BI 1703880, a novel STimulator of INterferon Genes (STING) agonist, has demonstrated preclinical antitumor activity. As STING activation can upregulate programmed death ligand 1 and human leukocyte antigen in tumor cells, a combination of BI 1703880 and an anti-programmed cell death protein 1-antibody, such as ezabenlimab, may improve efficacy. This first-in-human phase Ia study (NCT05471856) is evaluating BI 1703880 plus ezabenlimab in patients with advanced solid tumors. The study utilizes an innovative lead-in design; all patients receive BI 1703880 monotherapy in Cycle 1 and combination therapy from Cycle 2. The primary endpoint is dose-limiting toxicities during the maximum tolerated dose evaluation period. Results will inform the future development of BI 1703880 for treatment of metastatic or recurrent malignancies. Clinical Trial number: NCT05471856 There are many different types of treatments available for patients with cancer. One type of treatment aims to use the patient’s own immune system to target and destroy the cancer, known as immunotherapy. BI 1703880 is a new drug that has been developed to activate the immune system for the treatment of cancer. This study is evaluating BI 1703880 for patients with advanced cancers based on its ability to destroy cancer cells in animal studies. BI 1703880 is being investigated on its own and in combination with another drug, ezabenlimab. The reason for testing these two drugs together is because sometimes cancer cells can become resistant to one type of immunotherapy, making proteins to “turn off” the immune response targeting the cancer. Similar to BI 1703880, ezabenlimab is also an immunotherapy. However, it turns the immune system on in a different way from BI 1703880, which means they may work together to produce a better anticancer result. The objective of the study is to determine a suitable dose of BI 1703880 alone and in combination with ezabenlimab and to see if any side effects occur.

BI 1703880, a novel STimulator of INterferon Genes (STING) agonist, has demonstrated preclinical antitumor activity. As STING activation can upregulate programmed death ligand 1 and human leukocyte antigen in tumor cells, a combination of BI 1703880 and an anti-programmed cell death protein 1-antibody, such as ezabenlimab, may improve efficacy. This first-in-human phase Ia study (NCT05471856) is evaluating BI 1703880 plus ezabenlimab in patients with advanced solid tumors. The study utilizes an innovative lead-in design; all patients receive BI 1703880 monotherapy in Cycle 1 and combination therapy from Cycle 2. The primary endpoint is dose-limiting toxicities during the maximum tolerated dose evaluation period. Results will inform the future development of BI 1703880 for treatment of metastatic or recurrent malignancies. Clinical Trial number: NCT05471856 There are many different types of treatments available for patients with cancer. One type of treatment aims to use the patient’s own immune system to target and destroy the cancer, known as immunotherapy. BI 1703880 is a new drug that has been developed to activate the immune system for the treatment of cancer. This study is evaluating BI 1703880 for patients with advanced cancers based on its ability to destroy cancer cells in animal studies. BI 1703880 is being investigated on its own and in combination with another drug, ezabenlimab. The reason for testing these two drugs together is because sometimes cancer cells can become resistant to one type of immunotherapy, making proteins to “turn off” the immune response targeting the cancer. Similar to BI 1703880, ezabenlimab is also an immunotherapy. However, it turns the immune system on in a different way from BI 1703880, which means they may work together to produce a better anticancer result. The objective of the study is to determine a suitable dose of BI 1703880 alone and in combination with ezabenlimab and to see if any side effects occur.

Figure S1. Study design and pharmacokinetic/pharmacodynamic assessment. (a) phase I study design. (b) Overview of pharmacokinetic and pharmacodynamic profile assessment. Figure S2. MEDI0680 binding and specificity for PD-1. (a) MEDI0680 binding to activated primary human T cells. (b) Binding specificity of MEDI0680 to recombinant human proteins that share amino acid sequence homology with PD-1. Figure S3. Inhibition of ligand binding to native PD-1 by MEDI0680. (a) Blockade by MEDI0680 of recombinant human PD-L1 or (b) recombinant human PD-L2 binding to CHO cells expressing human PD-1 protein. Figure S4. In vitro T-cell activation and cytotoxicity mediated by MEDI0680. (a) IFNÎł release into cell culture media of allogeneic dendritic cellâ T cell mixed lymphocyte reactions. (b) Cellular cytotoxicity mediated by EBV-reactive CD8 T cells over time, as determined by non-invasive electrical impedance measurement in an xCelligence RTCA MP instrument as a surrogate for cell death. Figure S5. Representative examples of flow cytometry of peripheral blood from patients treated with MEDI0680. (a) Ki67 staining in CD4+ and CD8+ T cells at cycle 1 day 1 pre-treatment (C1D1) and at cycle 1 day 8 post-treatment, as indicated. (b) HLA-DR and CD38 co-staining on CD4+ effector memory T cells (CD4+ TEM) at the same time points. Figure S6. Lack of correlation between changes in peripheral pharmacodynamic markers and objective clinical response. (a) Fold change in the indicated cytokine and chemokine markers in all cohorts or (b) only in the 10 and 20mg/kg cohorts or (c) the fold change in T-cell proliferation and CD4+ TEM CD38high HLA-DRhigh (activated) T cells with respect to objective clinical responses are shown. Table S1. Key eligibility criteria. Table S2. Patient characteristics and samples evaluated for pharmacodynamic analysis. Table S3. In silico identification of PD-1 paralogs using the protein Basic Local Alignment Search Tool BLASTp. Table S4. Study disposition (as-treated population). (ZIP 5.02 mb)

Figure S1. Study design and pharmacokinetic/pharmacodynamic assessment. (a) phase I study design. (b) Overview of pharmacokinetic and pharmacodynamic profile assessment. Figure S2. MEDI0680 binding and specificity for PD-1. (a) MEDI0680 binding to activated primary human T cells. (b) Binding specificity of MEDI0680 to recombinant human proteins that share amino acid sequence homology with PD-1. Figure S3. Inhibition of ligand binding to native PD-1 by MEDI0680. (a) Blockade by MEDI0680 of recombinant human PD-L1 or (b) recombinant human PD-L2 binding to CHO cells expressing human PD-1 protein. Figure S4. In vitro T-cell activation and cytotoxicity mediated by MEDI0680. (a) IFNÎł release into cell culture media of allogeneic dendritic cellâ T cell mixed lymphocyte reactions. (b) Cellular cytotoxicity mediated by EBV-reactive CD8 T cells over time, as determined by non-invasive electrical impedance measurement in an xCelligence RTCA MP instrument as a surrogate for cell death. Figure S5. Representative examples of flow cytometry of peripheral blood from patients treated with MEDI0680. (a) Ki67 staining in CD4+ and CD8+ T cells at cycle 1 day 1 pre-treatment (C1D1) and at cycle 1 day 8 post-treatment, as indicated. (b) HLA-DR and CD38 co-staining on CD4+ effector memory T cells (CD4+ TEM) at the same time points. Figure S6. Lack of correlation between changes in peripheral pharmacodynamic markers and objective clinical response. (a) Fold change in the indicated cytokine and chemokine markers in all cohorts or (b) only in the 10 and 20mg/kg cohorts or (c) the fold change in T-cell proliferation and CD4+ TEM CD38high HLA-DRhigh (activated) T cells with respect to objective clinical responses are shown. Table S1. Key eligibility criteria. Table S2. Patient characteristics and samples evaluated for pharmacodynamic analysis. Table S3. In silico identification of PD-1 paralogs using the protein Basic Local Alignment Search Tool BLASTp. Table S4. Study disposition (as-treated population). (ZIP 5.02 mb)