Phase Ib study of BI 836880, a VEGF/Ang2-blocking nanobody, in combination with BI 754091, an anti-PD-1 antibody: Initial results in patients (pts) with advanced non-small cell lung cancer (NSCLC).

Abstract

9566 Background: Preclinical studies show that combining anti-VEGF/Ang2 with anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell destruction. BI 836880 is a humanized bispecific nanobody that targets VEGF and Ang2, and BI 754091 is an anti-PD-1 antibody. Each has shown manageable safety and preliminary activity as monotherapy. Here, we report initial results from a Phase Ib study assessing BI 836880 in combination with BI 754091. Methods: In Part 1 (dose escalation), pts with locally advanced or metastatic (m) non-squamous NSCLC who progressed during/after completion of ≥2 cycles of platinum-based chemotherapy (CT) ± a checkpoint inhibitor (CPI) were enrolled. Pts received BI 836880 (cohorts of 360, 500 and 720 mg intravenously [iv] 3-weekly [q3w]) plus fixed-dose BI 754091 (240 mg iv q3w). Dose escalation was guided by Bayesian logistic regression models with overdose control. Primary endpoint in Part 1 was maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), based on dose-limiting toxicities (DLTs) in Cycle 1. Initial safety and efficacy results of Part 1 are reported here. Part 2 will assess safety and efficacy in 6 expansion cohorts: mNSCLC after CPI monotherapy; mNSCLC after CT + CPI; mSCLC after CT ± CPI; immunotherapy-resistant m-melanoma; recurrent glioblastoma after 1st-line CT; and hepatocellular carcinoma after prior sorafenib or lenvatinib ± subsequent CPI. Results: 12 pts received BI 836880 plus BI 754091 (8 male; median age 59.5 years; 8 had received prior CPI). 4 pts remain on treatment (including 1 treated for 15 cycles). 1 pt had a DLT during Cycle 1 (360 mg; G3 pulmonary embolism). All pts experienced an adverse event (AE; any-cause; safety data cut-off Nov 2019), most commonly (all%/G3%) hypertension (58/25), vomiting (42/0), nausea (33/0), and asthenia (33/0). Hypertension was transient. No G4 AEs were reported; one G5 AE occurred (general physical health deterioration). 5 pts had immune-related AEs (G2 hypothyroidism in 2 pts; G2 pruritus, G1 papular rash, and G2 vomiting). To date (Jan 2020), 2 pts have achieved partial response; 1 pt (500 mg dose; CPI-naïve) had 58% target lesion reduction, and 1 (720 mg; prior CPI) had 35% target lesion reduction. 8 pts had stable disease. Conclusions: MTD/RP2D was BI 836880 720 mg plus BI 754091 240 mg q3w. The combination had a manageable safety profile, and preliminary anti-tumor activity was observed. Expansion cohorts are ongoing. Equal contribution: JA and BH Clinical trial information: NCT03468426 .