Phase 2 study of AK104 (PD-1/CTLA-4 bispecific antibody) plus lenvatinib as first-line treatment of unresectable hepatocellular carcinoma.

Abstract

4101 Background: Anti–PD-(L)1 plus anti-CTLA-4 therapies (e.g. nivolumab/ipilimumab, tremelimumab/durvalumab) produce durable immune responses in patients (pts) with advanced hepatocellular carcinoma (HCC). More recent data suggests that the combination of immune checkpoint inhibitors (ICIs) with a multi-kinase inhibitor is efficacious against unresectable HCC (uHCC). AK104 is a humanized IgG1 bispecific antibody that simultaneously binds to PD-1 and CTLA-4. Early data suggests that AK104 possesses encouraging anti-tumor activity in selected tumour types and an improved safety profile compared to the co-administration of anti-PD-1 plus anti-CTLA-4 antibodies. Lenvatinib is a multi-kinase inhibitor and approved for first-line treatment of uHCC. Here, we report results from a phase 2 study of AK104 plus lenvatinib in pts with uHCC. Methods: In this single-arm, multicenter phase II study (NCT04444167), pts with uHCC, BCLC stage B or C, Child-Pugh class A, who had not previously received systemic treatment received AK104 (6 mg/kg IV q2w or 15 mg/kg IV q3w) and lenvatinib (8 mg [bodyweight < 60 kg] or 12 mg [weight ≥ 60 kg] PO QD). Primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints include disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: As of February 1 2021, 30 pts (86.7% male, median age 52.5yrs [31-71], 30% was ECOG 1, 93.3% was HBV+) had received the combination therapy of (AK104 6 mg/kg q2w plus lenvatinib). Of 18 pts evaluable for antitumor activity (defined as pts with the opportunity to be followed for at least 2 scans [≥13 weeks]), ORR per RECIST v1.1 was 44.4% (8/18), DCR was 77.8% (8 PRs and 6 SDs including 2 pts who had 28.4% and 29.2% reduction in tumor size from baseline). Median PFS has not been reached. Treatment-related adverse events (TRAEs) occurred in 83.3% of pts (G3 TRAEs occurred in 26.7% [8/30], and no G4 TRAEs or TRAEs leading to death). Most common TRAEs (≥15%) were increased AST (36.7%) and ALT (36.7%), decreased platelet count (33.3%), decreased neutrophil count (30.0%), and increased blood bilirubin (26.7%), with the vast majority being grades 1 or 2. Conclusions: AK104 plus lenvatinib as first-line therapy for uHCC has showed promising antitumor activity and an acceptable safety profile. Toxicities were manageable, with no unexpected safety signals. Enrollment for AK104 15 mg/kg q3w plus lenvatinib is currently ongoing, and longer follow-up is needed to further evaluate the durability of response. Clinical trial information: NCT04444167.