Anlotinib/Penpulimab Enhances Survival vs Sorafenib in Unresectable HCC

The objective response rate in the anlotinib/penpulimab group was 21% vs 7% in the sorafenib group, and the disease control rate in respective groups was 73% vs 56%.

The combination of anlotinib with penpulimab-kcpx (Anike) elicited a significant improvement in overall survival (OS) and progression-free survival (PFS) outcomes vs sorafenib (Nexavar) as a frontline therapy in Chinese patients with unresectable hepatocellular carcinoma (HCC), according to results from the open-label, parallel-controlled, phase 3 APOLLO trial (NCT04344158) published in Lancet Oncology.¹

Efficacy results revealed that the median PFS by independent review committee (IRC) in the combination and control cohorts, respectively, was 6.9 months (95% CI, 5.8-8.0) vs 2.8 months (95% CI, 2.7-4.1; stratified HR, 0.52; 95% CI, 0.41-0.66; P <.0001). Furthermore, as of the data cut-off date of June 5, 2023, 47% of the anlotinib/penpulimab group and 54% of the sorafenib group had experienced disease progression or death, with 12-month PFS estimated rates of 27.4% (95% CI, 21.3%-33.9%) and 17.8% (95% CI, 10.8%-26.2%), respectively. Per investigator analysis, a PFS benefit was observed with the combination therapy per RECIST v1.1 criteria (HR, 0.57; 95% CI, 0.45-0.72; P <.0001).

Additionally, a second interim analysis for OS with a data cut-off date of January 29, 2024, revealed that the median OS was 16.5 months (95% CI, 14.7-19.0) in the investigational arm and 13.2 months (95% CI, 9.7-16.9) with sorafenib (stratified HR, 0.69; 95% CI, 0.55-0.87; P = .0014).

In respective arms, post-hoc 18- and 24-month OS rates were 47.0% (95% CI, 41.1%-52.6%) vs 37.6% (95% CI, 29.4%-45.8%) and 37.5% (95% CI, 31.2%-43.7%) vs 25.7% (95% CI, 17.7%-34.6%). A total of 50% of the anlotinib/penpulimab group and 56% of the sorafenib group had died as of data cut-off.

The objective response rate (ORR) in the anlotinib/penpulimab group was 21% (95% CI, 17%-25%) vs 7% (95% CI, 4%-12%) in the sorafenib group (P <.0001). The disease control rate (DCR) in respective groups was 73% (95% CI, 68%-77%) vs 56% (95% CI, 49%-62%; P <.0001).

“Survival benefits in terms of both [OS and PFS] were observed across most post-hoc subgroups and were particularly apparent in those with high-risk disease features, such as macrovascular invasion, extrahepatic metastasis, α-fetoprotein of at least 400 ng/mL, and Barcelona Clinic Liver Cancer [BCLC] stage C disease, which are associated with a poorer prognosis,” primary investigator Jian Zhou, MD, professor in the Department of Hepatobilary Surgery and Liver Transplantation at Zhongshan Hospital, Fudan University in Shanghai, China, wrote in the publication with study coinvestigators. “Anlotinib plus penpulimab improved efficacy without appearing to increase the risk of grade 3 or worse treatment-related adverse [effects (AEs) and] did not lead to more dose reduction or interruptions compared with sorafenib, with a minimal effect on treatment exposure.”

Investigators in the phase 3 trial randomly assigned patients aged 18 to 75 with unresectable HCC 2:1 to receive anlotinib plus penpulimab (n = 433) or sorafenib (n = 216). Patients in the investigational arm received 10 mg of once daily oral anlotinib on days 1 to 14 and 200 mg of intravenous penpulimab on day 1 of 21-day cycles. Sorafenib was given orally twice daily at 400 mg. Treatment persisted until unacceptable toxicity, confirmed disease progression, consent withdrawal, or other discontinuation criteria defined per protocol.

Among those in the combination and comparator arms, respectively, the median age was 57 years (IQR, 50-65) vs 56 years (IQR, 50-65), 86% vs 83% were male, and 57% vs 56% had an ECOG performance status of 0. In each respective group, 82% vs 81% had BCLC stage C disease, 92% vs 93% had a Child-Hugh score of A, and 84% each had Hepatitis B-positive disease etiology.

Macrovascular invasion or extrahepatic metastases was observed in 80% of each arm, with 23% of the combination arm and 24% of the comparator arm experiencing both. A total of 57% vs 52% of the anlotinib/penpulimab and sorafenib groups, respectively, received local treatment for HCC, including interventional therapy (35% vs 32%), surgery (27% vs 25%), and ablation (12% each). A total of 70% vs 67% of respective arms had lesions localized to one organ site, with 6% vs 4% having target lesions at 3 or more organ sites.

The co-primary end points of the study were OS and PFS assessed by IRC per RECIST v1.1 criteria. Secondary end points included ORR, DCR, duration of response, and safety.

Any-grade treatment-emergent AEs (TEAEs) occurred in 99% of the combination arm and 99% of the sorafenib-only arm. Grade 3 or higher TEAEs occurred in 59% vs 55% of respective groups. TEAEs leading to dose reductions, interruptions, and discontinuations, respectively, occurred in 20% vs 32%, 46% vs 39%, and 9% vs 4% of respective groups. Serious treatment-related AEs occurred in 21% and 9% of each arm, and TEAEs leading to death occurred in 5% each.

Reference

Zhou J, Luo J, Bai Y, et al. Anlotinib plus penpulimab versus sorafenib in the first-line treatment of unresectable hepatocellular carcinoma (APOLLO): a randomised, controlled, phase 3 trial. Lancet Oncol. Published online May 8, 2025. doi:10.1016/S1470-2045(25)00190-1