CARES-310 Age Subgroup Data: Supportive Signal, Not a Standalone Market Access Event

Elevar Therapeutics Presents Positive CARES-310 Subgroup Analysis in uHCC

Elevar Therapeutics announced a post hoc analysis of its Phase 3 CARES-310 study, demonstrating that camrelizumab plus rivoceranib improved progression-free survival (PFS) and overall survival (OS) across all age subgroups compared to sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). The findings, to be presented at the International Liver Cancer Association 2026 Annual Conference, showed a median OS of 21.5 months vs 15.2 months for patients <50 years (HR 0.7, P=0.0445) and 23.9 months vs 15.2 months for patients ≥50 years (HR 0.6, P<0.0001). Median PFS also improved across subgroups, with a manageable safety profile.

• The post hoc analysis revealed a significant improvement in median overall survival (mOS) for the camrelizumab/rivoceranib combination. Patients aged <50 years experienced an mOS of 21.5 months versus 15.2 months for sorafenib (HR 0.7; 95% CI, 0.47-1.06; P=0.0445), while those ≥50 years achieved 23.9 months versus 15.2 months (HR 0.6; 95% CI, 0.47-0.77; P<0.0001). A numerically longer mOS was also observed in patients <40 years (24.2 vs. 15.2 months).
• The combination therapy also demonstrated improved median progression-free survival (mPFS) across all age subgroups. Patients <50 years showed an mPFS of 5.5 months versus 2.7 months for sorafenib (HR 0.53; 95% CI, 0.37–0.77; P=0.0004), and those ≥50 years achieved 6.2 months versus 3.7 months (HR 0.56; 95% CI, 0.45–0.72; P<0.0001). Similar benefits were seen in patients <40 years (5.5 vs. 2.2 months).
• Treatment-related adverse events (TRAEs) were consistent across age subgroups. The most common Grade 3-4 TRAE for the combination was hypertension, while for sorafenib it was palmar-plantar erythrodysesthesia syndrome. These findings underscore the combination's potential to improve outcomes across diverse healthcare settings and various stages of HCC, reinforcing its role in multidisciplinary HCC management.

Consistent Efficacy of Camrelizumab/Rivoceranib Across uHCC Age Subgroups

Recent clinical investigations into unresectable hepatocellular carcinoma (uHCC) have evaluated immunotherapy-based combinations across real-world and multicenter settings. The studies below highlight key interventions alongside their efficacy and safety findings.

• Study: Safety and efficacy of atezolizumab/bevacizumab in unresectable hepatocellular carcinoma — a multicentric study | Intervention: Atezolizumab 1200 mg + bevacizumab 15 mg/kg IV every 3 weeks
  In a retrospective cohort of 104 patients (median age 67 years), median overall survival (OS) was 14.8 months (95% CI: 6.8–22.9) and median progression-free survival (PFS) was 6.2 months (95% CI: 2.5–9.9). Real-world OS and PFS rates were lower than those of the IMBrave150 trial, attributed in part to 43% of patients not meeting the IMBrave150 inclusion criteria. The combination was concluded to be a safe and effective option with manageable toxicities.

• Study: Atezolizumab-associated myositis in a patient with unresectable hepatocellular carcinoma | Intervention: Atezolizumab + bevacizumab (first-line, Child-Pugh Class A)
  This case report documented a rare immune-related adverse event — atezolizumab-associated myositis — in a 67-year-old male with stage IV unresectable HCC and underlying cirrhosis. Resolution was achieved through a combination of corticosteroids, intravenous immunoglobulins, and plasmapheresis, guided by American Society of Clinical Oncology guidelines for managing immune checkpoint inhibitor adverse events.

• Study: Multicenter study of bleeding and thromboembolic events with durvalumab tremelimumab vs. atezolizumab and bevacizumab in advanced HCC | Intervention: Atezolizumab/bevacizumab (A/B) vs. durvalumab ± tremelimumab (DT/D)
  In 490 patients (n = 325 A/B; n = 165 DT/D), 74 patients (22.8%) in the A/B group experienced a bleeding event of any grade versus 22 patients (13.3%) in the DT/D group (p = 0.016). High-grade (≥3) bleeding episodes occurred in 47 patients (14.5%) with A/B versus 12 patients (7.3%) with DT/D (p = 0.027). Kaplan-Meier analysis demonstrated a significantly shorter time to first bleeding with A/B (p = 0.037), and multivariate regression confirmed that A/B treatment was independently associated with an increased bleeding risk (p = 0.010). Variceal bleeding and thromboembolic events did not differ significantly between groups.

• Study: Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab | Intervention: Atezolizumab + bevacizumab
  This review highlighted that patients with unresectable HCC are at particular risk of gastrointestinal bleeding due to underlying liver disease and high likelihood of portal hypertension, a risk potentially exacerbated by antiangiogenic agents. Key safety signals requiring monitoring include proteinuria, hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection, alongside rarer but potentially life-threatening events such as pneumonitis and cardiovascular events.

CARES-310: Design and Endpoints for Unresectable HCC

Several key trials have evaluated systemic and locoregional treatment strategies in unresectable hepatocellular carcinoma (uHCC), spanning first-line and second-line settings. The studies below span phase 1b through phase 3 designs and capture a range of endpoints including overall survival, progression-free survival, objective response rate, and quality of life.

Camrelizumab/Rivoceranib's Potential in the Evolving uHCC Landscape

The first-line treatment landscape for unresectable hepatocellular carcinoma (uHCC) has grown increasingly competitive, with multiple regimens now generating comparative real-world and meta-analytic data. A meta-analysis of 10 retrospective cohort studies involving 1,659 East Asian patients demonstrated that lenvatinib combined with a PD-1/PD-L1 inhibitor was associated with significantly prolonged overall survival (HR: 0.69, 95% CI: 0.5–0.95, p = 0.023) and progression-free survival (HR: 0.73, 95% CI: 0.59–0.9, p = 0.004) compared with bevacizumab-based PD-1/PD-L1 combinations, though no significant differences were observed in objective response rate (RR: 1.09, 95% CI: 0.91–1.31, p = 0.304) or disease control rate (RR: 0.99, 95% CI: 0.92–1.06, p = 0.532). Separately, a real-world meta-analysis comparing lenvatinib monotherapy with atezolizumab plus bevacizumab found comparable outcomes, with pooled median OS of 18.4 months versus 18.5 months and pooled median PFS of 6.9 months versus 7.3 months, respectively, with no statistically significant differences in OS (HR: 0.91, 95% CI: 0.55–1.52, p = 0.72), PFS (HR: 0.79, 95% CI: 0.56–1.12, p = 0.19), or ORR (OR: 0.89, 95% CI: 0.65–1.20, p = 0.44).

Beyond the established regimens, emerging combination strategies are being evaluated in later-line settings. A phase II study of anti-PD-L1 envafolimab combined with the novel anti-VEGF agent suvemcitug in pretreated HCC patients — all of whom had received prior tyrosine kinase inhibitor therapy — reported an ORR of 10.0% (95% CI: 1.2–31.7), a DCR of 65.0% (95% CI: 40.8–84.6), a median PFS of 4.3 months (95% CI: 1.4–8.1), and a median OS of 10.7 months (95% CI: 6.0–not evaluable), with grade ≥3 treatment-related adverse events occurring in 40% of patients. In clinical practice, durvalumab plus tremelimumab demonstrated a disease control rate of 80.9% in the first-line setting versus 50% in later lines, with immune-related adverse events occurring in 24.3% of patients and a first-to-second-line transition rate of 94.7% following progressive disease.

Safety profiles across regimens remain a critical differentiator. A systematic review and meta-analysis of ICI-based therapies in prospective trials reported pooled incidences of all-grade treatment-related adverse events of 80.1% (95% CI: 73.8–85.2) and grade ≥3 events of 35.4% (95% CI: 27.2–44.6), with ICI combinations involving oral targeted agents carrying substantially higher odds of toxicity (all-grade OR: 17.07, 95% CI: 6.05–48.16, p < 0.001) relative to monotherapy. In real-world atezolizumab-bevacizumab data, pooled any-grade adverse event incidence was 79%, with proteinuria (exposure-adjusted incidence 55.7%), hypertension (45.3%), and fatigue (33.6%) among the most prominent signals, and notable heterogeneity in reporting practices across studies. For lenvatinib-based combinations specifically, hand-foot skin reaction and neutropenia were more frequent compared with bevacizumab-based regimens, whereas gastrointestinal haemorrhage was more common with bevacizumab-based therapy.

Broadening First-Line HCC Treatment Across All Ages

This latest post hoc analysis from the Phase 3 CARES-310 study provides compelling evidence for the broad applicability of camrelizumab plus rivoceranib as a first-line treatment for unresectable hepatocellular carcinoma (uHCC). The data, which will be presented at the International Liver Cancer Association 2026 Annual Conference, specifically highlights consistent improvements in both progression-free survival (PFS) and overall survival (OS) across all age subgroups – a critical insight for clinical practice.

The combination of the anti-PD-1 antibody camrelizumab and the VEGFR2-targeted tyrosine kinase inhibitor rivoceranib has already demonstrated significant superiority over sorafenib in the overall patient population, with a median OS of 23.8 months versus 15.2 months. The new subgroup analysis reinforces this benefit, showing median OS of 21.5 months for patients under 50 years and 23.9 months for those 50 years or older, both significantly outperforming sorafenib. This consistency across age demographics is particularly valuable, as age can often be a factor in treatment selection for advanced cancers. It suggests that the underlying synergistic mechanisms of immune checkpoint inhibition and anti-angiogenesis are effective regardless of a patient's age, potentially simplifying treatment algorithms and expanding the eligible patient population.

However, clinical teams must remain cognizant of the combination's safety profile. While manageable, the regimen is associated with a higher incidence of grade 3 or 4 treatment-related adverse events compared to sorafenib, including hypertension, increased AST/ALT, and palmar-plantar erythrodysesthesia syndrome. Proactive monitoring and management of these known toxicities, particularly those linked to the VEGFR2 TKI component, will be crucial for optimizing patient outcomes and maintaining adherence.

Furthermore, while the CARES-310 trial showed comparable efficacy across viral and non-viral HCC etiologies, the broader literature suggests that 'non-viral' HCC is a heterogeneous group, and preclinical data hint at potential differences in ICI response for specific etiologies like MASH-related HCC. Although current evidence does not support individualizing treatment based on etiology, this remains an area for ongoing research and clinical consideration. The robust efficacy across age groups, coupled with a manageable safety profile and demonstrated cost-effectiveness in certain regions, positions camrelizumab plus rivoceranib as a strong contender to reshape the first-line uHCC treatment landscape.