American Association for Cancer Research
10780432ccr211650-sup-265197_3_supp_7404716_qzjxgr.pdf (1022.89 kB)

Supplementary Figure 4 from Phase Ib/II Study of Cetuximab plus Pembrolizumab in Patients with Advanced RAS Wild-Type Colorectal Cancer

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journal contribution
posted on 2023-03-31, 23:04 authored by Christos Fountzilas, David L. Bajor, Sarbajit Mukherjee, Joel Saltzman, Agnieszka K. Witkiewicz, Orla Maguire, Hans Minderman, Ram Nambiar, Hanna R. Rosenheck, Erik S. 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

Multispectral immunofluorescence. Number of cells positive for exhaustion (PD-L1, TIM3, LAG3, CTLA4) and activation markers (OX40) in baseline tumor specimens (A); Quantitation of signals per specimen (B). There are more PDL1 positive tumor cell in the pre-treatment metastatic site biopsy. While there are more activated, partially activated T cell-1 and exhausted T cell-1 in the primary tumor specimens (*p<0.05, ***p<0.001); Changes in different intratumoral cell populations on-treatment (C). Statistics using paired Student T test based on mean value for Matched PIDs Pre Tx Vs Post Tx; Association of baseline number of activated OX40+ cells with PFS (D), and change in activated and partially activated-1 cells with changes in CEA on treatment (E).





We evaluated the antitumor efficacy of cetuximab in combination with pembrolizumab in patients with RAS 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%; 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). 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.