MedPath

ASP-1570 Advanced Drug Monograph

Published:Apr 30, 2025

Generic Name

ASP-1570

ASP-1570: An Investigational DGKZ Inhibitor for Cancer Immunotherapy

1. Introduction to ASP-1570

ASP-1570 (also referred to as ASP1570 or ASP 1570) is an investigational therapeutic agent currently under clinical development for the treatment of cancer.[1] It originated from and is being developed by Astellas Pharma Inc., a global pharmaceutical company.[1] The discovery of ASP-1570 was a collaborative effort between Astellas Pharma Inc. and Kotobuki Pharmaceutical Co., Ltd., highlighting potential partnerships in its early genesis.[5]

Chemically, ASP-1570 is classified as a small molecule drug.[1] This modality often allows for oral administration, potentially offering greater patient convenience compared to intravenously delivered biologics. It is designated as a New Molecular Entity (NME), signifying that its active component has not been previously approved by regulatory authorities like the FDA.[1] Therapeutically, ASP-1570 falls under the class of Antineoplastics [1] and is specifically being investigated within the rapidly evolving field of cancer immunotherapy, or immuno-oncology.[5]

The primary molecular target of ASP-1570 is Diacylglycerol Kinase Zeta (DGKZ, also denoted DGKζ).[1] Consequently, ASP-1570 functions mechanistically as a DGKZ protein inhibitor.[1] This mechanism is considered novel in the context of cancer therapy.[4] The intended route of administration for ASP-1570 is oral, typically as tablets taken once or twice daily.[3]

As of late 2024, ASP-1570 is advancing through clinical trials, with the highest reported development stage being Phase I/II studies investigating its use in patients with solid tumors.[1] The development of ASP-1570 signifies a strategic investment by Astellas into innovative immuno-oncology approaches that target intracellular signaling pathways.[1] This focus on an intracellular immune checkpoint, DGKZ [5], contrasts with established immunotherapies like anti-PD-1 or anti-CTLA4 antibodies, which primarily target extracellular receptors.[10] Pursuing an orally available small molecule inhibitor against such a target represents a diversification of therapeutic strategies, potentially offering distinct efficacy profiles, novel combination opportunities, or mechanisms to overcome resistance to existing checkpoint inhibitors.[4]

2. Mechanism of Action and Scientific Rationale

The therapeutic strategy behind ASP-1570 centers on modulating the immune system by inhibiting Diacylglycerol Kinase Zeta (DGKZ). Understanding the role of DGKZ in immune cell function is crucial to appreciating the drug's mechanism.

2.1 The Role of DGKZ in Immune Regulation

DGKZ is an enzyme belonging to the diacylglycerol kinase family, which catalyzes the phosphorylation of diacylglycerol (DAG) into phosphatidic acid (PA).[2] Within the immune system, particularly in lymphocytes like T cells and Natural Killer (NK) cells, DAG acts as a critical second messenger, relaying signals from activating receptors to downstream effector pathways.[2] DGKZ functions as a negative regulator of these DAG-mediated signaling cascades.[2] By converting DAG to PA, DGKZ effectively dampens the intensity and duration of activating signals, preventing excessive or prolonged immune responses.[5]

In T cells, the DGKα and DGKζ isoforms are predominantly expressed and play key roles in regulating signaling downstream of the T Cell Receptor (TCR).[5] Studies suggest DGKζ may have a predominant role over DGKα in this context.[5] Overexpression or heightened activity of DGKα/ζ has been linked to T cell anergy, a state of functional unresponsiveness that can impair anti-tumor immunity.[5] Conversely, genetic deletion (knockout) or inhibition of DGKζ has been shown to enhance the function of both T cells and NK cells upon receptor engagement.[2] Due to this role in suppressing immune activation, DGKZ is considered an intracellular immune checkpoint, analogous in function, though distinct in location and mechanism, to surface checkpoints like PD-1 or CTLA-4.[5]

2.2 DAG Signaling Pathway

Upon engagement of the TCR (in T cells) or various activating receptors (in NK cells), the enzyme Phospholipase Cγ1 (PLCγ1) is activated. PLCγ1 hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2​) in the cell membrane, generating two crucial second messengers: DAG and inositol triphosphate (IP3​).[5] While IP3​ primarily mediates calcium release, DAG remains membrane-bound and activates several key downstream signaling pathways essential for lymphocyte activation, proliferation, and effector function. These include the Ras-ERK-AP-1 pathway, the Protein Kinase C θ (PKCθ)-IκB Kinase (IKK)-Nuclear Factor-κB (NF-κB) pathway, and the AKT-Tuberous Sclerosis Complex 1/2 (TSC1/2)-mammalian Target of Rapamycin (mTOR) pathway.[5] DGKZ acts directly on DAG, limiting the substrate available to propagate these critical activating signals.[5]

2.3 ASP-1570's Molecular Action

ASP-1570 exerts its effect by directly targeting DGKZ. Its primary mechanism is the inhibition of the enzyme's kinase activity, preventing it from phosphorylating DAG into PA.[3] By blocking this conversion, ASP-1570 leads to an accumulation of intracellular DAG, thereby amplifying and sustaining the downstream signaling cascades crucial for immune cell activation.[2]

Intriguingly, preclinical investigations revealed an additional, unexpected mechanism of action for ASP-1570. Beyond inhibiting its kinase function, ASP-1570 was observed to induce the degradation of the DGKZ protein itself within cells. This degradation process was found to be dependent on the proteasome, a cellular machinery responsible for breaking down unwanted proteins.[5] This dual action—inhibiting enzymatic activity and promoting protein degradation—may lead to a more profound and durable suppression of the DGKZ checkpoint compared to kinase inhibition alone. While standard kinase inhibitors block activity, the target protein remains, potentially retaining non-catalytic functions or allowing rapid pathway reactivation upon drug removal. Physical elimination of the DGKZ protein via degradation could result in a more complete and sustained blockade, requiring new protein synthesis for the suppressive pathway to recover. This potentially more robust mechanism could be significant for achieving lasting immune potentiation in a clinical setting.

2.4 Impact on Immune Cell Function

The molecular actions of ASP-1570 translate into significant functional enhancements in key anti-tumor immune cells:

  • T Cells: ASP-1570 treatment enhances T cell activation following TCR stimulation.[5] It has been shown to release T cells from states of anergy or hyporesponsiveness, which can be induced by chronic antigen exposure or insufficient costimulation.[5] Essentially, it helps to "switch T-cells back on" when they have been functionally suppressed, a common occurrence in the tumor microenvironment.[13]
  • NK Cells: ASP-1570 also augments the function of NK cells. Studies demonstrate that it enhances DAG-mediated signaling in response to immunoreceptor stimulation in NK cells.[11] Functionally, this leads to increased production of Interferon-gamma (IFNγ), a critical cytokine for anti-tumor immunity, and enhanced degranulation, the process by which NK cells release cytotoxic molecules to kill target cells.[2]

2.5 Rationale for Cancer Immunotherapy

The overarching goal of using ASP-1570 in oncology is to leverage the patient's own immune system to fight cancer more effectively.[13] By inhibiting the intracellular checkpoint DGKZ, ASP-1570 aims to boost the activation and effector functions of both T cells and NK cells, two critical components of anti-tumor immunity.[2]

This approach offers an alternative or complementary strategy to existing immunotherapies that target extracellular checkpoints like PD-1, PD-L1, or CTLA-4.[10] Instead of blocking interactions outside the cell, ASP-1570 targets a negative regulatory mechanism within the immune cell itself.[5] A particularly compelling aspect of this strategy is the potential to overcome resistance to current therapies. The tumor microenvironment (TME) is often highly immunosuppressive, utilizing multiple mechanisms beyond the PD-1/PD-L1 axis to dampen immune responses. These include signals mediated by other checkpoints (e.g., CTLA-4, TIGIT) and soluble factors like Transforming Growth Factor-beta (TGF-β), Prostaglandin E2 (PGE2), and adenosine.[5] Preclinical evidence indicates that ASP-1570 can restore T cell function even when suppressed by these diverse signals.[5] Because DGKZ acts as a downstream convergence point potentially influenced by multiple upstream suppressive pathways, inhibiting it with ASP-1570 may offer a broader mechanism for immune reactivation. This suggests potential utility in complex TMEs where multiple resistance mechanisms are simultaneously active, possibly providing a more robust therapeutic effect than targeting a single suppressive pathway.

3. Preclinical Evidence

A substantial body of preclinical research underpins the development of ASP-1570, providing evidence for its mechanism of action and anti-tumor potential.

3.1 In Vitro Studies

Laboratory studies using isolated cells and biochemical assays have confirmed key aspects of ASP-1570's activity:

  • Target Inhibition: ASP-1570 demonstrated a direct inhibitory effect on the kinase activity of DGKZ.[5]
  • DAG Signaling: In NK cells stimulated via immunoreceptors, ASP-1570 treatment led to enhanced DAG-mediated signaling.[11]
  • NK Cell Function: Consistent with enhanced signaling, ASP-1570 augmented NK cell effector functions, including increased IFNγ production and enhanced degranulation upon activation.[2]
  • T Cell Function: ASP-1570 enhanced T cell activation and demonstrated the ability to reverse T cell anergy or hyporesponsiveness.[5]
  • Overcoming Immunosuppression: Critically, ASP-1570 was shown to restore T cell functions that were suppressed by a variety of inhibitory signals relevant to the TME, including those mediated by PD-1, CTLA-4, TIGIT, TGF-β, PGE2, and adenosine.[5] Notably, it appeared to completely reverse suppression mediated by the PD-1 pathway and partially reverse suppression via CTLA-4 and TIGIT pathways.[5]

3.2 In Vivo Studies

Experiments using syngeneic mouse tumor models (where tumor cells and the host mouse share the same genetic background, allowing for the study of intact immune responses) provided further validation:

  • NK Cell Activity: ASP-1570 treatment enhanced the clearance of tumors mediated by NK cells in vivo.[2]
  • T Cell-Dependent Anti-Tumor Efficacy:
  • In the MC38 colon carcinoma model, which is known to be sensitive to anti-PD-1 therapy, ASP-1570 induced significant, dose-dependent tumor growth inhibition. Its efficacy in this model was comparable or even superior to that of an anti-PD-1 antibody.[5]
  • In the B16F1/F10 melanoma model, which is considered poorly immunogenic and is largely insensitive or resistant to anti-PD-1 treatment, ASP-1570 monotherapy still induced significant tumor growth inhibition.[5] This finding is particularly important as it suggests potential activity in tumors that do not respond to standard checkpoint blockade.
  • The anti-tumor effect of ASP-1570 in these models was demonstrated to be dependent on CD8+ cytotoxic T cells. Depletion of CD8+ T cells using antibodies completely abolished the drug's efficacy, confirming that its therapeutic benefit is mediated through the activation of adaptive cellular immunity.[5]
  • Immune Cell Infiltration: Treatment with ASP-1570 led to an increase in both the proportion and the absolute number of CD4+ helper T cells and CD8+ cytotoxic T cells infiltrating the tumors.[5]

3.3 Contextual Significance

Collectively, these preclinical findings provide a strong biological rationale for the clinical development of ASP-1570 as a novel cancer immunotherapy.[5] The data consistently support the proposed mechanism of action involving DGKZ inhibition and subsequent enhancement of anti-tumor immune responses. The demonstration of efficacy in models resistant to existing therapies like anti-PD-1 is particularly encouraging.[5]

The robust activity observed in the anti-PD-1-insensitive B16 melanoma model [5] stands out as a critical preclinical observation. Resistance to PD-1/PD-L1 inhibitors represents a major clinical challenge.[9] The B16 model recapitulates certain features of this resistance, such as low immunogenicity and an immunosuppressive TME.[5] The ability of ASP-1570 to induce CD8+ T cell-dependent tumor control in this challenging setting [5] provides compelling evidence that DGKZ inhibition can engage anti-tumor immunity through mechanisms distinct from, or downstream of, PD-1 blockade. This strongly supports the investigation of ASP-1570 in patient populations who are refractory to standard CPIs.

Furthermore, the ability of ASP-1570, as a single agent, to enhance both adaptive immunity (T cells) and innate immunity (NK cells) [2] represents a potentially advantageous therapeutic profile. T cells and NK cells utilize distinct mechanisms to recognize and eliminate tumor cells. For instance, T cells typically recognize peptide antigens presented on Major Histocompatibility Complex (MHC) molecules, while NK cells can target cells that have downregulated MHC expression (a common immune escape mechanism). By simultaneously augmenting both effector cell types [2], ASP-1570 might orchestrate a more comprehensive anti-tumor attack, potentially reducing the likelihood of tumor escape and leading to more durable clinical responses, as hypothesized based on the combined T/NK cell effects.[11]

4. Clinical Development: The NCT05083481 Phase I/II Study

The primary vehicle for the clinical evaluation of ASP-1570 is a multi-center, international Phase I/II trial, identified by the ClinicalTrials.gov identifier NCT05083481 and the Astellas study ID 1570-CL-0101.[1] Associated identifiers include NCI-2022-01554 and KEYNOTE-E59.[16]

4.1 Trial Design and Objectives

This is an open-label (non-blinded) study designed in two parts [8]:

  • Part 1 (Dose Escalation): This initial phase aims to determine the safety, tolerability, and pharmacokinetic profile of ASP-1570 administered at increasing dose levels, both as monotherapy and potentially in combination. The key goals are to identify dose-limiting toxicities (DLTs), the Maximum Tolerated Dose (MTD), and the Recommended Phase 2 Dose (RP2D).[8]
  • Part 2 (Dose Expansion): Following determination of the RP2D from Part 1, this phase aims to further evaluate the safety and preliminary efficacy of ASP-1570 (at the RP2D) in specific patient cohorts defined by tumor type and treatment regimen (monotherapy or combination).[14]

The primary objectives focus on safety and tolerability, including the characterization of adverse events and the determination of the MTD/RP2D.[8] Secondary objectives include evaluating preliminary anti-tumor activity (efficacy), characterizing the pharmacokinetics (PK) of ASP-1570, and assessing pharmacodynamic (PD) markers to confirm target engagement and immune modulation.[8]

4.2 Study Population

The trial enrolls adult patients (18 years or older) with histologically confirmed solid tumors that are either locally advanced and unresectable (cannot be surgically removed) or metastatic (spread to other parts of the body).[1] A key eligibility criterion is that patients must have experienced disease progression on, or be ineligible for or intolerant to, all available standard therapies appropriate for their tumor type.[8] This defines a patient population with advanced disease and significant unmet medical need.

Specific inclusion criteria related to organ function (e.g., adequate kidney function with creatinine clearance ≥ 60 mL/min, acceptable liver function based on bilirubin levels) are stipulated.[15] Strict contraception requirements are in place for women of childbearing potential (WOCBP) and male participants to prevent pregnancy during and for a specified period after treatment.[15]

While Part 1 enrolls patients with various advanced solid tumors, Part 2 includes expansion cohorts focusing on specific tumor types. These planned cohorts include patients with Microsatellite Stable Colorectal Cancer (MSS-CRC), Non-Small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC), and Melanoma.[2] Other solid tumor types demonstrating response in Part 1 may also be included.[17]

4.3 Treatment Arms and Dosing

ASP-1570 is administered orally as tablets, either once daily (QD) or twice daily (BID), within repeating treatment cycles, typically lasting 21 or 28 days.[8] The dose escalation phase explored doses ranging from 10 mg up to 75 mg.[8]

The study evaluates ASP-1570 in several contexts:

  • Monotherapy: Includes dose escalation cohorts and various dose expansion cohorts in Part 2. Some expansion cohorts may explore alternative dosing strategies like stepwise intra-patient dose escalation, prophylactic medication use, intermittent dosing schedules, or the effect of food on absorption.[8]
  • Combination with Pembrolizumab: ASP-1570 is combined with the anti-PD-1 monoclonal antibody pembrolizumab (Keytruda®). Pembrolizumab is administered via intravenous (IV) infusion, likely at a standard dose (e.g., 400 mg), typically on day 1 of every other ASP-1570 cycle (i.e., once every 6 weeks).[9]
  • Combination with Standard Therapies: Depending on the tumor type in specific Part 2 cohorts, ASP-1570 is combined with established standard-of-care treatments:
  • For NSCLC cohorts: ASP-1570 is combined with docetaxel, a taxane chemotherapy agent commonly used in second-line NSCLC treatment.[15]
  • For MSS-CRC cohorts: ASP-1570 is combined with TAS-102 (trifluridine/tipiracil, Lonsurf®), an oral chemotherapy, plus bevacizumab (Avastin®), an antibody targeting Vascular Endothelial Growth Factor (VEGF).[16]
  • Standard therapies are administered according to their approved labeling.[15]

Patients continue treatment cycles unless they experience unacceptable toxicity, their cancer progresses, or the investigator decides treatment should stop.[15]

4.4 Study Logistics

  • Timeline: The trial initiated in October 2021 and has an estimated primary completion date of May 2028.[4]
  • Enrollment: There are conflicting reports on the target enrollment number, with some sources citing approximately 168 participants [10] and others indicating a target of 310 participants.[18] Such discrepancies can arise from protocol amendments or differences in reporting scope.
  • Status: As of late 2024, the trial is reported as actively recruiting participants globally.[4] However, recruitment status can vary by site; some specific locations may have completed enrollment or be temporarily paused.[7] This dynamic nature underscores the importance of consulting primary trial registries like ClinicalTrials.gov for the most current global and site-specific status.
  • Locations: This is a multinational study with participating sites in the United States, Japan, China, Spain, France, and Puerto Rico.[1] Numerous specific cancer centers and hospitals are involved.[18]
  • Special Conditions: A protocol-specific requirement exists for participants enrolled in Japan, who are hospitalized for observation for up to 21 days during their first treatment cycle, likely for intensive safety and pharmacokinetic monitoring.[15]

The concurrent investigation of ASP-1570 as monotherapy and in various combination regimens (with immunotherapy, chemotherapy, and targeted therapy) within a single, integrated Phase I/II protocol represents an efficient, albeit complex, clinical development strategy.[14] This approach allows for relatively rapid generation of safety and preliminary efficacy data across different therapeutic contexts and tumor types, potentially accelerating the identification of the most promising settings for ASP-1570. It facilitates early assessment of potential synergies, which are often necessary for meaningful clinical benefit in the heavily pre-treated patient populations being studied.[8] However, this design also presents challenges in managing diverse patient cohorts, potential drug interactions, overlapping toxicity profiles, and interpreting data from multiple non-randomized arms. This strategy likely reflects the current immuno-oncology landscape where combination approaches are paramount and the need to swiftly define the potential role of a novel agent like ASP-1570.

Table 1: NCT05083481 Trial Design Summary

FeatureDescription
Trial IdentifiersNCT05083481, 1570-CL-0101, NCI-2022-01554, KEYNOTE-E59
PhasePhase I/II
DesignOpen-label, multicenter, dose-escalation (Part 1) and dose-expansion (Part 2)
Primary ObjectivesEvaluate safety and tolerability; Determine MTD/RP2D of ASP-1570 alone and in combination
Key Secondary ObjectivesEvaluate preliminary anti-tumor activity (efficacy); Characterize pharmacokinetics (PK); Assess pharmacodynamics (PD) / biomarkers
Study PopulationAdults (≥18 yrs) with locally advanced (unresectable) or metastatic solid tumors who have progressed on, or are ineligible/intolerant to, standard therapies
Key Expansion CohortsMSS-CRC, NSCLC, SCLC, Melanoma (potentially others based on Part 1 signals)
Key Treatment Arms- ASP-1570 Monotherapy (Dose Escalation & Expansion) <br> - ASP-1570 + Pembrolizumab <br> - ASP-1570 + Docetaxel (for NSCLC) <br> - ASP-1570 + TAS-102 + Bevacizumab (for MSS-CRC)
Key LocationsUSA, Japan, China, Spain, France, Puerto Rico
Status (as of late 2024)Recruiting (global status; site status may vary)
Est. Primary CompletionMay 2028

Data synthesized from: [1]

5. Emerging Clinical Data from Phase I (ESMO 2024)

Initial clinical findings from the dose-escalation portion (Part 1) of the NCT05083481 study, focusing on ASP-1570 monotherapy, were presented at the European Society for Medical Oncology (ESMO) Congress in September 2024 (Abstract 1004P).[1]

5.1 Patient Cohort and Dosing

The presented data encompassed 43 patients with advanced solid tumors who received at least one dose of ASP-1570 monotherapy. The median age of the cohort was 61.0 years, and 55.8% were male. The data cutoff for this analysis was March 31, 2024. The dose levels evaluated ranged from 10 mg to 75 mg, administered orally either once daily (QD) or twice daily (BID) in 21-day cycles.[8]

5.2 Safety and Tolerability

The overall safety profile of ASP-1570 monotherapy was deemed acceptable based on this initial cohort.[8] Key safety findings included:

  • Treatment-Related Adverse Events (TRAEs): TRAEs of any grade were reported in 35 out of 43 patients (81.4%). The majority of these events were Grade 1 in severity and were reversible with minimal or no medical intervention.[8]
  • Severe TRAEs: Grade 3 TRAEs occurred in 18.6% of patients (8/43). Importantly, no Grade 4 (life-threatening) or Grade 5 (fatal) TRAEs were reported.[8]
  • Common TRAEs: The most frequently reported TRAEs (regardless of grade) were diarrhea (48.8%), nausea (34.9%), and rash (25.6%).[8] The occurrence of diarrhea and rash, common side effects of various immunotherapies, may hint at immune-related mechanisms contributing to the toxicity profile.
  • Serious TRAEs (sTRAEs): Serious TRAEs, defined by regulatory criteria (e.g., requiring hospitalization), occurred in 4 patients (9.3%).[8]
  • Discontinuations: Treatment discontinuation due to TRAEs occurred in 3 patients (7.0%).[8]
  • Dose-Limiting Toxicities (DLTs): DLTs, which are specific adverse events occurring within the first cycle that define the MTD, were observed in 4 patients during the dose escalation phase.[8] The specific nature of these DLTs was not detailed in the available abstract summary [8], but their identification is critical for establishing the RP2D for Phase 2.

The observed safety profile, particularly the common TRAEs like diarrhea and rash, alongside the occurrence of DLTs in four individuals, underscores the need for careful patient monitoring and management strategies.[8] Defining the RP2D based on these DLTs is crucial. Furthermore, understanding this monotherapy toxicity profile is essential for anticipating and managing potential overlapping or additive toxicities in the planned combination regimens with pembrolizumab (known for immune-related adverse events) and chemotherapy agents like docetaxel or TAS-102 (with their own distinct side effect profiles, such as myelosuppression or gastrointestinal toxicity).[9] Effective management will be key to maintaining dose intensity and patient eligibility in combination settings.

5.3 Pharmacokinetics (PK)

Pharmacokinetic analyses indicated that exposure to ASP-1570 (measured by parameters like Area Under the Curve (AUC) and Maximum Concentration (Cmax)) increased proportionally with the administered dose across the range studied (10–75 mg QD/BID). This suggests predictable and dose-linear pharmacokinetics within this range, simplifying dose selection and interpretation of exposure-response relationships.[8]

5.4 Pharmacodynamics (PD) and Biomarkers

Exploratory biomarker studies provided evidence of target engagement and biological activity in patients:

  • Peripheral Immune Activation: Dose-dependent increases were observed in circulating levels of inflammatory cytokines, as well as in the frequency of activated CD8+ T cells and activated NK cells in peripheral blood samples.[8]
  • Tumor Microenvironment (TME): Analysis of paired tumor biopsies obtained before and during treatment was limited (n=8 pairs) but showed trends within the TME that were consistent with ASP-1570's proposed mechanism of enhancing anti-tumor immunity.[8] More comprehensive biopsy data will be needed to draw definitive conclusions about TME modulation.

The observed pharmacodynamic changes in peripheral blood are particularly noteworthy. The dose-dependent increase in activated CD8+ T cells and NK cells provides direct clinical evidence that ASP-1570 is modulating the human immune system in line with its intended mechanism, as predicted by extensive preclinical studies.[2] This concordance between preclinical rationale and observed human pharmacodynamics offers crucial validation of the drug's biological activity and strengthens confidence in its potential as an immune-enhancing agent. It successfully bridges a critical gap in translational drug development.

5.5 Preliminary Efficacy (Monotherapy)

Early signals of anti-tumor activity were observed among the 24 patients evaluable for efficacy in the monotherapy dose-escalation cohorts [8]:

  • Disease Control Rate (DCR): A confirmed DCR of 50.0% (12 out of 24 patients) was reported using immune-based RECIST criteria (likely iRECIST). The DCR includes patients achieving complete response (CR), partial response (PR), or stable disease (SD). This indicates that half of the evaluable patients experienced tumor stabilization or shrinkage.[8]
  • Objective Response: One patient achieved a confirmed Partial Response (PR), signifying a substantial reduction in tumor burden.[8]

While modest, this preliminary efficacy signal (50% DCR, one PR) in a heavily pre-treated, heterogeneous population of patients with advanced solid tumors is considered clinically relevant.[8] Achieving durable disease control or objective responses with monotherapy in such late-line settings is challenging. The observed activity suggests that ASP-1570 possesses anti-tumor biological effects in a subset of patients, justifying progression to the Phase 2 expansion phase.[14] These expansion cohorts, focusing on specific tumor types and utilizing the RP2D, along with the combination arms [9], are expected to provide a clearer picture of ASP-1570's efficacy potential, potentially revealing greater activity in more defined populations or synergistic effects with other agents, as suggested by the preclinical data.[5]

5.6 Abstract Conclusion

The investigators concluded that ASP-1570 monotherapy demonstrated an acceptable safety profile and showed early signs of clinical activity, supporting its continued evaluation in patients with advanced solid tumors.[8]

Table 2: Summary of Key Phase 1 Monotherapy Findings (ESMO 2024, N=43 Safety / N=24 Efficacy Evaluable)

Finding CategoryMetricResult
SafetyAny Grade TRAE Rate81.4% (35/43)
Grade ≥3 TRAE Rate18.6% (8/43)
Most Common TRAEs (Any Grade)Diarrhea (48.8%), Nausea (34.9%), Rash (25.6%)
Serious TRAE (sTRAE) Rate9.3% (4/43)
Discontinuation Rate due to TRAE7.0% (3/43)
Dose-Limiting Toxicities (DLTs)4 patients
PharmacokineticsExposure vs. Dose (10-75 mg QD/BID)Proportional
PD / BiomarkersPeripheral Blood ChangesDose-dependent ↑ in inflammatory cytokines, activated CD8+ T cells, activated NK cells
Tumor Microenvironment (n=8 pairs)Trends consistent with MoA (enhancing anti-tumor immunity)
EfficacyConfirmed Disease Control Rate (DCR, iRECIST)50.0% (12/24)
Confirmed Objective Response Rate (ORR, iRECIST)4.2% (1 PR / 24)

Data source: [8]

6. Therapeutic Potential and Future Outlook

ASP-1570 is emerging as a novel therapeutic candidate within the immuno-oncology landscape, distinguished by its targeting of the intracellular immune checkpoint DGKZ via an orally administered small molecule.[1]

6.1 Potential Role in Oncology

The primary potential application for ASP-1570 lies in the treatment of patients with locally advanced or metastatic solid tumors, particularly those whose disease has progressed following standard therapies, representing a population with high unmet medical needs.[8] A key area of therapeutic interest, supported by strong preclinical rationale, is its potential utility in overcoming resistance to established immune checkpoint inhibitors like anti-PD-1 antibodies.[5] By activating immune cells through a mechanism distinct from PD-1 blockade and potentially counteracting multiple TME suppressive signals, ASP-1570 might offer benefit to patients who do not respond to, or develop resistance to, current CPIs.

6.2 Target Indications

While initial clinical development encompasses a broad range of advanced solid tumors [1], the Phase 2 expansion phase of the NCT05083481 trial is designed to gather more focused data in specific indications. These include Non-Small Cell Lung Cancer (NSCLC), Microsatellite Stable Colorectal Cancer (MSS-CRC), Small Cell Lung Cancer (SCLC), and Melanoma.[2] Broader therapeutic area classifications mentioned include Neoplasms, Digestive System Disorders, and Respiratory Diseases.[2]

6.3 Combination Strategies

Recognizing that combination therapies often yield superior outcomes in immuno-oncology, the clinical development plan for ASP-1570 heavily incorporates combination strategies:

  • Combination with Anti-PD-1: Pairing ASP-1570 with pembrolizumab is a core element, aiming to achieve synergistic immune activation by inhibiting two distinct checkpoint pathways (intracellular DGKZ and extracellular PD-1).[9]
  • Combination with Chemotherapy/Targeted Therapy: Exploring combinations with standard cytotoxic or targeted agents is also underway. This includes combining ASP-1570 with docetaxel for NSCLC [15] and with the TAS-102 plus bevacizumab regimen for MSS-CRC.[16] These combinations aim to potentially enhance the efficacy of chemo-immunotherapy or provide new options for specific resistant patient populations.

6.4 Current Status and Path Forward

ASP-1570 remains in the Phase I/II stage of clinical development.[1] The ongoing NCT05083481 trial serves as the cornerstone of its current evaluation, with initial monotherapy dose-escalation results now available and dose-expansion cohorts actively recruiting.[8] The trial's estimated completion date is in 2028.[4] Future development trajectories will be heavily influenced by the safety and efficacy data emerging from the Phase 2 expansion cohorts, encompassing both monotherapy and combination arms. The identification of predictive biomarkers associated with response or resistance could also significantly shape its future development path.

6.5 Regulatory Landscape

ASP-1570 holds the designation of a New Molecular Entity (NME).[1] Based on the available information, it has not been assigned Orphan Drug Status by regulatory bodies.[1] The pursuit of Phase 2 development in relatively common cancers like NSCLC and MSS-CRC [2], rather than focusing exclusively on rare diseases, aligns with this lack of initial orphan designation. This suggests a strategy targeting broader patient populations, although an application for Orphan Drug Designation for a specific, narrowly defined subset of patients could potentially be pursued later if supported by compelling clinical data demonstrating significant benefit in a rare condition.[1]

There is no information within the provided materials to indicate that ASP-1570 has received expedited pathway designations from the FDA, such as Fast Track or Breakthrough Therapy [22], or the PRIME (Priority Medicines) designation from the European Medicines Agency (EMA).[26] While these programs exist to accelerate the development and review of drugs addressing serious conditions with unmet medical needs, evidence of such designations for ASP-1570 is currently absent in the reviewed sources.

6.6 Commercial Aspects

It has been noted that ASP-1570 is available for licensing opportunities within the field of cancer.[1] Making this known during the Phase I/II stage could reflect various strategic considerations by Astellas. It might indicate an openness to partnerships to share the significant costs and risks associated with late-stage oncology development, a desire to leverage a partner's expertise in specific tumor types or combination therapies, or a strategy to accelerate global commercialization by collaborating with companies possessing established infrastructure in certain markets or regions. This stated availability suggests flexibility in Astellas's approach to maximizing the potential value and reach of ASP-1570.

7. Conclusion

ASP-1570 is a novel, orally bioavailable small molecule inhibitor targeting the intracellular immune checkpoint Diacylglycerol Kinase Zeta (DGKZ), currently under Phase I/II clinical development by Astellas Pharma for the treatment of advanced solid tumors.[1] Its mechanism of action involves enhancing anti-tumor immunity by preventing the degradation of the key signaling molecule DAG, thereby boosting the activation and effector functions of both T cells and NK cells.[2] Preclinical studies have provided strong validation for this mechanism, demonstrating ASP-1570's ability to counteract multiple immunosuppressive signals found in the tumor microenvironment and showing significant anti-tumor activity, notably even in tumor models resistant to conventional anti-PD-1 therapy.[5] An unexpected finding of DGKZ protein degradation adds another layer to its potential mechanism.[5]

The ongoing, multi-arm NCT05083481 trial is rigorously evaluating the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ASP-1570, both as a single agent and in combination with the established checkpoint inhibitor pembrolizumab, as well as with standard chemotherapy regimens in specific tumor types like NSCLC and MSS-CRC.[1] Initial data from the Phase 1 monotherapy portion, presented at ESMO 2024, revealed an acceptable safety profile, pharmacokinetic dose-proportionality, clear pharmacodynamic evidence of immune modulation in patients, and encouraging, albeit early, signals of clinical activity, including a 50% disease control rate in evaluable patients.[8]

ASP-1570 represents a promising next-generation immuno-oncology agent. Its distinct intracellular target, oral administration route, and potential to overcome resistance to existing therapies position it as a candidate for future combination strategies and potentially addressing significant unmet needs, particularly in CPI-refractory patient populations. The forthcoming results from the Phase 2 expansion cohorts of the NCT05083481 study will be critical in further defining the safety profile, confirming efficacy signals in specific tumor types and combinations, and ultimately determining the future therapeutic role of ASP-1570 in oncology.

Works cited

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Published at: April 30, 2025

This report is continuously updated as new research emerges.

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