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

Christos Fountzilas, David L. Bajor, Sarbajit Mukherjee, Joel Saltzman, Agnieszka K. Witkiewicz, Orla Maguire, Hans Minderman, Ram Nambiar, Hanna R. Rosenheck, Erik Knudsen, Jason B. Muhitch, Scott I. Abrams, Chong Wang, Alan D. Hutson, Kristopher Attwood, Karen A. Hicks, Jennifer A. Jurcevic, Pawel Kalinski, Renuka Iyer, Patrick M. Boland

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Purpose: We evaluated the antitumor efficacy of cetuximab in combination with pembrolizumab in patients with RAS 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%; P = 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 (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 pretreatment tumor cells from metastatic sites versus primary tumor samples (P < 0.05). Higher numbers of PD-L1+ tumor cells at baseline were associated with tumor shrinkage (P = 0.04). Analysis of immune populations in the blood demonstrated decreases in PD-1+ memory effector cells (P = 0.04) and granulocytic myeloid-derived suppressor cells (P = 0.03), with simultaneous increases in CD4+/CTLA4+ cells (P = 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 immunooncology combinations with enhanced efficacy and/or targeting additional or alternative immune checkpoints merits investigation.

Original languageEnglish (US)
Pages (from-to)6726-6736
Number of pages11
JournalClinical Cancer Research
Volume27
Issue number24
DOIs
StatePublished - Dec 15 2021
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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