Data from A Phase I Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer

<div>Abstract<p>Ovarian cancers and microsatellite stable (MSS) colorectal cancers are insensitive to anti–programmed cell death 1 (PD-1) immunotherapy, and new immunotherapeutic approaches are needed. Preclinical data suggest a relationship between immunotherapy resistance and elevated angiopoietin 2 levels. We performed a phase I dose escalation study of pembrolizumab and the angiopoietin 1/2 inhibitor trebananib (NCT03239145). This multicenter trial enrolled patients with metastatic ovarian cancer or MSS colorectal cancer. Trebananib was administered intravenously weekly for 12 weeks with 200 mg intravenous pembrolizumab every 3 weeks. The toxicity profile of this combination was manageable, and the protocol-defined highest dose level (trebananib 30 mg/kg weekly plus pembrolizumab 200 mg every 3 weeks) was declared the maximum tolerated dose. The objective response rate for all patients was 7.3% (90% confidence interval, 2.5%–15.9%). Three patients with MSS colorectal cancer had durable responses for ≥3 years. One responding patient’s colorectal cancer harbored a <i>POLE</i> mutation. The other two responding patients had left-sided colorectal cancers, with no baseline liver metastases, and genomic analysis revealed that they both had <i>KRAS</i> wild-type, <i>ERBB2</i>-amplified tumors. After development of acquired resistance, biopsy of one patient’s <i>KRAS</i> wild-type <i>ERBB2</i>-amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, <i>ERBB2</i> amplification, and left-sided tumors, can predict increased sensitivity to PD-1 immunotherapy combinations.</p></div>