Results of a dose-escalation phase 1 study indicated that AVB-500 is well-tolerated in combination with paclitaxel or pegylated liposomal doxorubicin, with higher antitumor activity seen in combination with paclitaxel, and no previous exposure to bevacizumab.
This phase 1 study (NCT03639246) evaluated the safety, tolerability, and preliminary efficacy of the first-in-class GAS6/AXL inhibitor, AVB-500, in combination with pegylated liposomal doxorubicin (PLD) or paclitaxel and determined the recommended phase 2 dose (RP2D) in patients with platinum-resistant high-grade serous ovarian cancer. The results of this trial were presented at the 2021 American Society of Clinical Oncology Annual Meeting.
The study enrolled patients with recurrent, platinum-resistant, high-grade serous ovarian cancer, Eastern Cooperative Oncology Group performance status 0-1, and 1 to 3 previous lines of therapy. Eligible patients were enrolled in cohorts with escalating doses of AVB-500 (from 10-20 mg/kg every 2 weeks) in combination with weekly paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days) or PLD (40 mg/m2 on day 1, every 28 days). The study evaluated safety and tolerability, efficacy, RP2D, pharmacokinetics, and pharmacodynamics.
A total of 53 patients were enrolled; of these, 23 patients received paclitaxel plus AVB-500, and 30 patients received PLD plus AVB-500. Grade 3 or 4 treatment-related adverse events were observed in 17% of patients who received paclitaxel and 7% of those who received PLD. No treatment discontinuations caused by adverse events were reported. Adverse events were mostly related to known side-effect profiles of paclitaxel and PLD. The RP2D was identified as 15 mg/kg.
Higher objective response rates (ORRs) were achieved in the paclitaxel-treated subgroup compared with the PLD cohort. Paclitaxel plus AVB-500 yielded an ORR of 35%, including 2 complete responses; whereas PLD plus AVB-500 yielded an ORR of 11%. The ORR was 19% in patients with a platinum-free interval (PFI) of <3 months versus 23% in patients with a PFI of 3 to 6 months. Moreover, the ORR was 11% (2/18) in patients with 1 previous treatment versus 27% (9/33) in patients with 2 to 3 previous lines of therapy. A higher ORR of 33% (9/27) was achieved in patients who had not been exposed to bevacizumab versus 8% (2/24) in those with previous exposure to bevacizumab. Higher efficacy outcomes were achieved in the paclitaxel combination cohort, in which AVB-500 trough levels were above the minimal efficacious concentration (MEC) of 13.8 mg/L, compared with those with trough levels below MEC in terms of ORR (43% [6/14] vs 22% [2/9]), median progression-free survival (3.9 months vs 2.8 months), and median overall survival (17.8 months vs 8.7 months).
Based on these results, the investigators concluded that AVB-500 was well-tolerated in combination with paclitaxel or PLD, with higher response rates seen in combination with paclitaxel, and trough levels >13.8 mg/L, in patients with no previous exposure to bevacizumab.
Source: Fuh KC, Bookman MA, Coleman RL, et al. Phase 1b study of GAS6/AXL inhibitor (AVB-500) in recurrent, platinum-resistant ovarian carcinoma. J Clin Oncol. 2021;39(suppl_15). Abstract 5566.