Phase Ib study of AVB-S6-500 (axl inhibition) in combination with durvalumab (MEDI4736) in patients with platinum-resistant, recurrent epithelial ovarian cancer (NCT04019288) (320)

ABSTRACT

Objectives: Immune checkpoint blockade (ICB) has demonstrated efficacy in a small fraction of patients with platinum-resistant ovarian cancer (PROC), some with durable responses. The receptor tyrosine kinase AXL and its sole ligand, GAS6, are possible mediators of T cell exclusion and an attractive target due to the expected synergy between AXL inhibition and immune targeting agents. The recommended phase II dose (RP2D), safety, and efficacy of the combination of AXL inhibition via AVB-S6-500 with durvalumab (MEDI4736) were evaluated in patients with PROC. Methods: In this open-label Phase Ib open-label study, patients with PROC received AVB-S6-500 and durvalumab therapy in escalating dosing regimens guided by a Bayesian optimal interval (BOIN) design: durvalumab (1500 mg Q4W) and AVB-S6-500 (10mg/kg Q2W, 15mg/kg Q2W, 20mg/kg Q2W) with durvalumab infused prior to AVB-S6-500. The response was evaluated using modified RECIST v1.1. Pharmacokinetic/pharmacodynamic (PK/PD) studies were collected, and PD-L1 status and tumor/tumor microenvironment AXL and GAS6 staining pre and on-treatment were assessed. Results: Eleven patients with epithelial ovarian cancer (six clear cells [55%], four high-grade serous [36%], one endometrioid histology [1%]) received treatment per protocol. The median number of prior lines of therapy was 3 (range 1-5);73% (8/11) of patients had received prior bevacizumab. There were no DLTs noted over the 6-week period and no grade ≥3 adverse events attributed to study drugs. Five patients experienced an immune-related AE, most commonly liver enzyme elevations (36%). Infusion reaction with AVB-S6- 500 was noted in the first two subjects, prompting the institution of a premedication regimen, after which only one of the nine additional patients experienced an infusion reaction. Dose delays greater than one week occurred in six (55%) patients;three patients experienced delays for cancer-related complications (small bowel obstruction, pneumonia, severe fatigue), while three patients experienced delays for non-medical causes (COVID/travel, weather). Patients received therapy for a median of two cycles (range 1-6), and there were no responses noted across all dosing levels. One patient had stable disease, with a duration of response of three months. Only two patients had strong (2+) AXLstaining on pretreatment biopsy, both with high-grade serous histology. The majority of serum AXL levels were within previously demonstrated ranges (range 5.6-112ng/mL), though two patients had comparatively high levels (102, 112ng/mL). PK/PD analysis revealed expected AVB-S6-500 levels at initial postdose (C1D1), but low levels at trough (C2D1 predose) when compared to prior AVB-S6-500 data [1]. Conclusions: The combination of AVB-S6-500 and durvalumab was tolerable in this PROC patient population at all dosing levels tested. Exploratory studies to correlate lack of response to AXL-GAS6 pathway alterations, tumor microenvironment, and clinical characteristics, such as prior treatment, dosing delays, burden of disease, and ascites, are ongoing.