Phase Ib study of pembrolizumab and trebananib (angiopoietin-2 inhibitor [Ang-2]): Preliminary analysis of the colorectal cancer (CRC) cohort.

Abstract

e14160 Background: Ang-2 is produced by endothelial cells, predominantly in tissues undergoing vascular remodeling and in hypoxic microenvironments. Ang-2 partially suppresses T cell activation by increasing PD-L1 expression and decreasing monocyte activation. Our group demonstrated that high pre-treatment serum Ang-2 is associated with reduced overall survival (OS) in patients treated with PD-1 blockade. Methods: We initiated a phase 1b trial to evaluate the safety, efficacy, and immunological effect of the combination of pembrolizumab and trebananib, an Ang-1/2 neutralizing peptibody, in solid tumors. Treatment consisted of an induction phase of pembrolizumab 200 mg every 3 weeks and trebananib weekly (with an initial run-in dose escalation of 15-30 mg/kg) for 12 weeks followed by pembrolizumab alone for 2 years. Here we present the preliminary data in the fully enrolled CRC expansion cohort. Results: The study enrolled a total of 18 microsatellite stable (MSS) heavily pretreated CRC patients. There were no DLTs and 30mg/kg was deemed to be the MTD. This summary is based on 15 CRC patients treated with 30 mg/kg trebananib (3 in dose escalation, 12 in dose expansion) plus pembrolizumab. Nine patients (60%) were female and the median age was 51 years (43-63). The most common treatment-related adverse events (AEs) were abdominal distension, diarrhea, limb edema, transaminitis, and proteinuria (each reported in 40% of the patients). One grade 3 transaminitis and one grade 4 pneumonitis related to pembrolizumab were reported. As of the date of data retrieval, 11 patients were off treatment and four were continuing with a median follow-up of 6.1 months. The response rate was 7% (1 partial response for 14 months) and the disease control rate was 33% (4 stable disease with CEA trending down). Median time to progression and OS were 2.8 (90% CI: 1.5 to 4.9 months) and 11.4 months (90% CI: 2.6 months to ∞), respectively. Conclusions: The combination of pembrolizumab and trebananib is well tolerated and demonstrated promising activity in heavily pretreated MSS CRC. Paired biopsies and blood were collected for planned correlative immune analyses which will be presented at the meeting. Clinical trial information: NCT03239145.