Phase Ib dose-escalation/expansion study of BI 836880, a VEGF/Ang2-blocking nanobody®, in combination with BI 754091, an anti-PD-1 antibody, in patients with advanced solid tumours

Abstract

Background: Preclinical evidence shows that vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) promote an immunosuppressive state in the tumour microenvironment, and that the combination of anti-VEGF/Ang2 with anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell mediated tumour cell killing. BI 836880, a humanised bispecific nanobody that targets VEGF and Ang2, and BI 754091, an anti-PD-1 antibody, have shown safety and preliminary antitumour activity as monotherapies in phase I studies (RP2D, 720mg iv q3w for BI 836880 and 240 mg iv q3w for BI 754091). The safety and efficacy of BI 836880+ BI 754091 are being assessed in this phase Ib trial in patients (pts) with advanced solid tumours. Trial design: This open-label, dose-escalation/cohort-expansion trial is being conducted in two parts: Part 1, dose escalation of BI 836880 with BI 754091 in pts with advanced/ metastatic, PD-L1 positive, nonsquamousNSCLC; Part 2, exploratory expansion cohorts (A-F) in 6 pt populations (A: metastatic [m] NSCLC after checkpoint inhibitor [CPI] monotherapy; B:mNSCLC after chemotherapy [CTX]+ CPI; C: mSCLC after CTX with/ without CPI; D: immunotherapy-resistant m-melanoma; E: recurrent glioblastoma after 1st line CTX; F: hepatocellular carcinoma after prior sorafenib or lenvatinib with/without subsequent CPI therapy). In Part 1, pts will receive BI 836880 (cohorts of 360, 500 and 720mg iv q3w)+ fixed-dose BI 754091 240mg iv q3w, following a Bayesian logistic regression model with overdose control, with oversight froma safety monitoring committee. The primary endpoint in Part 1 is theMTD/RP2D, based on DLTs in Cycle 1. In Part 2, pts will receive BI 836880 at the RP2D+ BI 754091 240mg iv q3w. The primary endpoint in Part 2 is objective response; secondary endpoints are disease control, duration of response, PFS and tumour shrinkage. Safety, PK and exploratory biomarkers will be assessed.∼220 pts will enroll globally: 20-25 pts in Part 1 and∼200 in Part 2 (40 in Cohorts A/B; 30 in Cohorts C-F). As of May 2019, 6 pts have been treated in Part 1. Part 2 will begin once the RP2Dis established in Part 1.Updates will be presented.