Rivoceranib (Apatinib): A Comprehensive Oncological Monograph

Executive Summary

Rivoceranib, also known internationally as apatinib, is an orally bioavailable, small-molecule tyrosine kinase inhibitor (TKI) that functions primarily as a potent and highly selective antagonist of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2). Its principal mechanism of action is the inhibition of tumor angiogenesis, a critical process for cancer growth and metastasis. Beyond its antiangiogenic properties, preclinical and clinical evidence suggests that rivoceranib also possesses secondary activities, including mild inhibition of c-Kit and c-SRC kinases and a novel capacity to reverse multidrug resistance by inhibiting key cellular efflux pumps.[1]

The clinical development of rivoceranib has yielded significant, albeit mixed, results across different malignancies and therapeutic settings. In unresectable hepatocellular carcinoma (uHCC), rivoceranib has demonstrated landmark efficacy. The global Phase III CARES-310 trial, which evaluated rivoceranib in combination with the anti-PD-1 antibody camrelizumab, met its primary endpoints, showing statistically significant and clinically meaningful improvements in both overall survival (OS) and progression-free survival (PFS) compared to the then-standard-of-care, sorafenib. The final analysis reported a median OS of 23.8 months for the combination, establishing a new benchmark for first-line systemic therapy in this patient population.[3]

In contrast, the drug's performance as a monotherapy in heavily pre-treated advanced or metastatic gastric or gastroesophageal junction (GEJ) cancer has been more nuanced. The global Phase III ANGEL study failed to meet its primary endpoint of improving OS in the overall patient population. However, it demonstrated a significant benefit in PFS and, notably, a statistically significant improvement in OS within the prespecified subgroup of patients receiving treatment as a fourth-line or later therapy, suggesting a potential role in a more refractory setting.[7]

The regulatory landscape for rivoceranib is complex and geographically divided. In China, where it is known as apatinib, the drug has secured multiple approvals from the National Medical Products Administration (NMPA) for the treatment of advanced gastric cancer (since 2014) and hepatocellular carcinoma, both as a monotherapy and in combination with camrelizumab.[9] Conversely, its path to the U.S. market has been stalled. Despite the compelling efficacy data from the CARES-310 study, the U.S. Food and Drug Administration (FDA) has issued two Complete Response Letters (CRLs) for the combination therapy's New Drug Application (NDA). These rejections were not based on the clinical data but on unresolved Good Manufacturing Practice (GMP) deficiencies and inspection-related issues concerning its partner-supplied drug, camrelizumab.[11] An NDA has been resubmitted, with a Prescription Drug User Fee Act (PDUFA) target action date set for March 20, 2025.[3] In Europe, the combination has received Orphan Medicinal Product Designation from the European Medicines Agency (EMA) for HCC.[15]

In conclusion, rivoceranib is a clinically active agent with a well-defined mechanism of action. Its therapeutic potential appears to be maximized when used as a combination partner, particularly with immune checkpoint inhibitors, where it has demonstrated profound synergistic effects. However, its global market entry, especially in the United States, is contingent upon the resolution of significant manufacturing and regulatory hurdles associated with its combination partner. The future trajectory of rivoceranib will be dictated by its ability to navigate these regulatory challenges and to position itself within a competitive and rapidly evolving oncology landscape.

Section 1: Drug Profile and Physicochemical Properties

1.1. Nomenclature and Identifiers

Rivoceranib is a small molecule drug that has been developed and investigated under several different names, reflecting its complex global development history. The officially recognized International Nonproprietary Name (INN) and United States Adopted Name (USAN) is Rivoceranib.[17] However, it is widely known in scientific literature and is approved in China under the name

Apatinib.[1] The compound was also assigned the developmental code name

YN968D1 by its originators.[1] This multiplicity of names necessitates careful cross-referencing of clinical and preclinical data. The divergence arose from parallel development pathways, with "Apatinib" becoming established in China following its 2014 approval, while "Rivoceranib" was formally adopted in 2018 for global development outside of China.[22]

The drug is most commonly administered as a salt. The mesylate salt, rivoceranib mesylate (CAS Number: 1218779-75-9), is the form used in many clinical trials and commercial formulations.[21] The free base form corresponds to CAS Number 811803-05-1.[1] A comprehensive list of its identifiers is consolidated in Table 1, providing a definitive reference for this compound across major chemical and pharmacological databases.

Table 1: Drug Identification and Physicochemical Properties

Property	Value	Source(s)
Generic Name (INN/USAN)	Rivoceranib	17
DrugBank ID	DB14765	1
Type	Small Molecule	1
CAS Number (Free Base)	811803-05-1	1
CAS Number (Mesylate Salt)	1218779-75-9	21
IUPAC Name	N-(4-(1-Cyanocyclopentyl)phenyl)-2-((pyridin-4-ylmethyl)amino)nicotinamide	1
Synonyms	Apatinib, YN968D1, YN-968D1, Aitan (brand name in China)	1
Molecular Formula	C24​H23​N5​O	1
Molar Mass (Free Base)	397.482 g·mol⁻¹	1
Appearance	White solid powder	23
Solubility	Soluble in DMSO; not soluble in water	23
Formulation	Oral film-coated tablets	29

1.2. Chemical Structure and Formulation

The chemical structure of rivoceranib is defined by its IUPAC name, N-(4-(1-Cyanocyclopentyl)phenyl)-2-((pyridin-4-ylmethyl)amino)nicotinamide.[1] Its molecular formula is

C24​H23​N5​O, and its average molecular weight is 397.482 g·mol⁻¹.[1] For computational chemistry and database cross-referencing, its structure is represented by the following identifiers:

• SMILES: N#CC1(c2ccc(NC(=O)c3cccnc3NCc3ccncc3)cc2)CCCC1 [1]
• InChI: InChI=1S/C24H23N5O/c25-17-24(11-1-2-12-24)19-5-7-20(8-6-19)29-23(30)21-4-3-13-27-22(21)28-16-18-9-14-26-15-10-18/h3-10,13-15H,1-2,11-12,16H2,(H,27,28)(H,29,30) [1]
• InChIKey: WPEWQEMJFLWMLV-UHFFFAOYSA-N [19]

For clinical use, rivoceranib is formulated as an orally administered, film-coated tablet. Clinical trials have utilized various strengths, including 200 mg and 250 mg tablets, to allow for flexible dosing regimens.[29]

1.3. Physical and Chemical Properties

Rivoceranib in its pure form is a white solid powder.[23] A critical property influencing its formulation and laboratory handling is its solubility. It is soluble in organic solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) at concentrations of approximately 30 mg/mL, but it is poorly soluble in water and aqueous buffers.[23] This low aqueous solubility is typical for many small-molecule kinase inhibitors and necessitates specific formulation strategies to ensure adequate oral bioavailability.

For storage, rivoceranib requires dry and dark conditions. Long-term stability (months to years) is achieved by storing the compound at -20°C. For short-term storage (days to weeks), temperatures of 0–4°C are sufficient. The compound is stable enough at ambient temperatures to withstand ordinary shipping and customs processing for several weeks without degradation.[23]

Section 2: Comprehensive Pharmacological Profile

2.1. Primary Mechanism of Action: Selective VEGFR-2 Inhibition and Antiangiogenesis

Rivoceranib is a receptor tyrosine kinase inhibitor (TKI) whose primary antineoplastic activity is derived from its potent and highly selective inhibition of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2), also known as Kinase Insert Domain Receptor (KDR) or Fetal Liver Kinase 1 (Flk-1).[1] The VEGF signaling pathway is a cornerstone of tumor-driven angiogenesis, the process by which tumors form new blood vessels to secure the supply of oxygen and nutrients required for their growth, proliferation, and metastasis.[2]

Among the VEGF receptors, VEGFR-2 is considered the principal mediator of the mitogenic, migratory, and survival signals that drive endothelial cell proliferation and vascular permeability.[31] Rivoceranib binds to the ATP-binding site of the VEGFR-2 tyrosine kinase domain, preventing its autophosphorylation and subsequent activation of downstream signaling cascades, including the MAPK and PI3K-Akt pathways.[34] By blocking this pivotal step, rivoceranib effectively inhibits VEGF-stimulated endothelial cell migration and proliferation, leading to a reduction in tumor microvessel density and the suppression of new blood vessel formation.[1]

The potency of rivoceranib against its primary target is exceptionally high, with a reported half-maximal inhibitory concentration (IC50​) value of 1 nM for VEGFR-2. This high degree of selectivity allows for effective targeting of the angiogenesis pathway with minimal off-target activity on other kinases at therapeutic concentrations.[23]

2.2. Secondary and Novel Mechanisms

Beyond its primary antiangiogenic function, rivoceranib exhibits several other mechanisms of action that contribute to its overall antitumor effect and create a strong rationale for its use in combination therapies.

2.2.1. Other Kinase Inhibition

While highly selective for VEGFR-2, rivoceranib also demonstrates inhibitory activity, albeit at lower potencies, against other receptor tyrosine kinases implicated in oncogenesis. These include RET (IC50​ = 13 nM), c-Kit (IC50​ = 429 nM), and c-Src (IC50​ = 530 nM).[1] Inhibition of these kinases may contribute to its efficacy in certain tumor types where these pathways are active.

2.2.2. Reversal of Multidrug Resistance (MDR)

A particularly noteworthy and differentiating feature of rivoceranib is its ability to circumvent multidrug resistance. Preclinical studies have demonstrated that rivoceranib can reverse MDR mediated by ATP-binding cassette (ABC) transporters, specifically ABCB1 (also known as P-glycoprotein or P-gp) and ABCG2 (also known as breast cancer resistance protein or BCRP).[1] These transporters function as cellular efflux pumps, actively removing a wide range of chemotherapeutic agents from cancer cells and thereby reducing their efficacy. By inhibiting the function of these pumps, rivoceranib increases the intracellular accumulation and cytotoxic effect of conventional antineoplastic drugs.[1] This mechanism provides a strong scientific basis for combining rivoceranib with standard chemotherapy, particularly in tumors that have developed resistance.

2.2.3. Modulation of the Tumor Immune Microenvironment (TME)

Emerging evidence indicates that the VEGF/VEGFR-2 signaling pathway plays a significant role in creating an immunosuppressive tumor microenvironment (TME). VEGF can promote the proliferation and recruitment of immunosuppressive cell populations, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), while impairing the function and maturation of dendritic cells.[2] By inhibiting VEGFR-2, rivoceranib can help reverse these effects. It has been shown to decrease the expression of immune checkpoints like PD-1 on cytotoxic T lymphocytes (CTLs) and enhance the secretion of immune-activating cytokines such as interferon-gamma (

IFN−γ) and interleukin-2 (IL−2).[2] This immunomodulatory effect helps to convert an immunosuppressive TME into one that is more permissive to an antitumor immune response. This provides a compelling mechanistic rationale for the observed synergy between rivoceranib and PD-1 inhibitors like camrelizumab, as demonstrated in the CARES-310 trial.[38] Rivoceranib's ability to normalize tumor vasculature may also improve T-cell infiltration into the tumor, further enhancing the efficacy of immunotherapy.[38]

2.3. Pharmacodynamics: In Vitro and In Vivo Activity

The antitumor effects of rivoceranib have been extensively validated in both cell-based assays and animal models. In vitro studies using osteosarcoma cell lines have shown that rivoceranib effectively induces apoptosis, as demonstrated by an increase in the levels of cleaved poly (ADP-ribose) polymerase (PARP) and a higher number of TUNEL-positive cells. Furthermore, it causes cell-cycle arrest in the G0/G1 phase, which is associated with a corresponding decrease in the expression of cyclin D1.[23]

In vivo studies using human tumor xenograft models in mice have confirmed these findings, showing that oral administration of rivoceranib leads to significant inhibition of tumor growth. Analysis of tumor tissue from these models revealed molecular changes consistent with its mechanism of action, including decreased expression of VEGFR2, phosphorylated Signal Transducer and Activator of Transcription 3 (p-STAT3), and the anti-apoptotic protein BCL-2, alongside an increase in the pro-apoptotic protein Bax.[23] These preclinical data provided a robust foundation for its clinical development, demonstrating direct effects on cancer cell cycle and survival in addition to its primary anti-angiogenic activity.

2.4. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of rivoceranib has been characterized in several clinical studies, providing key insights into its absorption, metabolism, and potential for drug interactions.

2.4.1. Absorption and Food Effect

Rivoceranib is an orally bioavailable agent.[1] Following a single oral dose, absorption is relatively rapid, with the time to reach maximum plasma concentration (

Tmax​) ranging from approximately 2 to 6 hours, depending on the dose level.[39] A critical consideration for clinical administration is the effect of food on its absorption. Studies in healthy volunteers have shown that this effect is dose-dependent. At a lower dose of 81 mg, food intake does not significantly alter bioavailability. However, at a higher dose of 201 mg, co-administration with food can increase bioavailability by 20% to 40% and also delays the median

Tmax​.[40] This interaction implies that for consistent exposure, patients should be advised to take rivoceranib in a standardized manner relative to meals.

2.4.2. Metabolism and Drug-Drug Interactions

Rivoceranib is metabolized extensively in the liver. The primary pathway for its metabolism is via the cytochrome P450 (CYP) enzyme system, with CYP3A4/5 being the major contributor. Minor metabolic roles are played by CYP2D6, CYP2C9, and CYP2E1.[41] This reliance on CYP3A4/5 makes rivoceranib susceptible to interactions with strong inhibitors or inducers of this enzyme.

Furthermore, a dedicated drug-drug interaction (DDI) study revealed that rivoceranib itself is an inhibitor of several key CYP enzymes. It acts as a weak inhibitor of CYP2C9 and a moderate inhibitor of CYP2C19, CYP2D6, and CYP3A4.[41] This DDI profile presents a significant clinical management consideration, as co-administration of rivoceranib with drugs that are substrates for these enzymes could lead to increased exposure and potential toxicity of the co-administered agents. Given that cancer patients often receive multiple supportive care medications (e.g., antiemetics, analgesics, proton pump inhibitors) that are metabolized by these pathways, a thorough medication review is essential before initiating rivoceranib therapy, and dose adjustments of concomitant medications may be necessary.

In addition to CYP-mediated interactions, other clinically relevant interactions have been identified. Co-administration of rivoceranib with various local anesthetics (e.g., benzocaine, lidocaine, procaine) and certain other drugs can increase the risk of methemoglobinemia.[25] There is also an increased risk of thrombosis when rivoceranib is combined with erythropoiesis-stimulating agents such as darbepoetin alfa and erythropoietin.[25] These interactions are summarized in Table 2.

Table 2: Summary of Pharmacokinetic Parameters and Drug Interactions

PK Parameter / Interaction	Finding/Result	Clinical Implication	Source(s)
Administration Route	Oral	Orally bioavailable small molecule.	1
Food Effect	Dose-dependent: No significant effect at 81 mg; 20-40% increase in bioavailability at 201 mg. Tmax​ is delayed with food.	Patients should take rivoceranib consistently with respect to meals to ensure predictable exposure, especially at higher doses.	40
Tmax​ (Single Dose)	~2 to 6 hours.	Relatively rapid absorption.	39
Metabolism	Primarily hepatic, via CYP3A4/5, with minor roles for CYP2D6, CYP2C9, and CYP2E1.	Co-administration with strong CYP3A4/5 inhibitors or inducers should be approached with caution.	41
CYP Inhibition Profile	Weak inhibitor of CYP2C9. Moderate inhibitor of CYP2C19, CYP2D6, and CYP3A4.	May increase exposure of co-administered drugs that are substrates of these enzymes. Dose adjustments and/or careful monitoring may be required.	41
Other Interactions	Increased risk of methemoglobinemia with local anesthetics (e.g., benzocaine, lidocaine). Increased risk of thrombosis with erythropoiesis-stimulating agents.	Avoid or use with caution co-administration of these agents.	25

Section 3: Clinical Efficacy in Solid Tumors

The clinical development of rivoceranib has spanned multiple solid tumor types, with the most extensive data available for gastric/GEJ cancer and hepatocellular carcinoma. The results highlight a notable difference in its efficacy as a monotherapy versus its role as a synergistic partner in combination regimens.

3.1. Gastric and Gastroesophageal Junction (GEJ) Cancer

Rivoceranib was the first TKI to be approved for the treatment of gastric cancer, a milestone achieved based on robust clinical data from trials conducted in China.

3.1.1. Pivotal Trials in China Leading to NMPA Approval

The initial approval of rivoceranib (as apatinib) in China was supported by a randomized, double-blind, placebo-controlled Phase III trial in patients with advanced or metastatic gastric or GEJ adenocarcinoma who had failed at least two prior lines of chemotherapy.[42] The study demonstrated a statistically significant and clinically meaningful improvement in survival outcomes. Patients treated with apatinib (850 mg once daily) had a median overall survival (OS) of 6.5 months, compared to 4.7 months for those receiving placebo (Hazard Ratio 0.709; p = 0.0156). Similarly, median progression-free survival (PFS) was significantly prolonged, at 2.6 months for apatinib versus 1.8 months for placebo (HR 0.444; p < 0.001).[42] Based on these positive results, the China National Medical Products Administration (NMPA) approved apatinib in December 2014 for this indication.[1] Subsequent large-scale, real-world Phase IV studies, such as the AHEAD study involving over 2,000 patients, have confirmed the safety and efficacy of apatinib in clinical practice in China, reporting a median OS of 5.8 months.[45]

3.1.2. In-Depth Analysis of the Global Phase III ANGEL Study (NCT03042611)

To validate these findings in a global population, the ANGEL study was conducted. This multinational, randomized, double-blind, placebo-controlled Phase III trial enrolled 460 patients with advanced/metastatic gastric or GEJ cancer who had progressed after at least two lines of therapy.[7] The results of the ANGEL study, however, were more complex than the initial Chinese trials.

The study failed to meet its primary endpoint of overall survival in the full intent-to-treat (ITT) population. The median OS was 5.78 months in the rivoceranib arm (700 mg once daily) versus 5.13 months in the placebo arm, a difference that was not statistically significant (HR 0.93; 95% CI 0.74–1.15; p = 0.4724).[7] The discrepancy between the positive Chinese trial and the neutral global trial may be attributable to several factors, including potential differences in patient genetics, variations in prior lines of standard-of-care therapy across regions, and the increasing availability of effective post-study anticancer therapies in the global setting, which may have improved survival in the placebo arm and diluted the treatment effect.

Despite the negative primary endpoint, rivoceranib demonstrated clear biological activity, with statistically significant improvements in all key secondary endpoints. Median PFS, as assessed by a blinded independent central review (BICR), was significantly longer with rivoceranib at 2.83 months compared to 1.77 months with placebo (HR 0.58; p < 0.0001). The objective response rate (ORR) was 6.5% versus 1.3% (p = 0.0119), and the disease control rate (DCR) was 40.3% versus 13.2% (p < 0.0001).[7]

Crucially, a prespecified subgroup analysis revealed a significant OS benefit in the most heavily pre-treated patients—those receiving rivoceranib as a fourth-line or later therapy. In this cohort, median OS was 6.34 months with rivoceranib versus 4.73 months with placebo (p = 0.0192), suggesting a distinct clinical niche for rivoceranib monotherapy in a highly refractory patient population.[7] The key results are summarized in Table 3.

Table 3: Pivotal Phase III ANGEL Study Results in Gastric/GEJ Cancer

Endpoint	Rivoceranib + BSC	Placebo + BSC	Hazard Ratio (95% CI)	p-value
Median OS (ITT Population)	5.78 months	5.13 months	0.93 (0.74–1.15)	0.4724
Median OS (≥4th Line Subgroup)	6.34 months	4.73 months	0.65 (0.46–0.92)	0.0192
Median PFS (ITT, by BICR)	2.83 months	1.77 months	0.58 (0.47–0.71)	< 0.0001
Median PFS (≥4th Line, by BICR)	3.52 months	1.71 months	0.38 (0.27–0.53)	< 0.0001
ORR (ITT)	6.5%	1.3%	N/A	0.0119
DCR (ITT)	40.3%	13.2%	N/A	< 0.0001
Data sourced from.7 BSC: Best Supportive Care; ITT: Intent-to-Treat; BICR: Blinded Independent Central Review.

3.2. Hepatocellular Carcinoma (HCC)

In contrast to the mixed results of monotherapy in gastric cancer, rivoceranib has demonstrated profound and practice-changing efficacy in HCC when used in combination with immunotherapy. This shift highlights that the drug's optimal role may be as a synergistic partner rather than a standalone agent.

3.2.1. Landmark Phase III CARES-310 Study (NCT03764293)

The CARES-310 study was a global, randomized, open-label Phase III trial that established a new standard of care. It compared the combination of rivoceranib (250 mg once daily) and the anti-PD-1 antibody camrelizumab (200 mg every 2 weeks) against sorafenib monotherapy in 543 patients with previously untreated, unresectable HCC.[4]

The trial was a resounding success, meeting both of its primary endpoints. The final survival analysis, with a median follow-up of over 22 months in the combination arm, reported a median OS of 23.8 months for the rivoceranib/camrelizumab combination, compared to 15.2 months for sorafenib (HR 0.64; 95% CI 0.52–0.79; p < 0.0001). This result represents the longest median OS ever reported in a global Phase III trial for first-line uHCC.[3] The survival benefit was sustained over time, with a 36-month OS rate of 37.7% for the combination versus 24.8% for sorafenib.[6]

The combination also significantly improved median PFS, another primary endpoint: 5.6 months versus 3.7 months for sorafenib (HR 0.54; 95% CI 0.44–0.67; p < 0.0001).[5] Furthermore, the ORR was substantially higher at 26.8% for the combination compared to 5.9% for sorafenib, with a more durable response (median duration of response of 17.5 months vs. 9.2 months).[52] A key finding was the consistency of the treatment benefit across all major subgroups, including patients from different geographic regions (Asia vs. non-Asia) and those with viral (Hepatitis B or C) or non-viral etiologies of HCC.[53] These landmark results, summarized in Table 4, form the basis of regulatory submissions for this combination worldwide.

Table 4: Pivotal Phase III CARES-310 Study Results in Hepatocellular Carcinoma

Endpoint	Rivoceranib + Camrelizumab	Sorafenib	Hazard Ratio (95% CI)	p-value
Median OS (Final Analysis)	23.8 months	15.2 months	0.64 (0.52–0.79)	< 0.0001
OS Rate at 24 Months	49.0%	36.2%	N/A	N/A
OS Rate at 36 Months	37.7%	24.8%	N/A	N/A
Median PFS	5.6 months	3.7 months	0.54 (0.44–0.67)	< 0.0001
ORR	26.8%	5.9%	N/A	N/A
Median DoR	17.5 months	9.2 months	N/A	N/A
Data sourced from.3 DoR: Duration of Response.

3.2.2. Combination with Transarterial Chemoembolization (TACE)

Rivoceranib is also being explored in combination with locoregional therapies for HCC. The Phase II CARES-005 study found that adding camrelizumab and rivoceranib to TACE resulted in a significant improvement in PFS compared to TACE alone (10.8 months vs. 3.2 months; HR 0.34) in patients with unresectable HCC.[56] This promising strategy is being further investigated in ongoing Phase III trials (NCT05320692) and in the perioperative and conversion therapy settings (NCT05613478, NCT06796803).[58]

3.3. Adenoid Cystic Carcinoma (ACC)

Rivoceranib has shown promising activity in ACC, a rare and challenging malignancy. The Phase II RM-202 trial (NCT04119453), conducted in the U.S. and South Korea, evaluated rivoceranib monotherapy in patients with recurrent or metastatic ACC with documented disease progression.[61] The study reported an ORR of 15.3% and a median PFS of 9.0 months. The DCR was 65.3%.[61] These results are particularly encouraging in a disease with limited treatment options. In recognition of this potential, rivoceranib has received Orphan Drug Designation from the FDA for the treatment of ACC.[32]

3.4. Investigational Use in Other Malignancies

The broad mechanism of action of rivoceranib has prompted its investigation across a wide array of other solid tumors. Clinical trials are ongoing or have been completed to evaluate its efficacy, often in combination regimens, for metastatic colorectal cancer (with LONSURF), non-small cell lung cancer (NSCLC), breast cancer, ovarian cancer, and gastrointestinal stromal tumors (GIST).[1] These studies underscore the extensive effort to define the full therapeutic potential of rivoceranib across the oncological landscape.

Section 4: Safety, Tolerability, and Risk Management

4.1. Overview of the Safety Profile

Rivoceranib has been evaluated in a large patient population, with over 6,000 individuals treated in clinical trials worldwide.[3] Its safety profile is generally considered manageable and is consistent with the known class effects of VEGFR-2 inhibitors and other TKIs.[3] The most common adverse events (AEs) are predictable and can typically be managed through supportive care, dose interruption, or dose reduction, allowing many patients to continue treatment.[46]

4.2. Common and Serious Adverse Events

Across numerous clinical trials, a consistent pattern of treatment-related adverse events (TRAEs) has emerged. The most frequently reported toxicities are direct consequences of VEGFR pathway inhibition.

• Common Adverse Events (All Grades):
• Hypertension: This is the most common AE associated with rivoceranib, with an all-grade incidence often reported between 30% and 45%.[7]
• Proteinuria: Another common class effect, with an incidence of approximately 25% to 30%.[7]
• Hand-Foot Skin Reaction (HFSR) or Palmar-Plantar Erythrodysesthesia (PPES): Characterized by redness, swelling, and pain on the palms and soles, this occurs in about 10% to 15% of patients.[46]
• Constitutional and Gastrointestinal Symptoms: Fatigue or asthenia, decreased appetite, diarrhea, and nausea are also frequently observed.[7]
• Hematological Toxicities: Anemia, thrombocytopenia (decreased platelet count), and leukopenia (decreased white blood cell count) are common hematological AEs.[45]
• Grade ≥3 Adverse Events: The safety profile of rivoceranib is influenced by whether it is used as a monotherapy or in combination with other agents.
• Monotherapy (ANGEL Study): In patients receiving rivoceranib 700 mg daily, the most common Grade ≥3 TRAEs were hypertension (17.9%), anemia (10.4%), increased aspartate aminotransferase (AST) (9.4%), asthenia (8.5%), and proteinuria (7.5%).[7]
• Combination Therapy (CARES-310 Study): When combined with camrelizumab, the incidence of certain Grade ≥3 TRAEs was notably higher. The most frequent were hypertension (38.2%), increased AST (17%), increased alanine aminotransferase (ALT) (13%), and PPES (12%).[68] The higher rates of hypertension and hepatotoxicity (elevated liver enzymes) with the combination regimen underscore the need for vigilant monitoring, though the overall safety profile was deemed manageable in the context of the significant efficacy benefit. This increased toxicity represents a critical factor in clinical decision-making, where the potential for improved survival must be balanced against the need for more intensive management of side effects.
• Serious and Rare Adverse Events: Although less common, serious AEs have been reported. These include bleeding events, such as epistaxis (nosebleeds) and gastrointestinal hemorrhage, and, rarely, gastric perforation.47 One grade 5 (fatal) event of epistaxis was attributed to rivoceranib in a Phase II study.61

Table 5: Incidence of Common Grade ≥3 Treatment-Related Adverse Events

Adverse Event	ANGEL Study (Rivoceranib Monotherapy)	CARES-310 Study (Rivoceranib + Camrelizumab)
Hypertension	17.9%	38.2%
Increased AST	9.4%	17.0%
Proteinuria	7.5%	5.9%
Anemia	10.4%	5.1%
Decreased Platelet Count	N/A	10.7%
HFSR / PPES	N/A	12.1%
Asthenia / Fatigue	8.5%	3.7%
Data sourced from.7 N/A indicates the event was not reported as a most common Grade ≥3 AE in the specified source.

4.3. Drug-Drug and Drug-Food Interactions

The safe use of rivoceranib requires careful management of potential interactions.

• CYP450-Mediated Interactions: As rivoceranib is a substrate of CYP3A4/5 and a moderate inhibitor of CYP3A4, CYP2C19, and CYP2D6, caution is warranted. Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) or inducers (e.g., rifampin, St. John's Wort) could alter rivoceranib exposure. Conversely, rivoceranib can increase the plasma concentrations of other drugs metabolized by these enzymes, necessitating monitoring or dose adjustments.[41]
• Food Interactions: As detailed in the pharmacokinetics section, food can increase the bioavailability of higher doses of rivoceranib. Patients should be instructed to take the medication consistently with or without food to maintain stable drug levels.[40]
• Other Specific Interactions: Clinicians should be aware of the increased risk of methemoglobinemia when rivoceranib is used with local anesthetics and other specific agents, and the heightened risk of thrombosis when combined with erythropoiesis-stimulating agents.[25]

4.4. Contraindications and Special Populations

While a formal list of contraindications is not available from an approved U.S. or EU label, the exclusion criteria from pivotal clinical trials provide a strong indication of patient populations in whom rivoceranib should be used with caution or avoided. These include:

• Uncontrolled hypertension (e.g., blood pressure > 140/90 mmHg despite medication).[42]
• Patients with a significant bleeding tendency, active bleeding, or those requiring therapeutic anticoagulation.[42]
• History of recent (within 3-6 months) thrombotic or embolic events.[60]
• History of gastrointestinal perforation or fistula within 6 months.[60]
• Non-healing wounds or fractures.[60]
• Clinically significant cardiovascular disease.[60]

In elderly patients (≥60 years), a Phase II study demonstrated that rivoceranib was effective and relatively tolerable. However, hypertension remained a significant Grade 3/4 toxicity, suggesting that while age is not an absolute contraindication, careful monitoring is required in this population.[72]

Section 5: Dosage and Administration

5.1. Recommended and Investigational Dosing Regimens

The dosage of rivoceranib has varied significantly across clinical trials, depending on the indication and whether it is administered as a monotherapy or as part of a combination regimen. This variability reflects a strategy to balance efficacy with tolerability.

• Monotherapy Dosing:
• Early Phase I dose-escalation studies established a maximum tolerated dose (MTD) of 850 mg/day of the mesylate salt.[1]
• Subsequent Phase I/IIa studies determined a recommended Phase 2 dose (RP2D) of 685 mg once daily (equivalent to 850 mg of rivoceranib mesylate).[33]
• In the global Phase III ANGEL study for gastric cancer, a dose of 700 mg once daily was used.[7]
• The pivotal Chinese Phase III trial that led to NMPA approval for gastric cancer used a dose of 850 mg once daily.[42]
• Combination Therapy Dosing:
• A notable shift in dosing strategy is seen in combination regimens. In the landmark Phase III CARES-310 trial for HCC, a significantly lower dose of 250 mg once daily was used in combination with camrelizumab.[4]
• In a Phase I/II study evaluating rivoceranib with paclitaxel for advanced gastric cancer, the RP2D was determined to be 400 mg once daily.[64]

The substantial dose reduction from monotherapy (~700-850 mg) to the successful HCC combination regimen (250 mg) is a critical observation. It suggests that a lower, more tolerable dose may be sufficient to achieve the desired immunomodulatory and anti-angiogenic effects that synergize with checkpoint inhibition. In contrast, higher doses appear necessary to exert maximal direct antitumor pressure when rivoceranib is used as a single agent. This finding has important implications for the design of future TKI and immunotherapy combination trials, indicating that the optimal dose for synergy may be different from the MTD established for monotherapy.

5.2. Dose Modifications for Adverse Event Management

Across all clinical trials, a key component of the treatment protocol is the proactive management of adverse events through dose adjustments. Dose interruptions or reductions are standard practice for managing common toxicities such as Grade ≥3 hypertension, proteinuria, and hand-foot skin reaction.[46] For instance, in the Chinese Phase III gastric cancer trial, the protocol allowed for up to three dose reductions in a given cycle, down to a minimum dose of 375 mg once daily, to manage AEs while allowing patients to continue benefiting from the therapy.[42] This flexible dosing strategy is crucial for maintaining treatment duration and optimizing the therapeutic window of the drug.

Section 6: Regulatory and Development History

The journey of rivoceranib from laboratory synthesis to its current regulatory status is a complex narrative involving multiple companies, distinct regional strategies, and significant regulatory challenges that highlight the intricacies of global pharmaceutical development.

6.1. Discovery and Corporate Development Timeline

The development of rivoceranib began in the United States but quickly evolved into a dual-track program with separate commercial rights for China and the rest of the world. This bifurcation has profoundly influenced its naming, clinical trial programs, and regulatory outcomes.

The molecule was first synthesized in 2004 by Advenchen Laboratories, a company based in California, under the designation YN968D1.[1] Recognizing its potential, Advenchen licensed the commercial rights for the territory of China to

Jiangsu Hengrui Medicine Co., Ltd. in 2005. Subsequently, in 2007-2008, the rights for all other global territories were licensed to LSK BioPharma (LSKB), a U.S.-based company.[2]

Over the following decade, Jiangsu Hengrui successfully developed and commercialized the drug in China under the name apatinib. In parallel, LSKB advanced its global clinical program under the name rivoceranib. LSKB was later acquired by the South Korean company HLB Co., Ltd., and now operates as its subsidiary, Elevar Therapeutics. Elevar Therapeutics holds the global rights (ex-China), while another HLB affiliate, HLB Life Science, holds specific rights for Korea, Europe, and Japan.[1] This corporate history is summarized in Table 6.

Table 6: Timeline of Key Development and Regulatory Milestones

Year	Milestone	Key Corporate Entity	Significance	Source(s)
2004	Discovery and synthesis of YN968D1	Advenchen Laboratories	Origination of the molecule.	2
2005	Licensing of China rights	Jiangsu Hengrui Medicine	Initiated the drug's development pathway in China.	2
2007	Licensing of global rights (ex-China)	LSK BioPharma (Elevar)	Initiated the drug's development pathway for the U.S., Europe, and other regions.	2
2014	NMPA approval for advanced gastric cancer	Jiangsu Hengrui Medicine	First regulatory approval worldwide; established as standard therapy in China.	1
2018	Adoption of INN "Rivoceranib"	LSK BioPharma (Elevar)	Formalized the generic name for global development.	22
2020	NMPA approval for 2nd-line advanced HCC	Jiangsu Hengrui Medicine	Expanded indications within China.	9
2023	NMPA approval for 1st-line uHCC (combo)	Jiangsu Hengrui Medicine	First approval for the combination with camrelizumab.	3
2023	NDA submitted to U.S. FDA for 1st-line uHCC	Elevar Therapeutics	First submission for U.S. market approval based on CARES-310 data.	76
2024	First Complete Response Letter (CRL) from FDA	Elevar Therapeutics	U.S. approval denied due to manufacturing issues with partner drug camrelizumab.	11
2024	EMA Orphan Designation for HCC	Elevar Therapeutics	Provided regulatory incentives and support for European development.	15
2024	NDA resubmitted to and accepted by FDA	Elevar Therapeutics	Second attempt at U.S. approval after addressing initial CRL points.	3
2025	Second Complete Response Letter (CRL) from FDA	Elevar Therapeutics	U.S. approval denied again, citing unresolved issues with camrelizumab.	12

6.2. Global Regulatory Status

The regulatory status of rivoceranib is a tale of two distinct outcomes, reflecting differing regional standards and the complexities of combination drug approvals.

• China (NMPA): Rivoceranib (as apatinib, brand name Aitan®) is a well-established therapeutic agent. It holds three major approvals:

1. Advanced Gastric Cancer: Approved in December 2014 as a third-line or later treatment.[1]
2. Advanced HCC (Monotherapy): Approved in December 2020 as a second-line treatment for patients who have failed or are intolerant to first-line therapy.[9]
3. Unresectable HCC (Combination Therapy): Approved in January 2023 for first-line use in combination with camrelizumab.[3]

• United States (FDA): Rivoceranib is not approved in the United States. Elevar Therapeutics' NDA for the rivoceranib/camrelizumab combination in first-line uHCC has faced significant setbacks.
• The FDA issued a first CRL in May 2024, citing GMP deficiencies at the Hengrui Pharma manufacturing facility for camrelizumab and incomplete Bioresearch Monitoring (BIMO) clinical inspections, which were hindered by COVID-19 travel restrictions. The CRL did not raise concerns about the clinical efficacy or safety data from the CARES-310 trial, nor about the manufacturing of rivoceranib itself.[11]
• After resubmitting the NDA in September 2024, Elevar received a second CRL on March 20, 2025. This second rejection again declined approval, indicating that the issues related to the partner-supplied camrelizumab remained unresolved to the FDA's satisfaction.[12] The path to the U.S. market is therefore blocked until these external manufacturing and regulatory issues are fully addressed.
• Europe (EMA): Rivoceranib is not approved in Europe. However, in July 2024, the EMA granted Orphan Medicinal Product Designation to the rivoceranib/camrelizumab combination for the treatment of HCC.[15] This designation provides regulatory support and market incentives for its development in the EU. Elevar has stated its intention to submit a Marketing Authorisation Application (MAA).[75]

The divergent regulatory paths in China versus the West highlight a critical lesson in modern global drug development. Despite compelling clinical data from a global trial, approval in a major market like the U.S. is not guaranteed if any component of the therapy, particularly one sourced from an international partner, fails to meet the FDA's stringent manufacturing and inspection standards. This case underscores that regulatory risk for combination therapies is shared across all partners and components.

6.3. Orphan Drug Designations

In recognition of its potential to treat rare or serious diseases, rivoceranib has been granted multiple orphan drug designations by regulatory authorities, which provide benefits such as market exclusivity and fee waivers. These include designations for:

• Gastric Cancer: U.S. FDA, EMA, and South Korea's MFDS.[32]
• Adenoid Cystic Carcinoma: U.S. FDA.[3]
• Hepatocellular Carcinoma: U.S. FDA and EMA.[3]

Section 7: Expert Analysis and Future Perspectives

7.1. Synthesis of Efficacy and Safety: Rivoceranib's Place in Therapy

Rivoceranib has unequivocally demonstrated significant biological activity as an anti-cancer agent, primarily through its potent inhibition of VEGFR-2. However, its optimal place in the therapeutic armamentarium is highly dependent on the clinical context and its use as either a monotherapy or a combination agent.

As a monotherapy, its role appears limited. The global ANGEL study in gastric cancer showed that while rivoceranib can delay disease progression, it failed to confer a significant overall survival benefit in a broad, late-line patient population. The positive OS signal in the heavily pre-treated (≥4th line) subgroup suggests a potential niche, but this is unlikely to support broad development as a single agent in earlier settings.

In stark contrast, rivoceranib's potential is fully realized in combination therapy. The landmark results of the CARES-310 trial establish the rivoceranib/camrelizumab regimen as one of the most effective first-line treatments for unresectable HCC, setting a new survival benchmark. This success is not merely additive but synergistic, stemming from rivoceranib's dual ability to inhibit angiogenesis and favorably modulate the tumor immune microenvironment, thereby enhancing the efficacy of the PD-1 inhibitor. This positions rivoceranib as a highly attractive combination partner, not only for immunotherapy but also potentially for chemotherapy, given its ability to reverse multidrug resistance.

The benefit-risk assessment, however, requires careful consideration. The superior efficacy of the HCC combination comes at the cost of increased toxicity, with a substantially higher rate of Grade ≥3 adverse events compared to sorafenib, particularly hypertension and hepatotoxicity.[13] This necessitates proactive and vigilant patient monitoring and management. Furthermore, cost-utility analyses indicate that while the combination is a cost-effective strategy in China, its high price may pose a barrier to adoption in the U.S. market without significant price reductions.[5]

7.2. Analysis of Regulatory Challenges and Path to U.S. Market

The primary impediment to rivoceranib's global success is not clinical but regulatory and logistical. The repeated CRLs from the U.S. FDA, despite acknowledging the strength of the CARES-310 clinical data, have created a significant barrier. The rejections were explicitly tied to unresolved GMP and inspection-related issues at the manufacturing facility of its partner drug, camrelizumab, in China.[11] This situation highlights a critical vulnerability in global co-development strategies: the entire application is only as strong as its weakest regulatory link.

For Elevar Therapeutics and its parent company HLB, the path forward in the U.S. is entirely dependent on their partner, Jiangsu Hengrui, successfully remediating all manufacturing deficiencies to meet the FDA's stringent standards. Until this is accomplished, the compelling clinical data from CARES-310 will remain unactionable for U.S. patients, and rivoceranib will be unable to compete in one of the world's largest pharmaceutical markets.

7.3. Future Research Directions and Unmet Needs

The promising results seen with rivoceranib open several avenues for future research to further define and expand its clinical utility.

• Expanding Combination Strategies: Research should continue to focus on combination therapies. Ongoing trials combining rivoceranib with local therapies like TACE and hepatic arterial infusion chemotherapy (HAIC) for HCC are highly relevant.[57] Its potential to reverse MDR also warrants further investigation in combination with standard chemotherapies like paclitaxel or trifluridine/tipiracil (LONSURF) in indications such as gastric and colorectal cancer.[32]
• Advancing into Earlier Lines of Therapy: Given the profound efficacy of the rivoceranib/camrelizumab combination in the first-line metastatic setting, a logical next step is to evaluate its role in earlier disease stages. Investigating its use in the neoadjuvant or adjuvant settings for resectable gastric or liver cancer could potentially improve cure rates.[58]
• The "Comparator Problem" and Market Positioning: A significant challenge for the rivoceranib/camrelizumab combination in HCC is the evolution of the standard of care. The CARES-310 trial used sorafenib as its comparator, which was the standard when the trial was designed. However, in the intervening years, the combination of atezolizumab and bevacizumab became the established first-line standard of care in the U.S. and Europe. Even if approved, rivoceranib/camrelizumab will enter the market without direct, head-to-head data against the current market leader. While cross-trial comparisons of median OS appear favorable, the lack of direct evidence will create a significant hurdle for clinical adoption and reimbursement negotiations.[85] Future studies may need to address this evidence gap to secure a strong market position.
• Biomarker Development: A persistent unmet need for anti-angiogenic therapies is the lack of robust predictive biomarkers. To move beyond a one-size-fits-all approach, future research must focus on identifying molecular or clinical signatures that can predict which patients are most likely to respond to rivoceranib. This would allow for more personalized treatment selection, maximizing benefit and avoiding unnecessary toxicity for non-responders.[65]

In summary, rivoceranib stands as a potent and versatile anti-cancer agent whose full potential is best unlocked through strategic combination therapies. Its future in oncology will be shaped by its ability to overcome current regulatory hurdles, generate comparative effectiveness data against modern standards of care, and advance into earlier stages of disease.

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