Phase Ib/II study of Cetuximab Plus Pembrolizumab in Patients with Advanced RAS wild-type Colorectal Cancer.

Purpose We evaluated the antitumor efficacy of cetuximab in combination with pembrolizumab in patients with RAS wild-type (RASwt), metastatic colorectal adenocarcinoma (mCRC). Experimental design In this phase Ib/II study, cetuximab was combined with pembrolizumab in patients with RASwt mCRC with {greater than or equal to} 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. Results 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: 31%; p=0.52). Median PFS was 4.1 months (95% 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 cytotoxic T-cell lymphocytes post-treatment (p=0.035). These changes were more pronounced in patients with tumor shrinkage (p=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 pre-treatment tumor cells from metastatic sites vs. primary tumor samples (p Conclusions 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.