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 wild-type (RASwt), metastatic colorectal adenocarcinoma (mCRC).

PATIENTS AND METHODS

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.

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 (PFS): 31%; = 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 ( = 0.035). These changes were more pronounced in patients with tumor shrinkage ( = 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 ( < 0.05). Higher numbers of PD-L1 tumor cells at baseline were associated with tumor shrinkage ( = 0.04). Analysis of immune populations in the blood demonstrated decreases in PD-1 memory effector cells ( = 0.04) and granulocytic myeloid-derived suppressor cells ( = 0.03), with simultaneous increases in CD4/CTLA4 cells ( = 0.01).

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.