Abstract 5374
Background
PD-1/L1 blocking agents have transformed the treatment of multiple cancers, but some tumor types including MSS-CRC appear to be refractory. Monalizumab (anti-NKG2A) and Durvalumab (anti-PD-L1) may promote antitumor immunity via non-redundant mechanisms targeting innate and adaptive immunity. The safety and preliminary efficacy of this combination (NCT02671435) was previously reported (ASCO 2018). Here, we present the results of baseline and longitudinal pharmacodynamic biomarker assessments in peripheral blood and tumor in patients with MSS-CRC treated with Monalizumab plus Durvalumab.
Methods
Peripheral biomarkers evaluated included NKG2A receptor occupancy (RO), and frequency and functional status of immune cells (N = 23). In tumors, changes in NK and CD8 cells in pre/post-tumor biopsies were evaluated by immunohistochemistry (IHC, N = 7). Gene expression profiling of tumors was determined by RNAseq in N = 15 pretreated and N = 4 paired biopsies.
Results
In peripheral blood, full and sustained NKG2A RO was observed. Expansion of activated or proliferating NK cells was detected in 14/23 and 10/20 patients respectively, while increases in T cell proliferation (KI67+) were observed at levels expected for Durvalumab monotherapy (1.5-2-fold). In an in vitro assay system, similar changes on T/NK cell phenotyping were observed upon exposure to Monalizumab and Durvalumab. No consistent pharmacodynamics changes in tumoral NK and CD8 cells by gene expression or IHC were observed. However, modulation of pathways associated with metabolism, DNA repair and cell cycle were detected in tumors on treatment.
Conclusions
In peripheral blood, pharmacodynamic effects consistent with the proposed mechanism of action of Monalizumab and Durvalumab were observed in patients with MSS-CRC.
Clinical trial identification
NCT02671435; February 22, 2016.
Legal entity responsible for the study
MedImmune.
Funding
MedImmune.
Editorial Acknowledgement
Disclosure
N. Standifer, M.L. Ascierto, C. Morehouse, H. Ghadially, J. Rodriguez Canales, M.C. Rebelatto, X. Song, D.C. Jones, X. Li, S. Marshall, S. Abdullah, M. Jure-Kunkel: Employee: MedImmune. All other authors have declared no conflicts of interest.
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