China’s NMPA Accepts sNDA for Penpulimab Plus Anlotinib for Advanced HCC

China's National Medical Products Administration (NMPA) has accepted a supplemental new drug application (sNDA) seeking the approval of penpulimab (formerly AK105) in combination with anlotinib (AL3818) for the first-line treatment of patients with advanced hepatocellular carcinoma (HCC).¹

The sNDA is supported by data from the phase 3 APOLLO/ALTN-AK105-III-02 study (NCT04344158). Findings from the multicenter, randomized, open-label, parallel-controlled trial shared at the 2024 ESMO Congress demonstrated that patients treated with anlotinib plus penpulimab (n = 433) experienced a median progression-free survival (PFS) of 6.9 months (95% CI, 5.7-8.0) compared with 2.8 months (95% CI, 2.7-4.1) for those given sorafenib (Nexavar) monotherapy (n = 216; HR, 0.53; 96% CI, 0.41-0.68; P < .0001).²

The median overall survival (OS) was 16.5 months (95% CI, 14.7-19.7) vs 13.2 months (95% CI, 9.7-16.9) for penpulimab plus anlotinib and sorafenib, respectively (HR, 0.69; 98.8% CI, 0.52-0.92; P = .0012).

Investigators enrolled patients with histologically confirmed HCC who were classified as Child-Pugh class A or B (≤ 7). Eligible patients also needed to have Barcelona Clinic Liver Cancer stage B (unsuitable for radical surgery and/or locoregional treatment) or C disease; an ECOG performance status of 0 or 1; and at least 1 measurable lesion per RECIST 1.1 criteria. No prior systemic therapy was permitted.

Investigators randomly assigned patients 2:1 to receive oral anlotinib at 10 mg once per day on days 1 through 14 of each 21-day cycle and 200 mg of intravenous penpulimab once every 3 weeks; or oral sorafenib at 400 mg twice per day.

The trial’s dual primary end points included PFS per independent review committee assessment and OS; secondary end points were PFS by investigator assessment, overall response rate, disease control rate, duration of response, and safety/tolerability.

Regarding safety, the combination was tolerable and manageable. The median duration of exposure for both anlotinib and penpulimab was 10.0 cycles (interquartile range [IQR], 4.0-16.0), and the median duration of exposure was 4.0 cycles (IQR, 2.0-8.0) for sorafenib. Any-grade treatment-emergent adverse effects (TEAEs) were reported in 98.8% of patients in the combination arm vs 98.6% of patients in the control arm; the rates of grade 3 or higher TEAEs were 58.6% and 54.5%, respectively.

Treatment-related AEs (TRAEs) occurred in 96.5% of patients in the experimental arm and 94.8% of patients in the control arm; the respective rates of grade 3 or higher TRAEs were 48.2% and 47.4%. The rates of serious TRAEs were 20.4% for the combination and 9.0% for sorafenib.

TEAEs led to dose reductions of anlotinib in 16.2% of patients and sorafenib in 29.9% of patients. TEAEs led to dose interruptions of penpulimab in 34.0% of patients, anlotinib in 43.8% of patients, and sorafenib in 38.9% of patients. The rates of TEAEs leading to treatment discontinuation were 6.7% for both anlotinib and penpulimab compared with 4.3% for sorafenib.

The most common any-grade TRAEs reported in at least 20% of patients included hypertension (penpulimab/anlotinib, 44.0%; sorafenib, 37.4%), decreased platelet count (37.5%; 32.2%), increased aspartate aminotransferase level (34.5%; 34.6%), increased blood bilirubin level (31.0%; 28.0%), decreased white blood cell count (27.8%; 18.5%), increased alanine aminotransferase level (27.3%; 22.8%), decreased neutrophil count (19.0%; 12.3%), and palmar-plantar erythrodysesthesia (18.8%; 32.2%).

Per investigator assessment, any-grade immune-mediated AEs reported in the anlotinib plus penpulimab arm included pneumonitis (0.9%), enterocolitis (0.5%), hepatitis (0.5%), hypothyroidism (0.2%), myositis (0.2%), and neuropathy (0.2%). No instances of immune-mediated myocarditis were reported.

References

1. Akeso's penpulimab combination therapy for first-line treatment of hepatocellular carcinoma accepted by NMPA. Akeso. News release. November 22, 2024. Accessed November 25, 2024. https://akesobio.com/en/media/akeso-news/akesos-penpulimab-combination-therapy-for-first-line-treatment-of-hepatocellular-carcinoma-accepted-by-nmpa/
2. Zhou J, Fan J, Jiao S, et al. Primary results from the phase III ALTN-AK105-III-02 study: Anlotinib plus penpulimab versus sorafenib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2024;35(suppl 2):S1231. doi:10.1016/j.annonc.2024.08.2280