monalizumab (IPH2201)

P3, N=370, Active, not recruiting, AstraZeneca | Trial completion date: Sep 2025 --> Sep 2026

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.

P2, N=900, Recruiting, SWOG Cancer Research Network | Not yet recruiting --> Recruiting

P1, N=26, Completed, National Cancer Institute (NCI) | Trial completion date: Apr 2026 --> Sep 2025 | Active, not recruiting --> Completed

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.

P2, N=52, Not yet recruiting, Montefiore Medical Center

P3, N=1027, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

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.

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.

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).

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 .

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.