AVB-500/Paclitaxel Demonstrates Clinical Benefit in Platinum-Resistant Ovarian Cancer

Author(s):

The GAS6/AXL inhibitor AVB-500, when combined with paclitaxel, elicited clinical benefit with favorable tolerability in patients with platinum-resistant ovarian cancer, according to data from a phase 1b study.

Katherine Fuh, MD, PhD

Among patients treated with the combination, the objective response rate (ORR) was 36.8% for the entire cohort (n = 19). Patients who had AVB-500 trough levels above minimal efficacious concentration (MEC; n = 10) experienced an even higher ORR of 50.0% with the combination, while those with no prior exposure to bevacizumab (Avastin; n = 9) reported the highest ORR of 66.7%. Additionally, investigators noted that the proprietary serum soluble AXL/GAS6 ratio may be able to determine patients who will best respond to treatment.

When the ligand GAS6 binds to the receptor tyrosine kinase AXL, it can lead to therapy resistance and induce the epithelial mesenchymal transition, lead study author Katherine Fuh, MD, PhD, assistant professor in Obstetrics and Gynecology at the Washington University School of Medicine and surgeon in Gynecologic Oncology at Siteman Cancer Center, said during a presentation on the data from the early-phase research.

AXL activation can then lead to cell proliferation, cell motility, and cell survival. Additionally, it has been shown that chemotherapy-resistant tumors have higher AXL expression by immunohistochemistry than tumors that are sensitive to chemotherapy, and tumors with no recurrence, Fuh added. Moreover, high AXL expression is known to be associated with poor progression-free survival (PFS) and poor overall survival (OS).

“We found that increased AXL expression is associated with increased RNA expression of drug resistance transporters ABCA3 and ABCB9,” Fuh said. “This is associated with patients who are alive with disease or dead [from] disease, compared with those who have no evidence of disease. We also found that inactivation of AXL leads to increased accumulation of paclitaxel, which is one of the mechanisms for how inhibition of AXL improves sensitivity to paclitaxel.”

AVD-500 is a novel, high-affinity, AXL decoy protein that binds GAS6 and inhibits GAS6/AXL signaling. The decoy receptor was designed to have very high affinity for GAS6 by utilizing a protein engineering strategy, which resulted in a 200-fold greater affinity than native AXL. AVB-500 has also demonstrated a favorable safety profile in a normal healthy volunteer study.^2,3 As such, this phase 1b trial is the second trial examining AVB-500, according to Fuh.

To be eligible for enrollment, patients had to have high-grade serous ovarian cancer (HGSOC), endometrioid cancer, or undifferentiated adenocarcinoma that was resistant to platinum. Additionally, participants had to have received 1 to 3 prior lines of therapy and have an ECOG performance status of 0 or 1.

Study participants were treated with AVD-500 plus paclitaxel at doses of 10 mg/kg (n = 16), 15 mg/kg (n = 3), or 20 mg/kg (n = 4) or AVD-500 with pegylated liposomal doxorubicin (PLD) at the same doses of 10 mg/kg (n = 24), 15 mg/kg (n = 3), or 20 mg/kg (n = 3). Overall, 53 patients were enrolled to the study; of these patients, 23 were in the paclitaxel cohort and 30 in the PLD cohort.

The mean age of study participants was 64 years, a majority were White (96%), and most patients had HGSOC (83%). In the paclitaxel cohort, 56% of patients (n = 13) had received prior treatment with bevacizumab compared with 40% of patients (n = 12) in the PLD cohort. Additionally, patients in the paclitaxel cohort had more prognostic factors, Fuh noted.

Clinical activity with AVB-500 in the paclitaxel cohort appeared higher compared with the PLD cohort, despite the higher rate of poor prognostic factors in that group, noted Fuh. When evaluating the 10-mg/kg and 15-mg/kg cohorts within the paclitaxel group collectively, results showed 2 complete responses (CR; 10.5%) and 5 partial responses (PR; 26.3%). In the PLD group, when evaluating both dosing cohorts collectively, no CRs were observed, but there were 4 PRs (16.0%).

Additionally, within the paclitaxel group, the clinical benefit rate (CBR) in those given the 10-mg/kg dose was 62.5%, while it was 100.0% in those who received the 15 mg/kg dose. The overall CBR was 68.4% in this cohort. Within the PLD group, the CBRs in the 10 mg/kg and 15 mg/kg subsets were 56.5% and 100.0%, respectively. The overall CBR was 60.0% in this cohort.

Within the paclitaxel cohort, the median PFS in those who received the 10 mg/kg dose was 3.0 months (95% CI, 1.8-7.3), while it was 6.5 months (95% CI, 3.6–not determined [ND]) in those who received the 15 mg/kg dose. The median PFS across doses in this cohort was 3.6 months (95% CI, 1.8-7.3). In the PLD cohort, the median PFS was 3.6 months (95% CI, 1.7-5.0) and 3.8 months (ND-ND) in the 10-mg/kg and 15-mg/kg subsets, respectively. The median PFS in this cohort was also 3.6 months (95% CI, 1.8-5.0).

In the paclitaxel cohort, the median OS was 10.3 months (95% CI, 6.7-19.3) in those who received the 10 mg/kg dose, while it was not reached in those given the 15 mg/kg dose. Overall, the median OS in this cohort was 14.1 months (95% CI, 8.1-19.3). In the PLD cohort, the median OS in those who received the 10 mg/kg dose was 12.7 months (95% CI, 10.2-15.6), while it was 7.6 months (95% CI, 6.0-9.1) in those who received the 15 mg/kg dose. Overall, the median OS was 12.6 months (95% CI, 9.1-14.2) in this cohort.

When evaluating the pharmacokinetics with AVB-500 trough levels drawn before day 15 of cycle 1, the MEC was defined with a trough level of 13.8 mg/L, according to Fuh. For patients treated with 10 mg/kg and 15 mg/kg dosing, the clinical activity correlated with AVB-500 trough levels above MEC. In patients with AVB-500 trough levels above MEC, the median PFS was 7.5 months (95% CI, 1.8-9.3) and the median OS was 19 months (95% CI, 8.1-ND).

“These data led to the recommended phase 2 dose of 15 mg/kg, given this was the primary objective of the trial,” Fuh said.

Clinical responses were also correlated with prior exposure to bevacizumab in the paclitaxel cohort. The patients who had not previously received bevacizumab experienced a CBR of 77.8% vs 60% in those who had. The median PFS was longer in those who did not receive prior bevacizumab vs those who did, at 7.7 months (95% CI, 1.7-9.3) vs 2.8 months (95% CI, 1.8-5.5), respectively, as was the median OS, at 19.3 months (95% CI, 6.7-ND) and 9.2 months (95% CI, 2.3-17.8), respectively.

Baseline serum soluble AXL/GAS6 was also found to correlate with clinical response in the study. Serum AXL/GAS6 ratio remains a significant predictor of RECIST response in the study sample, according to Fuh, and patients with AXL/GAS6 ratios above 0.773 were more likely to have achieved a response with a calculated sensitivity of 100% and a specificity of 60%.

In terms of safety, the majority of patients in both cohorts experienced at least 1 treatment-emergent adverse effect (TEAE). The most common TEAEs reported in the paclitaxel cohort included fatigue (26.1%), infusion-related reaction (21.7%), anemia (21.7%) and nausea (13%).

In the phase 3 GOG 3059/ENGOT OV66 trial, investigators will compare weekly AVB-500 in combination with paclitaxel vs weekly paclitaxel alone. The trial is anticipated to begin enrollment in Q1 2021.

References

Fuh K, Bookman M, Coleman R, et al. Phase I study of GAS6/AXL inhibitor (AVB-500) in recurrent, platinum resistant ovarian carcinoma. Presented at: Society of Gynecological Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-21, 2021. Accessed March 22, 2021.
Kariolis MS, Miao YR, Jones DS, et al. An engineered Axl ‘decoy receptor’ effectively silences the Gas6-Axl signaling axis. Nat Chem Biol. 2014;10(11):977-983. doi:10.1038/nchembio.1636
Kariolis MS, Miao YR, Diep A, et al. Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies. J Clin Invest. 2017;127(1):183-198. doi:10.1172/JCI85610