monalizumab (IPH2201) / AstraZeneca, Innate - LARVOL DELTA

INTERLINK-1: Assessment of Efficacy and Safety of Monalizumab Plus Cetuximab Compared to Placebo Plus Cetuximab in Recurrent or Metastatic Head and Neck Cancer (clinicaltrials.gov) - P3 | N=370 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Sep 2025 ➔ Sep 2026

Checkpoint inhibition • Trial completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Monalizumab PACIFIC-9 on track to deliver data in H2 2026 (Businesswire)

P3 data • Non Small Cell Lung Cancer

A2AR-phospho-STAT1 (Y701)-HLA-E axis as a potential immune modulatory pathway in radiotherapy-resistant triple negative breast cancer. (PubMed, Carcinogenesis) - "Interestingly, STAT1 phosphorylation (Y701) by adenosine (ADO) aligned with the HLA-E expression pattern by ADO, and fludarabine, a STAT1 inhibitor, effectively reduced phospho-STAT1 (Y701) levels, but not phospho-STAT1 (S727) levels. Moreover, Monalizumab, an NKG2A monoclonal antibody, significantly reduced tumor progression and lung metastasis with increased population of cytotoxic NK cells (CD25+NK1.1+ and CD69+NK1.1+) in the inguinal lymph nodes of RT-R-MDA-MB-231-injected mice. This study suggests that the A2AR-phospho-STAT1 (Y701)-HLA-E axis may serve as an alternative target for overcoming RT-resistance in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD69 • HLA-E • IL2RA • KLRC1 • STAT1

Targeting the NK cell checkpoint NKG2A promotes lung fibrosis resolution by enhancing immune clearance of senescent myofibroblasts (ACR Convergence 2025) - "The bleomycin-induced lung fibrosis model and in vitro cultures were used to investigate the effect of NKG2A-inhibition on lung fibrosis and the elimination of senescent primary human lung fibroblasts. Proteomics and transcriptomics analyses revealed that NKG2A exhibits the highest and most selective expression among NK checkpoints in human ILD. In summary, NKG2A checkpoint blockade selectively enhances elimination of senescent myofibroblasts by NK cells and promotes the resolution of fibrosis in preclinical models."

Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • KLRC1

S2409: Using Biomarker Tests to Select and Test New, Personalized Treatments for Extensive Stage Small Cell Lung Cancer, PRISM Study (clinicaltrials.gov) - P2 | N=900 | Recruiting | Sponsor: SWOG Cancer Research Network | Not yet recruiting ➔ Recruiting

Biomarker • Enrollment open • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • SLFN11

The Selective Personalized Radio-Immunotherapy for Locally Advanced NSCLC Trial 2 (SPRINT2) (IASLC-WCLC 2025) - "Introduction : In the S elective P ersonalized R adio- I mmunotherapy for locally advanced N SCLC T rial (SPRINT), patients with locally advanced NSCLC (LA-NSCLC) with PD-L1 tumor proportion score (TPS) of ≥50% were treated with induction pembrolizumab, followed by a 20-fraction course of risk-adapted thoracic radiotherapy, followed by consolidation pembrolizumab to complete a 1-year treatment course...We hypothesize that dual-agent immunotherapy with durvalumab and either monalizumab or oleclumab will enhance the efficacy of the SPRINT approach...The primary study endpoint is response on FDG-PET after induction immunotherapy, evaluated using PERCIST criteria. Other endpoints include progression-free survival, overall survival, clinician- and patient-reported adverse events, and physical activity metrics captured using wearable devices."

Metastases • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor

Testing the Safety of Adding Either Monalizumab (IPH2201) or Oleclumab (MEDI9447) to Durvalumab (MEDI4736) Plus Standard Radiation Therapy for Locally Advanced Non-small Cell Lung Cancer (NSCLC), ARCHON-1 Trial (clinicaltrials.gov) - P1 | N=26 | Completed | Sponsor: National Cancer Institute (NCI) | Trial completion date: Apr 2026 ➔ Sep 2025 | Active, not recruiting ➔ Completed

Trial completion • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • PD-L1

CD40L and IL-4 suppress NK cell-mediated antibody-dependent cellular cytotoxicity through the HLA-E:NKG2A axis. (PubMed, Immunother Adv) - "NKG2A blockade potentiated NK cell-mediated ADCC against malignant B cells treated with CD40L and IL-4 and improved anti-CD20 antibody therapy in a murine model of B cell lymphoma. These results reveal a novel mechanism of resistance to anti-CD20 therapy in B cell malignancies and demonstrate that the combination of anti-NKG2A with anti-CD20 could improve the treatment of patients with CLL or NHL."

Journal • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD40LG • HLA-E • IL4 • KLRC1

Innate Pharma Reports First Half 2025 Business Update… (Innate Pharma Press Release) - "Monalizumab: AstraZeneca Phase 3 PACIFIC-9 enrollment is completed and high level read-out is expected in H2 2026."

P3 data • Non Small Cell Lung Cancer

SPRINT 2: The Selective Personalized Radio-Immunotherapy for Locally Advanced Non-Small Cell Lung Cancer Trial 2 (clinicaltrials.gov) - P2 | N=52 | Not yet recruiting | Sponsor: Montefiore Medical Center

New P2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

PACIFIC-9: A Global Study to Assess the Effects of Durvalumab With Oleclumab or Durvalumab With Monalizumab Following Concurrent Chemoradiation in Patients With Stage III Unresectable Non-Small Cell Lung Cancer (clinicaltrials.gov) - P3 | N=1027 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • PD-L1

Durvalumab Alone or Combined With Novel Agents for Unresectable Stage III Non-Small Cell Lung Cancer: Update From the COAST Randomized Clinical Trial. (PubMed, JAMA Netw Open) - P2 | "Novel immunotherapy combinations involving the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab have the potential to build on the durvalumab standard of care. This finding supports further investigation of these novel combinations in the phase 3 PACIFIC-9 trial. ClinicalTrials.gov Identifier: NCT03822351."

Clinical • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLRC1

The Role of NKG2A+ NK Cells in the Control of Epstein-Barr Virus Positive Post-Transplant Lymphoproliferative Disorders (WTC 2025) - "Together, our findings indicate that disruption of the NKG2A:HLA-E immune checkpoint axis, either through the decrease of HLA-E on target cells or the more clinically-relevant blocking of NKG2A on NK cells, enhances killing of EBV-infected B cells. Our results support that NKG2A+ NK cells are educated and functionally cytotoxic against EBV-infected B cells and suggest that therapeutics, such as Monalizumab, that target the NKG2A:HLA-E immune checkpoint axis could be beneficial in treatment of EBV+ PTLD."

Post-transplantation • Epstein-Barr Virus Infections • Infectious Disease • Pediatrics • Transplantation • HLA-E • KLRC1 • KLRD1

Safety and Feasibility of Blockade of NK Group-2 Member-A Receptor in Natural Killer Cells Combined with Cetuximab Antibody in Patients with Advanced Gastric Adenocarcinoma. (PubMed, Adv Pharm Bull) - "However, two patients showed progressive disease (PD) after 12 weeks and the level of CA19-9 was increased in all three patients after 24 weeks. In conclusion, this study demonstrated the safety and feasibility of infusing high doses of anti-NKG2A pretreated NK cells combined with cetuximab in patients with GAC."

Journal • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • CA 19-9 • KLRC1 • NCAM1

M6A-METTL3-dependent nuclear PANC754/PSPC1/H3K4me1 repression complex regulate immune evasive LGALS7 signal to enhance immunotherapy against colorectal cancer. (PubMed, Cell Death Dis) - "Furthermore, we confirmed that prominent upregulation of the immune checkpoint inhibitory (ICI) capability of anti-NKG2A, monalizumab when it was combined with PANC754 overexpression...Effect is that novel nuclear PANC754/PSPC1/H3K4me1 repression complex down-regulates the level "Don't eat me" signal LGALS7 to improve the immune efficiency of ICB and induce NK or CTL cell to release perforin and cytokine to kill tumor cells. (Created by Figdraw)."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • KLRC1 • METTL3

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

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

INTERLINK-1: A Phase III, Randomized, Placebo-Controlled Study of Monalizumab Plus Cetuximab in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. (PubMed, Clin Cancer Res) - P3 | "Monalizumab plus cetuximab did not improve OS compared with placebo plus cetuximab. The safety profile of the combination was consistent with safety observations for cetuximab monotherapy."

Journal • P3 data • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A phase II study of monalizumab and durvalumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: results of the I2 cohort of the EORTC-HNCG-1559 trial (UPSTREAM). (PubMed, ESMO Open) - "The I2 substudy failed to demonstrate an activity of D + M in heavily pretreated patients with SCCHN previously exposed to anti-PD(L)1. No benefit was seen in PFS and OS."

IO biomarker • Journal • P2 data • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • KLRC1

Testing the Safety of Adding Either Monalizumab (IPH2201) or Oleclumab (MEDI9447) to Durvalumab (MEDI4736) Plus Standard Radiation Therapy for Locally Advanced Non-small Cell Lung Cancer (NSCLC), ARCHON-1 Trial (clinicaltrials.gov) - P1 | N=26 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=48 ➔ 26 | Trial completion date: Mar 2025 ➔ Apr 2026

Enrollment change • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • PD-L1

Cytomegalovirus Infection Drives Tumor Human Leukocyte Antigen E Expression and Promotes Adaptive Natural Killer Cell Functions in Human Bladder Cancer (AUA 2025) - "HCMV reactivation post-BCG may impact treatment response and offers therapeutic potential, especially through the role of HLA-E in immune checkpoint modulation. These insights enable exploration of therapies blocking NKG2A (e.g., monalizumab) or enhancing NKG2C+NK cell response via adaptive cell therapy."

Bladder Cancer • Cytomegalovirus Infection • Genito-urinary Cancer • Infectious Disease • Oncology • Solid Tumor • CD8 • HLA-E • KLRC1

S2409: Using Biomarker Tests to Select and Test New, Personalized Treatments for Extensive Stage Small Cell Lung Cancer, PRISM Study (clinicaltrials.gov) - P2 | N=900 | Not yet recruiting | Sponsor: SWOG Cancer Research Network | Initiation date: Mar 2025 ➔ Sep 2025

Trial initiation date • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • SLFN11

Anti-NKG2A Monoclonal Antibody for AML or MDS Patients Undergoing Haploidentical Transplantation (clinicaltrials.gov) - P2 | N=42 | Recruiting | Sponsor: Istituto Clinico Humanitas

New P2 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • Transplantation

Nationwide multi-centric prospective study for the identification of biomarkers to predict the treatment responses of nivolumab through comprehensive analyses of pretreatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT study). (PubMed, Front Immunol) - "The PEX mRNA signature could be useful as a companion diagnostic of nivolumab. The combination of an anti-NKG2A antibody (i.e., monalizumab) and nivolumab may serve as a treatment option for non-survivors predicted by a RT-qPCR-based pre-treatment measurement of PEX mRNAs."

Biomarker • Journal • PD(L)-1 companion diagnostic • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HLA-E • KLRC1

Combination Strategies Enhance NK Cell Therapy for Multiple Myeloma (MM): Memory-like Differentiation, NKG2A Blockade, and Improved Recognition Via BCMA CAR or MM-Targeting Antibodies (TCT-ASTCT-CIBMTR 2025) - "Human NK cells were adoptively transferred into MM-bearing NSG mice to test ML differentiation, NKG2A blockade (monalizumab, IgG4), and BCMA CAR, or combinations, for pre-clinical activity...To complement these strategies, we tested anti-SLAMF7 mAb (elotuzumab) and BMCA CAR (41BB,CD3z) with ML NK cell differentiation... MM patient blood NK cells are functionally intact, and ML differentiation, NKG2A checkpoint blockade, and use of CAR or MM-targeting mAb to enhance recognition significantly improve NK cell anti-MM attack. However, combinations of these resulted in marked improvements to NK cell control of MM. These combinations for anti-MM NK cellular therapy warrant further study in early phase clinical trials."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • HLA-E • IFNG • IL12A • IL15 • IL18 • KLRC1 • NKG2D • SLAMF7