Dalpiciclib (SHR-6390): A Comprehensive Oncological and Pharmacological Monograph

Section 1: Molecular and Physicochemical Profile of Dalpiciclib

1.1. Chemical Identity and Structure

Dalpiciclib is an investigational small molecule drug developed as a targeted therapy for various cancers.[1] Its identity is established through a series of standardized chemical and regulatory identifiers that ensure its precise tracking and characterization in research, clinical, and commercial settings. The generic name for the compound is Dalpiciclib.[1] It is cataloged in major drug databases under the DrugBank Accession Number DB17456 and is uniquely identified by the Chemical Abstracts Service (CAS) Number 1637781-04-4.[1] In developmental and research contexts, it is most commonly referred to by its code, SHR-6390 or SHR6390, and is also known by the synonym "Cdk4/6 inhibitor shr6390".[2] For clinical use and formulation, it is prepared as a salt, Dalpiciclib Isethionate.[5]

The molecule's structure is defined by its formal chemical nomenclature and formula. The International Union of Pure and Applied Chemistry (IUPAC) name for Dalpiciclib is 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperidin-4-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one.[2] This name precisely describes the arrangement of its constituent atoms, which corresponds to the molecular formula

C25​H30​N6​O2​.[1] This formula yields a calculated average molecular weight of 446.555 g/mol and a monoisotopic weight of 446.24302423 Da, values that are critical for analytical chemistry and mass spectrometry.[1] The complex three-dimensional structure is represented computationally by standardized identifiers, including the Simplified Molecular Input Line Entry System (SMILES) string

CC1=C(C(=O)N(C2=NC(=NC=C12)NC3=NC=C(C=C3)C4CCNCC4)C5CCCC5)C(=O)C and the International Chemical Identifier Key (InChIKey) SGJLSPUSUBJWHO-UHFFFAOYSA-N.[2]

A defining feature of Dalpiciclib's molecular architecture is a deliberate design choice made by its developer, Jiangsu Hengrui Pharmaceuticals. The molecule was engineered to lack a 1,4 p-phenylenediamine structure.[7] This modification was a rational design strategy intended to circumvent a specific toxicity mechanism. Previous research has demonstrated that molecules containing this particular moiety can undergo metabolic activation to reactive intermediates that form adducts with glutathione. The accumulation of these glutathione adducts has been mechanistically linked to drug-induced hepatotoxicity.[7] By engineering a molecule that avoids this structural feature, the developers aimed to create a "bio-better" compound with an improved safety profile, specifically a lower risk of liver toxicity, compared to other molecules. This design hypothesis is a cornerstone of Dalpiciclib's potential value proposition and is later supported by clinical data showing a favorable liver safety profile.[7]

Table 1: Key Physicochemical and Identification Properties of Dalpiciclib

Property	Value	Source(s)
Generic Name	Dalpiciclib	1
DrugBank ID	DB17456	1
CAS Number	1637781-04-4	1
Synonyms / Dev. Codes	SHR-6390, SHR6390, Cdk4/6 inhibitor shr6390	2
IUPAC Name	6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperidin-4-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one	2
Molecular Formula	C25​H30​N6​O2​	1
Average Mol. Weight	446.555 g/mol	1
SMILES	CC1=C(C(=O)N(C2=NC(=NC=C12)NC3=NC=C(C=C3)C4CCNCC4)C5CCCC5)C(=O)C	2
InChIKey	SGJLSPUSUBJWHO-UHFFFAOYSA-N	1
Formulation/Trade Name	Dalpiciclib Isethionate tablets / AiRuiKang® (in China)	5

1.2. Physicochemical Properties and Formulation

As a solid compound, Dalpiciclib presents as an off-white to light yellow powder.[8] Its solubility characteristics are critical for both research and clinical formulation. It is soluble in dimethyl sulfoxide (DMSO), a common laboratory solvent, at concentrations up to 50 mg/mL; however, achieving this may require physical assistance such as sonication and warming, as well as pH adjustment.[8] The stability of the compound is dependent on storage conditions. In its powdered form, it is stable for up to three years when stored at -20°C and for two years at 4°C. Once dissolved in a solvent, its stability is more limited, lasting for six months at -80°C or one month at -20°C.[4] These parameters necessitate careful handling and storage protocols in both preclinical and clinical settings to ensure the integrity and potency of the active pharmaceutical ingredient.

For clinical application, Dalpiciclib is formulated for oral administration, a key feature that enhances patient convenience and facilitates outpatient treatment regimens.[7] In China, where it has received marketing approval, it is available as Dalpiciclib Isethionate tablets under the brand name AiRuiKang®.[5] These tablets are manufactured in several strengths, including 50 mg, 125 mg, and 150 mg, allowing for dose flexibility based on patient tolerance and clinical response.[9] For research purposes, a hydrochloride salt form of the molecule is also commercially available.[11]

Section 2: Pharmacodynamics and Mechanism of Action

2.1. Primary Target Engagement: Selective Inhibition of CDK4 and CDK6

The pharmacodynamic activity of Dalpiciclib is defined by its function as a potent and highly selective inhibitor of two key enzymes in the cell cycle: cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6).[2] These serine/threonine kinases are fundamental regulators of cell proliferation and are frequently dysregulated in cancer, making them validated therapeutic targets.[2] Dalpiciclib demonstrates robust and comparable inhibitory potency against both isoforms. Biochemical assays have determined its half-maximal inhibitory concentration (

IC50​), a measure of drug potency, to be 12.4 nM for CDK4 and 9.9 nM for CDK6.[4] This high potency at low nanomolar concentrations ensures that the drug can effectively engage its targets at clinically achievable plasma levels, which is a prerequisite for its therapeutic effect.

2.2. The CDK4/6-Cyclin D-Retinoblastoma (Rb) Axis

Dalpiciclib exerts its antineoplastic effect by intervening in a critical cell cycle control pathway known as the CDK4/6-Cyclin D-Retinoblastoma (Rb) axis. This pathway governs the transition of a cell from the G1 (first gap) phase to the S (synthesis) phase, a point of no return where the cell commits to replicating its DNA and undergoing division.[2]

The mechanism of action proceeds as follows:

1. In normal and malignant cells, progression through the G1 phase is driven by mitogenic signals, such as those from estrogen receptor pathways in hormone receptor-positive (HR+) breast cancer. These signals lead to the expression of D-type cyclins (Cyclin D1, D2, D3).[6]
2. These cyclins form active enzymatic complexes with their kinase partners, CDK4 and CDK6. This pathway is often hyperactivated in cancer due to overexpression of cyclins or amplification of the CDK genes themselves.[6]
3. The primary substrate for the active Cyclin D-CDK4/6 complex is the retinoblastoma tumor suppressor protein (Rb).[2] The complex phosphorylates Rb at multiple sites.
4. In its active, hypophosphorylated state, Rb binds to and sequesters the E2F family of transcription factors, preventing them from activating gene expression.[6]
5. Upon phosphorylation by CDK4/6, Rb undergoes a conformational change and releases E2F. The liberated E2F then translocates to the nucleus and initiates the transcription of a suite of genes essential for DNA synthesis and S-phase entry, thereby driving cell proliferation.[6]
6. Dalpiciclib selectively binds to the ATP-binding pocket of CDK4 and CDK6, competitively inhibiting their kinase activity. This blockade prevents the phosphorylation of Rb.[2]
7. By preventing Rb phosphorylation, Dalpiciclib ensures that Rb remains in its active, growth-suppressive state, tightly bound to E2F. This effectively halts the cell cycle at the G1/S checkpoint.[6]

The ultimate outcome of this targeted inhibition is a state of cytostasis, or arrested cell growth, which is dependent on the presence of a functional Rb protein.[16] This G1 arrest suppresses the uncontrolled proliferation of tumor cells and, in some contexts, can induce cellular senescence or apoptosis (programmed cell death).[2] The functionality of the Rb pathway is therefore a critical determinant of sensitivity to Dalpiciclib. Tumors that have lost the Rb protein through mutation are intrinsically resistant to CDK4/6 inhibitors, as the key downstream effector of the drug's action is absent. This Rb-dependency is a crucial concept, positioning Rb status as a powerful predictive biomarker for treatment response and a primary mechanism of resistance for this entire class of drugs.[18]

2.3. Preclinical Antineoplastic Activity

The therapeutic hypothesis for Dalpiciclib was extensively validated in preclinical models before advancing to human trials. This foundational research established its antitumor activity and provided the rationale for its clinical development strategy, particularly in combination therapies.

In Vitro Evidence:

Laboratory studies using cancer cell lines have confirmed Dalpiciclib's ability to inhibit proliferation in a dose-dependent manner, specifically in tumor types with a functional retinoblastoma pathway.8 It has demonstrated significant activity against a panel of esophageal squamous cell carcinoma (ESCC) cell lines, including Eca 109, Eca 9706, and KYSE-510.8 Furthermore, it has shown potent inhibitory effects on breast cancer cell lines, such as the HR-positive MCF7 line and the HER2-positive BT-474 line. Notably, this activity was maintained even in cell line models engineered for resistance to other therapies, such as tamoxifen-resistant MCF7/TR cells, with IC50 values of 229.5 nM.8

In Vivo Evidence:

When tested in animal models, specifically human tumor xenografts implanted in immunodeficient mice, oral administration of Dalpiciclib resulted in robust antitumor activity.8 It effectively suppressed the growth of ESCC xenografts at doses of 150 mg/kg.8 Critically, these preclinical studies also provided the first evidence of synergistic effects with other anticancer agents. In ESCC models, combining Dalpiciclib with standard chemotherapies like paclitaxel (PTX) or cisplatin (CDDP) produced greater tumor inhibition than either agent alone.8 In HR-positive breast cancer xenograft models, Dalpiciclib not only exhibited potent activity but was also shown to overcome acquired resistance to endocrine therapy. Furthermore, combining Dalpiciclib with endocrine therapy resulted in synergistic antitumor effects.12 This preclinical evidence of synergy was not merely an academic finding; it formed the scientific bedrock for the clinical development program. The subsequent human trials, which are heavily focused on combining Dalpiciclib with endocrine agents (fulvestrant, letrozole) and other targeted therapies (pyrotinib), are a direct translation of these foundational preclinical discoveries, demonstrating a well-executed "bench-to-bedside" research strategy.19

Section 3: Clinical Pharmacokinetics and Metabolism

The clinical pharmacology of Dalpiciclib, encompassing its absorption, distribution, metabolism, and excretion (ADME), dictates its dosing regimen, potential for drug interactions, and overall therapeutic window. Studies in healthy volunteers and patients have characterized these key pharmacokinetic (PK) parameters.

3.1. Absorption, Distribution, and Bioavailability

Dalpiciclib is formulated for oral use and is well absorbed from the gastrointestinal tract.[22] Following a single oral dose in healthy volunteers, the time to reach maximum plasma concentration (

Tmax​) is approximately 3.0 to 6.0 hours, indicating a relatively rapid absorption profile.[1]

The bioavailability of Dalpiciclib is significantly influenced by food. A dedicated food-effect study in healthy Chinese volunteers demonstrated that administration with a high-fat, high-calorie meal markedly increased drug exposure. Compared to the fasting state, co-administration with food resulted in a 56.9% increase in the maximum plasma concentration (Cmax​) and approximately a 38% increase in the total drug exposure as measured by the area under the concentration-time curve (AUC).[22] This positive food effect has important clinical implications. To ensure consistent drug exposure and minimize intra-patient variability, which could impact both efficacy and safety, it is crucial that patients receive clear and consistent instructions regarding administration with respect to meals. Inconsistent intake could lead to suboptimal troughs or unexpected peak concentrations.

Once in systemic circulation, Dalpiciclib and its metabolites show preferential distribution into blood cells. A mass balance study using radiolabeled [14C]SHR6390 in healthy male subjects reported a mean blood-to-plasma (B/P) radioactivity AUC ratio of 1.81.[23] This value, being greater than 1, indicates that the drug-related material partitions more readily into the cellular components of blood (e.g., red blood cells) than it remains in the plasma.

Pharmacokinetic analyses from a Phase 1 dose-escalation study in patients with advanced breast cancer showed that Dalpiciclib exhibits dose-proportional kinetics within the clinically relevant dose range of 50 mg to 175 mg. Both steady-state Cmax​ and AUC increased in a nearly linear fashion with increasing doses, indicating predictable and scalable exposure.[24]

3.2. Metabolism and Excretion

Dalpiciclib undergoes extensive metabolism prior to elimination. In vitro investigations using human liver microsomes and recombinant enzymes have identified the cytochrome P450 (CYP) system as the primary driver of its biotransformation. Specifically, CYP3A4 is the main metabolic enzyme, with minor metabolic contributions also mediated by CYP2C9 and CYP2C8.[22] The primary metabolic pathways involve oxidative reactions, such as dehydrogenation and mono-oxidation of the cyclopentane and piperidine rings, followed by Phase II conjugation reactions, including glucuronidation and sulfation, to form more water-soluble metabolites for excretion.[22]

A human mass balance study identified a total of 13 metabolites. In pooled plasma samples, only the parent drug (SHR6390) was quantifiable, likely due to the low concentrations of individual metabolites in circulation. However, analysis of excreta revealed a more complete picture. The parent drug was the most abundant single component found in both urine and feces. In urine, five metabolites were identified, with M462-3 (an oxidized form) being the most significant. In feces, twelve metabolites were identified, with three major metabolites—M478 (di-oxidized), M464-1 (di-oxidized), and M542 (mono-oxidized and sulfated)—accounting for 7.16%, 7.07%, and 9.03% of the dose, respectively.[23]

The primary route of elimination for Dalpiciclib and its metabolites is through the feces. Over a 13-day (312-hour) collection period following a single oral dose of radiolabeled drug, an average of 94.6% of the total administered radioactivity was recovered. Of this, the majority, 71.9%, was excreted in the feces, while 22.7% was recovered in the urine.[23] The terminal elimination half-life (

t1/2​) of Dalpiciclib is relatively long, supporting a once-daily dosing schedule. Reports vary slightly between studies, with one study in healthy volunteers citing a mean terminal half-life of 42.9–45.5 hours for doses of 100–150 mg [22], while the mass balance study reported a half-life of approximately 17.5 hours for the parent compound and its related components in plasma.[23]

3.3. Clinically Relevant Drug-Drug Interactions

The heavy reliance on CYP3A4 for its metabolism makes Dalpiciclib highly susceptible to clinically significant drug-drug interactions (DDIs).[10] This is a critical management consideration, as patients with advanced cancer are often on multiple concomitant medications (polypharmacy) for supportive care, many of which can modulate CYP3A4 activity.[25]

• Interaction with CYP3A4 Inhibitors: Co-administration of Dalpiciclib with strong CYP3A4 inhibitors (e.g., azole antifungals like ketoconazole, macrolide antibiotics like clarithromycin, protease inhibitors like ritonavir) is expected to significantly increase plasma concentrations of Dalpiciclib. This elevated exposure can increase the risk and severity of its characteristic adverse events, particularly myelosuppression. Therefore, concomitant use should be avoided if possible. If unavoidable, dose reduction of Dalpiciclib and careful monitoring for toxicity would be required.[10]
• Interaction with CYP3A4 Inducers: Conversely, co-administration with strong CYP3A4 inducers (e.g., rifampin, certain anticonvulsants like carbamazepine and phenytoin, and the herbal supplement St. John's wort) can dramatically decrease plasma concentrations of Dalpiciclib. This can lead to sub-therapeutic exposure and a potential loss of efficacy. Concomitant use with strong inducers is generally not recommended.[25]
• Potential for QTc Prolongation: While specific data on Dalpiciclib's effect on the corrected QT (QTc) interval is limited in the provided materials, this is a known risk for other CDK4/6 inhibitors, notably ribociclib.[25] QTc prolongation can lead to a potentially fatal cardiac arrhythmia known as Torsades de Pointes. As a matter of precaution for the drug class, care should be taken when co-administering Dalpiciclib with other drugs known to prolong the QTc interval, such as certain antiemetics (ondansetron), antipsychotics, and fluoroquinolone antibiotics.[25]

Section 4: Clinical Efficacy in Hormone Receptor-Positive (HR+) Breast Cancer

The clinical development program for Dalpiciclib has rigorously established its efficacy across the full spectrum of hormone receptor-positive (HR+) breast cancer, from the front-line metastatic setting to adjuvant therapy for early-stage disease. A series of large, randomized Phase III trials, primarily conducted in China, form the evidence base for its clinical utility.

4.1. First-Line Treatment of Advanced HR+/HER2- Breast Cancer

The role of Dalpiciclib as a first-line treatment for patients with advanced or metastatic HR+/HER2- breast cancer was established in the pivotal DAWNA-2 trial.

• Pivotal Trial: DAWNA-2 (SHR6390-III-302 / NCT03966898)
• Design: The DAWNA-2 study was a multi-center, randomized, double-blind, placebo-controlled Phase III trial that enrolled 456 Chinese patients with systemic treatment-naïve, locally advanced or metastatic HR+/HER2- breast cancer.[1]
• Intervention: Patients were randomized in a 2:1 ratio to receive either Dalpiciclib (150 mg once daily, 3 weeks on/1 week off) plus a non-steroidal aromatase inhibitor (AI), either letrozole or anastrozole, or a matching placebo plus an AI.[14]
• Primary Endpoint: The primary measure of efficacy was investigator-assessed Progression-Free Survival (PFS).[14]
• Key Efficacy Results: The trial successfully met its primary endpoint at a pre-planned interim analysis, demonstrating a profound benefit for the Dalpiciclib combination. The median PFS was significantly extended to 30.6 months in the Dalpiciclib arm, compared to 18.2 months in the placebo arm.[15] This represents a full-year improvement in the time to disease progression. The hazard ratio (HR) indicated a 49% reduction in the risk of disease progression or death for patients receiving Dalpiciclib.[27] These results firmly position Dalpiciclib as a highly effective first-line option in this patient population.

4.2. Treatment of Relapsed/Progressed Advanced HR+/HER2- Breast Cancer

Dalpiciclib's first marketing approval was based on its demonstrated efficacy in patients whose disease had progressed on prior endocrine therapy, as shown in the DAWNA-1 trial.

• Pivotal Trial: DAWNA-1 (NCT03927456)
• Design: This was a multi-center, randomized, double-blind, placebo-controlled Phase III study conducted in China. It enrolled 361 patients with HR+/HER2- advanced breast cancer who had experienced relapse or progression during or after previous endocrine therapy.[7]
• Intervention: Patients were randomized 2:1 to receive Dalpiciclib (150 mg schedule) plus the selective estrogen receptor degrader (SERD) fulvestrant, or placebo plus fulvestrant.[7]
• Primary Endpoint: The primary endpoint was investigator-assessed PFS.[7]
• Key Efficacy Results: The trial yielded highly statistically significant and clinically meaningful results.
• Progression-Free Survival: The median PFS was more than doubled in the treatment arm, reaching 15.7 months for the Dalpiciclib-fulvestrant combination versus only 7.2 months for the placebo-fulvestrant arm.[7]
• Hazard Ratio: This translated to a 58% reduction in the risk of disease progression or death, with a hazard ratio of 0.42 (95% CI: 0.31–0.58; one-sided p < 0.0001).[7]
• Secondary Endpoints: The combination also led to a significant delay in the median time to first subsequent chemotherapy or death, a crucial outcome for patient quality of life.[7]

4.3. Adjuvant Therapy in Early-Stage HR+/HER2- Breast Cancer

Following the success of CDK4/6 inhibitors in the metastatic setting, the focus shifted to preventing recurrence in patients with high-risk early breast cancer. The DAWNA-A trial evaluated Dalpiciclib in this adjuvant setting.

• Pivotal Trial: DAWNA-A (NCT04842617)
• Design: This was a large, randomized, double-blind, placebo-controlled Phase III trial designed to assess Dalpiciclib as an adjuvant therapy. It enrolled patients with stage II-III, pathologically confirmed node-positive, HR+/HER2- early breast cancer who had completed definitive local therapy.[28]
• Intervention: Patients were randomized 1:1 to receive two years of Dalpiciclib (125 mg schedule) in combination with standard adjuvant endocrine therapy (for 5 years), or placebo plus endocrine therapy.[28]
• Primary Endpoint: The primary endpoint was Invasive Disease-Free Survival (iDFS), which measures the time until disease recurrence or death.[28]
• Key Efficacy Results: At the first pre-planned interim analysis, with a median follow-up of 20.3 months, the trial met its primary endpoint. The addition of Dalpiciclib to endocrine therapy led to a statistically significant and clinically meaningful improvement in iDFS, reducing the risk of an iDFS event by 44% (HR = 0.56; 95% CI: 0.43–0.71; one-sided p < 0.0001).[28] This benefit was observed consistently across all major patient subgroups, supporting its use to reduce the risk of recurrence in this high-risk population.[28]

4.4. Efficacy in HER2-Positive and HER2-Low Subtypes

Clinical development has strategically expanded into HER2-positive and HER2-low breast cancer, leveraging the biological rationale that the CDK4/6 pathway is a key downstream mediator of HER2 signaling and a potential mechanism of resistance to anti-HER2 therapies.[30]

• ER+/HER2+ Advanced Breast Cancer: The PLEASURABLE (NCT04293276) and MUKDEN 01 trials investigated an all-oral, chemotherapy-sparing regimen of Dalpiciclib, the pan-HER tyrosine kinase inhibitor (TKI) pyrotinib, and endocrine therapy.[15] In the Phase II PLEASURABLE trial, which enrolled patients in the first- or second-line advanced setting, this triple combination demonstrated impressive activity. The investigator-confirmed objective response rate (ORR) was 70.2%, with a disease control rate (DCR) of 100% and a median PFS of 22.0 months.[21] These results suggest this regimen could be a potent and more tolerable alternative to chemotherapy for this patient subset.
• HR+/HER2-Low Advanced Breast Cancer: Acquired resistance to CDK4/6 inhibitors is a major clinical challenge. The Phase II trial NCT05806671 is designed to address this by evaluating a triple combination of Dalpiciclib, fulvestrant, and pyrotinib specifically in patients with HR+/HER2-low advanced breast cancer whose disease has progressed on a prior CDK4/6 inhibitor plus an AI.[20] This trial targets a key unmet need and explores whether targeting the HER2-low pathway can re-sensitize tumors to CDK4/6 inhibition. Similarly, the DAWNA-FES trial (NCT05861830) is explicitly designed to test the strategy of switching to Dalpiciclib plus a different endocrine therapy after failure of a prior CDK4/6 inhibitor, a critical question in clinical practice.[33]

The consistent success across these pivotal trials underscores Dalpiciclib's robust efficacy. However, a crucial aspect of this evidence base is its geographic concentration. The DAWNA trials were conducted exclusively or predominantly in China.[7] While this has successfully supported regulatory approval within China, it presents a significant challenge for global expansion. Regulatory bodies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) typically require clinical data that is representative of their diverse populations. Therefore, to achieve approval in Western markets, the sponsor will likely need to conduct new, multi-regional pivotal trials, a costly and time-intensive undertaking that currently limits Dalpiciclib's global competitive standing.

Table 2: Summary of Key Dalpiciclib Clinical Trials in Breast Cancer

Trial Name / Identifier	Phase	Indication / Setting	Patient Population (N)	Intervention Regimen	Primary Endpoint	Key Efficacy Results	Source(s)
DAWNA-2 (NCT03966898)	III	1L Advanced/Metastatic HR+/HER2- BC	456	Dalpiciclib + AI vs. Placebo + AI	PFS	Median PFS: 30.6 months vs. 18.2 months	14
DAWNA-1 (NCT03927456)	III	2L+ Advanced/Metastatic HR+/HER2- BC (post-ET)	361	Dalpiciclib + Fulvestrant vs. Placebo + Fulvestrant	PFS	Median PFS: 15.7 months vs. 7.2 months; HR 0.42 (p<0.0001)	7
DAWNA-A (NCT04842617)	III	Adjuvant, High-Risk Early HR+/HER2- BC	---	Dalpiciclib (2 yrs) + ET vs. Placebo + ET	iDFS	HR 0.56 (p<0.0001); 44% reduction in risk of invasive disease or death	28
PLEASURABLE (NCT04293276)	II	1L/2L Advanced/Metastatic ER+/HER2+ BC	48	Dalpiciclib + Pyrotinib + ET (single arm)	ORR	ORR: 70.2%; Median PFS: 22.0 months	1

Abbreviations: 1L = First-line; 2L+ = Second-line or greater; AI = Aromatase Inhibitor; BC = Breast Cancer; ET = Endocrine Therapy; HR = Hazard Ratio; iDFS = Invasive Disease-Free Survival; ORR = Objective Response Rate; PFS = Progression-Free Survival.

Section 5: Investigational Use in Other Malignancies

While breast cancer remains the primary focus, the clinical development of Dalpiciclib has strategically expanded into other tumor types where dysregulation of the CDK4/6 pathway is a known oncogenic driver. This expansion reflects a modern, biology-driven approach to cancer therapy, moving beyond histology alone to target specific molecular vulnerabilities.

5.1. Esophageal Squamous Cell Carcinoma (ESCC)

The rationale for investigating Dalpiciclib in ESCC is supported by strong preclinical data demonstrating its antitumor activity in ESCC cell lines and xenograft models.[4] This has led to the initiation of several clinical trials.

• NCT06684600: This is a single-arm, Phase II clinical trial designed to evaluate the combination of Dalpiciclib and pyrotinib (a pan-HER TKI) as a second-line treatment for patients with advanced ESCC whose disease has progressed after first-line chemotherapy.[34] This study addresses a significant unmet need, as there is currently no established standard of care in this setting.
• NCT06225921: This Phase 1 trial takes a different approach, exploring Dalpiciclib in the neoadjuvant (pre-surgical) setting for patients with resectable ESCC. It combines Dalpiciclib with Adebrelimab, an anti-PD-L1 immunotherapy agent.[36] This trial is based on the hypothesis that inducing G1 cell cycle arrest with Dalpiciclib may have immunomodulatory effects that synergize with checkpoint inhibition to enhance anti-tumor immune responses before surgery.

5.2. Head and Neck Mucosal Melanoma (HNMM)

The investigation of Dalpiciclib in HNMM is a prime example of a precision medicine strategy. Rather than targeting all melanomas, the research focuses on a specific molecularly defined subset.

• Rationale: A subset of mucosal melanomas, a rare and aggressive form of the disease, is characterized by amplification of the CDK4 gene. This genetic alteration provides a direct and compelling biological rationale for treatment with a CDK4 inhibitor.[38]
• Clinical Trial (ChiCTR2000031608): A clinical trial was conducted specifically enrolling patients with advanced recurrent and/or metastatic HNMM whose tumors were confirmed to have CDK4 amplification. Patients were treated with Dalpiciclib monotherapy (125 mg schedule).[38]
• Results: The trial demonstrated remarkable and durable clinical benefit in this biomarker-selected population. Among 16 evaluable patients, the disease control rate (DCR) was 81.3%. The estimated median PFS was 9.9 months, and the median overall survival (OS) had not been reached at the time of analysis. The estimated OS rate at 24 months was an impressive 51.6%.[38]
• Conclusion: This study provides powerful proof-of-concept for a biomarker-driven approach. In a disease with otherwise poor outcomes, selecting patients based on the presence of the drug's target led to significant and lasting benefit. This success validates the potential for expanding Dalpiciclib's use to other CDK4/6-dysregulated cancers, irrespective of their tissue of origin.

5.3. Other Tumors and Future Directions

The biological rationale for CDK4/6 inhibition is being explored in other malignancies.

• Gynecologic Solid Tumors: A Phase II study (NCT06243185) is currently underway to investigate the combination of Dalpiciclib and letrozole in patients with recurrent, unresectable HR+/HER2- gynecologic tumors. This includes cancers of the ovary and uterus, extending the successful HR+ treatment paradigm from breast cancer to other hormone-driven malignancies.[39]
• Malignant Melanoma (Broader): While Phase I/II development for malignant melanoma has been reported, the most compelling data comes from the HNMM study focused on CDK4 amplification.[5] This suggests that future development in melanoma will likely continue to focus on biomarker-selected patient populations.
• Stalled Development: According to industry development trackers, clinical programs for Dalpiciclib in gastric cancer, head and neck cancer (non-melanoma), and broad, unselected solid tumors have not been actively pursued or have been discontinued.[5] This further reinforces the strategic shift away from broad, histology-based trials toward more focused, biomarker-driven investigations where the probability of success is higher.

Section 6: Safety, Tolerability, and Risk Management

A comprehensive understanding of a drug's safety profile is as critical as its efficacy. The clinical trial program for Dalpiciclib has generated a large body of safety data, revealing a predictable and manageable toxicity profile that is characteristic of the CDK4/6 inhibitor class, but with potential points of differentiation.

6.1. Comprehensive Adverse Event Profile

Across all major Phase III trials (DAWNA-1, DAWNA-2, DAWNA-A), the most frequently reported and dose-limiting adverse events (AEs) are hematologic, stemming from the on-target effect of CDK4/6 inhibition on the proliferation of hematopoietic progenitor cells in the bone marrow.

• Myelosuppression (Hematologic Toxicity):
• Neutropenia: This is the hallmark toxicity of Dalpiciclib. The incidence of Grade 3 or 4 neutropenia (a severe decrease in a type of white blood cell) is high, reported in 84.2% of patients in the DAWNA-1 trial, 86% in the DAWNA-2 trial, and 52.5% in the initial Phase 1 study.[15]
• Leukopenia: A decrease in the total white blood cell count is also very common. Grade 3/4 leukopenia occurred in 62.1% of patients in DAWNA-1 and 67% in DAWNA-2.[15]
• Thrombocytopenia: A decrease in platelets is observed less frequently but remains a notable AE.[16]
• Non-Hematologic Adverse Events: These are generally less frequent and of lower severity than the hematologic toxicities. Commonly reported non-hematologic AEs include fatigue, nausea, diarrhea, constipation, and mild-to-moderate elevations in liver transaminases (ALT/AST).[6]

Despite the high rates of Grade 3/4 laboratory abnormalities (particularly neutropenia), the clinical consequences are generally manageable. The incidence of febrile neutropenia (neutropenia accompanied by fever), which is a serious medical condition, is low. This indicates that the neutropenia is typically asymptomatic and reversible. The predictable nature of this toxicity allows for effective management through routine blood count monitoring and, if necessary, dose interruptions or reductions as specified in treatment protocols.

6.2. Serious Adverse Events (SAEs) and Discontinuation Rates

The overall incidence of serious adverse events with Dalpiciclib is low and, in placebo-controlled trials, has been shown to be comparable to the control arm.

• Incidence of SAEs: In the DAWNA-1 study, treatment-related SAEs were reported in 5.8% of patients receiving the Dalpiciclib combination, compared to 6.7% in the placebo group.[7] In the adjuvant DAWNA-A trial, the rate was slightly higher in the Dalpiciclib arm (3.7%) versus the placebo arm (1.5%).[28]
• Treatment Discontinuation: Critically, the rate of treatment discontinuation due to adverse events is very low, underscoring the manageability of the side effects. In the DAWNA-A trial, only 2.1% of patients stopped Dalpiciclib due to a treatment-related AE (versus 0.8% for placebo).[28] In the DAWNA-1 trial, the discontinuation rate was 2.5% (versus 3.3% for placebo).[7]
• Treatment-Related Deaths: Fatal toxicities are rare. No treatment-related deaths were reported in the DAWNA-1 or DAWNA-A trials.[7] Two deaths of unknown cause were reported in the Dalpiciclib arm of the DAWNA-2 trial.[15]

A key element of Dalpiciclib's safety profile is its favorable differentiation on certain non-hematologic toxicities when compared to its competitors. Gastrointestinal toxicity, particularly diarrhea, is a significant and burdensome side effect associated with abemaciclib. In contrast, data from the DAWNA-1 trial noted that GI toxicity was "rarely observed with dalpiciclib".[7] Furthermore, the rational molecular design to avoid hepatotoxicity appears to be validated by clinical data. In DAWNA-1, the incidence of elevated ALT was numerically lower in the Dalpiciclib group (15.0% all grades) than in the placebo group (26.7%), with no Grade 3/4 events, which compares favorably to the known risk of hepatotoxicity with ribociclib.[7] This differentiated safety profile could be a significant factor in treatment selection for patients who may be susceptible to GI or liver-related side effects.

6.3. Contraindications and Special Populations

Formal contraindications are established upon regulatory approval. Based on the drug class and data from clinical trial exclusion criteria, the following can be inferred:

• Contraindications:
• Known hypersensitivity to Dalpiciclib or any of its excipients.[41]
• As with all CDK4/6 inhibitors that interfere with cell proliferation, Dalpiciclib is contraindicated during pregnancy and breastfeeding due to the high potential for fetal harm.[10]
• Patients with severe hepatic impairment are likely to be contraindicated.[10]
• Precautions and High-Risk Populations (based on trial exclusions):
• Cardiac Conditions: Patients with a recent history of significant cardiac events (e.g., myocardial infarction, severe/unstable angina, clinically significant arrhythmias) were excluded from trials, suggesting caution is warranted in this population.[35]
• Infections and Immunodeficiency: Patients with active severe infections, known immunodeficiency (e.g., HIV), or active viral hepatitis were excluded.[35]
• Gastrointestinal Conditions: Patients with conditions that could affect drug absorption, such as an inability to swallow or chronic intestinal disorders, were excluded.[34]
• Primary Endocrine Resistance: Some trials specifically excluded patients with primary resistance to endocrine therapy, focusing on those with acquired resistance.[43]

Section 7: Comparative Analysis and Regulatory Landscape

Dalpiciclib enters a mature and competitive therapeutic class. Its strategic positioning, regulatory pathway, and future prospects must be evaluated in the context of the established CDK4/6 inhibitors: palbociclib, ribociclib, and abemaciclib.

7.1. Positioning Against Other CDK4/6 Inhibitors

As the fourth major CDK4/6 inhibitor to emerge, Dalpiciclib is benchmarked against its predecessors on multiple fronts.[15]

• Efficacy: In cross-trial comparisons, which should be interpreted with caution due to differences in trial populations and methodologies, Dalpiciclib's efficacy in terms of Progression-Free Survival (PFS) appears robust and comparable to that seen in the pivotal trials for the other three agents (PALOMA, MONALEESA, MONARCH series).[7] However, a critical differentiator at present is the maturity of Overall Survival (OS) data. Both ribociclib and abemaciclib have demonstrated a statistically significant OS benefit in the metastatic setting, a high bar that Dalpiciclib's OS data, which is still immature, has yet to meet.[27] In the adjuvant setting, abemaciclib has shown a sustained benefit in invasive disease-free survival (iDFS), while trials for palbociclib did not meet their primary endpoints, creating a complex landscape for new entrants like Dalpiciclib, whose positive iDFS data from DAWNA-A is promising.[28]
• Toxicity Profile: This is arguably the most important area of differentiation for Dalpiciclib. While all agents in the class cause some degree of myelosuppression, their non-hematologic side effect profiles vary significantly, allowing for tailored therapy based on patient characteristics.
• Dalpiciclib & Palbociclib: Both have toxicity profiles dominated by hematologic events, primarily neutropenia, which is predictable and manageable.[7]
• Ribociclib: Is associated with high rates of neutropenia but is also distinguished by risks of hepatotoxicity (requiring liver function monitoring) and QTc interval prolongation (requiring ECG monitoring).[18]
• Abemaciclib: Is unique in that it is less myelosuppressive, which allows for a continuous daily dosing schedule. However, it is characterized by a high incidence of gastrointestinal toxicity, particularly diarrhea, which can be treatment-limiting for some patients.[18]

Dalpiciclib's profile of low GI toxicity and potentially lower hepatotoxicity positions it as a favorable alternative for patients who may not tolerate abemaciclib or for whom the risks of ribociclib are a concern.7

• Dosing Schedule: Dalpiciclib is administered on an intermittent schedule (3 weeks on, 1 week off), which is identical to the schedules for palbociclib and ribociclib. This contrasts with the continuous twice-daily dosing of abemaciclib.[13]

The challenge for a latecomer like Dalpiciclib in a crowded market is significant. To displace established therapies, a new drug typically needs to demonstrate clear superiority in efficacy (e.g., a better OS), a significantly improved safety and tolerability profile, greater convenience, or a lower cost. With comparable PFS and immature OS data, Dalpiciclib's most viable path to success in global markets likely hinges on leveraging its differentiated safety profile. It may not be "best-in-class" on efficacy until mature OS data is available, but it could be positioned as "best-in-profile" for specific patient archetypes, such as the elderly or those with pre-existing GI or liver conditions.

Table 3: Comparative Profile of Approved and Investigational CDK4/6 Inhibitors

Feature	Palbociclib (Ibrance®)	Ribociclib (Kisqali®)	Abemaciclib (Verzenio®)	Dalpiciclib (AiRuiKang®)
Dosing Schedule	Intermittent (3 wks on / 1 wk off)	Intermittent (3 wks on / 1 wk off)	Continuous (Twice Daily)	Intermittent (3 wks on / 1 wk off)
Metastatic OS Benefit	No (PALOMA-2)	Yes (MONALEESA-2, -3, -7)	Yes (MONARCH 2)	Data Immature
Adjuvant iDFS Benefit	No (PALLAS)	Yes (NATALEE)	Yes (monarcHER)	Yes (DAWNA-A)
Primary Grade 3/4 Toxicity	Neutropenia	Neutropenia, Hepatotoxicity, QTc Prolongation	Diarrhea, Neutropenia, VTE	Neutropenia, Leukopenia
Key Differentiating Safety	Generally well-tolerated	Liver & Cardiac monitoring required	High rate of GI toxicity	Low GI toxicity, potentially lower hepatotoxicity
Regulatory Approvals	FDA, EMA, NMPA, etc.	FDA, EMA, NMPA, etc.	FDA, EMA, NMPA, etc.	NMPA (China) only

Sources:.[7] Abbreviations: OS = Overall Survival; iDFS = Invasive Disease-Free Survival; VTE = Venous Thromboembolism; FDA = U.S. Food and Drug Administration; EMA = European Medicines Agency; NMPA = National Medical Products Administration (China).

7.2. Global Regulatory Status and Market Access

Dalpiciclib's regulatory journey is a case study in a regionally focused development and commercialization strategy.

• China (NMPA): Dalpiciclib is approved and marketed in China. It achieved its first approval from the National Medical Products Administration (NMPA) on January 3, 2021, for use with fulvestrant in relapsed/progressed HR+/HER2- advanced breast cancer, based on the DAWNA-1 trial results. This made it the first domestically developed CDK4/6 inhibitor to be approved in China.[3] Its approval was later expanded to include first-line use with an AI based on the DAWNA-2 trial.[15] The NMPA granted Dalpiciclib both Breakthrough Therapy Designation and Priority Review, which greatly accelerated its path to market.[7] It is now included in China's national medical insurance, ensuring broad patient access within the country.[15]
• United States (FDA): Dalpiciclib is not approved by the FDA and remains an investigational agent in the U.S. The established standard of care for CDK4/6 inhibition in the U.S. consists of palbociclib, ribociclib, and abemaciclib.[12]
• European Union (EMA): Dalpiciclib is not approved by the EMA. The EMA has also approved the three established CDK4/6 inhibitors for use across the EU.[12] A search of the EU Clinical Trials Register reveals no evidence of a current marketing authorization application or ongoing review for Dalpiciclib.[50]

The successful development, approval, and launch of Dalpiciclib in China highlight the rapid maturation of the country's domestic biopharmaceutical industry. It demonstrates a complete ecosystem capable of taking an innovative drug from rational design through high-quality pivotal trials to regulatory approval and market access, all within its own borders. This presents a new competitive dynamic for global pharmaceutical companies, who now face formidable local competition in one of the world's largest healthcare markets.

Conclusions

Dalpiciclib (SHR-6390) has emerged as a potent and highly selective oral inhibitor of CDK4 and CDK6, establishing itself as a significant therapeutic agent within its class. The comprehensive body of evidence from preclinical studies and a robust clinical trial program demonstrates its consistent and clinically meaningful efficacy across the continuum of hormone receptor-positive (HR+) breast cancer. Pivotal Phase III trials (DAWNA-1, DAWNA-2, and DAWNA-A) have successfully shown that the addition of Dalpiciclib to standard endocrine therapy significantly improves progression-free survival and invasive disease-free survival in the first-line advanced, relapsed/progressed advanced, and adjuvant early breast cancer settings, respectively.

The primary differentiating characteristic of Dalpiciclib lies in its potentially advantageous safety and tolerability profile. Its molecular structure was rationally designed to avoid a chemical moiety associated with hepatotoxicity, a feature supported by clinical data showing low rates of liver enzyme elevation. Furthermore, it exhibits a markedly lower incidence of gastrointestinal toxicity, particularly diarrhea, compared to abemaciclib. While its dominant toxicity is myelosuppression (neutropenia and leukopenia), this is a predictable, manageable, and known class effect that rarely leads to treatment discontinuation. This favorable safety profile could position Dalpiciclib as the preferred CDK4/6 inhibitor for patients with pre-existing liver conditions or those who cannot tolerate the GI side effects of other agents.

The drug's development and commercialization strategy represent a landmark achievement for China's domestic pharmaceutical industry. Its rapid approval by the NMPA, facilitated by accelerated review pathways, and its subsequent inclusion in national insurance have secured its place in the Chinese market. However, this "China-first" approach presents a substantial barrier to global expansion. The lack of data from multi-regional trials that include Western populations and the current immaturity of its overall survival data make near-term approval by the FDA or EMA unlikely without further investment in global clinical development.

Future prospects for Dalpiciclib are twofold. First, within breast cancer, its development is strategically targeting key areas of unmet need, such as HER2-positive disease and, most importantly, the setting of acquired resistance to prior CDK4/6 inhibitors. Success in these trials could carve out a unique and valuable niche. Second, its expansion into other malignancies is guided by a sophisticated, biomarker-driven precision oncology approach. The impressive results in CDK4-amplified mucosal melanoma validate this strategy and provide a blueprint for future investigations in other tumors with defined cell cycle pathway alterations.

In summary, Dalpiciclib is a clinically validated and effective CDK4/6 inhibitor with a compelling safety profile. While currently a regional player, its future impact will be determined by its ability to generate mature overall survival data, successfully navigate global regulatory pathways, and leverage its unique safety and biomarker-driven strategies to establish a distinct and valuable role in the global oncology armamentarium.

Works cited

1. Dalpiciclib: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 13, 2025, https://go.drugbank.com/drugs/DB17456
2. Dalpiciclib | C25H30N6O2 | CID 86279927 - PubChem, accessed August 13, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Dalpiciclib
3. Dalpiciclib - Wikipedia, accessed August 13, 2025, https://en.wikipedia.org/wiki/Dalpiciclib
4. Dalpiciclib (SHR-6390) | CAS 1637781-04-4 | AbMole BioScience, accessed August 13, 2025, https://www.abmole.com/products/dalpiciclib.html
5. Dalpiciclib - Jiangsu Hengrui Medicine Co - AdisInsight - Springer, accessed August 13, 2025, https://adisinsight.springer.com/drugs/800044669
6. What is the mechanism of Dalpiciclib Isethionate? - Patsnap Synapse, accessed August 13, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-dalpiciclib-isethionate
7. Jiangsu Hengrui Pharmaceuticals Co., Ltd., accessed August 13, 2025, https://www.hengrui.com/en/media/detail-149.html
8. HY-114338-50mg | Dalpiciclib [1637781-04-4] Biotrend USA, accessed August 13, 2025, https://www.biotrend-usa.com/other-products-186/dalpiciclib-1637781-04-4-231090980.html
9. Dalpiciclib - MedPath, accessed August 13, 2025, https://trial.medpath.com/drug/7eab9af481eaaafc/dalpiciclib
10. What is Dalpiciclib Isethionate used for?, accessed August 13, 2025, https://synapse.patsnap.com/article/what-is-dalpiciclib-isethionate-used-for
11. Dalpiciclib (SHR-6390) | CDK4/6 Inhibitor - MedchemExpress.com, accessed August 13, 2025, https://www.medchemexpress.com/dalpiciclib.html
12. A phase 1 study of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor in Chinese patients with advanced breast cancer - PubMed Central, accessed August 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8042970/
13. Dalpiciclib in combination with letrozole/anastrozole or fulvestrant in HR-positive and HER2-negative advanced breast cancer: results from a phase Ib study - PubMed Central, accessed August 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11369877/
14. Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Hengrui Pharma) announced that the phase III placebo-controlled, double-blind SHR6390-III-302 trial evaluating dalpiciclib, a CDK4/6 inhibitor, in combination with aromatase inhibitors (letrozole or anastrozole) in hormone receptor (HR), accessed August 13, 2025, https://www.hengrui.com/en/media/detail-252.html
15. Advancements in Dalpiciclib for the Treatment of Breast Cancer Patients: A Review - PMC, accessed August 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12226994/
16. Dalpiciclib plus Fulvestrant in HR-Positive and HER2-Negative ..., accessed August 13, 2025, https://jhoponline.com/special-issues/2021-year-in-review-breast-cancer/dalpiciclib-plus-fulvestrant-in-hr-positive-and-her2-negative-advanced-breast-cancer
17. Dalpiciclib plus Fulvestrant in Pretreated HR-positive, HER2-negative Advanced Breast Cancer | ESMO, accessed August 13, 2025, https://www.esmo.org/oncology-news/dalpiciclib-plus-fulvestrant-in-pretreated-hr-positive-her2-negative-advanced-breast-cancer
18. Full article: CDK4/6 inhibitors in breast cancer: differences in toxicity profiles and impact on agent choice. A systematic review and meta-analysis, accessed August 13, 2025, https://www.tandfonline.com/doi/full/10.1080/14737140.2021.1852934
19. Dalpiciclib Recruiting Phase 2 Trials for Metastatic Breast Cancer Treatment - DrugBank, accessed August 13, 2025, https://go.drugbank.com/drugs/DB17456/clinical_trials?conditions=DBCOND0030200&phase=2&purpose=treatment&status=recruiting
20. Dalpiciclib Not Yet Recruiting Phase 2 Trials for Breast Cancer Treatment | DrugBank Online, accessed August 13, 2025, https://go.drugbank.com/drugs/DB17456/clinical_trials?conditions=DBCOND0028036&phase=2&purpose=treatment&status=not_yet_recruiting
21. Dalpiciclib combined with pyrotinib and endocrine therapy in women with ER-positive, HER2-positive advanced breast cancer: A prospective, multicenter, single-arm, phase 2 trial | PLOS Medicine - Research journals, accessed August 13, 2025, https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004669
22. A Randomized, Open‐Label, Phase I Clinical Study of Dalpiciclib With Different Specifications After Process Modification in Healthy Chinese Volunteers | Request PDF - ResearchGate, accessed August 13, 2025, https://www.researchgate.net/publication/364741262_A_Randomized_Open-Label_Phase_I_Clinical_Study_of_Dalpiciclib_With_Different_Specifications_After_Process_Modification_in_Healthy_Chinese_Volunteers
23. A mass balance study of [14C]SHR6390 (dalpiciclib), a ... - Frontiers, accessed August 13, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1116073/full
24. A phase 1 study of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor in Chinese patients with advanced breast cancer - PubMed, accessed August 13, 2025, https://pubmed.ncbi.nlm.nih.gov/33845905/
25. Drug-drug interactions in breast cancer patients treated with CDK4/6 inhibitors | Request PDF - ResearchGate, accessed August 13, 2025, https://www.researchgate.net/publication/330504446_Drug-drug_interactions_in_breast_cancer_patients_treated_with_CDK46_inhibitors
26. Drug Interactions Associated With CDK 4/6 Inhibitors - U.S. Pharmacist, accessed August 13, 2025, https://www.uspharmacist.com/article/drug-interactions-associated-with-cdk-4-6-inhibitors
27. Dalpiciclib in advanced breast cancer: introducing CDK4/6 inhibitors as a first-line treatment might not be the best strategy – Author's reply - ResearchGate, accessed August 13, 2025, https://www.researchgate.net/publication/373594427_Dalpiciclib_in_advanced_breast_cancer_introducing_CDK46_inhibitors_as_a_first-line_treatment_might_not_be_the_best_strategy_-_Author's_reply
28. Dalpiciclib (Dalp) plus endocrine therapy (ET) as adjuvant treatment ..., accessed August 13, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.515
29. Dalpiciclib Plus Endocrine Therapy Prolonged Invasive Disease-Free Survival in HR+/HER2– Breast Cancer - Pharmacy Times, accessed August 13, 2025, https://www.pharmacytimes.com/view/dalpiciclib-plus-endocrine-therapy-prolonged-invasive-disease-free-survival-in-hr-her2-breast-cancer
30. Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study - Frontiers, accessed August 13, 2025, https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.775081/full
31. Dalpiciclib Unknown Status Phase 2 Trials for Metastatic Breast Cancer Treatment, accessed August 13, 2025, https://go.drugbank.com/drugs/DB17456/clinical_trials?conditions=DBCOND0030200&phase=2&purpose=treatment&status=unknown_status
32. Dalpiciclib Plus Fulvestrant With Pyrotinib in Hormone Receptor-positive, HER2-low Advanced Breast Cancer That Progressed on Previous CDK4/6i Plus AI Therapy | ClinicalTrials.gov, accessed August 13, 2025, https://clinicaltrials.gov/study/NCT05806671
33. Study Details | Dalpiciclib With Endocrine Therapy for Advanced Breast Cancer After CDK4/6 Inhibitor Failure (DAWNA-FES) | ClinicalTrials.gov, accessed August 13, 2025, https://clinicaltrials.gov/study/NCT05861830?term=NCT03481998%20NCT03772353%20NCT03927456%20NCT04095390%20NCT04236310%20NCT04293276%20NCT04355858%20NCT04733417%20NCT04842617%20NCT04997798%20NCT05176080%20NCT05431504%20NCT05463601%20NCT05469750%20NCT05512416%20NCT05515289%20NCT05574881%20NCT05577923%20NCT05582499%20NCT05586841%20NCT05594095%20NCT05638594%20NCT05759546%20NCT05759572%20NCT05792410%20NCT05800756%20NCT05806671%20NCT05861830&rank=1
34. Study of Dalpiciclib Isethionate Plus Pyrotinib Maleate in the Treatment of Advanced Esophageal Squamous Cell Carcinoma | ClinicalTrials.gov, accessed August 13, 2025, https://clinicaltrials.gov/study/NCT06684600?cond=Isethionate&viewType=Table&rank=1
35. Study of Dalpiciclib Isethionate Plus Pyrotinib Maleate i... - Clinical Trial Discovery, accessed August 13, 2025, https://clinicaltrial.be/en/details/458332?per_page=100&only_recruiting=0&only_eligible=0&only_active=0
36. Study Details | Neoadjuvant Adebrelimab With Dalpiciclib for Resectable Esophageal Squamous Cell Carcinomas | ClinicalTrials.gov, accessed August 13, 2025, https://clinicaltrials.gov/study/NCT06225921
37. Neoadjuvant Adebrelimab With Dalpiciclib for Resectable Esophageal Squamous Cell Carcinomas | Clinical Research Trial Listing - CenterWatch, accessed August 13, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06225921/neoadjuvant-adebrelimab-with-dalpiciclib-for-resectable-esophageal-squamous-cell-carcinomas?page=11&id=163&slug=esophageal-cancer
38. The efficacy and safety of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor, in patients with advanced head and neck mucosal melanoma harboring CDK4 amplification - PubMed, accessed August 13, 2025, https://pubmed.ncbi.nlm.nih.gov/38807144/
39. Study Details | Dalpiciclib Combined With Letrozole in HR+/HER2 - Gynecologic Solid Tumors | ClinicalTrials.gov, accessed August 13, 2025, https://clinicaltrials.gov/study/NCT06243185
40. Efficacy and safety of dalpiciclib plus toremifene in advanced HR-positive HER2-negative breast cancer as first-line treatment: A multicenter, single-arm phase II trial. - ASCO Publications, accessed August 13, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e13062
41. The Efficacy and Safety of Dalpiciclib Plus Endocrine Therapy in HR-positive / HER2-negative Advanced Breast Cancer Patients With Visceral Crisis | TrialScreen, accessed August 13, 2025, https://app.trialscreen.org/trials/phase-2-advanced-breast-cancer-efficacy-safety-dalpiciclib-plus-endocrine-trial-nct05431504
42. Study Details | Dalpiciclib as Adjuvant Therapy for HR-positive/HER2-negative Early-stage Patients | ClinicalTrials.gov, accessed August 13, 2025, https://clinicaltrials.gov/study/NCT07101159
43. Dalpiciclib in combination with endocrine therapy by Physicians, accessed August 13, 2025, https://ichgcp.net/zh/clinical-trials-registry/NCT05431504
44. Advancements in Dalpiciclib for the Treatment of Breast Cancer Patients: A Review, accessed August 13, 2025, https://pubmed.ncbi.nlm.nih.gov/40620909/
45. Selecting Patients for Frontline CDK4/6 Inhibitors in Metastatic Breast Cancer, accessed August 13, 2025, https://dailynews.ascopubs.org/do/selecting-patients-frontline-cdk4-6-inhibitors-metastatic-breast-cancer
46. Confirming the efficacy and safety of CDK4/6 inhibitors in the first-line treatment of HR+ advanced breast cancer: a systematic review and meta-analysis - Frontiers, accessed August 13, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1369420/full
47. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors: existing and emerging differences | JNCI Cancer Spectrum | Oxford Academic, accessed August 13, 2025, https://academic.oup.com/jncics/article/7/4/pkad045/7208873
48. Ibrance | European Medicines Agency (EMA), accessed August 13, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/ibrance
49. New treatment for breast cancer | European Medicines Agency (EMA), accessed August 13, 2025, https://www.ema.europa.eu/en/news/new-treatment-breast-cancer
50. Search for clinical trials - EMA - CTIS, accessed August 13, 2025, https://euclinicaltrials.eu/search-for-clinical-trials