monalizumab (IPH2201) / AstraZeneca, Innate - LARVOL DELTA

Immune Imbalance Drives Keloid Pathogenesis: Emerging Targets for Precision Immunotherapy. (PubMed, Adv Wound Care (New Rochelle)) - "The absence of validated keloid models and large-scale trials limits translation. Future research must integrate immune profiling, biomarker validation, and mechanistic modeling to enable personalized interventions. Immune dysregulation is not merely an epiphenomenon-it is the Achilles' heel of keloids, offering unprecedented opportunities for targeted therapy and recurrence prevention."

IO biomarker • Journal • Review • Dermatology • Fibrosis • Pruritus • IL13 • IL4 • IL6 • KLRC1 • KLRD1 • STAT3 • TGFB1 • TSLP

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

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

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

MOZART: MOnaliZumab in Combination With durvAlumab (MEDI4736) Plus Platinum-based chemotheRapy for First-line Treatment of Extensive Stage Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=38 | Suspended | Sponsor: Hirva Mamdani | Trial completion date: Jan 2027 ➔ Jan 2028 | Recruiting ➔ Suspended | Trial primary completion date: Jan 2026 ➔ Jan 2027

Trial completion date • Trial primary completion date • Trial suspension • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Stochastic Gates for Covariate Selection in Population Pharmacokinetics Modeling. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "In real clinical data from a monalizumab study, the method successfully identified covariates that matched those found by experts. However, for tixagevimab/cilgavimab, it identified a superset of covariates, indicating a potential need for further pruning. This machine learning-based method enhances the covariate preselection process in population pharmacokinetics model development, offering significant time savings and improving efficiency even under challenging scenarios."

Journal • PK/PD data

Unleashing NK- and CD8 T cells by combining monalizumab and trastuzumab for metastatic HER2-positive breast cancer: Results of the MIMOSA trial. (PubMed, Breast) - "Therefore, the MIMOSA-trial did not meet its primary endpoint. In summary, despite the strong preclinical rationale, the novel combination of monalizumab and trastuzumab does not induce objective responses in heavily pre-treated HER2-positive MBC patients."

Journal • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Immune Modulation • Oncology • Solid Tumor • CD8 • HER-2 • KLRC1

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

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

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

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

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

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

ENHANCE: A Trial of Durvalumab (MEDI4736) Plus Monalizumab in Non-Muscle-Invasive Bladder Cancer (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: John Sfakianos | Trial completion date: Dec 2026 ➔ Dec 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • PD-L1

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

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

Phase 1/2 study of monalizumab plus durvalumab in patients with advanced solid tumors. (PubMed, J Immunother Cancer) - P1/2 | "Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME."

Journal • Metastases • P1/2 data • P2 data • Cervical Cancer • Colorectal Cancer • Dermatology • Endometrial Cancer • Fatigue • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pruritus • Solid Tumor • CXCL10 • CXCL11 • GZMB • KLRC1 • KLRD1

CD40L and IL-4 Lymph Node-Associated Signals Protect B Cells from Rituximab-Induced ADCC via KIR and NKG2A. (PubMed, Clin Exp Immunol) - "Overall, this study identifies a novel mechanism of resistance of B cells to NK cell cytotoxicity and indicates that blockade of the HLA-E:NKG2A and HLA:KIR checkpoint axes could be beneficial for improving B cell depletion in patients with autoimmune diseases."

Journal • Immunology • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • Systemic Lupus Erythematosus • CD40LG • HLA-E • IL4 • KLRC1

The CD94/NKG2A-HLA-E axis as a target in cancer immunotherapy: a critical perspective. (PubMed, Clin Cancer Res) - "First, the effectiveness of blocking the NKG2A-HLA-E interaction in vitro and in pre-clinical models as well as the presence of infiltrating NKG2A+ CD8+ T cells in some solid tumors has led to the generation of clinical grade NKG2A-specific monoclonal antibodies, pioneered by monalizumab, currently tested in clinical trials. Second, controlling NKG2A expression by genetic engineering constitutes a promising approach to improve advanced adoptive NK cell-based immunotherapies. Challenges include identifying predictive biomarkers of responsiveness, selecting appropriate clinical settings and optimizing combinatorial regimens."

IO biomarker • Journal • Oncology • Solid Tumor • CD8 • CTLA4 • HLA-E • KLRC1 • KLRD1 • PD-1 • PD-L1

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 | Trial completion date: Feb 2028 ➔ Aug 2028 | Initiation date: Sep 2025 ➔ Mar 2026 | Trial primary completion date: Apr 2027 ➔ Oct 2027

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

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