Pharmacokinetics of cetuximab and tumor uptake of 89Zr-cetuximab as potential predictive biomarkers for benefit of cetuximab in patients with advanced colorectal cancer.

Abstract

e15117 Background: One third of patients with RAS wild-type metastatic colorectal cancer (mCRC) do not benefit from anti-EGFR inhibitors. Thus, predictive biomarkers to identify patients with primary resistant mCRC are urgently needed. Methods: Patients with chemotherapy refractory mCRC received 500 mg/m2 cetuximab 2-weekly (NCT02117466 and NCT01691391). Patients underwent a 89Zr-cetuximab PET/CT 6 days post-injection after a therapeutic dose of cetuximab. In case of lack of tumor targeting on 89Zr-cetuximab PET, the cetuximab dose was escalated. Pharmacokinetic (PK) analyses included 89Zr-cetuximab plasma levels, EGFR saturation in skin, soluble EGFR (sEGFR), and tumor uptake and biodistribution on 89Zr-cetuximab PET. We defined treatment benefit as response or stable disease (according to RECIST v1.1) at 2 months. Results: Of the 44 patients, median age was 64 years, 25% had a right-sided primary tumor, 5 patients had a BRAF mutated (mt) tumor and 62% had treatment benefit. Cetuximab treatment dose was escalated to maximally 1250 mg/m2 in 8 patients. Visual and semiquantitative data of 89Zr-cetuximab uptake in the tumor, biodistribution and plasma activity 6 days post-injection were not correlated with treatment benefit. Although EGFR saturation in skin after 2 cycles cetuximab had a wide range (21 – 98%), saturation did not correlate with treatment benefit. On-treatment levels of sEGFR were higher than baseline (median 4.1 vs 2.0 ng/ml; p < 0.001), but levels and change of sEGFR did not correlate with PK or treatment efficacy. PFS and OS correlated with right-sided mCRC (p < 0.001 and p = 0.002 respectively) and the presence of a BRAF mt (p < 0.001 and p = 0.004 respectively). In a multivariate Cox-regression only BRAF mt remained correlated with PFS and OS (p = 0.003 and p = 0.027). Conclusions: Interpatient variances in PK and tumor uptake of 89Zr-cetuximab as performed in this setting do not predict treatment benefit of cetuximab in patients with mCRC. In contrast, BRAF status correlated with treatment benefit and warrants further research to confirm the predictive value. Clinical trial information: NCT02117466 and NCT01691391.