@article{0bc7f372e1d34983889885c2cc872fdb,
title = "Phase Ib/II Study of Cetuximab plus Pembrolizumab in Patients with Advanced RAS Wild-Type Colorectal Cancer",
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.",
author = "Christos Fountzilas and Bajor, {David L.} and Sarbajit Mukherjee and Joel Saltzman and Witkiewicz, {Agnieszka K.} and Orla Maguire and Hans Minderman and Ram Nambiar and Rosenheck, {Hanna R.} and Knudsen, {Erik S.} and Muhitch, {Jason B.} and Abrams, {Scott I.} and Chong Wang and Hutson, {Alan D.} and Kristopher Attwood and Hicks, {Karen A.} and Jurcevic, {Jennifer A.} and Pawel Kalinski and Renuka Iyer and Boland, {Patrick M.}",
note = "Funding Information: The study was funded by a grant provided by Merck Sharp & Dohme Corp who also provided pembrolizumab free of charge. Funding Information: C. Fountzilas reports grants from Merck during the conduct of the study as well as grants and other support from Merck and other support from Incyte, Medimmune, Dragonfly Therapeutics, Kadmon, and Pfizer outside the submitted work. D.L. Bajor reports grants from Seagen, Rafael Pharmaceuticals, and Calithera Biosciences outside the submitted work. P.M. Boland reports grants from Merck during the conduct of the study as well as grants and non-financial support from Merck; grants from Taiho, Processa, Macrogenics, AbbVie, and Athenex; grants and personal fees from Ipsen; and personal fees from Bayer and Celgene outside the submitted work. No disclosures were reported by the other authors. Funding Information: This work was partially supported by NCI grants P30CA016056 and R50CA2111108 (H. Minderman) involving the use of Roswell Park Comprehensive Cancer Center{\textquoteright}s Flow and Image Cytometry Shared Resource, the Biostatistics and Bioinformatics Shared Resource, and the Pathology Network Shared Resource. This study was presented in part in the American Society of Clinical Oncology 2020 Annual Meeting, the European Society of Medical Oncology 2020 World Congress on Gastrointestinal Cancer, and the European Society of Medical Oncology 2020 Immuno-Oncology Congress. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
month = dec,
day = "15",
doi = "10.1158/1078-0432.CCR-21-1650",
language = "English (US)",
volume = "27",
pages = "6726--6736",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "24",
}