Advanced hepatocellular carcinoma (aHCC) has a dire prognostic outlook, with an 18.4% five-year survival rate in non-metastatic and a 2% survival in metastatic disease. At the European Society of Medical Oncology (ESMO) Congress 2024, the results of the Phase III APOLLO trial, assessing the viability of an immunotherapy-tyrosine kinase inhibitor (IO-TKI) combination for treating aHCC in the first line were presented.
The study evaluated Chia Tai Tianqing Pharmaceutical’s Focus V (anlotinib) in combination with Akeso’s penpulimab. Focus V is a novel multi-kinase inhibitor that acts on vascular endothelial, fibroblast, and platelet-derived growth factor receptors effectively fulfilling a potent multirole in tumor angiogenesis, and penpulimab is a programmed cell death protein 1 (PD-1) checkpoint inhibitor. The study randomised 649 patients 2:1 to the Focus V plus penpulimab combination (n=423) or the long-established sorafenib (n=212). The progression-free survival (PFS) showed significant benefit with the Focus V arm, with a median PFS of 6.9 months compared to sorafenib’s 2.8 months (p<0.0001). Overall survival (OS) improved similarly to PFS in the Focus V treatment arm (16.5 vs 13.2 months; p=0.0012). The safety profile of the Focus V arm was manageable, with fewer treatment-related adverse events (TRAEs) compared to sorafenib.
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This news was well received at ESMO owing to the previous failure of the LEAP-002 trial, where Merck & Co’s Keytruda (pembrolizumab) could not prove clinically significant benefit in combination with levantinib.
Elevar Therapeutics’ PD-1 IO camrelizumab and TKI rivoceranib had clinical data presented in the Phase III CARES-310 trial, which enrolled 543 patients. Like Focus V and penpulimab, this IO-TKI combination was compared against sorafenib in first-line HCC. The trial demonstrated similar results to APOLLO, with the IO-TKI arm generating significant benefits to PFS (5.6 vs 3.7 months, p<0.0001) and OS (22.1 vs 15.2 months, p<0.0001). One area where Focus V and penpulimab seem to hold an edge is in their safety profile. There were fewer TRAEs when compared to sorafenib. This wasn’t seen with the camrelizumab and rivoceranib combination. Focus V and penpulimab are competitive IO-TKIs in the first-line landscape for treating aHCC and generally exhibit a well-tolerated safety profile.
Ultimately, the greatest competition lies outside of the IO-TKI domain. The field has seen Roche’s Tecentriq (atezolizumab) with bevacizumab rise as a first-line standard-of-care in the aHCC space. This approval was granted on the back of a Phase III trial that showed Tecentriq and bevacizumab combination significantly improved median PFS compared to sorafenib alone (6.8 vs. 4.3 months, p<0.001) and had a relatively indifferent safety profile.
GlobalData’s patient-based HCC forecast predicts Tecentriq sales will grow to $980m across the eight major markets (US, UK, Spain, Germany, Italy, France, China, and Japan) by 2029. While the Focus V and penpulimab combination is offering strong performance, it is not the first in the IO-TKI space to demonstrate tangible results and they will face great difficulty toppling Tecentriq from its current seat atop the aHCC first-line treatment paradigm.
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