oleclumab (MEDI9447) / AstraZeneca - LARVOL DELTA

COAST: An Open-Label, Phase II, Multidrug Platform Study of Durvalumab Alone or in Combination With Oleclumab or Monalizumab in Patients With Unresectable, Stage III Non-Small-Cell Lung Cancer. (PubMed, J Clin Oncol) - "Both combinations increased ORR and prolonged PFS versus durvalumab alone. Safety was similar across arms with no new or significant safety signals identified with either combination. These data support their further evaluation in a phase III trial."

Combination therapy • Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLRC1

Durvalumab Plus Paclitaxel, with or without Capivasertib or Oleclumab, in Patients with Locally Advanced/Metastatic Triple-Negative Breast Cancer. (PubMed, Clin Cancer Res) - P1/2 | "These findings support the clinical activity and tolerability of durvalumab plus paclitaxel in locally advanced unresectable/mTNBC, as expected for an immune checkpoint inhibitor in combination with chemotherapy. Addition of capivasertib or oleclumab to this treatment combination showed no substantial additional benefit. PD-L1 expression was associated with enhanced antitumor activity across all arms."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AKT1 • PIK3CA • PTEN

Primary endpoint results of the Neo-CheckRay phase II trial evaluating stereotactic body radiation therapy (SBRT) +/- durvalumab (durva) +/- oleclumab (ole) combined with neo-adjuvant chemotherapy (NACT) for early-stage, high risk ER+/HER2- breast cancer (BC) (ESMO 2024) - P2 | "Neo-CheckRay (NCT03875573) is the first prospective, international, phase 2, randomized trial investigating this treatment. Eligible patients (pts) with newly diagnosed cT1c-3 (≥ 2 cm) cN0 or cT1c-3 (≥ 1.5 cm) cN1-3, grade 2 (Ki67 ≥ 15%) or grade 3, MammaPrint (MP) high risk, invasive ER+/HER2- BC were randomized 1:1:1 to arm 1: neo-adjuvant paclitaxel q1w x12 with SBRT at week 5 (3x8 Gy targeting the primary tumour, avoiding lymph nodes and normal breast tissue), followed by dose-dense epirubicin/cyclophosphamide q2w x4; arm 2: arm 1 + durva 1500mg q4w x5; and arm 3: arm 2 + ole 3000 mg q2w x4 then q4w x3. The addition of durva+/- ole numerically increases pCR and RCB 0/1 rates compared to NACT+SBRT. Final statistical analysis will be presented at the conference. Ongoing translational research will shed light on the mechanisms of response."

Clinical • Late-breaking abstract • P2 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Platform study of neoadjuvant durvalumab (D) alone or combined with novel agents in patients (pts) with resectable, early-stage non-small cell lung cancer (NSCLC): Pharmacodynamic correlates and circulating tumor DNA (ctDNA) dynamics in the NeoCOAST study (ESMO 2022) - P2 | "NeoCOAST (NCT03794544) is a phase 2 study of the anti-PD-L1 monoclonal antibody (mAb) D alone or combined with the anti-CD73 mAb oleclumab (O), the anti-NKG2A mAb monalizumab (M), or the anti-STAT3 antisense oligonucleotide danvatirsen (Da) as neoadjuvant therapy. Association of tumor mutational burden and additional biomarkers with clinical outcomes will be reported. Conclusions Single cycle of D+O and D+M resulted in greater intra-tumoral immunomodulation than D alone."

Circulating tumor DNA • Clinical • IO biomarker • PK/PD data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • CD8 • EGFR • KLRC1 • KRAS • STAT3 • STK11 • TMB

COLUMBIA-1: a randomised study of durvalumab plus oleclumab in combination with chemotherapy and bevacizumab in metastatic microsatellite-stable colorectal cancer. (PubMed, Br J Cancer) - P1/2 | "The safety profile of FOLFOX and bevacizumab in combination with durvalumab and oleclumab was manageable; however, the efficacy results do not warrant further development of this combination in patients with microsatellite stable mCRC."

Combination therapy • Journal • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Neoadjuvant durvalumab (D) + chemotherapy (CT) + novel anticancer agents and adjuvant D ± novel agents in resectable non-small-cell lung cancer (NSCLC): Updated outcomes from NeoCOAST-2. (ASCO 2025) - P2 | " Pts were stratified by PD-L1 expression (<1% vs ≥1%) and randomized to neoadjuvant D + platinum-doublet CT + oleclumab (anti-CD73 monoclonal antibody [mAb]) then adjuvant D + oleclumab (Arm 1), neoadjuvant D + platinum-doublet CT + monalizumab (anti-NKG2A mAb) then adjuvant D + monalizumab (Arm 2), or neoadjuvant D + single-agent platinum CT + Dato-DXd (TROP2-directed antibody-drug conjugate [ADC]) then adjuvant D (Arm 4). All arms show that novel perioperative combinations may improve pCR rates and maintain tolerability and feasibility of surgery in resectable NSCLC. The final analysis of pCR and mPR rates in Arm 4 is the first for an ADC in this setting and confirms the encouraging efficacy and manageable safety profile of D + CT + Dato-DXd. Presurgical ctDNA clearance is associated with pathological responses."

Clinical • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLRC1

Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase 2 NeoCOAST Platform Trial. (PubMed, Cancer Discov) - "Eighty-three patients received a single cycle of treatment: 26 received durvalumab (anti-PD-L1) monotherapy, 21 received durvalumab plus oleclumab (anti-CD73), 20 received durvalumab plus monalizumab (anti-NKG2A), and 16 received durvalumab plus danvatirsen (anti-STAT3 antisense oligonucleotide). Safety profiles for the combinations were similar to that of durvalumab alone. Multiplatform immune profiling suggested improved MPR rates in the durvalumab plus oleclumab and durvalumab plus monalizumab arms were associated with enhanced effector immune infiltration of tumors, interferon responses and markers of tertiary lymphoid structure formation, and systemic functional immune-cell activation."

Immuno-oncology • IO biomarker • Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLRC1 • STAT3

First-line durvalumab plus chemotherapy with or without oleclumab for locally advanced or metastatic triple-negative breast cancer: SYNERGY overall survival and circulating tumor DNA analysis. (ASCO 2025) - P1/2 | " 133 patients received weekly carboplatin and paclitaxel x12 plus durvalumab, with (arm A) or without (arm B) oleclumab (6 in phase I, 63 in arm A, 64 in arm B). The addition of oleclumab to chemo-immunotherapy did not improve PFS or OS in advanced TNBC. However, a subgroup of patients experienced exceptional long-lasting response, indicating potential benefit in selected cases. CtDNA detection was strongly associated with poorer outcomes at all timepoints, underscoring its potential as a biomarker in this disease/setting."

Circulating tumor DNA • Clinical • IO biomarker • Metastases • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Neocoast-2: Efficacy and Safety of Neoadjuvant Durvalumab (D) + Novel Anticancer Agents + CT and Adjuvant D ± Novel Agents in Resectable NSCLC (IASLC-WCLC 2024) - P2 | "Methods : Patients with untreated, histologicallyconfirmed, resectable Stage IIA-IIIB NSCLC were stratified by PD-L1 expression(<1% vs ≥1%) and randomised to Arm 1: neoadjuvant D + platinum-doublet CT +oleclumab (anti-CD73 mAb), Arm 2: D + platinum-doublet CT + monalizumab (anti-NKG2AmAb), or Arm 4: D + single-agent platinum CT + Dato-DXd (TROP2 directed antibody-drug conjugate [ADC]).Neoadjuvant therapy was given Q3W for 4 cycles prior to surgery, followed byadjuvant treatment with D + oleclumab (Arm 1) or monalizumab (Arm 2) or alone(Arm 4) until disease progression per RECIST v1.1 or for up to 1 year. Treatments in all arms led to improvementsin mPR rates along with a manageable safety profile and surgical ratescomparable to currently approved neoadjuvant and perioperativeimmunotherapy-based regimens (Forde NEJM 2022; Wakelee NEJM 2023). This is the first global Ph2 platform study showing encouragingefficacy and a manageable safety profile of an ADC in the..."

Clinical • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLRC1

Perioperative durvalumab plus chemotherapy plus new agents for resectable non-small-cell lung cancer: the platform phase II NeoCOAST-2 trial. (PubMed, Nat Med) - P2 | "In the phase II NeoCOAST-2 platform study, 202 patients with untreated, resectable stage IIA-IIIB non-small-cell lung cancer (NSCLC) were randomized to receive neoadjuvant durvalumab plus platinum-doublet chemotherapy with oleclumab, a CD73 inhibitor (Arm 1), or with monalizumab, a NKG2A inhibitor (Arm 2), or neoadjuvant durvalumab plus single-agent platinum chemotherapy with the TROP-2 antibody-drug conjugate (ADC) datopotamab deruxtecan (Arm 4), followed by surgical resection and adjuvant durvalumab with oleclumab or monalizumab (Arms 1 and 2) or durvalumab alone (Arm 4). In NeoCOAST-2, the first neoadjuvant trial examining an ADC plus chemo-immunotherapy in resectable NSCLC, pCR rates were highest in the datopotamab-deruxtecan-containing arm, warranting further investigation in larger trials of ADCs and checkpoint inhibition in the neoadjuvant setting. ClinicalTrials.gov identifier: NCT05061550 ."

Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD73 • KLRC1

CD73 Serves as a Prognostic Biomarker and Therapeutic Target in Combination With Lorlatinib for ALK-Positive NSCLC (IASLC-WCLC 2026) - "A tumor-T cell co-culture system was used to evaluate the therapeutic efficacy of ALK-TKI Lorlatinib in combination with CD73 inhibitor Oleclumab or adenosine A2A receptor antagonist CPI-444. The ALK-CD73-adenosine axis drives immune suppression and tumor progression. ALK-TKI combined with CD73 inhibitor or adenosine A2A receptor inhibitors exerts significant immune-activating effects, offering a novel therapeutic strategy for ALK -positive NSCLC."

Biomarker • Combination therapy • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • ADORA2A • ALK • CD73 • CD8 • IFNG • NT5E • TNFA

Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2- breast cancer: a randomized phase 2 trial. (PubMed, Nat Med) - P2 | "These findings suggest that iSBRT + anti-PD-L1 may convert immune-cold ER+HER2- BC into more inflamed tumors and improve response, particularly in PD-L1-negative disease. ClinicalTrials.gov registration: NCT03875573 ."

IO biomarker • Journal • P2 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Updated results from COAST, a phase 2 study of durvalumab (D) ± oleclumab (O) or monalizumab (M) in patients (pts) with stage III unresectable non-small cell lung cancer (uNSCLC). (ASCO 2024) - P2, P3 | "D+O and D+M increased ORR and prolonged PFS and OS vs D alone. Safety was similar across arms, with no new safety signals. Further investigation of D, D+O, and D+M in this population is ongoing in the Phase 3 PACIFIC-9 study (NCT05221840)."

Clinical • IO biomarker • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Solid Tumor • HLA-E • KLRC1 • NT5E • PD-L1

Precision immuno-oncology for advanced non-small cell lung cancer (NSCLC) patients with PD-(L)1 inhibitors resistance (PIONeeR): A phase Ib/IIa clinical trial targeting identified resistance pathways (ESMO 2024) - P2 | "Pts were randomly allocated to Arm A: Durvalumab (Du) + Monalizumab, Arm B: Du + Oleclumab, Arm C: Du + Ceralasertib, Arm E: Du + Savolitinib or Arm D (control): Docetaxel. With its innovative and adaptive design, the PIONeeR trial was able to explore several options to overcome resistance to ICIs. Although no experimental arm performed better than outcomes observed with docetaxel, some pts had long DoR, suggesting durvalumab combinations can be highly effective. Biomarker work is ongoing to identify patients most likely to benefit from combination treatment."

Clinical • Immuno-oncology • IO biomarker • Late-breaking abstract • Metastases • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Primary endpoint results of SYNERGY, a randomized phase II trial, first-line chemo-immunotherapy trial of durvalumab, paclitaxel, and carboplatin with or without the anti-CD73 antibody oleclumab in patients with advanced or metastatic triple-negative breast cancer (TNBC) (ESMO 2022) - "Conclusions The addition of oleclumab to durvalumab with carboplatin/paclitaxel did not increase CBR at week 24 in first-line advanced TNBC. Ongoing translational research aims to better understand the mechanisms of responses to the study combination."

Clinical • IO biomarker • Late-breaking abstract • P2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

NeoCOAST: open-label, randomized, phase 2, multidrug platform study of neoadjuvant durvalumab alone or combined with novel agents in patients (pts) with resectable, early-stage non-small-cell lung cancer (NSCLC) (AACR 2022) - P2 | "NeoCOAST (NCT03794544) is a global, randomized phase 2 study of the anti-PD-L1 monoclonal antibody (mAb) durvalumab (D) alone or combined with the anti-CD73 mAb oleclumab (O), the anti-NKG2A mAb monalizumab (M), or the anti-STAT3 antisense oligonucleotide danvatirsen (Da) as neoadjuvant therapy. Pts with previously untreated, cytologically/histologically documented, resectable, Stage I [>2 cm]-IIIA NSCLC and ECOG PS 0-1 were randomized 1:1:1:1 (stratified by lymph node involvement) to receive D 1500 mg IV alone Q4W or combined with O 3000 mg IV Q2W, M 750 mg IV Q2W, or Da 200 mg IV QW, for one 28-day cycle, followed by surgery. One cycle of D + O, M or Da improved MPR and pCR rates vs D alone, with no new safety signals. Responses were associated with baseline tumor PD-L1 and CD73 expression levels. Pts with MPR receiving D+O or D+M had peripheral transcriptomic signatures related to immune cell function."

Clinical • IO biomarker • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLRC1 • NT5E • STAT3

Paclitaxel plus carboplatin and durvalumab with or without oleclumab for women with previously untreated locally advanced or metastatic triple-negative breast cancer: the randomized SYNERGY phase I/II trial. (PubMed, Nat Commun) - P1/2 | "Exploratory median progression-free survival was 5.9 months in arm A as compared to 7.0 months in arm B (p = 0.90). The safety profile was manageable in both arms."

Journal • Metastases • P1/2 data • P2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

HUDSON: An Open-Label, Multi-Drug, Biomarker-Directed Phase 2 Study in NSCLC Patients Who Progressed on Anti-PD-(L)1 Therapy (IASLC-WCLC 2022) - P2 | "Here we present mature efficacy and safety results for the initial combinations - durvalumab plus: olaparib (PARP inhibitor; Module 1), danvatirsen (STAT3 inhibitor; Module 2), ceralasertib (ATR inhibitor; Module 3), and oleclumab (anti-CD73 antibody; Module 5). Durvalumab plus ceralasertib demonstrated a promising efficacy signal, with a tolerable safety profile, in patients with advanced/metastatic NSCLC following failure of anti-PD-1/PD-L1-containing immunotherapy and ≥1 platinum-doublet regimen."

Biomarker • Clinical • IO biomarker • P2 data • Anemia • Fatigue • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Phase 3 Study of Durvalumab Combined with Oleclumab or Monalizumab in Patients with Unresectable Stage III NSCLC (PACIFIC-9) (IASLC-WCLC 2022) - P2, P3 | "Other secondary endpoints include objective response rate and duration of response (RECIST v1.1; BICR), patient-reported outcomes, PD-L1 expression on tumor cells relative to efficacy outcomes, and safety/tolerability. Enrolment in PACIFIC-9 is ongoing."

Clinical • IO biomarker • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • CD8 • EGFR • HLA-E • KLRC1 • TIGIT

Adapting radiation therapy to immunotherapy: Delineation and treatment planning of pre-operative immune-modulating breast iSBRT in 151 patients treated in the randomized phase II Neo-CheckRay trial. (PubMed, Radiother Oncol) - "In the Neo-CheckRay trial, the predefined organs at risk dose constraints were feasible and the TDLN were adequately spared."

Journal • P2 data • Breast Cancer • Oncology • Solid Tumor

Neo-CheckRay, radiation therapy and adenosine pathway blockade to potentiate benefit of immuno-chemotherapy in early stage luminal B breast cancer: results of the safety run-in phase. (ESMO-BC 2022) - P2 | "Here, we present the results of the safety run-in.Methods The safety run-in was an open-label, single arm trial in which 6 patients (pts) with early stage luminal B BC received the following neo-adjuvant regimen: paclitaxel q1w x 12 → doxorubicin/cyclophosphamide q2w x 4; durvalumab (anti-PD-L1) q4w x 5; oleclumab (anti-CD73) q2w x 4 → q4w x 3 and 3x8Gy SBRT to the primary tumour at week 5. No grade 2-3 radiation dermatitis or pneumonitis was reported. Overall cosmetic breast evaluation after surgery was 'excellent' (4/6) and 'good' (2/6).Conclusions This novel combination treatment was considered safe, leading to the activation of the Neo-Checkray phase II randomized trial which is currently recruiting in French and Belgian sites."

Clinical • Atopic Dermatitis • Breast Cancer • Cardiovascular • Conjunctivitis • Dermatitis • Dermatology • Endocrine Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Immunology • Inflammation • Ocular Infections • Ocular Inflammation • Oncology • Ophthalmology • Pneumonia • Solid Tumor • ER • HER-2

A Phase 1b/2 Randomized Clinical Trial of Oleclumab with or without Durvalumab plus Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma. (PubMed, Clin Cancer Res) - P1b/2 | "Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint."

Clinical • Journal • Metastases • P1/2 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD73 • NT5E

PACIFIC-9: Phase III trial of durvalumab + oleclumab or monalizumab in unresectable stage III non-small-cell lung cancer. (PubMed, Future Oncol) - P3 | "Both agents demonstrated antitumor activity in early-phase trials. PACIFIC-9 (NCT05221840) is an international, double-blind, randomized, placebo-controlled, Phase III trial comparing durvalumab plus either oleclumab or monalizumab with durvalumab plus placebo in patients with unresectable, stage III NSCLC and no disease progression following cCRT.Clinical Trial Registration: NCT05221840 (ClinicalTrials.gov)."

Journal • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD73 • KLRC1

Heating up cold tumors: single-cell mapping of immune and adenosine pathway reprogramming in luminal B breast cancer (Neo-CheckRay trial) (SABCS 2025) - P2 | "Adding durvalumab (arm 2) ± oleclumab (arm 3) to SBRT+NACT (arm 1) doubled pCR rates (from 16.7% to 33.3% and 31.1%). In contrast, non-responders and arm 1 accumulated CD73 on myeloids (p = 0.009), CAFs (p = 0.05), and epithelium (p = 0.024) while lacking degradation enzymes, maintaining suppression.ConclusionIn immune-cold luminal B breast cancer, effective therapy likely requires: pre-existing immune organization (CXCL13+ myeloid), anti-tumor priming by SBRT+NACT, sustained T-cell activity via PD-L1 blockade, and relief of adenosine-mediated suppression via CD73 blockade. Notably, our data suggest oleclumab's efficacy may stem not from mere CD73 inhibition, but from its redistribution to the vascular niche, where it may preserve perfusion and immune accessibility, without triggering the immunosuppressive effects seen with CD73 upregulation on myeloid, CAF, or epithelial cells."

IO biomarker • Breast Cancer • ADORA2A • ADORA2B • APOC1 • CD4 • CD73 • CXCL10 • CXCL13 • ENTPD1 • IL2RA • SPP1 • STING

Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study (clinicaltrials.gov) - P1/2 | N=43 | Active, not recruiting | Sponsor: MedImmune LLC | Trial completion date: Apr 2026 ➔ Nov 2026

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR