Oleclumab (MEDI9447): A Comprehensive Monograph on a Novel Anti-CD73 Immunotherapy

Executive Summary

Oleclumab (development code: MEDI9447) is an investigational, human IgG1λ monoclonal antibody developed by AstraZeneca that targets the ectoenzyme CD73, a novel immune checkpoint. The drug's mechanism of action is centered on inhibiting the production of immunosuppressive adenosine within the tumor microenvironment (TME). By blocking the enzymatic conversion of adenosine monophosphate (AMP) to adenosine, Oleclumab is designed to reverse adenosine-mediated immune cell suppression, thereby enhancing the body's innate anti-tumor immune response. This involves increasing the activity of cytotoxic CD8+ T cells and macrophages while reducing the populations of regulatory T cells and myeloid-derived suppressor cells.

The clinical development of Oleclumab has been characterized by a sharp dichotomy of outcomes. The most significant promise for the drug lies in its potential application for unresectable, Stage III non-small cell lung cancer (NSCLC) following concurrent chemoradiation (cCRT). The Phase II COAST trial demonstrated that the combination of Oleclumab with the PD-L1 inhibitor durvalumab resulted in clinically meaningful and statistically significant improvements in objective response rate and progression-free survival compared to durvalumab monotherapy, the current standard of care. These encouraging results have led to the initiation of the large-scale, potentially registrational Phase III PACIFIC-9 trial, the outcome of which will be the primary determinant of Oleclumab's future.

In stark contrast to the success in this specific NSCLC setting, Oleclumab has faced a series of significant setbacks across multiple other indications. Clinical programs in bladder, colorectal, ovarian, and prostate cancer have been discontinued. Furthermore, trials in metastatic pancreatic ductal adenocarcinoma (PDAC) and advanced triple-negative breast cancer (TNBC) failed to meet their primary endpoints, with one trial being halted early for futility. This pattern suggests that Oleclumab's efficacy may be highly context-dependent, potentially requiring the specific immunological priming afforded by prior chemoradiation, and that its utility as a broad-spectrum anti-cancer agent is limited without a predictive biomarker for patient selection.

The safety profile of Oleclumab is considered manageable. As a monotherapy, it is generally well-tolerated, with fatigue being the most common treatment-related adverse event (TRAE). When used in combination with other immunotherapies or chemotherapy, the incidence and severity of TRAEs increase, consistent with the known toxicity profiles of the combination agents.

Currently, Oleclumab remains an investigational agent with no marketing authorizations from the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Its strategic value to AstraZeneca is almost entirely dependent on a positive outcome from the PACIFIC-9 trial. A successful result would establish a new standard of care in a significant oncology market, whereas a failure would likely relegate the asset to a portfolio of limited clinical utility.

Introduction to Oleclumab and the CD73-Adenosine Axis

Oleclumab: An Investigational Immunotherapy

Oleclumab is a fully human, immunoglobulin G1 lambda (IgG1λ) monoclonal antibody developed as a targeted immunotherapy for the treatment of cancer.[1] Identified in research and early clinical development by the code MEDI9447, it represents a strategic asset in the oncology pipeline of AstraZeneca, which is developing the agent through its subsidiary MedImmune.[4] As a biologic therapeutic, Oleclumab is classified as an antineoplastic agent and an immunotherapy, placing it at the forefront of modern cancer treatment paradigms that seek to leverage the patient's own immune system to combat malignancies.[5] Its development is focused on addressing unmet needs in solid tumors, particularly those that are resistant to existing immunotherapies.

The Scientific Rationale: Targeting the CD73 Immune Checkpoint

The therapeutic strategy behind Oleclumab is rooted in modulating the purinergic signaling pathway, a critical regulator of immune function within the tumor microenvironment (TME). The TME is frequently characterized by conditions of high metabolic stress, inflammation, and hypoxia, which lead to the death of tumor cells and the subsequent release of large quantities of adenosine triphosphate (ATP) into the extracellular space.[3]

While extracellular ATP can initially act as a pro-inflammatory "danger signal," it is rapidly catabolized by a cascade of cell-surface enzymes known as ectonucleotidases. The first enzyme in this cascade, CD39 (Ectonucleoside Triphosphate Diphosphohydrolase-1), converts ATP and ADP into adenosine monophosphate (AMP). The second, and rate-limiting, step is performed by the enzyme CD73 (also known as ecto-5'-nucleotidase or NT5E), which hydrolyzes AMP to produce adenosine.[1]

Extracellular adenosine is a potent immunosuppressive signaling molecule. It functions as a key immune checkpoint by binding to A2A and A2B adenosine receptors expressed on the surface of various immune cells, including T cells, natural killer (NK) cells, dendritic cells, and macrophages.[9] This binding event triggers intracellular signaling cascades that broadly dampen anti-tumor immunity. The effects include:

• Inhibition of T-cell receptor activation, proliferation, and cytokine production.
• Suppression of the cytotoxic activity of CD8+ T cells and NK cells.
• Promotion of the differentiation and function of immunosuppressive cell types, such as regulatory T cells (Tregs) and M2-polarized macrophages.
• Inhibition of antigen presentation by dendritic cells.

This accumulation of adenosine effectively creates an "immunosuppressive halo" around the tumor, allowing it to evade immune surveillance and destruction.[1] High expression of CD73 on tumor cells and stromal cells within the TME is observed across a wide range of malignancies—including lung, pancreatic, colorectal, and breast cancers—and is frequently correlated with poor patient prognosis, increased metastasis, angiogenesis, and resistance to conventional therapies and other immunotherapies.[3]

The development of Oleclumab is based on the central hypothesis that targeted inhibition of CD73 can disrupt this immunosuppressive axis. By blocking the enzymatic activity of CD73, Oleclumab is designed to prevent the generation of adenosine in the TME. The expected therapeutic consequence is the restoration of a pro-inflammatory, immune-active environment where effector immune cells can effectively recognize and eliminate cancer cells.[4] This approach represents a distinct strategy from first-generation checkpoint inhibitors like anti-PD-1/PD-L1 antibodies. While PD-1/PD-L1 blockade primarily works by restoring the function of already-activated T cells at the immune synapse, CD73 inhibition aims to address a more upstream mechanism of immune suppression, potentially enabling the activation and trafficking of immune cells that would otherwise be paralyzed by adenosine. This provides a strong rationale for combining Oleclumab with agents like the anti-PD-L1 antibody durvalumab, with the goal of synergistically dismantling two separate, non-redundant mechanisms of tumor immune evasion.

Molecular and Pharmacological Profile

Physicochemical and Structural Characteristics

Oleclumab is a large biotech therapeutic, a characteristic reflected in its complex molecular structure and high molar mass. As a fully human monoclonal antibody, it is designed to minimize immunogenicity in patients. The fundamental properties and identifiers of Oleclumab are summarized below [7]:

• DrugBank Accession Number: DB15088
• CAS Number: 1803176-05-7
• UNII (Unique Ingredient Identifier): 5CRY01URYQ
• International Nonproprietary Name (INN): Oleclumab
• Molecular Formula: C6348​H9826​N1710​O1998​S40​
• Molar Mass: 143350.81 g/mol
• Structure: Oleclumab is a human IgG1λ antibody, meaning it is composed of two identical heavy chains and two identical lambda light chains. These chains are linked by disulfide bonds to form a classic Y-shaped antibody structure. The molecule is a dimer of two heavy-light chain heterodimers. The detailed amino acid sequences for the heavy chains (Subunits 1 and 2, 447 residues each) and light chains (Subunits 3 and 4, 216 residues each) define its specific antigen-binding capabilities and effector functions.[15]

Mechanism of Action and Target Engagement

Oleclumab exerts its therapeutic effect through high-affinity, selective binding to its molecular target, the human ectoenzyme CD73.[1] Its mechanism of inhibition is multifaceted and robust, characterized by a dual, non-competitive mode of action that ensures potent and sustained suppression of CD73's enzymatic function.[17]

The two primary mechanisms are:

1. Non-Competitive Catalytic Inhibition: Oleclumab binds to an epitope on CD73 that is distinct from the enzyme's active site. This binding is believed to induce conformational changes or sterically hinder the necessary structural movements that CD73 must undergo to catalyze the hydrolysis of AMP. By locking the enzyme in an inactive state, Oleclumab prevents the conversion of AMP to adenosine, irrespective of the substrate concentration in the TME.[17] This non-competitive nature is a key pharmacological feature, as it suggests the drug's efficacy would not be easily overcome by the high levels of AMP that can accumulate in necrotic tumor regions.
2. Target Internalization: Upon binding to CD73 on the cell surface, Oleclumab induces the clustering of CD73 dimers. This clustering triggers receptor-mediated endocytosis, leading to the internalization of the antibody-enzyme complex into the cell.[1] This process effectively removes CD73 from the cell membrane, depleting the cell's capacity to generate extracellular adenosine. This provides a second, complementary mechanism of inhibition that is more durable than simple enzymatic blockade. Furthermore, this internalization has been hypothesized to confer an additional anti-metastatic benefit by reducing CD73-mediated cancer cell migration.[1]

The downstream immunological consequences of this target engagement are profound. By reducing the concentration of free adenosine, Oleclumab abrogates the immunosuppressive signals transmitted through adenosine receptors on immune cells. This leads to a cascade of immune-activating events within the TME, including [1]:

• Enhanced T-Cell Function: Increased activation and cytotoxic activity of CD8+ effector T cells.
• Macrophage Reprogramming: Activation of macrophages, likely shifting them from an immunosuppressive M2 phenotype to a pro-inflammatory, anti-tumor M1 phenotype.
• Reduction of Suppressive Cells: A decrease in the frequency and function of both myeloid-derived suppressor cells (MDSCs) and regulatory T-lymphocytes (Tregs).

Pharmacodynamic data from the first-in-human clinical trial (NCT02503774) provided critical in-vivo validation of this mechanism. The study demonstrated that administration of Oleclumab resulted in a sustained decrease in both free soluble CD73 levels in the serum and CD73 expression on the surface of peripheral T cells. Moreover, analysis of tumor biopsy samples confirmed a reduction in CD73 enzymatic activity and a corresponding increase in the infiltration of CD8+ T cells into the tumor following treatment.[20] These findings confirm that Oleclumab effectively engages its target and induces the intended biological effects in patients.

Pharmacokinetic Profile

Oleclumab is administered via intravenous (IV) infusion, typically on a bi-weekly or monthly schedule depending on the specific clinical trial protocol.[20] Pharmacokinetic (PK) properties have been characterized in early-phase clinical trials, most notably in a Phase I study conducted in Japanese patients with advanced solid tumors (NCT03736473).[3]

Key PK parameters from this study following a single IV infusion are:

• Maximum Serum Concentration (Cmax​): Oleclumab reaches its peak concentration in the blood very rapidly post-infusion. The geometric mean Cmax​ was 548.1 µg/mL for a 1500 mg dose and 841.7 µg/mL for a 3000 mg dose.[3]
• Time to Maximum Concentration (tmax​): The median tmax​ was 0.1 days (approximately 2.4 hours) for both dose levels, consistent with IV administration.[3]
• Drug Exposure (Area Under the Curve, AUC): Total drug exposure increased with the dose. The geometric mean AUC0−t​ (AUC from time zero to the last quantifiable concentration) was 3796.9 µg·day/mL for the 1500 mg dose and 5610.2 µg·day/mL for the 3000 mg dose.[3]
• Dose Proportionality: Analysis of the PK data from this study suggested that drug exposure increased in a less than dose-proportional manner. For example, a twofold increase in dose (from 1500 mg to 3000 mg) resulted in only a 1.54-fold increase in the geometric mean Cmax​.[3] This nonlinearity often indicates the presence of target-mediated drug disposition (TMDD), a phenomenon where a significant portion of the drug binds to its target (CD73) at lower concentrations and is cleared from circulation along with the target. As the dose increases and the target becomes saturated, clearance mechanisms become less dominant, and the PK behavior approaches linearity.
• Accumulation: With repeated dosing every two weeks, Oleclumab showed modest accumulation, with accumulation ratios for Cmax​ and trough concentration (Ctrough​) ranging from 1.2 to 1.7.[3]

Data from the larger first-in-human study (NCT02503774) corroborated these findings, noting that the highest two dose levels tested were sufficient to exceed the minimum target serum concentration required for sustained biological activity, thereby saturating the target and overcoming the effects of TMDD.[20] This work was crucial in establishing the recommended Phase II dose (RP2D) of 3000 mg used in subsequent trials.[25]

Comprehensive Review of the Clinical Development Program

The clinical development of Oleclumab has been extensive, spanning multiple phases, tumor types, and combination strategies. The program's trajectory is marked by a significant and promising signal in a specific subset of non-small cell lung cancer, contrasted by a series of failures and discontinuations in other settings. This suggests a narrow therapeutic window where its unique mechanism of action provides a substantial clinical benefit.

Early Phase Development: The First-in-Human Study (NCT02503774)

The foundational trial for Oleclumab was a Phase I, multicenter, open-label, dose-escalation and dose-expansion study (NCT02503774) initiated in 2015.[2] The primary objectives were to evaluate the safety, tolerability, and MTD of Oleclumab, both as a monotherapy and in combination with the anti-PD-L1 antibody durvalumab.[27] The study initially enrolled patients with advanced, microsatellite stable colorectal cancer (MSS-CRC) and pancreatic ductal adenocarcinoma (PDAC), later expanding to include a cohort of patients with EGFR-mutant (EGFRm) NSCLC.[2]

Key outcomes from this pivotal early study included:

• Safety and Dosing: The treatment was well-tolerated. No dose-limiting toxicities (DLTs) were observed during the dose-escalation phase for either monotherapy or the combination with durvalumab, establishing a manageable safety profile and allowing for the determination of a recommended Phase II dose.[20]
• Pharmacodynamics: The study provided the first human evidence of potent and sustained target engagement. Across all dose levels, treatment with Oleclumab led to a marked and durable decrease in free soluble CD73 in serum and CD73 expression on peripheral T cells. Furthermore, analysis of paired tumor biopsies confirmed reduced CD73 enzymatic activity within the tumor itself.[20]
• Preliminary Efficacy: In these heavily pretreated and typically immunotherapy-resistant populations, objective responses were rare. The objective response rate (ORR) during the escalation phase was 0%. However, the dose-expansion cohorts showed modest but durable signs of anti-tumor activity. The ORRs were 2.4% in MSS-CRC (1 complete response), 4.8% in PDAC (1 complete response, 1 partial response), and 9.5% in EGFRm NSCLC (4 partial responses).[22] While low, the durability of these responses provided the critical proof-of-concept needed to justify further investigation in more defined patient populations.

Pivotal Trials in Non-Small Cell Lung Cancer (NSCLC)

The modest signal in EGFRm NSCLC, combined with a strong preclinical rationale, prompted a focused development strategy in NSCLC, particularly in the curative-intent setting following chemoradiation.

The COAST Trial (NCT03822351): A Signal of Promise

The COAST study is a Phase II, open-label, randomized, multi-drug platform trial that represents the most significant positive clinical data for Oleclumab to date.[6] The trial was designed to build upon the standard of care established by the PACIFIC trial, which made durvalumab monotherapy the cornerstone of treatment for patients with unresectable, Stage III NSCLC whose disease has not progressed after cCRT. COAST randomized 186 such patients into three arms: durvalumab monotherapy, durvalumab plus Oleclumab, or durvalumab plus monalizumab (an anti-NKG2A antibody).[6]

The results for the Oleclumab combination arm were highly encouraging and demonstrated clear superiority over the standard-of-care control arm:

• Objective Response Rate (ORR): The confirmed ORR for the durvalumab plus Oleclumab arm was 30.0%, compared to 17.9% for the durvalumab monotherapy arm.[14]
• Progression-Free Survival (PFS): The combination significantly prolonged PFS. The hazard ratio (HR) for progression or death was 0.44 (95% CI, 0.26 to 0.75), representing a 56% reduction in risk compared to durvalumab alone.[33] The 12-month PFS rate was 62.6% for the combination arm versus 33.9% for the monotherapy arm.[14]

These data provided the first strong clinical evidence that blocking the CD73-adenosine pathway could synergize with PD-L1 inhibition to meaningfully improve patient outcomes in this specific clinical setting. The magnitude of the benefit observed in this randomized Phase II study provided a robust rationale for advancing the combination into a definitive Phase III trial.

The PACIFIC-9 Trial (NCT05221840): The Registrational Study

Building directly on the success of COAST, AstraZeneca launched the PACIFIC-9 trial, a large-scale, international, Phase III, randomized, double-blind, placebo-controlled study.[30] This trial is designed to confirm the findings of COAST and potentially establish the durvalumab plus Oleclumab combination as a new global standard of care.

The study has a three-arm design, randomizing approximately 999 patients with unresectable, Stage III NSCLC post-cCRT on a 1:1:1 basis to:

1. Durvalumab plus Oleclumab
2. Durvalumab plus Monalizumab
3. Durvalumab plus Placebo

The primary endpoint of the trial is PFS as assessed by blinded independent central review (BICR).[30] The trial began in February 2022 and has completed enrollment, with an estimated primary completion date in June 2026.[34] The outcome of PACIFIC-9 is the single most critical determinant of Oleclumab's future regulatory and commercial success.

Other NSCLC Trials

Additional studies have explored Oleclumab in other NSCLC contexts. The Phase I ARCHON-1 trial (NCT03801902) investigated the safety of adding Oleclumab to durvalumab plus radiation therapy.[37] A Phase Ib/II study (NCT03381274) evaluated combinations of Oleclumab with osimertinib or AZD4635 in patients with advanced EGFRm NSCLC.[38] The recently initiated Phase II LADOGA trial (NCT06606847) is a single-arm study designed to gather further efficacy and safety data for the durvalumab plus Oleclumab combination in the post-cCRT Stage III setting.[39]

Investigations in Other Malignancies: A Story of Mixed Results and Failures

In contrast to the focused success in NSCLC, Oleclumab's development in other solid tumors has been fraught with challenges and has failed to yield positive results.

• Pancreatic Ductal Adenocarcinoma (PDAC): A randomized Phase Ib/II study (NCT03611556) evaluated the addition of Oleclumab with or without durvalumab to standard-of-care chemotherapy (gemcitabine plus nab-paclitaxel) in patients with metastatic PDAC.[25] The trial did not meet its primary endpoint of improving the ORR. While the safety profile was acceptable, the lack of efficacy led the investigators to conclude that future studies in this indication would require a biomarker-based patient selection strategy.[41]
• Triple-Negative Breast Cancer (TNBC): The Phase II SYNERGY trial (NCT03616886) investigated a triplet combination of Oleclumab, durvalumab, and chemotherapy in the first-line setting for advanced TNBC. The trial was stopped prematurely in June 2021 after an interim analysis for futility showed that the addition of Oleclumab provided no improvement in the 24-week clinical benefit rate compared to the control arm (43% vs. 44%).[42]
• Sarcoma: A Phase II multi-arm study at MD Anderson Cancer Center (ID2020-0159) is actively investigating the combination of Oleclumab and durvalumab in patients with various subtypes of recurrent or metastatic sarcoma, including angiosarcoma, dedifferentiated liposarcoma, and osteosarcoma.[43] Results from this ongoing study are pending.

Discontinued and Withdrawn Development Programs

The challenges in demonstrating broad efficacy are further underscored by several strategic decisions to halt development programs.

• DOME Multi-Cancer Platform Study (NCT04262388): This Phase II study was designed to evaluate the Oleclumab plus durvalumab combination in PDAC, NSCLC, and squamous cell carcinoma of the head and neck. The trial was withdrawn prior to enrolling any patients. The sponsor's stated reason was that the "Overall clinical activity (ORR) for oleclumab + durvalumab is minimal across tumor types and does not support further evaluation of this doublet".[44] This preemptive withdrawal represents a significant negative signal regarding the combination's perceived efficacy in a broad, unselected metastatic setting.
• Prostate Cancer: A trial combining Oleclumab with the A2A receptor antagonist imaradenant (AZD4635) was discontinued due to safety or efficacy concerns.[5] A separate Phase II trial (NCT04089553) of AZD4635 plus Oleclumab in metastatic castration-resistant prostate cancer (mCRPC) showed minimal clinical activity, with no objective responses observed.[47]
• Other Indications: Development has also been officially discontinued for bladder cancer, colorectal cancer, and ovarian cancer, with these programs not advancing beyond Phase I.[5] While specific data on Oleclumab's failure in these tumor types is limited, the general challenges of immunotherapy in these settings, such as disease progression and toxicity, were likely contributing factors.[48]

The starkly different outcomes between the Stage III NSCLC post-cCRT setting and various metastatic settings suggest that the biological context is critical for Oleclumab's efficacy. The inflammatory and antigen-rich TME created by chemoradiation may be uniquely suited to benefit from the subsequent blockade of the immunosuppressive adenosine pathway, a synergy that does not appear to translate to less immunologically active or more advanced metastatic tumors.

Safety and Tolerability Analysis

The safety profile of Oleclumab has been extensively characterized across its clinical development program, both as a monotherapy and in combination with other anti-cancer agents. The overall assessment indicates a manageable safety profile, though toxicity increases, as expected, with the addition of combination partners.

Monotherapy Safety Profile

Data from the monotherapy dose-escalation cohorts of the first-in-human study (NCT02503774) provide the clearest picture of Oleclumab's intrinsic safety profile.[2] In this setting, the drug was well-tolerated.

• Incidence of Adverse Events: Treatment-related adverse events (TRAEs) of any grade were reported in approximately 55% of patients.[2]
• Severe Adverse Events: The rate of severe (Grade 3-4) TRAEs was low, occurring in only 7.1% of patients.[2]
• Common Adverse Events: The most frequently reported TRAE was fatigue, affecting 17% of patients. Nausea was also noted in 10% of patients.[2]
• Dose-Limiting Toxicities: No dose-limiting toxicities were observed during dose escalation, allowing for the progression to higher doses.[2]

Combination Therapy Safety Profile

When Oleclumab is combined with other agents, particularly the PD-L1 inhibitor durvalumab and cytotoxic chemotherapy, the incidence and severity of adverse events increase.

• Combination with Durvalumab: In the NCT02503774 study, the combination of Oleclumab and durvalumab resulted in a similar overall rate of any-grade TRAEs (54%) compared to monotherapy. However, the rate of Grade 3-4 TRAEs tripled to 20.8%.[2] The most common TRAEs in the combination expansion cohorts of this study were diarrhea (8.7%), pyrexia (8.7%), fatigue (6.5%), and increases in liver enzymes (ALT and AST, both 6.5%).[20] In the COAST trial, all-cause Grade ≥3 treatment-emergent adverse events occurred in 40.7% of patients receiving durvalumab plus Oleclumab, compared to 39.4% for those receiving durvalumab alone, indicating a relatively modest increase in severe toxicity in that specific patient population.[33]
• Combination with Chemotherapy: The addition of chemotherapy significantly elevates the toxicity burden. In the Phase Ib/II trial in pancreatic cancer (NCT03611556), which combined Oleclumab and durvalumab with gemcitabine and nab-paclitaxel, Grade ≥3 treatment-emergent adverse events occurred in 90.0% of patients in the triplet arm, with neutropenia being a common event.[25]

Serious Adverse Events and Risk Management

Across the clinical program, several serious safety events have been reported. A critical event was a single TRAE resulting in death due to systemic inflammatory response syndrome, which occurred in the expansion phase of the NCT02503774 trial.[2]

Patient information from the PACIFIC-9 trial outlines other potential risks associated with Oleclumab, including skin rash, fever, joint pain, allergic reactions, and potential worsening of cardiovascular issues such as heart problems or blood clots.[35]

Discontinuation of treatment due to adverse events is an important measure of tolerability. In the COAST trial, 15.3% of patients in the durvalumab plus Oleclumab arm discontinued treatment due to AEs.[54] This rate was higher in the more intensive chemotherapy combination trial for pancreatic cancer, where TEAEs led to discontinuation in 24.3% of patients receiving the triplet therapy.[25] This trend underscores a key challenge in developing combination therapies: the balance between enhancing efficacy and maintaining a tolerable safety profile. While the toxicity of the Oleclumab-durvalumab combination appears acceptable in the context of the significant efficacy benefit seen in the COAST trial, the unfavorable risk-benefit profile in settings with minimal efficacy, such as metastatic pancreatic cancer, likely contributed to the discontinuation of those programs.

Regulatory Landscape and Future Outlook

Current Regulatory Status

Oleclumab is an investigational drug and has not received marketing approval from any major global regulatory agency, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).[55] Its use is restricted to clinical trials and, in some cases, may be available through expanded access programs for patients who are not eligible for ongoing studies.[34] The numerous FDA and EMA approval announcements included in the research materials pertain to other drugs, most frequently its combination partner durvalumab for various indications, and serve as negative evidence confirming that Oleclumab itself remains unapproved.

Paediatric Investigation Plan (PIP) Waiver

A significant regulatory milestone for Oleclumab in Europe was the decision by the EMA's Paediatric Committee (PDCO) on September 9, 2022, to grant a product-specific waiver for its Paediatric Investigation Plan (PIP).[60] A PIP is a mandatory development plan to ensure that necessary data on a medicine's use in children are generated.

The waiver granted to Oleclumab (EMEA-003234-PIP01-22) is comprehensive, covering:

• All paediatric age groups: From birth to adolescence.
• All conditions/indications: Specifically for the treatment of lung cancer and pancreatic cancer.
• All pharmaceutical forms and routes of administration.

Such waivers are typically granted when the disease in question occurs almost exclusively in adults, or when the medicine is likely to be ineffective or unsafe in children.[61] Given that lung and pancreatic cancers are overwhelmingly diseases of older adults, this waiver is a pragmatic regulatory step. It allows AstraZeneca to streamline its development program and focus resources exclusively on the relevant adult patient populations without the obligation of planning or conducting complex and likely unfeasible paediatric studies.[62]

Strategic Analysis and Future Outlook

The development trajectory of Oleclumab presents a compelling case study in the context-dependent nature of modern immunotherapies. Its future is almost singularly dependent on the outcome of the ongoing Phase III PACIFIC-9 trial in unresectable, Stage III NSCLC.

• The Bull Case: A New Standard of Care in NSCLC: A positive result from PACIFIC-9, replicating the substantial PFS benefit seen in the Phase II COAST trial, would be a major success. It would position the durvalumab-Oleclumab combination as the new global standard of care in a large, commercially valuable, curative-intent setting. As one of the most clinically advanced anti-CD73 antibodies, Oleclumab has a first-mover advantage, and success in this indication would validate the entire therapeutic hypothesis of targeting the adenosine pathway in conjunction with PD-L1 blockade.[14]
• The Bear Case: A Niche Drug with Limited Applicability: The consistent failures across multiple metastatic cancer settings (pancreatic, breast, prostate, colorectal) cast a long shadow over the program. The withdrawal of the DOME platform study due to "minimal clinical activity" is a particularly strong negative signal from the sponsor about the combination's lack of broad efficacy.[45] This suggests that without the unique immunological priming provided by prior chemoradiation, Oleclumab's contribution to anti-tumor immunity is insufficient to produce meaningful clinical benefit in advanced, established tumors.
• The Path Forward: The critical challenge for AstraZeneca beyond NSCLC is the identification of a predictive biomarker. The conclusion from the failed pancreatic cancer trial—that future studies must incorporate biomarker-based selection—is a lesson that likely applies to all other potential indications.[41] Whether this biomarker is high tumoral CD73 expression, a specific gene signature related to adenosine metabolism, or a marker of an "inflamed but suppressed" TME remains to be determined. Without such a tool, further exploration in unselected patient populations is unlikely to be successful.

In conclusion, Oleclumab is a high-risk, high-reward asset. Its fate is tied to the PACIFIC-9 trial. Success would not only bring a new treatment option to patients with Stage III NSCLC but would also provide a major validation for the entire class of CD73 inhibitors. Failure, however, would likely confirm that its utility is confined to a very narrow biological niche, significantly limiting its overall therapeutic and commercial potential.

Appendix

Table A1: Oleclumab Drug Identifiers and Properties

Property	Value	Source(s)
International Nonproprietary Name (INN)	Oleclumab	7
Development Code	MEDI9447	7
DrugBank ID	DB15088	7
CAS Number	1803176-05-7	7
UNII	5CRY01URYQ	7
Type / Class	Biotech, Human Monoclonal Antibody (IgG1λ)	1
Developer	AstraZeneca / MedImmune	4
Molecular Target	CD73 (5'-nucleotidase, NT5E)	7
Molecular Formula	C6348​H9826​N1710​O1998​S40​	7
Molar Mass	143350.81 g/mol	7

Table A2: Comprehensive Summary of Oleclumab Clinical Trials

NCT Number	Trial Name/Acronym	Phase	Status	Condition(s) Studied	Intervention Arms (Selected)	Key Findings/Rationale	Source(s)
NCT02503774	First-in-Human Study	I	Active, not recruiting	Advanced Solid Tumors (CRC, PDAC, EGFRm NSCLC)	Oleclumab Mono; Oleclumab + Durvalumab	Manageable safety, no DLTs. Confirmed PD target engagement. Modest but durable responses in expansion cohorts.	2
NCT03736473	Phase I Study in Japan	I	Completed	Advanced Malignant Solid Tumor	Oleclumab	Well-tolerated in Japanese patients. Provided key PK data showing less than dose-proportional exposure.	3
NCT03822351	COAST	II	Active, not recruiting	Unresectable, Stage III NSCLC	Durvalumab; Durvalumab + Oleclumab; Durvalumab + Monalizumab	Positive signal: Oleclumab arm showed superior ORR (30% vs 18%) and PFS (HR 0.44) vs Durvalumab alone.	6
NCT05221840	PACIFIC-9	III	Active, not recruiting	Unresectable, Stage III NSCLC	Durvalumab + Oleclumab; Durvalumab + Monalizumab; Durvalumab + Placebo	Pivotal, registrational trial based on COAST results. Primary endpoint is PFS. Outcome will determine drug's future.	34
NCT06606847	LADOGA	II	Active, not recruiting	Unresectable, Stage III NSCLC	Durvalumab + Oleclumab	Single-arm study to gather further efficacy/safety data for the combination in the post-cCRT setting.	39
NCT03801902	ARCHON-1	I	Active, not recruiting	Locally Advanced NSCLC	Durvalumab + Oleclumab + RT	Investigating safety of adding Oleclumab to durvalumab and conventionally fractionated radiation therapy.	37
NCT03611556	Phase Ib/II in PDAC	Ib/II	Active, not recruiting	Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)	Chemo; Oleclumab + Chemo; Oleclumab + Durvalumab + Chemo	Negative: Did not meet primary endpoint of improving ORR. Concluded biomarker selection is needed for future studies.	25
NCT03616886	SYNERGY	II	Terminated	Advanced Triple-Negative Breast Cancer (TNBC)	Durvalumab + Chemo; Oleclumab + Durvalumab + Chemo	Negative: Halted early for futility. No improvement in 24-week clinical benefit rate.	42
NCT04262388	DOME	II	Withdrawn	PDAC, NSCLC, Head & Neck Cancer	Durvalumab + Oleclumab	Withdrawn before enrollment. Rationale: "minimal clinical activity... does not support further evaluation of this doublet."	44
ID2020-0159	Phase II in Sarcoma	II	Active	Recurrent/Metastatic Sarcoma	Oleclumab + Durvalumab	Multi-arm study testing efficacy in various sarcoma subtypes.	43
NCT04089553	Phase II in mCRPC	II	Completed	Metastatic Castration-Resistant Prostate Cancer (mCRPC)	AZD4635 + Durvalumab; AZD4635 + Oleclumab	Negative: Minimal clinical activity. No objective responses in the Oleclumab arm.	47

Table A3: Summary of Treatment-Related Adverse Events (TRAEs) from Key Trials

Trial (Population)	Treatment Arm	Any TRAE (%)	Grade ≥3 TRAE (%)	Most Common TRAEs (%)	Discontinuation due to AE (%)	Source(s)
NCT02503774 (Escalation)	Oleclumab Monotherapy	54.8	7.1	Fatigue (17), Nausea (10)	4.8	2
NCT02503774 (Escalation)	Oleclumab + Durvalumab	54.2	20.8	Fatigue (25), Increased AST (13), Vomiting (13), Nausea (13)	8.3	2
NCT02503774 (Expansion, CRC)	Oleclumab + Durvalumab	60.0	19.0	Fatigue (17), Diarrhea (12)	7.1	26
NCT02503774 (Expansion, PDAC)	Oleclumab + Durvalumab	57.0	17.0	Fatigue (12), Vomiting (12)	2.4	26
COAST (NCT03822351) (Stage III NSCLC)	Durvalumab Monotherapy	N/A	39.4 (All-cause TEAE)	N/A	15.2	33
COAST (NCT03822351) (Stage III NSCLC)	Durvalumab + Oleclumab	N/A	40.7 (All-cause TEAE)	N/A	15.3	33
NCT03611556 (Metastatic PDAC)	Oleclumab + Durvalumab + Chemo	N/A	77.1 (Grade ≥3 TRAE)	Neutropenia (17.1)	24.3	25

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