394 Interleukin-8–neutralizing monoclonal antibody BMS-986253 plus nivolumab (NIVO) in biomarker-enriched, primarily anti–PD-(L)1–experienced patients with advanced cancer: initial phase 1 results

Abstract

<h3>Background</h3> Interleukin 8 (IL-8) is a C-X-C chemokine that exerts protumorigenic effects in the tumor microenvironment, including recruiting immunosuppressive PMN-MDSCs and promoting angiogenesis.^1–3 Elevated serum IL-8 (sIL-8) is a negative prognostic indicator in patients with solid tumors and may have predictive value in patients treated with immunotherapies.^{2 4 5} BMS-986253, a fully human-sequence IgG1κ anti–IL-8 monoclonal antibody, binds IL-8 and prevents signaling through CXCR1/CXCR2 and has been shown to be safe in patients with advanced cancers.³ We present initial results of BMS-986253 + NIVO from a phase 1/2a trial in patients with advanced cancers who had detectable sIL-8 levels, the majority of whom had progressed on/after prior anti–PD-(L)1 (NCT03400332). <h3>Methods</h3> During safety evaluation/dose exploration, patients with advanced metastatic solid tumors (melanoma, NSCLC, SCCHN, RCC, or UCC) and detectable sIL-8 (&gt;10 pg/mL at screening) received BMS-986253 600 (n=16), 1200 (n=15), or 2400 mg (n=18) Q4W, or 1200 (n=12) or 2400 mg (n=59) Q2W, + NIVO 480 mg intravenously Q4W. Safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity were evaluated (investigator-assessed, RECIST v1.1). <h3>Results</h3> As of March 20, 2020, 120 patients (median age, 63 years [range, 35–87 years]) received BMS-986253 + NIVO; 97% of patients received prior anti–PD-(L)1 therapy, and 25% received prior anti–CTLA-4 therapy. BMS-986253 + NIVO was well tolerated with no dose-limiting toxicities observed. Most TRAEs were grade 1–2. The most common (≥5% of patients) TRAEs (any grade; grade 3–4) were fatigue (9%; 1%), nausea (7%; 0%), rash/rash maculopapular (6%; 0%), pruritus (5%; 0%), and decreased appetite (5%; 0%). Grade 3–4 serious TRAEs were reported in 2 patients (infusion-related reaction, BMS-986253 2400 mg Q2W + NIVO; AST/ALT increased, BMS-986253 1200 mg Q4W + NIVO). BMS-986253 exposure increased dose proportionally and was not altered with NIVO. BMS-986253 resulted in dose-dependent reductions in free sIL-8 levels, with tumor IL-8 suppression detected in most patients evaluated; additional pharmacodynamic endpoints will be presented. Partial responses were observed in multiple tumor types, including 5 of 28 patients with melanoma who had progressed on/after prior anti–PD-(L)1; 4 of the 5 patients were also previously treated with anti–CTLA-4. <h3>Conclusions</h3> BMS-986253 + NIVO demonstrated a tolerable safety profile with dose-proportional pharmacokinetics and robust sIL-8 suppression. Preliminary antitumor activity was observed across a range of doses/regimens in this biomarker-enriched, anti–PD-(L)1–experienced, heterogeneous patient population with advanced cancers. These findings support further evaluation of BMS-986253 in select advanced tumors. <h3>Acknowledgements</h3> The authors acknowledge Dr Charles Drake while at Columbia University Medical Center, New York, NY, USA, for his contributions to the study. <h3>Trial Registration</h3> NCT03400332 <h3>Ethics Approval</h3> This study was approved by the WCG Independent Review Board, approval number 20172711. <h3>References</h3> David JM, Dominguez C, Hamilton DH, et al. The IL-8/IL-8R axis: a double agent in tumor immune resistance. <i>Vaccines</i> (Basel) 2016;<b>4</b>:22. Schalper KA, Carleton M, Zhou M, et al. Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors. <i>Nat Med</i>. 2020;<b>26</b>:688–692. Bilusic M, Heery CR, Collin JM, et al. Phase I trial of HuMax-IL-8 (BMS-986253), an anti–IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. <i>J Immunother Cancer</i> 2019;<b>7</b>:240. Yuen KC, Liu L-F, Gupta V, et al. High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade. <i>Nat Med</i> 2020;<b>26</b>:683–698. Sanmamed MF, Perez-Gracia JL, Schalper KA, et al. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti–PD-1 treatment in melanoma and non-small-cell lung cancer patients. <i>Ann Oncol</i> 2017;<b>28</b>:1988–1995.