Safety and efficacy of combination of GT90001, an anti-activin receptor-like kinase-1 (ALK-1) antibody, and nivolumab in patients with metastatic hepatocellular carcinoma (HCC).

Abstract

326 Background: GT90001, a fully human anti-ALK-1 mAb (IgG2) that may inhibit ALK-1/ TGF-β signaling and tumor angiogenesis, has shown good single-agent safety profile in humans. This study aimed to assess the safety and efficacy of GT90001 in combination with nivolumab in patients with advanced HCC who had progressive disease after or were intolerant to first-line sorafenib or lenvatinib therapy (NCT03893695). Methods: We did a phase I/II, open-label, single arm, dose de-escalation and expansion trial of GT90001 in combination with nivolumab in patients with histologically or cytologically confirmed HCC with Child-Pugh class A, ECOG performance status of 0 or 1 at three sites in Taiwan. Patients previously treated with immune checkpoint inhibitors were excluded. Stage 1 (dose de-escalation cohort) tested 3 doses of GT90001 (7 (starting dose), 4.5, and 3 mg/kg every 2 weeks) plus nivolumab 3 mg/kg every 2 weeks in 6 subjects at each dose level. Dose-limiting toxicity (DLT) was defined as any treatment-emergent grade 3-4 adverse events (AEs) (CTCAE V5.0) in the first 28 days of treatment. Stage 2 (expansion cohort) tested the combination regimen in 14 patients until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was investigator-assessed objective response as per RECIST v1.1. Results: Between July 9th, 2019 and June 26th, 2020, twenty eligible patients were treated. No DLT was observed in stage 1, and GT90001 7.0 mg/kg + nivolumab 3.0 mg/kg every 2 weeks were given in stage 2. The pharmacokinetics of GT90001 and nivolumab were similar to those observed in monotherapy. As of June 26, 2020, 20 patients were evaluable for safety. The common AEs (occurring to more than 20%) included platelet count decreased, rash, fatigue, dizziness, peripheral edema, and constipation. Three patients had treatment-related serious AEs (renal dysfunction, autoimmune hepatitis, hyperamylasemia). Nine patients had GT90001 dose interruption due to AEs and the most common reasons were platelet count decrease (3 patients). No patient discontinued the treatment due to AEs. The median duration of follow-up was 3.7 months (range 0.6-11.1). An objective response assessed was observed in 7 patients (43.75%) out of 16 evaluable patients, all were partial response and 4 of them had confirmed responses. The disease control rate (complete response + partial response + stable disease) was 56.2%. Updated efficacy data will be presented at the congress. Conclusions: The combination of GT90001 with nivolumab showed a manageable safety profile, and no new safety signals were identified. The promising preliminary antitumor activities show the potential of GT90001 combined with nivolumab as second-line treatment for advanced HCC. Clinical trial information: NCT03893695.