Abstract IA012: Targeting AXL in platinum-resistant ovarian cancer: from the lab bench to Phase 3 trial
Authors: Katherine Fuh
Journal: Cancer Research (2024)

Abstract The receptor tyrosine kinase AXL was first isolated in 1988 in a screen for transforming genes in CML and later characterized in 1991 as an overexpressed, transforming cDNA in AML. AXL has been identified as a promising therapeutic target based on diverse functions in cancer cells and immune cells. AXL has an amino acid sequence within its intracellular tyrosine kinase domain that shares close homology to RET, FGFR, EGFR, and PDGFR. The main ligand of AXL is GAS6. AXL is frequently overexpressed in many tumor types, even though genetic mutation and amplification events are relatively rare. This suggests a significant role for post-transcriptional regulation of AXL expression. We found that AXL was highly expressed in 60% of high-grade serous ovarian and FT primary tumors and in over 50% of metastatic omentum and peritoneal tumors. We initially identified AXL as a critical mediator of metastasis (Rankin 2010) and subsequently demonstrated that therapeutic inhibition of AXL improved sensitivity to platinum and taxane in ovarian cancer (Quinn 2018). We identified that 41% of chemoresistant tumors had high AXL expression at baseline. We also found that genetic and therapeutic inhibition of AXL through a tyrosine kinase inhibitor led to improved sensitivity to paclitaxel and carboplatin in preclinical models through increased uptake of paclitaxel in AXL inhibitor treated tumor cells. A novel engineered Axl decoy receptor was developed to bind Gas6 with femtomolar affinity by 80-fold (Kariolis 2014). These preclinical findings led to a Phase 1b trial of AVB-500 (a high affinity soluble decoy AXL receptor) every 2 weeks in combination with weekly paclitaxel (n=23) or pegylated liposomal doxorubicin (n=30) q28 days in platinum-resistant, recurrent ovarian cancer (Dec 2018-April 2020). PK was measured by serum AVB-500 levels, and PD determined by serum GAS6 levels. There was an objective response rate (ORR) of 34.8% including 2 complete responses. AVB-500 dose levels completely suppressed GAS6 to below the level of quantitation on C1D15. An exploratory, exposure-response analysis was conducted using the 10mg/kg cohort. This identified that a higher AVB-500 trough level at C1D15 was associated with longer PFS, which defined a model-based, minimally efficacious concentration (MEC) of AVB-500 of 13.8mg/L. Higher clinical activity was seen in patients who had a C1D15 above the MEC. This Phase 1b trial was performed using a model-informed drug development (MIDD) approach to inform the RP2D. Based on these results, GOG 3059/ENGOT OV-66: AXLerate-OC Phase 3, international, randomized, double blinded, placebo-controlled trial in platinum-resistant ovarian cancer comparing weekly paclitaxel vs weekly paclitaxel + batiraxcept (formerly AVB-500) was initiated. There were 366 patients enrolled between 4/2021-12/2022. Topline data was announced on 8/2/2023 that the median PFS in batiraxcept plus paclitaxel arm was 5.1 months compared to 5.5 months in the paclitaxel arm with no statistically significant difference. Further translational work is ongoing. Citation Format: Katherine Fuh. Targeting AXL in platinum-resistant ovarian cancer: from the lab bench to Phase 3 trial [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA012.