With the rapid evolution of immunotherapy–targeted therapy combinations, the management of advanced hepatocellular carcinoma (HCC) has entered a new era. Yet for patients with traditionally high-risk features—such as macrovascular invasion or extrahepatic spread—clinical outcomes have historically remained poor, posing a persistent therapeutic challenge.Data from the CARES-310 trial demonstrated that camrelizumab plus apatinib (the so-called “dual-A” regimen) delivers clinically meaningful survival benefits, even in patients with impaired liver function or adverse baseline characteristics, effectively overcoming historical prognostic disadvantages. More recently, perioperative investigations revealed that this regimen can facilitate downstaging and conversion to surgery in the neoadjuvant setting, while adjuvant therapy significantly reduces recurrence risk, with a doubling of median event-free survival (EFS)—underscoring its transformative potential across disease stages.
Oncology Frontier invited Arndt Vogel, Professor at the University of Toronto, for an in-depth discussion on how immunotherapy combinations are reshaping the HCC treatment landscape—from advanced first-line therapy to perioperative integration.
Q1: What Clinical Observations Led Your Team to Focus on Unresectable HCC With Macrovascular Invasion and Extrahepatic Spread in CARES-310?
Professor Arndt Vogel: Over the past few years, treatment outcomes in hepatocellular carcinoma have improved substantially, largely driven by the introduction of highly effective immunotherapy-based combinations. However, it has long been recognized that certain baseline clinical characteristics—such as elevated AFP levels, compromised liver function, vascular invasion, or extrahepatic metastases—are strongly associated with poor prognosis.
From a clinical research perspective, it was therefore critical to determine whether systemic combination therapies could meaningfully benefit precisely these high-risk patient populations. Based on the overall positive results of CARES-310, we were particularly interested in understanding whether the dual-A regimen could neutralize or mitigate the negative prognostic impact of macrovascular invasion and extrahepatic disease—conditions that traditionally predict inferior survival outcomes.
Q2: What Key Findings Emerged From CARES-310, and How Should They Inform Clinical Practice?
Professor Arndt Vogel: The findings from CARES-310 were highly consistent with our prior analyses and post-hoc evaluations. One of our central questions was whether there existed specific biomarkers or patient subgroups that might fail to benefit from this combination therapy.
Across all analytical dimensions—including earlier subgroup analyses based on underlying liver disease—the camrelizumab plus apatinib regimen consistently demonstrated superior efficacy. Importantly, the current analysis confirmed our original hypothesis:
- In the sorafenib control arm, patients with extrahepatic spread or macrovascular invasion exhibited clearly worse survival outcomes.
- In contrast, within the combination therapy arm, these adverse baseline characteristics no longer translated into inferior prognosis.
In other words, compared with historical expectations, patients traditionally considered high-risk achieved far better outcomes than anticipated with immunotherapy-based combination treatment. This is a highly significant observation, as it suggests that potent immune-targeted regimens may overcome the prognostic burden imposed by baseline disease characteristics, thereby substantially improving survival for patients who previously had limited therapeutic prospects.
Q3: From the Patient Perspective, How Tolerable Is Camrelizumab Plus Apatinib, and What Factors Influence Adherence?
Professor Arndt Vogel: Effective therapies often come with a degree of toxicity, and this regimen is no exception. Tyrosine kinase inhibitors are known to cause characteristic adverse events, such as cutaneous and gastrointestinal toxicities, and with the dual-A regimen we also observed hypertension and elevations in liver enzymes.
When reviewing the overall CARES-310 dataset, it is clear that most patients experienced at least one adverse event. From a purely numerical standpoint, this underscores that efficacy is indeed accompanied by toxicity. However, what truly matters is the nature and clinical relevance of these events.
The majority of adverse events were related to liver enzyme elevations, which were generally mild, transient, and clinically manageable. This is particularly important given that patients with impaired liver function still derived substantial benefit from treatment—suggesting that these laboratory abnormalities did not meaningfully compromise efficacy.
Moreover, clinicians have become increasingly adept at anticipating, monitoring, and managing these toxicities, allowing the vast majority of patients to remain on treatment with acceptable tolerability and adherence.
Q4: What Are the Current Trends in HCC Clinical Research, and What Challenges Lie Ahead?
Professor Arndt Vogel: Despite significant progress, the overall prognosis of hepatocellular carcinoma remains suboptimal, highlighting the need for continued innovation. One of the most important emerging strategies is the optimal integration of local and systemic therapies, always guided by the principle of maximizing patient benefit.
At the recent ESMO Congress, results from the CARES-009 trial were particularly encouraging. This study evaluated perioperative camrelizumab plus apatinib versus surgery alone in patients with resectable HCC at intermediate-to-high risk of recurrence. The findings were striking:
- Median EFS was more than doubled with perioperative combination therapy (42.1 vs 19.4 months).
These data strongly suggest that immunotherapy combinations should not be confined to advanced disease, but rather moved earlier in the treatment continuum and strategically combined with surgery.
In addition, other studies have explored combining this regimen with stereotactic body radiotherapy, reporting objective response rates as high as 65%. The field is clearly shifting away from viewing systemic therapy as a standalone modality, toward rational, science-driven combinations with local treatments.
If these strategies are implemented thoughtfully and supported by robust evidence, they hold the potential to fundamentally transform long-term outcomes for patients with HCC.
Conclusion
From advanced first-line therapy to perioperative intervention, immunotherapy-based combinations are rapidly redefining the therapeutic boundaries of hepatocellular carcinoma. The CARES program illustrates a paradigm shift: high-risk features are no longer insurmountable barriers, and earlier integration of systemic therapy may unlock curative opportunities previously out of reach.
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