The synergistic potential of camrelizumab and rivoceranib in advanced hepatocellular carcinoma: a review of current evidence

Abstract

Camrelizumab, a PD-1 inhibitor, and rivoceranib, a VEGFR tyrosine kinase inhibitor, have emerged as a promising combination therapy for advanced or unresectable hepatocellular carcinoma (HCC). This review explores the clinical efficacy and therapeutic potential of this dual treatment approach. A comprehensive literature search was conducted using PubMed/MEDLINE and Google Scholar to evaluate key clinical trials, including the pivotal CARES-310 trial. The final analysis of CARES-310 demonstrated a median overall survival (OS) of 23.8 months with camrelizumab plus rivoceranib, significantly higher than the 15.2 months observed with sorafenib (HR, 0.64; 95% CI, 0.52-0.79; P < 0.0001). The 24-month OS rate was 49.0% for the combination therapy versus 36.2% for sorafenib, while the 36-month OS rate was 37.7% compared to 24.8%. Progression-free survival (PFS) was also notably improved at 5.6 months versus 3.7 months for sorafenib (HR, 0.54; P < 0.0001). These findings highlight the superiority of this combination over traditional treatments, positioning it as a viable first-line option. With a manageable safety profile and significant survival benefits, camrelizumab plus rivoceranib represents a major advancement in HCC treatment. Ongoing research will further define its role in clinical practice and optimize outcomes for patients with limited treatment options.

Introduction

Liver cancer remains a major global health concern, ranking as the third leading cause of cancer-related deaths and the sixth most common malignancy, according to GLOBOCAN 2020 data^[1]. By 2040, it is estimated that 1.4 million individuals will be diagnosed with liver cancer annually, with 1.3 million succumbing to the disease due to its rising incidence^[2]. Among primary liver malignancies, hepatocellular carcinoma (HCC) is the most prevalent form. Due to its often-asymptomatic progression, many patients present with advanced, unresectable disease at the time of diagnosis, necessitating a comprehensive clinical assessment to guide treatment decisions.

HIGHLIGHTS

• Camrelizumab (PD-1 inhibitor) and rivoceranib (VEGFR tyrosine kinase inhibitor) show promising efficacy for advanced or unresectable hepatocellular carcinoma (HCC).

• The pivotal CARES-310 trial demonstrated a median overall survival (OS) of 23.8 months with camrelizumab plus rivoceranib, significantly outperforming sorafenib (15.2 months).

• 24-month OS rate was 49.0% for the combination therapy versus 36.2% for sorafenib, and the 36-month OS rate was 37.7% compared to 24.8% for sorafenib.

• Combination therapy improved progression free survival to 5.6 months versus 3.7 months with sorafenib.

• This dual therapy demonstrates substantial survival benefits and a manageable safety profile, making it a strong candidate for first-line treatment in HCC.

HCC management requires evaluating tumor burden, liver function, and underlying comorbidities such as chronic hepatitis and cirrhosis. The Child-Pugh classification is widely used to assess liver function, incorporating parameters such as ascites severity, serum albumin and bilirubin levels, prothrombin time, and hepatic encephalopathy status^[3]. Additionally, the Barcelona Clinic Liver Cancer (BCLC) staging system provides a standardized approach for stratifying patients based on tumor characteristics, liver function, and performance status, guiding therapeutic decision-making. BCLC categorizes HCC into five stages (0, A, B, C, and D), with treatment options ranging from curative interventions (e.g., resection, transplantation, ablation) in early stages to systemic therapies in advanced disease^[4,5]. For patients with advanced HCC who are ineligible for curative or loco regional therapies, systemic treatment remains the primary option for prolonging survival^[6].

The landscape of systemic therapy for HCC has evolved significantly with advances in targeted therapies and immunotherapy. For over a decade, sorafenib was the only approved first-line treatment for advanced HCC, based on the results of two landmark phase III trials, SHARP and Asia-Pacific. It is a multikinase inhibitor targeting Raf-1, B-Raf, VEGFR, PDGFR, and c-Kit receptors. In the SHARP trial, sorafenib improved median overall survival (OS) from 7.9 months (placebo) to 10.7 months (HR: 0.69; P < 0.001)^[7]. Similarly, in the Asia-Pacific trial, sorafenib extended median OS from 4.2 months (placebo) to 6.5 months (HR: 0.68; P = 0.014)^[8,9]. However, with the emergence of immunotherapy and novel targeted agents, the standard of care for advanced HCC has undergone a paradigm shift.

Camrelizumab, a humanized IgG4 monoclonal antibody targeting PD-1, has demonstrated promising antitumor activity in HCC. A phase II study reported a 6-month OS probability of 74.4% and an objective response rate (ORR) of 14.7% in previously treated HCC patients^[10]. Rivoceranib (also known as apatinib), a selective VEGFR2 tyrosine kinase inhibitor (TKI), inhibits tumor growth and angiogenesis while modulating the tumor microenvironment to enhance immune responses^[11]. Both agents have been approved as monotherapies in China for second-line treatment of advanced HCC due to their demonstrated efficacy and safety^[12]. The combination of camrelizumab plus rivoceranib has demonstrated promising efficacy in advanced HCC. Clinical trials have shown encouraging antitumor activity and tolerability, with improvements in response rates and survival outcomes compared to historical monotherapies^[13,14]. Given these findings, camrelizumab plus rivoceranib represents a potential new treatment option for advanced HCC. In this review, we will explore the mechanisms of action, clinical evidence, and the evolving role of this combination therapy in the management of HCC.

Methodology

A structured literature search was conducted in accordance with PRISMA guidelines. PubMed/MEDLINE and Google Scholar were queried using the Boolean string: (“Camrelizumab” AND “Rivoceranib”) AND (“hepatocellular carcinoma” OR “HCC”). The initial search yielded 753 records (PubMed: 97; Google Scholar: 656). After removing 37 duplicate records and excluding 23 clearly irrelevant articles, 683 records remained for screening. Titles and abstracts were reviewed, resulting in the exclusion of 600 articles due to lack of relevance or unsuitable study design. The remaining 83 articles underwent full-text review. Of these, 41 were excluded for reasons including non-relevant patient populations, unrelated interventions, incomplete data, non-English language, or being review articles, commentaries, editorials, case reports, or case series. Ultimately, 42 studies met all eligibility criteria and were included in this narrative review. These include pivotal trials such as CARES-310, TRIPLET, and RESCUE, along with relevant Phase II/III studies. The selection process is illustrated in a PRISMA flow diagram (Fig. 1).

Figure 1.

Study selection process illustrated using a PRISMA-style flow diagram.

Mechanism of action

Programmed cell death protein-1 (PD-1) is an immune checkpoint receptor found on the surface of multiple immune cells. Its primary ligand, PD-L1, is predominantly expressed on tumor cells. The binding between PD-1 and PD-L1 is a key mechanism through which tumors evade immune detection and suppress the body’s anti-tumor response, as shown in Figure 1^[15]. Their binding produces an inhibitory signal that decreases T-cell activation, cytokine production and cytotoxic activity, as illustrated in Figure 2^[16]. By primarily reducing the activity of effector T cells and boosting the function of immunosuppressive regulatory T cells (Tregs), this interaction negatively regulates adaptive immune response. This helps to maintain immune homeostasis, and guards against dysregulated immunity and detrimental immune responses. Unluckily, in order to promote immune escape, cancer cells exploit this PD-1/PD-L1 axis^[17]. Camrelizumab, a humanized monoclonal antibody against PD-1, improves T cell responses, increases anti-tumor immunity and reduces T cell immunosuppression, as illustrated in Figure 3^[18].

Figure 2.

Mechanism of immune checkpoint evasion of tumor cells and mechanism of action of camrelizumab.

Figure 3.

Mechanism of action of camrelizumab and rivoceranib.

Vascular endothelial growth factor receptor 2 (VEGFR2) controls endothelial migration and proliferation by acting as a major responder to the vascular endothelial growth factor signal. Although endothelial cells and some vascular malignancies express this receptor, multiple research also describe its expression in lymphomas and carcinomas^[19]. Rivoceranib is a tyrosine kinase inhibitor (TKI) that actively targets VEGFR2^[20]. This inhibition decreases the density of tumor micro vessels leading to nutrient deprivation and tumor shrinkage, as shown in Figure 3.

As first shown in the IMbrave150 research, the combination of PD-(L)1 inhibitors with VEGF-targeting medicines has signaled a significant change in the treatment of HCC^[21]. Compared to anti-PD-1 treatment alone, antiangiogenic medications and anti-PD-1 treatments reduce immune checkpoint activation and improve T-cell function, resulting in a stronger antitumor response^[21,22].

Clinical evidence

Numerous clinical trials have assessed the safety and therapeutic effectiveness of the camrelizumab plus rivoceranib combination; the most notable of them is the CARES-310 trial, which produced crucial phase III evidence in favor of its usage in advanced HCC^[13].

Key findings from CARES-310: OS and PFS results; comparison with sorafenib

Camrelizumab in combination with rivoceranib has shown a statistically significant and clinically relevant enhancement in both progression-free survival (PFS) and overall survival (OS) when compared to sorafenib for patients suffering from unresectable hepatocellular carcinoma (HCC). This combination presents a promising first-line treatment alternative for this patient population. The findings stem from the CARES-310 study, an international, randomized, open-label phase 3 trial conducted between 28 June 2019, and 24 March 2021. The study’s participants had advanced or metastatic hepatocellular carcinoma (HCC) that was categorized as stage B or C Barcelona Clinic Liver Cancer (BCLC). They had not been treated systemically before and had to be in good functional state (ECOG 0 or 1), have preserved liver function (Child-Pugh A), and have quantifiable illness according to RECIST 1.1 criteria. A total of 543 individuals were randomized to either the sorafenib group (271) or the camrelizumab-rivoceranib group (272). The prognosis for these patients was generally bad, and a considerable percentage of them died or had their disease worsen during the research.

The trial showed that the combination group’s survival results were significantly better than those of the sorafenib group. A summary of long-term outcomes and safety of CARES-310 final analysis is illustrated in Table 1.

Table 1.

Long-term outcomes and safety in CARES-310 final analysis

Outcome	Camrelizumab + rivoceranib	Sorafenib
Median OS (months)	23.8	15.2
24-month OS rate (%)	49.0	36.2
36-month OS rate (%)	37.7	24.8
Median PFS (months)	5.6	3.7
Grade ≥3 TRAEs (%)	24	6

Extended follow-up: The final analysis of CARES-310 (data cut-off: 14 June 2023) increased the median follow-up to 22.1 months in the camrelizumab plus rivoceranib group and 14.9 months in the sorafenib group.

Median overall survival (OS): The combination therapy resulted in a significantly lower mortality risk and a much longer OS than sorafenib Median overall survival (OS) improved to 23.8 months (95% CI, 20.6–27.2) for camrelizumab plus rivoceranib versus 15.2 months (95% CI, 13.2–18.5) for sorafenib (HR, 0.64; 95% CI, 0.52–0.79; P < 0.0001). 24-month OS rates and 36-month OS rates were 49.0% (combination) versus 36.2% (sorafenib) 37.7% (combination) versus 24.8% (sorafenib), respectively.

Progression-free survival (PFS):The camrelizumab-rivoceranib group’s median progression-free survival (PFS) was noticeably longer, demonstrating improved disease management (5.6 months for the combination vs. 3.7 months for sorafenib).These results demonstrate that camrelizumab plus rivoceranib is more effective and has a longer-lasting response than sorafenib.

Safety and tolerability

Adverse events were more frequent with the combination therapy as compared to sorafenib alone. They were recorded in 6% of patients receiving sorafenib and 24% of patients receiving camrelizumab with rivoceranib. The most frequently reported treatment-related adverse events (TRAEs) included hypertension, palmar-plantar erythrodysaesthesia syndrome, elevated aspartate aminotransferase and elevated alanine aminotransferase. These effects were in line with the expected side effects of PD-1 and VEGFR inhibitors^[23]. It was reported that two patients died as a result of their treatment: one in the sorafenib group (respiratory failure and circulatory collapse) and one in the camrelizumab + rivoceranib group (multiple organ dysfunction syndrome).

Subsequent therapies

After study treatment, 36% of patients in the combination group and 42% in the sorafenib group received subsequent targeted therapy; 17% and 36% received subsequent immunotherapy, respectively. This is now discussed as a factor potentially influencing long-term survival.

Heterogeneity analysis within CARES-310

Understanding the heterogeneity of the study population is critical for evaluating the generalizability and robustness of trial outcomes. The CARES-310 trial enrolled a diverse cohort of patients with advanced hepatocellular carcinoma (HCC), and subgroup analyses were conducted to assess the consistency of treatment benefit across different demographic and clinical variables. This section reviews key baseline characteristics, regional distribution, and subgroup findings to contextualize the applicability of the trial results to broader patient populations.

Regional distribution

83% of patients were Asian, and 17% were non-Asian, reflecting the global epidemiology of HCC but also indicating a predominance of Asian patients in the trial population. Outcomes were analyzed by subgroup, and the overall survival benefit of camrelizumab plus rivoceranib was consistent across both Asian and non-Asian populations.

Baseline characteristics

The median age was 58 years in the combination group and 56 years in the sorafenib group. Males comprised 83% of the combination group. Most patients had ECOG performance status 0 or 1, and Child-Pugh class A liver function. Alpha-fetoprotein (AFP) levels, BCLC stage, and etiology (HBV, HCV, alcohol, or non-viral) were also reported and balanced between groups. A summary of baseline characteristics and regional distribution is shown in Table 2.

Table 2.

Baseline characteristics and regional distribution in CARES-310

Characteristic	Camrelizumab + rivoceranib	Sorafenib
Number of patients	272	271
Median age (years)	58	56
Male (%)	83%	83%
ECOG 0/1 (%)	44/56	42/58
Child-Pugh A (%)	100%	100%
BCLC Stage B/C (%)	14/86	13/87
AFP <400/≥400 ng/mL (%)	65/35	65/35
Asian (%)	83%	84%
Non-Asian (%)	17%	16%

Subgroup analyses

Subgroup analyses demonstrated that the observed survival benefit was maintained regardless of geographic region, race, BCLC stage, baseline AFP, and etiology of liver disease, supporting the robustness of the findings^[24]

TRIPLET study: camrelizumab plus apatinib/rivoceranib and hepatic artery infusion chemotherapy in advanced hepatocellular carcinoma; a phase II study

The TRIPLET study, a phase II clinical trial, assessed the efficacy of camrelizumab (PD-1 inhibitor) plus apatinib (VEGFR-2 inhibitor, also known as rivoceranib) and hepatic artery infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC), Barcelona Clinic Liver Cancer stage C^[25]. The study demonstrated strong anti-tumor activity, with an objective response rate (ORR) of 73.3% and a disease control rate (DCR) of 96.7%, indicating a high proportion of patients experiencing clinical benefit.

Survival outcomes were also promising, with a median progression-free survival (PFS) of 10.3 months and a median overall survival (OS) of 22.3 months, suggesting a significant improvement in disease control and patient survival compared to historical controls. The safety profile was manageable, with adverse events consistent with those expected from the individual agents. These findings highlight the potential of this combination therapy as an effective treatment strategy for advanced HCC and support further investigation in larger randomized trials.

RESCUE trial: camrelizumab plus rivoceranib/apatinib in advanced HCC

A nonrandomized, open-label, multicenter phase II study further supports the efficacy of camrelizumab plus rivoceranib (apatinib) in advanced HCC, demonstrating significant clinical benefit in both first-line and second-line settings. Among treatment-naïve patients, the combination achieved an objective response rate (ORR) of 34.3% and a median progression-free survival (PFS) of 5.7 months, while previously treated patients had an ORR of 22.5% and a median PFS of 5.5 months. The 12-month overall survival rate remained high in both groups, at 74.7% in first-line patients and 68.2% in second-line patients, underscoring the regimen’s durable clinical benefit^[26].

Comparison with other therapies

Sorafenib, a multitargeted tyrosine-kinase inhibitor (TKI), was approved in 2007^[27]. It has been the first efficacious systemic therapy approved for patients with advanced HCC based on the results of SHARP trial^[8], with an overall survival (OS) of 10.7 versus 7.9 months with the placebo (HR, 0.69, CI, 0.55–0.87, P < 0.001) and a prolonged time to radiologic progression (5.5 vs. 2.8 months, P < 0.001). The main side effects were diarrhea, weight loss and a hand–foot skin reaction.

The phase III REFLECT trial showed that the tyrosine kinase inhibitor (TKI) lenvatinib was not inferior to sorafenib in terms of overall survival (OS)^[28]. Lenvatinib also outperformed sorafenib in progression-free survival (PFS) and overall response rate (ORR), which were secondary endpoints of the trial. The most common side effects of lenvatinib included hypertension, proteinuria, and diarrhea. However, the study only enrolled patients with advanced hepatocellular carcinoma (HCC) who had no involvement of the main portal vein or bile duct and whose tumor burden was less than 50% of the liver volume^[29].

The phase III IMbrave150 trial assessed the effectiveness of atezolizumab–bevacizumab as a first-line treatment for unresectable hepatocellular carcinoma (HCC), comparing 336 patients receiving the combination therapy to 165 patients treated with sorafenib. The results showed a significant improvement in overall survival (OS) for atezolizumab–bevacizumab (67.2% [95% CI, 61.3–73.1] vs. 54.6% [95% CI, 45.2–64.0] at 12 months) and progression-free survival (PFS) (6.8 months [95% CI, 5.7–8.3] vs. 4.3 months [95% CI, 4.0–5.6]) compared to sorafenib^[30].

The phase III HIMALAYA trial evaluated the combination of tremelimumab (an anti-CTLA-4 agent) and durvalumab (an anti-PD-L1 agent), collectively known as the STRIDE regimen, against sorafenib in patients resistant to systemic therapy. The tremelimumab–durvalumab combination demonstrated superiority over sorafenib in overall survival (OS) (HR, 0.78; 96% CI, 0.65–0.92; P = 0.0035) but not in progression-free survival (PFS). At the time of analysis, the median OS was 16.43 months in the STRIDE group compared to 13.77 months in the sorafenib group, while PFS was similar across all groups (STRIDE: 3.78 months, durvalumab: 3.65 months, sorafenib: 4.07 months). Additionally, esophageal variceal bleeding events were rare in the STRIDE group (0.26%)^[31].

The results of the CARES-310 trial indicate the preferential use of combination therapy of camrelizumab and rivoceranib over other therapies. As compared with other therapies, the overall survival and progression-free survival rates were more. However, the study reported the following adverse effects: hypertension, increased aspartate aminotransferase, and increased alanine aminotransferase^[13].

Discussion

The combination of camrelizumab and rivoceranib has shown significant promise in the treatment of advanced or unresectable hepatocellular carcinoma (HCC), demonstrating superior efficacy compared to conventional therapies like sorafenib. The phase III CARES-310 trial provided strong evidence supporting the safety and effectiveness of this combination. Despite a higher incidence of treatment-related adverse events, including hypertension and elevated liver enzymes, these were largely manageable with dose adjustments and supportive care. If regulatory agencies approve this combination therapy, it could be integrated into clinical guidelines as a first-line treatment option.

Beyond its effectiveness in advanced HCC, emerging evidence suggests that camrelizumab plus rivoceranib may also benefit patients in earlier stages of the disease^[32]. A study evaluating perioperative camrelizumab plus apatinib (rivoceranib) in resectable HCC demonstrated promising outcomes, with an increased pathological response rate, suggesting its potential role in down staging tumors and improving surgical outcomes. These findings reinforce the broad applicability of this combination, supporting its use not only in advanced disease but also in patients eligible for curative resection.

Economic considerations also play a crucial role in the therapy’s adoption. Early cost-effectiveness analyses suggest that camrelizumab plus rivoceranib may provide better value than sorafenib in certain healthcare settings, particularly in China, where the incremental cost-effectiveness ratio (ICER) has been estimated at approximately $33 620 per quality-adjusted life year (QALY)^[14]. This figure falls below the local cost-effectiveness threshold, potentially supporting its inclusion in various healthcare systems. However, pricing, reimbursement strategies, and insurance coverage will be critical in determining its real-world accessibility. Despite the promising results, there are important limitations in the available data on the safety and efficacy of this combination therapy. The CARES-310 trial enrolled 543 patients (271 on sorafenib, 272 on camrelizumab plus rivoceranib), which, while statistically sufficient, may not fully capture the diverse responses across different patient populations given the variability of HCC presentations. A potential limitation in generalizing the results of the CARES-310 trial lies in the heterogeneity of the included populations. While the study enrolled a predominantly Asian cohort (83%), subgroup analyses revealed that the survival benefit was consistent across both Asian and non-Asian populations. However, given the regional predominance of patients from East Asia, the findings may be less directly applicable to populations in other regions with differing HCC risk factors and disease profiles. Additionally, the trial’s balanced inclusion of patients across various baseline characteristics such as age, ECOG performance status, and liver function suggests that the results are applicable to a broad spectrum of patients within the Asian population, though further research in more diverse groups is necessary. While the primary analysis of the CARES-310 trial reported a median follow-up of 14.5 months for overall survival (OS) and 7.8 months for progression-free survival (PFS), raising questions about the durability of benefit and long-term safety, these concerns have been partially addressed in the final analysis. With an extended follow-up (data cut-off: 14 June 2023), the median follow-up increased to 22.1 months in the camrelizumab plus rivoceranib group and 14.9 months in the sorafenib group. The updated findings reaffirmed the survival advantage of the combination therapy and did not reveal new or unexpected safety signals, supporting the long-term effectiveness and tolerability of this regimen^[24].

Furthermore, while the trial included patients from 13 different countries, it may not fully represent the global HCC population. Since most participants were from specific regions, it’s unclear if the results would be the same for people from different backgrounds, environments, and healthcare systems. Research shows that race influences both survival rates and the management of HCC, further highlighting the need for diverse, global studies^[33]. Additionally, American Association for the Study of Liver Diseases (AASLD) prioritizes immunotherapy-based combinations over sorafenib alone for the management of HCC^[34]. So, sorafenib used as the comparator in CARES-310 trial raises the question of whether the observed survival improvements from combination therapy are due to a truly superior therapy or simply the result of comparing against a less effective treatment option.

A major obstacle in the adoption of camrelizumab plus rivoceranib has been regulatory approval delays. In May 2024, the FDA issued a complete response letter (CRL) citing manufacturing deficiencies at the Hengrui Pharma facility and incomplete Bioresearch Monitoring (BIMO) inspections due to travel restrictions. Notably, the clinical data supporting the therapy’s efficacy were not questioned, nor was the production of rivoceranib. However, these manufacturing concerns delayed regulatory approval and patient access.

Following the CRL, the manufacturer resubmitted the New Drug Application (NDA), which was accepted by the FDA in July 2023 after confirming that the necessary responses to manufacturing deficiencies were adequate. Nonetheless, additional inspections and quality control improvements may further extend the approval timeline. However, the Prescription Drug User Fee Act (PDUFA) target action date is set for 20 March 2025 and this points toward a potential approval of camrelizumab plus rivoceranib combination as first line treatment for advanced HCC^[35].

Additionally, effective implementation of this therapy requires a multidisciplinary approach, involving oncologists, hepatologists, and other healthcare providers. Proper training on treatment administration, monitoring for side effects, and managing comorbidities will be essential to ensure patient safety and maximize clinical benefits.

Future directions

There are several potential future possibilities that might improve the effectiveness and suitability of this treatment plan as research continues to advance. One of the most significant future directions is exploring this combination therapy in other malignancies beyond HCC. Current literature suggests potential applications in various solid tumors.

Ongoing clinical trials are investigating the efficacy of camrelizumab plus rivoceranib in patients with advanced gastric cancer. Preliminary results indicate that this combination may enhance antitumor responses. In comparison to SOX alone, the researchers found that low dose rivoceranib and camrelizumab added to SOX dramatically enhanced pCR in the DRAGON IV/CAP 05 study. It was observed that this regimen was well tolerated^[36]. Similar to gastric cancer, studies are assessing the effectiveness of this regimen in esophagogastric junction cancer^[37], which shares some pathophysiological characteristics with gastric tumors. When compared to SOX alone, the SOXRC regimen dramatically increased pCR in patients with G/GEJ adenocarcinoma while maintaining a manageable safety profile^[38]. Studies are also being done on tumors like cervical cancer^[39], adenocarcinoma of lung^[36], oral squamous cell carcinoma^[40] where the anti-angiogenic qualities of rivoceranib and the immunomodulatory effects of camrelizumab may work in combination to provide positive results.

HCC, classic Hodgkin lymphoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma, and non-small cell lung cancer have shown promising results when treated with camrelizumab and rivoceranib. With positive safety profiles and initial efficacy findings, the ongoing research indicates that this combination may be promising for advanced colorectal cancer^[41]. For patients with metastatic nasopharyngeal carcinoma, especially those who have advanced following chemotherapy or other immunotherapies, this combination may offer a unique course of treatment^[42]. When compared to traditional therapy, the combination of camrelizumab and rivoceranib appears to produce positive early outcomes in triple-negative breast cancer (TNBC), with some improvements in response rates and progression-free survival (PFS)^[43] (shown in Table 3).

Table 3.

Use of combination therapy in various cancers

Study title	Cancer type	Phase	Status	Study design	Primary outcome	Reference
Perioperative camrelizumab plus rivoceranib and chemotherapy vs. chemotherapy for locally advanced gastric cancer (DRAGON IV/CAP 05)	Gastric cancer	3	Active, not recruiting	Open-label, multicenter, randomized	Pathologic response	Li et al, 2024 (PMID: 39383487)
Camrelizumab combined with chemotherapy followed by camrelizumab plus apatinib as first-line therapy for advanced gastric or gastroesophageal junction adenocarcinoma	Gastric cancer or gastroesophageal junction adenocarcinoma	2	Recruiting	Open-label, multicenter, randomized	Objective response rate (ORR)	PMID: 33766817
Combination of camrelizumab and rivoceranib in patients with advanced esophageal squamous cell carcinoma	Esophagogastric junction cancer	2	Recruiting	Open-label, multicenter	Objective response rate (ORR)	PMID: 39307038
Neoadjuvant camrelizumab plus apatinib for locally advanced microsatellite instability-high or mismatch repair-deficient colorectal cancer (NEOCAP): a single-arm, open-label, phase 2 study	Colorectal cancer	2	Recruiting	Open-label, multicenter	Pathological or clinical complete response	PMID: 38852601
Efficacy, safety, and biomarker analysis of neoadjuvant camrelizumab and apatinib in patients with resectable NSCLC: a phase 2 clinical trial	Non-small cell lung cancer	2	Recruiting	Open-label, multicenter, single-arm	Major pathologic response (MPR) rate	PMID: 36870519
Efficacy and safety of camrelizumab combined with apatinib in advanced triple-negative breast cancer: an open-label phase II trial	Advanced triple-negativebreast cancer	2	Recruiting	Open-label, multicenter	ORR	PMID: 32448804

Long-term studies are urgently required to assess the impact on quality of life and the durability of response, despite promising first findings. Knowing how long patients can maintain a response to this combination medication is necessary to establish its role in routine clinical practice. Additionally, quality-of-life assessments will provide evidence on how these treatments affect patients’ daily routines and overall well-being. To maximize treatment plans, creative trial designs should be taken into account. Adaptive trial designs are particularly beneficial as they allow adjustments based on intermediate findings. Innovative designs could facilitate the modification of treatment plans or dosages based on patient responses, potentially improving outcomes while minimizing side effects. The growing evidence for the combination of camrelizumab and rivoceranib may transform the treatment approach for advanced hepatocellular carcinoma (HCC) and other cancers. As more data from ongoing studies and clinical trials emerges, medical practitioners may need to reassess existing treatment plans. Including this combo medication in normal care may lead to improved management strategies and higher survival rates for patients with advanced cancers.

Finally, the future of camrelizumab and rivoceranib is promising. Long-term studies, creative trial designs, extending research into new uses, and even changing treatment paradigms will all be required to improve cancer care. Collaboration among researchers, physicians, and regulatory authorities is necessary to realize the full potential of this therapeutic combination.

Conclusion

The combination of camrelizumab and rivoceranib represents a significant advancement in the treatment of advanced or unresectable hepatocellular carcinoma (HCC). Clinical evidence, particularly from the phase 3 CARES-310 trial, demonstrates its superiority over sorafenib, with substantial improvements in overall survival and progression-free survival. The dual blockade of PD-1 and VEGFR pathways offers a synergistic effect, enhancing antitumor activity while maintaining a manageable safety profile. Given these findings, this combination is emerging as a promising first-line treatment option for patients with limited therapeutic choices. However, further research is needed to refine patient selection, optimize treatment sequencing, and explore potential combination strategies with other emerging therapies. Continued clinical evaluation and real-world studies will be crucial in solidifying its role in the evolving HCC treatment landscape.

Ethical approval

Ethics approval was not required for this review.

Consent

Informed consent was not required for this review.

Sources of funding

No funding was acquired for this paper.

Author contributions

B.D., S.H., A.R., A.M., M.Z., A.A., R.M., Z.K., Z.S., and B.U.: writing and editing; K.A.: conceptualizing, editing, reviewing, and critically revising the manuscript; W.K. and M.H.: reviewing. All the authors have approved the final version and agreed to the accuracy of the work. All the authors have read and agreed to the final version of the manuscript.

Conflicts of interest disclosure

The authors declare that they have no conflict of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Mohammed Mahmmoud Fadelallah Eljack.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.