Futuximab/Modotuximab

Sym004 is an equimolar mixture of two monoclonal antibodies, futuximab and modotuximab, which non-competitively block the epidermal growth factor receptor (EGFR). Sym004 has been clinically tested for treatment of solid tumors. The present work characterizes the non-linear pharmacokinetics (PK) of Sym004 and its constituent antibodies and investigates two types of covariate models for interpreting the interindividual variability of Sym004 exposure. Sym004 serum concentration data from 330 cancer patients participating in four Phase 1 and 2 trials (n = 247 metastatic colorectal cancer, n = 87 various types advanced solid tumors) were pooled for non-linear mixed effects modeling. Dose regimens of 0.4-18 mg/kg Sym004 dosed by i.v. infusion weekly or every 2nd week were explored. The PK profiles for futuximab and modotuximab were parallel, and the parameter values for their population PK models were similar. The PK of Sym004 using the sum of the serum concentrations of futuximab and modotuximab was well captured by a 2-compartment model with parallel linear and saturable, Michaelis-Menten-type elimination. The full covariate model including all plausible covariates included in a single step showed no impact on Sym004 exposure of age, Asian race, renal and hepatic function, tumor type and previous anti-EGFR treatments. The reduced covariate model contained statistically and potentially clinically significant influences of body weight, albumin, sex and baseline tumor size. Population PK modeling and covariate analysis of Sym004 were feasible using the sum of the serum concentrations of the two constituent antibodies. Full and reduced covariate models provided insights into which covariates may be clinically relevant for dose modifications and thus may need further exploration.

Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is an effective treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients receive clinical benefits from anti-EGFR therapies, due to the development of resistance mechanisms. In this regard, HER2 has emerged as an actionable target in the treatment of mCRC patients with resistance to anti-EGFR therapy.

We have used SW48 and LIM1215 human colon cancer cell lines, quadruple wild-type for KRAS, NRAS, BRAF and PI3KCA genes, and their HER2-amplified (LIM1215-HER2 and SW48-HER2) derived cells to perform in vitro and in vivo studies in order to identify novel therapeutic strategies in HER2 gene amplified human colorectal cancer.

LIM1215-HER2 and SW48-HER2 cells showed over-expression and activation of the HER family receptors and concomitant intracellular downstream signaling including the pro-survival PI3KCA/AKT and the mitogenic RAS/RAF/MEK/MAPK pathways. HER2-amplified cells were treated with several agents including anti-EGFR antibodies (cetuximab, SYM004 and MM151); anti-HER2 (trastuzumab, pertuzumab and lapatinib) inhibitors; anti-HER3 (duligotuzumab) inhibitors; and MEK and PI3KCA inhibitors, such as refametinib and pictilisib, as single agents and in combination. Subsequently, different in vivo experiments have been performed. MEK plus PI3KCA inhibitors treatment determined the best antitumor activity. These results were validated in vivo in HER2-amplified patient derived tumor xenografts from three metastatic colorectal cancer patients.

These results suggest that combined therapy with MEK and PI3KCA inhibitors could represent a novel and effective treatment option for HER2-amplified colorectal cancer.