Chiauranib (Ibcasertib): A Comprehensive Monograph on a Novel Triple-Pathway Kinase Inhibitor

Executive Summary

Chiauranib, also known by its proposed International Nonproprietary Name (INN) Ibcasertib and developmental code CS-2164, is an orally administered, investigational small molecule antineoplastic agent representing a novel approach to cancer therapy.[1] It is a new chemical entity originally designed and developed by the Chinese biopharmaceutical firm Shenzhen Chipscreen Biosciences, which holds its global patent protection.[4] The core innovation of Chiauranib lies in its unique and synergistic triple-pathway mechanism of action, which is engineered to simultaneously attack three distinct hallmarks of cancer: tumor angiogenesis, unregulated cell mitosis, and the immunosuppressive tumor microenvironment.[4] This multi-pronged strategy distinguishes it from many single-target tyrosine kinase inhibitors (TKIs) and is intended to overcome the therapeutic limitations and resistance mechanisms often associated with more narrowly focused agents.[8]

At the molecular level, Chiauranib functions as a high-potency inhibitor of several key protein kinases. It demonstrates inhibitory concentrations in the half-maximal range () within the single-digit nanomolar scale against its primary targets.[9] These targets include: 1) angiogenesis-related kinases such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs); 2) the mitosis-related serine/threonine kinase Aurora B; and 3) the chronic inflammation-related kinase, colony-stimulating factor 1 receptor (CSF-1R).[1] Preclinical studies have underscored the high selectivity of Chiauranib, with minimal activity against a wide panel of off-target kinases and proteins, suggesting a potentially favorable safety profile.[9]

The clinical development program for Chiauranib is focused on addressing significant unmet needs in oncology. The most advanced investigations are in heavily pre-treated small cell lung cancer (SCLC) and platinum-resistant or refractory ovarian cancer, indications where conventional therapies have limited efficacy.[9] Preliminary results from Phase I and II clinical trials have demonstrated encouraging anti-tumor activity in these challenging patient populations.[9] The therapeutic potential of Chiauranib has been recognized by regulatory authorities; it has received "Breakthrough Therapy Designation" from China's National Medical Products Administration (NMPA) for both SCLC and ovarian cancer.[6] Furthermore, it has been granted Investigational New Drug (IND) clearance and Orphan Drug Designation for SCLC by the U.S. Food and Drug Administration (FDA), facilitating its clinical evaluation in the United States.[6] These milestones highlight Chiauranib's promise as an important emerging therapy in the global oncology landscape.

Section 1: Physicochemical Characteristics and Formulation

1.1. Drug Identification and Nomenclature

Chiauranib is identified by a consistent set of names and chemical registry numbers across scientific literature, clinical trial databases, and commercial datasheets. This standardization is crucial for accurate tracking and research. The primary identifiers for the compound are as follows:

• Generic Name (pseudo INN): Chiauranib [18]
• Proposed INN: Ibcasertib [1]
• Developmental Codes: CS-2164, CS2164 [1]
• DrugBank ID: DB16124 [3]
• CAS Number: 1256349-48-0 [2]
• IUPAC Name: N-(2-aminophenyl)-6-((7-methoxyquinolin-4-yl)oxy)-1-naphthamide [2]

1.2. Chemical Structure and Properties

Chiauranib is a synthetic organic compound classified as a fused-ring heterocyclic compound, specifically a derivative of naphthalenes and quinolines.[18] Its chemical formula is

, corresponding to a molecular weight of approximately 435.48 g/mol.[2] In its purified form, it presents as a white solid powder.[2]

The compound's solubility profile is characteristic of many orally administered kinase inhibitors. It is soluble in organic solvents such as dimethyl sulfoxide (DMSO) and methanol but demonstrates very low water solubility, with a predicted value of 0.000363 mg/mL.[2] This inherent hydrophobicity is a key consideration for its pharmaceutical formulation to ensure adequate bioavailability upon oral ingestion. Its lipophilicity is reflected in a high predicted partition coefficient (logP) of approximately 4.8.[18] Despite this, the molecule's properties are consistent with established guidelines for oral drug candidates, such as Lipinski's Rule of Five, which it is predicted to pass.[18] A comprehensive summary of its identifiers and physicochemical properties is provided in Table 1.

Table 1: Key Identifiers and Physicochemical Properties of Chiauranib (Ibcasertib)
Identifier/Property	Value	Source
DrugBank ID	DB16124	18
CAS Number	1256349-48-0	18
IUPAC Name	N-(2-aminophenyl)-6-((7-methoxyquinolin-4-yl)oxy)-1-naphthamide	2
InChI Key	BRKWREZNORONDU-UHFFFAOYSA-N	18
Molecular Formula		2
Molecular Weight	435.48 g/mol	2
Water Solubility	0.000363 mg/mL (predicted)	18
logP	4.82 (predicted)	18
pKa (Strongest Basic)	5.69 (predicted)	18
Polar Surface Area	86.47 Ų (predicted)	18
Rule of Five Compliance	Yes (predicted)	18
Ghose Filter Compliance	Yes (predicted)	18
Bioavailability	1 (predicted)	18

1.3. Formulation and Administration

For clinical use, Chiauranib is formulated as an oral capsule, facilitating patient self-administration and continuous daily dosing regimens.[9] Clinical investigations have explored a range of once-daily (QD) doses, from 10 mg up to 65 mg.[20] The Phase I dose-escalation study established 50 mg QD as both the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for monotherapy, and this dose has been carried forward into later-stage pivotal trials.[9]

Section 2: Preclinical Pharmacology and Mechanism of Action

2.1. Multi-Target Kinase Inhibition Profile

Chiauranib is a potent, orally active inhibitor that targets a select group of serine-threonine and receptor tyrosine kinases that are fundamental to tumor progression.[1] Its inhibitory activity is highly potent, with

 values in the single-digit nanomolar range for its primary targets. This high potency is a critical attribute, as it allows for effective target engagement at clinically achievable drug concentrations.[9] The specific kinases inhibited by Chiauranib can be categorized by their primary biological function:

• Angiogenesis-Related Kinases: Chiauranib potently inhibits key receptor tyrosine kinases that drive the formation of new blood vessels (angiogenesis), a process essential for tumor growth and metastasis. These include VEGFR1 ( = 8 nM), VEGFR2 ( = 7 nM), VEGFR3 ( = 9 nM), PDGFRα ( = 1 nM), PDGFRβ ( = 93 nM), and c-Kit ( = 4 nM).[12]
• Mitosis-Related Kinase: The drug targets Aurora B, a serine-threonine kinase that plays a crucial role in cell division ( = 9 nM).[12]
• Inflammation-Related Kinase: Chiauranib inhibits CSF-1R, also known as c-Fms, a receptor tyrosine kinase that regulates the function of macrophages ( = 7 nM).[12]

A defining feature of Chiauranib's pharmacological profile is its high selectivity. Extensive in vitro screening has demonstrated that it has minimal activity against a broad panel of over 70 other kinases, as well as numerous G-protein coupled receptors (GPCRs), phosphatases, and ion channels.[9] This high degree of selectivity for its intended targets over off-targets is a key aspect of its design, as it is expected to minimize off-target toxicities and contribute to a more favorable clinical safety profile compared to less selective kinase inhibitors.

2.2. The Synergistic Triple-Pathway Anti-Tumor Mechanism

The therapeutic strategy of Chiauranib is rooted in its ability to simultaneously disrupt three distinct but interconnected biological processes that are critical for cancer progression. This integrated approach, built into a single molecule, represents a rational design intended to produce a more robust and durable anti-tumor effect than could be achieved by inhibiting any single pathway alone. By concurrently targeting angiogenesis, cell division, and the tumor microenvironment, Chiauranib may be better equipped to overcome the intrinsic and acquired resistance mechanisms that frequently limit the long-term efficacy of single-target agents.

2.2.1. Inhibition of Angiogenesis

By potently inhibiting the VEGFR family of receptors (VEGFR1, 2, and 3), as well as PDGFRs and c-Kit, Chiauranib effectively blocks the primary signaling pathways that tumor cells exploit to induce neovascularization.[11] These receptors, when activated by their respective ligands (VEGF, PDGF), initiate a cascade of events leading to the proliferation and migration of endothelial cells, ultimately forming the new blood vessels that supply tumors with oxygen and nutrients. Preclinical studies have validated this anti-angiogenic activity, showing that Chiauranib inhibits the VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) and reduces tumor vascularization in mouse xenograft models, thereby restricting tumor growth.[13]

2.2.2. Disruption of Mitosis via Aurora B Inhibition

The inhibition of Aurora B kinase is a key mechanistic feature that differentiates Chiauranib from many other anti-angiogenic TKIs. Aurora B is a central component of the chromosomal passenger complex, a master regulator of the mitotic process that ensures the accurate segregation of chromosomes and the completion of cytokinesis.[4] By inhibiting Aurora B, Chiauranib disrupts these essential functions. A direct downstream consequence of Aurora B inhibition is the suppression of its substrate, histone H3, at serine 10. This leads to defects in chromosome condensation and alignment, ultimately causing an arrest of the cell cycle in the G2/M phase and preventing tumor cell proliferation.[12]

This specific anti-mitotic action provides a powerful second mechanism of anti-tumor activity and is particularly relevant for malignancies characterized by rapid cell division and dysregulated cell cycle control, such as neuroendocrine tumors. Small cell lung cancer (SCLC), a primary indication for Chiauranib, is a neuroendocrine carcinoma defined by its aggressive proliferation and a general lack of identifiable and targetable oncogenic driver mutations.[15] For such a disease, directly targeting the machinery of cell division is a highly rational therapeutic strategy. The dual mechanism of Chiauranib—combining the anti-proliferative effect of Aurora B inhibition with the anti-angiogenic effect of VEGFR blockade—provides a compelling mechanistic basis for its observed efficacy in SCLC, offering a potential advantage over agents that target angiogenesis alone.[4]

2.2.3. Modulation of the Tumor Microenvironment

The third pillar of Chiauranib's mechanism is its ability to modulate the tumor microenvironment through the inhibition of CSF-1R.[4] CSF-1R signaling is critical for the recruitment, differentiation, and survival of tumor-associated macrophages (TAMs), a major component of the tumor stroma.[22] TAMs typically adopt an M2-like phenotype, which is immunosuppressive and pro-tumorigenic; they promote angiogenesis, facilitate tumor invasion, and suppress the activity of cytotoxic T-cells. By blocking CSF-1R, Chiauranib can reduce the infiltration and activity of these immunosuppressive TAMs.[4] This action can help to reprogram the tumor microenvironment from an immunosuppressive to an immune-permissive state. This immune-modulatory effect not only contributes to its direct anti-tumor activity but also provides a strong rationale for its use in combination with immunotherapy agents, such as PD-1 or PD-L1 inhibitors. The potential for synergy, where Chiauranib renders the tumor microenvironment more susceptible to T-cell-mediated killing enhanced by immune checkpoint blockade, is a key area of ongoing clinical investigation.[4]

2.3. Elucidation of Downstream Signaling Cascades

Preclinical research has begun to map the specific downstream signaling pathways through which Chiauranib exerts its cellular effects. The most clearly defined cascade involves the VEGFR2/ERK/STAT3 signaling pathway.[24] In preclinical models of follicular lymphoma, treatment with Chiauranib was shown to directly reduce the phosphorylation of VEGFR2. This initial inhibition leads to a sequential blockade of downstream signaling nodes, including reduced phosphorylation of MEK1/2 and its substrate, ERK1/2. The attenuation of the MAPK/ERK pathway, in turn, leads to decreased phosphorylation and activation of the transcription factor STAT3. The ultimate consequence is the altered expression of STAT3 target genes, which are involved in cell survival, proliferation, and angiogenesis, thus culminating in the observed anti-tumor effects of decreased proliferation, increased apoptosis, and reduced angiogenesis in these models.[24]

In addition to this pathway, studies in other cancer models have identified further downstream effects. In acute myeloid leukemia cells, Chiauranib was found to inhibit the Src/Fyn/p38 and Erk/MEK signaling pathways.[7] In models of KRAS wild-type colorectal cancer, Chiauranib's anti-tumor activity was linked to the induction of reactive oxygen species (ROS) and subsequent activation of the p53 tumor suppressor signaling pathway, leading to apoptosis.[26] Together, these findings illustrate how Chiauranib's inhibition of upstream kinases translates into the disruption of multiple critical downstream pathways that govern cancer cell survival and proliferation.

Section 3: Clinical Pharmacokinetics and Metabolism

3.1. Absorption, Distribution, and Elimination

The pharmacokinetic (PK) profile of Chiauranib in humans has been characterized in a Phase I dose-escalation study (NCT02122809) involving patients with advanced solid tumors.[8] Following oral administration, Chiauranib exhibits

rapid absorption into the systemic circulation, followed by a slow elimination phase.[20] This combination of rapid absorption and slow elimination is a favorable characteristic for an oral once-daily therapy, as it allows for the quick attainment of therapeutic concentrations and sustained drug exposure over the dosing interval.

The study demonstrated that the pharmacokinetics of Chiauranib are linear and dose-dependent across the clinically evaluated range of 10 mg to 65 mg. This was observed in both single-dose and multiple-dose analyses, indicating that increases in dose result in proportional increases in plasma concentration and overall drug exposure (as measured by area under the curve, AUC).[8] This predictable PK behavior simplifies dosing and reduces the risk of unexpected accumulation or underexposure at different dose levels.

3.2. Steady-State Dynamics

With continuous once-daily oral administration, plasma concentrations of Chiauranib accumulate over time due to its slow elimination rate. The drug reaches steady-state conditions, where the rate of administration equals the rate of elimination, within approximately 8 days of initiating therapy.[8] At steady state, the total drug exposure was found to be approximately

two-fold higher than the exposure observed after a single dose.[8] This moderate degree of accumulation is consistent with its pharmacokinetic properties and is factored into the long-term dosing strategy to ensure sustained target engagement without excessive accumulation leading to toxicity.

3.3. Metabolism and Excretion

A comprehensive understanding of a drug's absorption, distribution, metabolism, and excretion (ADME) is fundamental to its safe and effective clinical use. While the specific results are not detailed in the available documentation, a critical milestone in characterizing Chiauranib's ADME profile has been achieved. The sponsor, Chipscreen Biosciences, has completed a dedicated mass balance study using radiolabeled [14C]Chiauranib (NCT05371899).[29] The use of a carbon-14 tracer allows for the precise tracking of the drug and all of its metabolites throughout the body following administration.[31]

The completion of such a study is a standard and essential component of a late-stage drug development program, providing definitive data required for regulatory submissions like a New Drug Application (NDA). This type of study quantifies the routes of elimination (i.e., the proportion of the drug and its metabolites excreted in urine versus feces), identifies the major circulating and excretory metabolites, and elucidates the primary metabolic pathways (e.g., oxidation, glucuronidation). This information is vital for several reasons: it helps determine the primary organ of clearance (hepatic vs. renal), informs dosing recommendations for patients with liver or kidney impairment, and provides the basis for predicting and managing potential drug-drug interactions. For instance, understanding the specific cytochrome P450 (CYP) enzymes involved in Chiauranib's metabolism is necessary to issue guidance regarding co-administration with strong inhibitors or inducers of those enzymes, a consideration already reflected in the exclusion criteria of some clinical trials.[32]

Section 4: Clinical Development and Efficacy Analysis

4.1. Efficacy in Small Cell Lung Cancer (SCLC)

Small cell lung cancer represents a major focus of Chiauranib's clinical development, driven by the disease's aggressive nature, propensity for early relapse, and the limited availability of effective targeted therapies.

4.1.1. Monotherapy in Relapsed/Refractory SCLC (≥2 Prior Lines)

The efficacy of Chiauranib as a monotherapy was evaluated in a single-arm, exploratory Phase II study (NCT03216343) in a heavily pre-treated SCLC patient population.[33] The study enrolled 28 patients in China who had experienced disease progression after receiving a platinum-based regimen and at least one other line of chemotherapy.[14] Patients received Chiauranib at the recommended dose of 50 mg once daily.

The results, reported with a median follow-up of 25.6 months, demonstrated clinically meaningful anti-tumor activity.[14] The key efficacy outcomes were:

• Objective Response Rate (ORR): 17.9% (95% Confidence Interval [CI]: 6.06%–36.89%)
• Disease Control Rate (DCR): 64.3% (95% CI: 44.07%–81.36%), indicating that nearly two-thirds of patients experienced either tumor shrinkage or stabilization of their disease.
• Median Progression-Free Survival (PFS): 3.6 months
• Median Duration of Response (DOR): An impressive 8.2 months
• Median Overall Survival (OS): 8.4 months

These efficacy results are particularly noteworthy when placed in the context of the treatment landscape for third-line and later SCLC. Historically, response rates to chemotherapy in this setting are typically in the low single digits, and median overall survival is poor, often in the range of 4 to 5 months. An ORR of nearly 18% and a median OS of over 8 months represent a significant improvement over these historical benchmarks. Furthermore, the durability of the responses, with a median DOR exceeding 8 months, suggests that for the subset of patients who respond, the clinical benefit can be substantial and long-lasting. This promising data provided a strong foundation for advancing Chiauranib into a pivotal Phase 3 study (NCT04830813) to confirm these findings in a larger, randomized setting.[9]

4.1.2. Combination Therapy in First-Line Extensive-Stage SCLC (ES-SCLC)

Building on the positive results in the relapsed/refractory setting, the development strategy for Chiauranib has expanded into first-line therapy for extensive-stage SCLC (ES-SCLC). The current standard of care for this population is a combination of platinum-based chemotherapy and an immune checkpoint inhibitor (anti-PD-L1). While this regimen has improved outcomes compared to chemotherapy alone, long-term survival remains a significant challenge.[4] The therapeutic hypothesis is that adding Chiauranib to this backbone can further enhance efficacy. The rationale is multi-faceted: Chiauranib's anti-angiogenic effects can help normalize the tumor vasculature, improving the delivery of chemotherapy, while its immune-modulatory effects via CSF-1R inhibition may synergize with the PD-(L)1 inhibitor to create a more robust anti-tumor immune response.[4] In November 2024, the NMPA approved the initiation of a Phase III clinical trial to evaluate this triple combination of Chiauranib, a PD-(L)1 monoclonal antibody, and standard chemotherapy in the first-line treatment of ES-SCLC.[4]

4.2. Efficacy in Recurrent Ovarian Cancer

Recurrent, platinum-resistant ovarian cancer is another area of significant unmet need where Chiauranib is being actively investigated, owing to its dual anti-angiogenic and anti-mitotic mechanisms.

4.2.1. Monotherapy and Combination with Chemotherapy in Platinum-Resistant/Refractory Disease

A sequential Phase Ib/II clinical trial program (NCT03166891 and NCT03901118) was conducted to evaluate Chiauranib in Chinese patients with recurrent ovarian cancer.[11]

• Phase Ib (Monotherapy): The initial phase enrolled 25 patients and evaluated Chiauranib as a single agent. This part of the study established preliminary activity, demonstrating a median PFS of 3.7 months.[11]
• Phase II (Combination Therapy): The subsequent phase evaluated Chiauranib in combination with standard single-agent chemotherapies. A total of 43 evaluable patients were randomized to one of two arms:
• Chiauranib + Etoposide (CE group): This arm demonstrated a median PFS of 5.4 months (95% CI: 2.8–5.6).
• Chiauranib + Weekly Paclitaxel (CP group): This arm showed a median PFS of 5.6 months (95% CI: 3.4–7.0).

The results suggest that adding Chiauranib to single-agent chemotherapy improves progression-free survival in this difficult-to-treat population. The median PFS values of 5.4 and 5.6 months in the combination arms compare favorably to the 3.7-month median PFS observed with Chiauranib monotherapy and also exceed the historical median PFS of 3 to 4 months typically seen with single-agent non-platinum chemotherapy in platinum-resistant ovarian cancer. This supports the preclinical hypothesis that Chiauranib can act synergistically with chemotherapy, potentially by increasing tumor sensitivity through its Aurora B inhibition or by exerting a complementary anti-tumor effect through its anti-angiogenic properties.[11] These encouraging Phase II results have prompted a large, randomized, double-blind, placebo-controlled Phase III trial (CHIPRO, NCT04921527) to definitively assess the efficacy of Chiauranib plus weekly paclitaxel versus placebo plus weekly paclitaxel.[41]

4.3. Activity in Other Solid Tumors and Malignancies

The initial Phase I dose-escalation study (NCT02122809) enrolled 18 patients with a variety of refractory advanced solid tumors and lymphomas.[8] While no objective responses (complete or partial) were observed in this diverse, heavily pre-treated cohort, a notable

66.7% of patients (12 out of 18) achieved stable disease (SD).[8] This high rate of disease stabilization provided the first clinical signal of Chiauranib's broad anti-tumor activity and supported its further development across multiple cancer types.

Based on this early signal and the drug's broad mechanism of action, Chiauranib is being investigated in a range of other malignancies. Ongoing or planned Phase II clinical trials in China and the United States are exploring its efficacy in:

• Triple-negative breast cancer [4]
• Advanced or unresectable soft tissue sarcoma (NCT05497843) [4]
• Locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) [4]
• Relapsed/refractory Non-Hodgkin's Lymphoma [18]
• Advanced hepatocellular carcinoma [29]

A summary of the key efficacy outcomes from the most mature clinical trials is presented in Table 2.

Table 2: Summary of Key Efficacy Outcomes from Chiauranib Clinical Trials
Trial ID	Indication	Patient Population (Treatment Line)	Treatment Regimen	N	ORR (%)	DCR (%)	Median PFS (months)
NCT03216343 14	SCLC	Relapsed/Refractory (≥2 prior lines)	Chiauranib 50 mg QD	28	17.9	64.3	3.6
NCT03166891 11	Ovarian Cancer	Platinum-Resistant/Refractory	Chiauranib Monotherapy	25	N/A	N/A	3.7
NCT03901118 11	Ovarian Cancer	Platinum-Resistant/Refractory	Chiauranib + Etoposide	22	N/A	N/A	5.4
NCT03901118 11	Ovarian Cancer	Platinum-Resistant/Refractory	Chiauranib + Paclitaxel	21	N/A	N/A	5.6
NCT02122809 20	Advanced Solid Tumors	Refractory	Chiauranib Monotherapy	18	0	66.7	N/A

Section 5: Safety, Tolerability, and Risk Management

5.1. Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicities (DLT)

The safety and tolerability of Chiauranib were formally established in the Phase I dose-escalation study (NCT02122809).[28] In this study, the

maximum tolerated dose (MTD) was determined to be 50 mg once daily.[8] This conclusion was based on the observation of dose-limiting toxicities (DLTs) at the next highest dose level of 65 mg/day. Specifically, two patients treated at 65 mg experienced

Grade 3 hypertension, which met the protocol-defined criteria for a DLT.[8] Consequently, the 50 mg dose was selected as the MTD and the recommended dose for subsequent Phase II and III studies.

5.2. Analysis of Adverse Events (AEs)

Across clinical trials, Chiauranib has demonstrated a manageable and generally predictable safety profile, with most adverse events (AEs) being mild to moderate (Grade 1-2) in severity.[20]

Monotherapy Profile

In the monotherapy setting, the most frequently reported treatment-related AEs are consistent with the known class effects of its targeted pathways. Data from the Phase I study identified the following as the most common AEs [20]:

• Fatigue (61.1%)
• Proteinuria (44.4%)
• Hematuria (38.9%)
• Hypothyroidism (38.9%)
• Hypertriglyceridemia (33.3%)
• Hypertension (33.3%)

Combination Therapy Profile

When Chiauranib is administered in combination with chemotherapy, the safety profile reflects the toxicities of both agents. In the Phase II ovarian cancer study, the addition of Chiauranib to etoposide or paclitaxel led to an increase in hematological toxicities. Neutropenia and leucopenia were the most prominent AEs, with Grade 3-4 neutropenia occurring in 25.0% of patients in the etoposide arm and 54.5% in the paclitaxel arm.[11]

Clinically Significant (Grade ≥3) AEs

The most common clinically significant (Grade 3 or higher) AEs reported across studies include hypertension (up to 27.3% in the paclitaxel combination cohort), hyponatremia (14.3% in the SCLC monotherapy study), and the aforementioned hematological toxicities in combination regimens.[11]

The overall pattern of adverse events observed with Chiauranib is largely consistent with its multi-target mechanism of action. Many of the most common toxicities are well-recognized class effects of agents that inhibit the VEGF signaling pathway. For example, hypertension, proteinuria, and an increased risk of bleeding are on-target effects related to the inhibition of VEGFR, which plays a role in maintaining endothelial cell function and vascular homeostasis. Similarly, fatigue and hypothyroidism are known side effects associated with various TKIs. This predictable safety profile suggests that the adverse events are mechanistically driven and, for the most part, can be anticipated and managed with standard supportive care, monitoring, and dose modifications as required by experienced clinicians. The fact that the majority of AEs have been low-grade and manageable supports the developer's claim of a favorable overall safety profile.[20]

5.3. Contraindications, Warnings, and High-Risk Populations

A comprehensive understanding of populations at higher risk for adverse events can be derived from the exclusion criteria applied across Chiauranib's clinical trial protocols. These criteria effectively function as a list of contraindications and warnings for the investigational use of the drug. Key patient groups excluded from trials, and therefore considered high-risk, include those with the following conditions [8]:

• Cardiovascular Conditions:
• Uncontrolled hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg on a single agent).
• Recent major cardiovascular events (within 6 months), including myocardial infarction, unstable angina, or congestive heart failure (NYHA Class II or higher).
• Clinically significant arrhythmias requiring treatment.
• Reduced cardiac function, defined as a Left Ventricular Ejection Fraction (LVEF) < 50%.
• History of significant QT interval prolongation (e.g., QTc > 470 ms).
• Hemorrhagic and Thrombotic Risk:
• Active bleeding or conditions associated with a high risk of bleeding, such as tumors invading or encircling major blood vessels.
• History of deep vein thrombosis (DVT) or pulmonary embolism (PE) within the past 6 months.
• Concurrent use of therapeutic anticoagulation (e.g., warfarin).
• Renal Function:
• Significant proteinuria, defined as ≥1g/24h.
• Pulmonary Conditions:
• History of or current interstitial lung disease (ILD), pulmonary fibrosis, or pneumonitis requiring treatment.
• Prior and Concomitant Medications:
• Previous treatment with other Aurora kinase inhibitors or VEGF/VEGFR inhibitors.
• Co-administration with strong inhibitors or inducers of the CYP3A4 enzyme, particularly during dose-escalation phases.
• General Medical Conditions:
• Symptomatic central nervous system (CNS) metastases.
• Major surgery within 28 days prior to starting treatment, or the presence of non-healing wounds, ulcers, or fractures.
• History of organ transplantation.
• Active, uncontrolled infections requiring systemic treatment.
• Positive serology for HIV.
• Reproductive Status:
• Pregnant or breastfeeding women are strictly excluded.
• Women of childbearing potential and male participants must agree to use highly effective contraception during the study and for at least 12 weeks after the last dose.

Section 6: Regulatory Status and Future Outlook

6.1. Global Regulatory and Development Trajectory

The clinical development of Chiauranib is advancing on a global scale, with significant progress being made primarily in China and the United States.

• China (NMPA): Chiauranib has achieved several key regulatory milestones in its country of origin. It was granted "Breakthrough Therapy Designation" by the NMPA for the treatment of SCLC in December 2020, and subsequently for ovarian cancer.[6] This designation is intended to expedite the development and review of drugs that show substantial improvement over available therapies for serious conditions. The pivotal Phase III trial of Chiauranib monotherapy in later-line SCLC has been completed, and the company is in pre-NDA communication with the NMPA.[4] In a significant recent development in November 2024, the NMPA approved the initiation of a new Phase III trial for Chiauranib in combination with immunotherapy and chemotherapy for the first-line treatment of ES-SCLC.[4]
• United States (FDA): The regulatory pathway in the U.S. is also progressing. In April 2021, Chipscreen Biosciences received IND clearance from the FDA to begin a Phase Ib/II clinical study (NCT05271292) of Chiauranib monotherapy in patients with SCLC and other advanced solid tumors.[6] Further supporting its development, the FDA granted Chiauranib Orphan Drug Designation for the treatment of SCLC in September 2021.[17] This status provides incentives to support the development of drugs for rare diseases.
• Other Regions (EMA/TGA): The provided documentation does not contain specific information regarding regulatory filings or approvals with the European Medicines Agency (EMA) or Australia's Therapeutic Goods Administration (TGA).[50] The current development focus appears to be concentrated on securing approvals in China and advancing clinical trials in the United States.

6.2. Expert Analysis and Strategic Positioning

Chiauranib is positioned as a potentially best-in-class, next-generation multi-targeted TKI. Its developer claims a superior efficacy and safety profile compared to other drugs with similar mechanisms, a claim supported by its high selectivity and manageable on-target toxicities.[1] The drug's most significant strategic advantage lies in its unique triple-pathway mechanism, particularly the inclusion of Aurora B inhibition. This anti-mitotic component provides a strong competitive differentiator, especially in neuroendocrine tumors like SCLC, a therapeutic area that has seen few advances in targeted therapy and remains dominated by chemotherapy.[5]

Should the pivotal trials confirm the promising results seen in Phase II, Chiauranib has the potential to become a new standard of care for patients with later-line SCLC and for those with platinum-resistant ovarian cancer when used in combination with chemotherapy. In both indications, it addresses a profound unmet clinical need for more effective and durable treatment options.[11]

6.3. Future Research and Development Directions

The future development of Chiauranib is likely to proceed along several key strategic paths:

• Biomarker Exploration: A critical objective of the ongoing clinical trials is the identification of predictive biomarkers that can help select patients most likely to benefit from Chiauranib.[9] This is essential for a personalized medicine approach. The preclinical finding that Chiauranib shows selective activity in KRAS wild-type colorectal cancer cells is a prime example of the type of biomarker-driven hypothesis that will likely be explored clinically to optimize its use.[26]
• Expansion of Indications: The broad anti-tumor activity suggested by its mechanism and early clinical data has prompted a wide-ranging investigation into other malignancies. The ongoing Phase II trials in soft tissue sarcoma, pancreatic cancer, and other tumors signal a clear strategy to leverage Chiauranib's unique mechanism across a diverse spectrum of cancers.[1]
• Novel Combination Strategies: The advancement of Chiauranib into a first-line SCLC trial in combination with chemo-immunotherapy is a clear indicator of a key future direction. Its demonstrated ability to modulate the tumor microenvironment by targeting CSF-1R provides a strong scientific rationale for exploring further combinations with a variety of immune-oncology agents, such as other checkpoint inhibitors, CAR-T therapies, or cancer vaccines, to unlock even greater synergistic potential.

Works cited

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