Abstract 779: A phase I study of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), in combination with BI 754091, an anti-PD-1 mAb: Biomarker analyses from the microsatellite stable metastatic colorectal cancer (MSS mCRC) cohort
Authors: Bendell Johanna , Ulahannan Susanna V. , Chu Quincy , Patel Manish , George Ben , Auguste Aurélie , Leo-Kress Theresia , Stadermann Kai Bernd , Kraemer Nicole , Elgadi Mabrouk , Johnson Melissa 
Published: September 2020

Abstract
Introduction: LAG3 is an immune checkpoint receptor, often co-expressed with PD-1 on immune cell surfaces. PD-1 and LAG-3 signaling contribute to immune cell exhaustion in the tumor microenvironment. Dual blockade of PD-1 and LAG-3 is thus expected to improve response versus PD-1 blockade alone. A dose escalation/expansion trial (NCT03156114) is evaluating BI 754111, an anti-LAG-3 mAb, plus BI 754091, an anti-PD-1 mAb, in patients (pts) with advanced solid tumors. Here, we report data in pts with MSS mCRC, for whom checkpoint inhibitors (CPIs) have shown limited activity. We broadly evaluated biomarkers to provide information on mode of action and for their potential to predict responses.
Methods: In this dose expansion cohort, pts with PD-(L)1-naïve, previously treated MSS mCRC tumors were enrolled. Pre- and on-treatment tumor biopsies and blood samples for biomarker analyses were collected. Cytokines, including interferon-gamma (IFN-γ), were quantified in plasma samples by multiplexed and high-sensitivity immunoassays. Activated effector memory T cell and other peripheral blood mononuclear cell counts were determined by flow cytometry. PD-L1, LAG-3 and CD8 expression was determined by immunohistochemistry (IHC). Exploratory gene expression analyses to determine immuno-oncology (IO)-related markers were conducted.
Results: 40 pts with MSS mCRC received BI 754111 600 mg in combination with BI 754091 240 mg every 3 weeks. Pts had received a median (range) of 3.5 (1–10) prior treatments. To date (Sep 2019), 3 (7.5%) pts achieved a partial response (PR) and 11 (27.5%) had stable disease (SD) as best response. Peripheral blood analysis showed treatment led to coordinated upregulation of pro-inflammatory cytokines in some pts. Pts with greater cytokine induction were more likely to have SD. Also, upregulation of activated CD8 effector memory T cells in peripheral blood was observed in many pts. IHC analysis indicated that, in tumors that had CD8 T cells and PD-L1 expression at the tumor periphery at baseline, treatment led to infiltration of CD8 T cells into the tumor and an increase in PD-L1 expression. Analyses of pre-treatment tumors suggested that high PD-L1 gene expression was associated with clinical benefit. In addition, a treatment-associated increase of the IFN-γ gene signature scores was observed, supporting a treatment-induced activation of the immune system in the tumor; the effect was more pronounced in pts with PR/SD versus those with progressive disease. LAG-3 IHC levels at baseline were not predictive of outcome in this anti-PD-(L)1 naïve setting.
Conclusion: BI 754111 plus BI 754091 showed encouraging results in this IO-refractory MSS mCRC population. Biomarker analyses showed activation of the immune system in peripheral blood and the tumor, consistent with other CPIs.
Citation Format: Johanna Bendell, Susanna V. Ulahannan, Quincy Chu, Manish Patel, Ben George, Aurélie Auguste, Theresia Leo-Kress, Kai Bernd Stadermann, Nicole Kraemer, Mabrouk Elgadi, Melissa Johnson. A phase I study of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), in combination with BI 754091, an anti-PD-1 mAb: Biomarker analyses from the microsatellite stable metastatic colorectal cancer (MSS mCRC) cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 779.