The phase 3 APOLLO trial represents an important step forward in expanding therapeutic options for patients with unresectable hepatocellular carcinoma (HCC). This randomized study demonstrated that the combination of anlotinib, a multi-target tyrosine kinase inhibitor (TKI), and penpulimab, a programmed-cell death 1 (PD-1) inhibitor, significantly improved both overall survival (OS) and progression-free survival (PFS) compared with sorafenib, thereby meeting its co-primary endpoints (1). These results provide compelling new evidence supporting the efficacy and tolerability of a novel immune checkpoint inhibitor (ICI)-TKI combination regimen in the first-line setting.
A notable strength of the APOLLO trial lies in its patient population, which included a higher proportion of individuals with adverse prognostic features compared with previous landmark studies (Table 1) (2-4). Nearly half of the participants had α-fetoprotein concentrations ≥400 ng/mL, and approximately 80% presented with macrovascular invasion or extrahepatic metastases. Furthermore, 8% of patients had Child-Pugh class B liver function, a subgroup typically underrepresented in pivotal phase 3 trials. Remarkably, the combination of anlotinib plus penpulimab yielded consistent efficacy across these high-risk subgroups, underscoring the robustness of the therapeutic effect. Nevertheless, the exclusion of patients with Vp4 portal vein invasion warrants consideration when extrapolating these results to the broader HCC population.
Table 1. Patient characteristics of key phase III trials in advanced hepatocellular carcinoma.
| Characteristics | APOLLO (1) | HIMALAYA (2) | CheckMate 9DW (3) | IMbrave150 (4) |
|---|---|---|---|---|
| Investigational regimen | Anlotinib + penpulimab (n=432) | Tremelimumab + durvalumab (n=393) | Nivolumab + ipilimumab (n=335) | Atezolizumab + bevacizumab (n=336) |
| Comparator | Sorafenib (n=211) | Sorafenib (n=389) | Lenvatinib or sorafenib (n=333) | Sorafenib (n=165) |
| Alpha-fetoprotein ≥400 ng/mL (%) | 49 | 37 | 32 | 38 |
| Extrahepatic spread (%) | 62 | 53 | 56 | 63 |
| Macrovascular invasion (%) | 41 | 26 | 23 | 38 |
| Child-Pugh grade B (%) | 8 | 1 | 3 | 0 |
| BCLC A/B/C (%) | 0/18/82 | 0/20/80 | 8/18/73 | 2/15/82 |
BCLC, Barcelona Clinic Liver Cancer.
From a geographical and etiological perspective, the APOLLO trial exclusively enrolled Chinese patients, the majority of whom had hepatitis B virus (HBV)-related HCC. While this reflects the predominant etiology in East Asia, it limits the generalizability of the findings to regions where hepatitis C virus (HCV) infection, metabolic dysfunction-associated fatty liver disease (MAFLD), or alcohol-related liver disease are more common. The choice of sorafenib as the comparator arm was appropriate given the study’s initiation timeline; however, when interpreting the magnitude of benefit, one should consider that lenvatinib—a more potent TKI—was the control treatment in more recent trials such as CheckMate 9DW. Accordingly, cross-trial comparisons should be interpreted with caution, and direct comparative data against newer standards of care will be critical to contextualizing the efficacy of the anlotinib-penpulimab regimen.
The safety profile of the combination was favorable and consistent with expectations for an antiangiogenic agent combined with an ICI. Despite dual therapy, the incidence of grade ≥3 treatment-related adverse events (50%) was similar to that observed with sorafenib (48%) and within the range reported in other first-line ICI combination studies. Notably, penpulimab was designed with an IgG1 constant region engineered to reduce Fc receptor binding and thereby minimize immune-related adverse events (irAEs). The incidence of irAEs was 24% for any grade and 6% for grade 3 or higher. However, comparisons of adverse event profiles across trials enrolling patients from different geographic regions and with distinct baseline characteristics should be made cautiously. In the IMbrave150 trial, adverse events were categorized as atezolizumab-related or bevacizumab-related, and therefore are not strictly limited to irAEs. When interpreted in this context, the incidence of irAEs observed in the APOLLO trial appears relatively low (5).
From a clinical standpoint, the efficacy of ICI-TKI combinations in advanced HCC has been heterogeneous across phase 3 trials. While some regimens, such as pembrolizumab plus lenvatinib (LEAP-002) and atezolizumab plus cabozantinib (COSMIC-312), did not demonstrate a significant OS benefit, others, including camrelizumab plus rivoceranib, showed positive results. In this context, the APOLLO trial adds to the evolving evidence supporting selected ICI-TKI strategies (Table 2). The predominantly Asian study population also highlights the need for validation in more diverse populations.
Table 2. Phase III trials in advanced HCC comparing combination therapy (anti-PD-1/anti-PD-L1) plus anti-CTLA-4 or anti-angiogenic therapy versus TKI.
| Trial characteristics | Positive trials | CARES-310 (NCT03764293) | HEPATORCH NCT04723004 | Negative trials | |||||
|---|---|---|---|---|---|---|---|---|---|
| IMbrave150 (NCT03434379) | HIMALAYA (NCT03298451) | CheckMate 9DW (NCT04039607) | APOLLO (NCT04344158) | ORIENT 32 (NCT03794440) | COSMIC-312 (NCT03755791) | LEAP-002 (NCT03713593) | |||
| Agents | Atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGFA) vs. sorafenib (MKI) (n=501) | Tremelimumab (anti-CTLA-4) plus durvalumab (anti-PD-L1) (STRIDE regimen) vs. sorafenib (MKI) vs. durvalumab (anti-PD-L1) (n=1,171) | Nivolumab + ipilimumab vs. lenvatinib (MKI) 85% vs. sorafenib (MKI) (n=668) | Anlotinib (MKI) + penpulimab (anti-PD-1) vs. sorafenib (MKI) (n=649) | Sintilimab (anti-PD-1) + bevacizumab biosimilar (IBI305) vs. sorafenib (MKI) (n=595) | Camrelizumab (anti-PD-1) + VEGFR2-targeted TKI rivoceranib (apatinib) vs. sorafenib (MKI) (n=543) | Toripalimab (anti-PD-1) + bevacizumab vs. sorafenib (MKI) (n=326) | Cabozantinib (MKI) plus atezolizumab (anti-PD-L1) vs. sorafenib (MKI) vs. cabozantinib (MKI) (n=837) | Lenvatinib (MKI) plus pembrolizumab (anti-PD-1) vs. lenvatinib (MKI) (n=794) |
| Population | HBV: 49% | HBV: 31% | HBV: 34% | HBV: 84% | HBV: 94% | HBV: 76% | – | HBV: 30% | HBV: 48.6% |
| HCV: 21% | HCV: 28% | HCV: 27% | HCV: 4% | HCV: 8% | HCV: 28% | HCV: 23.8% | |||
| Non-viral: 30% | Non-viral: 41% | Non-viral: 42% | Non-viral: 30% | ||||||
| CP-A: 100% | CP-A: 100% | CP-5-6: 97% | CP-A: 92% | CP-A: 96% | CP-A: 100% | CP-A: 100% | CP-A: 100% | ||
| PS 0/1: 100% | PS 0/1: 100% | PS 0/1: 100% | PS 0/1: 100% | PS 0/1: 100% | PS 0/1: 100% | PS 0/1: 100% | PS 0/1: 100% | ||
| BCLC B/C: 15%/82% | BCLC B/C: 19.6%/80.4% | BCLC B/C: 18%/73% | BCLC B/C: 18%/82% | BCLC B/C: 15%/85% | BCLC B/C: 14%/86% | BCLC B/C: 33%/67% | BCLC B/C: 21.5%/78.5% | ||
| MVI: 38% | MVI: 26% | MVI: 23% | MVI: 41% | MVI: 28% | MVI: 15% | MVI: 34% | MVI: 18% | ||
| ES: 63% | ES: 53% | ES: 56% | ES: 62% | ES: 73% | ES: 64% | ES: 54% | ES: 63% | ||
| AFP >400 ng/mL: 38% | AFP >400 ng/mL: 37% | AFP >400 ng/mL: 32% | AFP >400 ng/mL: 49% | AFP >400 ng/mL: 43% | AFP >400 ng/mL: 35% | AFP >400 ng/mL: 34% | AFP >400 ng/mL: 30% | ||
| Overall survival | [ATZ + BVZ] 19.2 vs. [Sor] 13.4 months; HR =0.66 (95% CI: 0.52–0.85) | [T300 + D] 16.4 (range, 14.2–19.6) vs. [Sor]: 13.8 (range, 12.3–16.1) months; HR =0.78 (95% CI: 0.65–0.92. [D]: 16.6 (range, 14.1–19.1) months vs. [Sor]; HR =0.86 (95% CI: 0.73–1.03) | [Nivo + Ipi] 23.7 vs. [Len/ Sor] 20.6 months; HR =0.79 (95% CI: 0.65–0.96) | [An/Pen] 16.5 (range, 14.7–19.0) vs. [Sor] 13.2 (range, 9.7–16.9) months; HR =0.69 (95% CI: 0.55–0.87) | [Sin/Bev] not reached vs. [Sor] 10.4 (range, 8.5–not reached) months; HR =0.57 (95% CI: 0.43–0.75) | [Cam/Riv] 22.1 (range, 19.1–27.2) vs. [Sor] 15.2 (range, 13.0–18.5) months; HR =0.62 (95% CI: 0.49–0.80) | [Tor/Bev] 20.0 (range, 15.3–23.4) vs. [Sor] 14.5 (range, 11.4–18.8) months; HR =0.76 (95% CI: 0.58–0.99) | [CBZ + ATZ] 15.4 (range, 13.7–17.7) vs. [Sor] 15.5 (range, 12.1–NE) months; HR =0.90 (95% CI: 0.69–1.18) | [Len + Pem] 21.2 (range, 19.0–23.6) vs. [Len] 19.0 (range, 17.2–21.7) months; HR =0.84 (95% CI: 0.708–0.997) |
| Progression-free survival | [ATZ + BVZ] 6.8 (range, 5.7–8.3) vs. [Sor] 4.3 (range, 4.0–5.6) months; HR =0.59 (95% CI: 0.47–0.76) | [T300 + D] 3.78 (range, 3.68–5.32) vs. [Sor] 4.07 (range, 3.75–5.49) months; HR =0.90 (95% CI: 0.77–1.05). [D] 3.65 (range, 3.19–3.75) months vs. [Sor]; HR =1.02 (95% CI: 0.88–1.19) | – | [An/Pen] 6.9 (range, 5.8–8.0) vs. 2.8 (range, 2.7–4.1) months; HR =0.52 (95% CI: 0.41–0.66) | [Sin/Bev] 4.6 (range, 4.1–5.7) vs. 2.8 (range, 2.7–3.29) months; HR =0.56 (95% CI: 0.46–0.70) | [Cam/Riv] 5.6 (range, 5.5–6.3) vs. 3.7 (range, 2.8–3.7) months; HR =0.52 (95% CI: 0.41–0.65) | [Tor/Bev] 5.8 (range, 4.6–7.2) vs. [Sor] 4.0 (range, 2.8–4.2) months; HR =0.69 (95% CI: 0.53–0.91) | [CBZ + ATZ] 6.8 (range, 5.6–8.3) vs. [Sor] 4.2 (range, 2.8–7.0) months; HR =0.63 (95% CI: 0.44–0.91). [CBZ] 5.8 (range, 5.4–8.2) months vs. [Sor]; HR =0.71 (95% CI: 0.51–1.01) | [Len + Pem] 8.2 (range, 6.3–8.3) vs. [Len] 8.1 (range, 6.3–8.3) months; HR =0.834 (95% CI: 0.712–0.978) |
| Objective response | [ATZ + BVZ]: 29.8% | [T300 + D]: 20% | [Nivo + Ipi]: 36% | [An/Pen]: 21% | [Sin/Bev]: 21% | [Cam/Riv]: 35% | – | [CBZ + ATZ]: 11% | [Len + Pem]: 26.1% |
| RECIST 1.1 | [Sor]: 11.3% | [Sor]: 5% | [LEN/SOR]: 13% | [Sor]: 7% | [Sor]: 4% | [Sor]: 9% | [Sor]: 4% | [Len]: 17.5% | |
| [D]: 17% | [CBZ]: 6% | ||||||||
| Disease control rate | [ATZ + BV]: 73.6% | [T300 + D]: 60% | – | [An/Pen]: 73% | [Sin/Bev]: 72% | [Cam/Riv]: 78% | – | [CBZ + ATZ]: 78% | [Len + Pem]: 81.3% |
| [Sor]: 55.3% | [Sor]: 60.7% | [Sor]: 56% | [Sor]: 64% | [Sor]: 54% | [Sor]: 65% | [Len]: 78.4% | |||
| [D]: 54.8% | [CBZ]: 84%. | ||||||||
| Grade 3 or 4 adverse events | [ATZ + BV]: 56.5% | [T300 + D]: 50.5% | [Nivo + Ipi]: 41% | [An/Pen]: 50% | [Sin/Bev]: 53% | [Cam/Riv]: 81% | [Tor/Bev]: 63% | [CBZ+ATZ]: 64% | [Len + Pem]: 61.5% |
| [Sor]: 55.1% | [Sor]: 52.4% | [Len/Sor]: 42% | [Sor]: 47% | [Sor]: 45% | [Sor]: 52% | [Sor]: 61% | [Sor]: 46% | [Len]: 56.7% | |
| [D]: 37% | [CBZ]: 60% | ||||||||
AFP, alpha-fetoprotein; An, anlotinib; ATZ, atezolizumab; BCLC, Barcelona Clinic Liver Cancer; Bev, bevacizumab; BVZ, bevacizumab; Cam, camrelizumab; CBZ, cabozantinib; CI, confidence interval; CP, Child-Pugh; CTLA-4, cytotoxic T-lymphocyte antigen 4; D, durvalumab; ES, extrahepatic spread; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; HR, hazard ratio; Ipi, ipilimumab; Len, lenvatinib; MKI, multi-kinase inhibitor; MVI, macrovascular invasion; NE, not estimable; Nivo, nivolumab; PD-1, programmed-cell death 1; PD-L1, programmed cell death 1- ligand 1; Pem, pembrolizumab; Pen, penpulimab; PS, performance status; Riv, rivoceranib; Sin, sintilimab; Sor, sorafenib; T300, tremelimumab 300 mg; TKI, tyrosine kinase inhibitor; Tor, toripalimab; VEGFA, vascular endothelial growth factor A; VEGFR-2, vascular endothelial growth receptor-2.
Despite advances in ICI-based combination therapies, objective responses are observed only in approximately one-third of patients, and acquired resistance remains common. In addition, no validated predictive biomarkers are currently available to guide treatment selection. More intensive strategies, including triple-combination approaches such as dual immune checkpoint blockade with anti-VEGF therapy (6) or the addition of novel agents (e.g., anti-TIGIT) (7), have been evaluated but have not demonstrated clear additional benefit. Because histological features and molecular classifications (8) are not yet incorporated into treatment algorithms, more precise biological characterization of HCC will be essential to enable personalized therapy and improve outcomes.
Another important consideration is the potential impact of post-progression therapies on OS. Although detailed data on subsequent treatments were limited, differences in post-progression management between treatment arms may have influenced OS and should be considered when interpreting the results.
Accordingly, although the outcomes with anlotinib plus penpulimab are encouraging, comparisons with other established regimens should be interpreted cautiously because of differences in patient characteristics, follow-up duration, and trial design.
In summary, the APOLLO trial provides robust evidence that the combination of anlotinib plus penpulimab achieves meaningful and clinically relevant improvements in survival outcomes with an acceptable safety profile in patients with unresectable HCC. These data position this regimen as a promising new first-line option, particularly for patients with HBV-related or high-risk disease. Future research should focus on defining its optimal placement among existing ICI-based therapies, exploring potential biomarkers of response, and confirming its benefit in non-Asian populations.
Supplementary
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Acknowledgments
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Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Footnotes
Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-857/coif). The authors have no conflicts of interest to declare.
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