Phase Ib/II Study of Cetuximab plus Pembrolizumab in Patients with Advanced RAS Wild-Type Colorectal Cancer.

Abstract

We evaluated the antitumor efficacy of cetuximab in combination with pembrolizumab in patients with <i>RAS</i> wild-type (RASwt), metastatic colorectal adenocarcinoma (mCRC). In this phase Ib/II study, cetuximab was combined with pembrolizumab in patients with RASwt mCRC with ≥ one prior line of therapy for advanced disease. We analyzed baseline on-treatment tumor tissues for changes in the tumor microenvironment (TME), using flow cytometry and multispectral immunofluorescence. Forty-four patients were evaluable for efficacy. The study was negative for the primary efficacy endpoint [overall response rate: 2.6%, 6-month progression-free survival (PFS): 31%; <i>P</i> = 0.52]. Median PFS was 4.1 months [95% confidence interval (CI): 3.9-5.5 months]. No increase in adverse effects was identified. We observed favorable immunomodulation with 47% increase in the number of intratumoral CTLs posttreatment (<i>P</i> = 0.035). These changes were more pronounced in patients with tumor shrinkage (<i>P</i> = 0.05). The TME was characterized by high numbers of TIM3⁺ and CTLA4⁺ cells; there were few activated OX40⁺ cells. PD-L1 expression was higher in pretreatment tumor cells from metastatic sites versus primary tumor samples (<i>P</i> < 0.05). Higher numbers of PD-L1⁺ tumor cells at baseline were associated with tumor shrinkage (<i>P</i> = 0.04). Analysis of immune populations in the blood demonstrated decreases in PD-1⁺ memory effector cells (<i>P</i> = 0.04) and granulocytic myeloid-derived suppressor cells (<i>P</i> = 0.03), with simultaneous increases in CD4⁺/CTLA4⁺ cells (<i>P</i> = 0.01). The combination of cetuximab and pembrolizumab is inactive in patients with RASwt mCRC, despite its partial local immunologic efficacy. Further development of immuno-oncology combinations with enhanced efficacy and/or targeting additional or alternative immune checkpoints merits investigation.