The National Medical Products Administration (NMPA) of China has accepted a supplemental new drug application (sNDA) for penpulimab (formerly AK105) in combination with anlotinib (AL3818) for the first-line treatment of patients with advanced hepatocellular carcinoma (HCC). This regulatory milestone is based on data from the phase 3 APOLLO/ALTN-AK105-III-02 study, demonstrating significant improvements in both progression-free survival (PFS) and overall survival (OS) compared to sorafenib monotherapy. The acceptance marks penpulimab’s fifth indication in China.
APOLLO/ALTN-AK105-III-02 Study Results
The multicenter, randomized, open-label, parallel-controlled phase 3 trial (NCT04344158) compared the combination of anlotinib plus penpulimab (n = 433) to sorafenib monotherapy (n = 216) in patients with advanced HCC. The results, presented at the 2024 ESMO Congress, showed a median PFS of 6.9 months (95% CI, 5.7-8.0) in the combination arm compared to 2.8 months (95% CI, 2.7-4.1) in the sorafenib arm (HR, 0.53; 96% CI, 0.41-0.68; P < .0001). The median OS was 16.5 months (95% CI, 14.7-19.7) for the combination versus 13.2 months (95% CI, 9.7-16.9) for sorafenib (HR, 0.69; 98.8% CI, 0.52-0.92; P = .0012).
Study Design and Patient Population
Eligible patients had histologically confirmed HCC, classified as Child-Pugh class A or B (≤ 7), 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. Prior systemic therapy was not permitted. Patients were randomized 2:1 to receive oral anlotinib at 10 mg once daily on days 1-14 of each 21-day cycle and 200 mg of intravenous penpulimab once every 3 weeks, or oral sorafenib at 400 mg twice daily.
The dual primary endpoints were PFS per independent review committee assessment and OS. Secondary endpoints included PFS by investigator assessment, overall response rate, disease control rate, duration of response, and safety/tolerability.
Safety and Tolerability
The combination of penpulimab and anlotinib was generally tolerable and manageable. The median duration of exposure for both anlotinib and penpulimab was 10.0 cycles (IQR, 4.0-16.0), while it was 4.0 cycles (IQR, 2.0-8.0) for sorafenib. Any-grade treatment-emergent adverse events (TEAEs) were reported in 98.8% of patients in the combination arm and 98.6% in the sorafenib arm; grade 3 or higher TEAEs occurred in 58.6% and 54.5%, respectively.
Treatment-related AEs (TRAEs) occurred in 96.5% of patients receiving the combination and 94.8% receiving sorafenib; grade 3 or higher TRAEs occurred in 48.2% and 47.4%, respectively. Serious TRAEs were reported in 20.4% of patients on the combination and 9.0% on 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%), and increased aspartate aminotransferase level (34.5%; 34.6%).
