A phase Ia/IIb trial of the CXCR4 inhibitor X4P-001 and nivolumab for advanced renal cell carcinoma (RCC) that is unresponsive to nivolumab monotherapy

Abstract

Background: X4P-001 is an oral, selective, allosteric, CXCR4 inhibitor. In melanoma patients (pts), single agent X4P-001 increased tumor inflammatory signature and antigen presentation/processing gene expression scores in the tumor microenvironment (TME) and promoted activated, cytotoxic T cell infiltration. It is hypothesized thatX4P-001 has the ability to restore immunity within the TME and potentially enhance the antitumor activity of checkpoint inhibitors. Methods: This is an open-label study to evaluate the safety and clinical activity of X4P001 in combination with nivolumab for advanced RCC. Pts receiving standard-ofcare nivolumab monotherapy who had a best response of stable disease (SD) or progressive disease (PD) received 400 mg QD of X4P-001 while continuing 240 mg IV nivolumab infusions every 2 weeks. Blood and serum biomarkers were also assessed. Results: Of 9 enrolled pts (8 males/1 female; median age, 65 years), 1 remains on study and 8 have discontinued due to PD (4 pts), or treatment-related adverse events (AEs, 4 pts). Drugrelated AEs (≥ 25%) were diarrhea (5 pts); nasal congestion (4 pts); dry eye and alanine aminotransferase increase (3 pts each). Grade≥3 drug-related AEs of autoimmune hepatitis; mucosal inflammation; rash; and increased lipase, alanine and aspartate aminotransferase were reported in 1 pt each. The best responses observed were partial response (PR; n=1), SD (SD; n=7), and PD (n=1). Of the 5 pts with SD on earlier nivolumab monotherapy, 1 had a subsequent confirmed PR, and all 4 pts with PD on monotherapy at study entry had SD with the X4P-001 combination (median duration: 6.5 months; range: 3.7-10.6). Cytokine/chemokine concentrations in pt serum, pre- and post-combination treatment, will be presented. Conclusions: X4P-001 and nivolumab combination therapy in advanced RCC pts demonstrated potential antitumor activity and a manageable safety profile. These results, together with previously presented data from our melanoma study, suggest that CXCR4 inhibition mediated by X4P-001 may synergize with PD-1 blockade to enhance antitumor immune responses in pts that fail to respond to checkpoint inhibitor therapy alone.