Platform trial of ezabenlimab (BI 754091), an anti-PD-1 antibody, in patients (pts) with previously treated advanced solid tumors: Combination with BI 836880, a VEGF/Ang2-blocking nanobody.
Authors: Hussein Maen A. , Percent Ivor John , Bendell Johanna C. , Arrowsmith Edward , Arkenau Hendrik-Tobias , Chu Quincy S. , Hansen Aaron Richard , Erzen Damijan , Qiu Sheng , Lucarelli Anthony , Ulahannan Susanna Varkey 
Published: June 2021

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Background: The combination of anti-PD-1 antibodies with other immunomodulatory or targeted therapies has the potential for synergistic effects. This open-label, Phase II platform trial is assessing ezabenlimab, an anti-PD-1 antibody, in combination with other agents. Here, we report preliminary data from Module C, which assesses ezabenlimab in combination with BI 836880, a humanized bispecific nanobody that targets vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2). VEGF and Ang2 play key roles in tumor angiogenesis and have an immunosuppressive effect in the tumor microenvironment. Combining anti-VEGF/Ang2 with an anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell death. Methods: Pts are being enrolled into 5 cohorts: locally advanced/metastatic gastric or gastroesophageal adenocarcinoma with ≥1 prior treatment (anti-PD-[L]1 naïve; Cohort 1); any advanced/metastatic solid tumor (excluding non-squamous NSCLC or melanoma) with prior anti-PD-(L)1 treatment, which progressed after achieving at least stable disease (SD) for ≥4 months (Cohort 2); advanced/metastatic solid tumors with no benefit from prior anti-PD-(L)1 treatment (SD or progressive disease [PD] in < 4 months; Cohort 3); locally advanced/metastatic microsatellite stable (MSS) colorectal cancer with ≥1 prior treatment (anti-PD-[L]1 naïve; Cohort 4); advanced MSS and mismatch repair-proficient endometrial carcinoma, which progressed after 1 line of chemotherapy (anti-PD-[L]1 naïve; Cohort 5). Pts will receive BI 836880 720 mg and ezabenlimab 240 mg IV every 3 weeks. The primary endpoint is investigator-assessed objective response (complete response [CR] or partial response per RECIST v1.1). Safety is also being assessed. Results: As of Jan 2021, 29 pts have received ezabenlimab plus BI 836880; 26 pts remain on treatment. Cohorts 1/2/3/4/5 included 0/6/3/19/1 pts; median age 63 yrs; 20 (69%) pts were male . Overall, 22 (76%) pts experienced an adverse event (AE; any-cause), most commonly (all%/G3%) nausea (31/3), hypertension (28/7) and fatigue (21/0). No G4/5 AEs were reported; 5 (17%) pts experienced serious AEs. One pt had an immune-related AE (G1 rash). Eighteen (62%) pts had a drug-related AE, most commonly nausea (24%), vomiting, fatigue, and hypertension (all 14%). Three pts had infusion-related reactions (G1, n = 2; G2, n = 1) and 1 pt had an AE that led to treatment discontinuation (non-related G3 bile duct stone). Of 7 pts evaluable for response prior to cycle 3, 5 have SD (Cohort 2, n = 2; Cohort 4, n = 3), and 2 have PD (Cohorts 3 and 4, n = 1 each). Updated data will be presented. Conclusions: These preliminary data suggest that ezabenlimab in combination with BI 836880 has a manageable safety profile. Cohorts are continuing to recruit (approximately 30 pts per cohort). Clinical trial information: NCT03697304.