCRC N = 131 (68%)d||10.6 (6.8, 13.1) N = 47||12.8 (9.7, 14.7) N = 46||7.3 (6.3, 8.8) N = 38|
amedian survival in M
b95% confidence intervals
cthe subgroup analyses excluded pts due to different medical practice
dwith biomarker data
Although the study was negative in ITT population, treatment with Sym004 was associated with remarkable response when compared with any 4th-line treatment of mCRC. The promising results in the molecularly selected population provide guidance to design a pivotal ctDNA-guided pivotal trial in EGFR inhibitor refractory mCRC.
Clinical trial identification
NCT02083653 or EMR200637-002
Legal entity responsible for the study
J. Tabernero: Advisory boards: Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, Takeda. F. Ciardiello: Advisory boards: Roche, Merck, Lilly, BMS, Pfizer, Amgen, Bayer. C. Montagut: Advisory boards: Amgen, Bayer, Merck Serono, Sanofi, Symphogen. C. Ding, T. Tuxen Poulsen, M. Kragh, I.D. Horak: Employee of Symphogen. S. Kopetz: Advisory boards: Amgen, Merrimack, Bayer, Sanofi, Array BioPharma, Genentech, Molecular Match, Symphogen, Guardant Health, EMD Serono, Merck. V. Zagonel: Advisory boards: Celgene, Bayer, Roche, Amgen, Novartis, Pfizer. J. Bennouna: Honoraria: Roche, Boehringer Ingelheim, AstrZeneca, Shire, MSD, BMS; consulting or advisory role: Roche, Boehringer Ingelheim, AstraZeneca, Shire, MSD, BMS. S. Siena: Advisory boards: Amgen, Roche, Bayer, Merck-Serono, Sanofi, Merrimack. A. Falcone: Advisory boards and research grants to Institution: Amgen, Merck, Roche, Bayer, Servier, Lilly, Sanofi. All other authors have declared no conflicts of interest.