Abstract C005: Exploratory Biomarker Evaluation of the Randomized Phase 2 Cohort of CM24 in Combination with Nivolumab and Chemotherapy in Advanced/metastatic Pancreatic Cancer
Cancer Research(2024)
摘要
Abstract Background: CM24 (mAb) blocks CEACAM1 interactions, has key roles in cancer progression, immune escape and metastasis. CEACAM1 is part of the neutrophil extracellular trap (NET) complex, involved in tumor immune evasion, metastasis and cancer-associated thrombosis, affecting patient survival. We demonstrated that CM24 binds to NET and suppresses NET-induced migration of cancer cells (AACR Cancer Metastasis Nov.2022) and that CM24+nivolumab (nivo) treatment of pancreatic ductal adenocarcinoma (PDAC) patients markedly reduced serum levels of the NET marker, Myeloperoxidase (MPO; AACR on pancreatic cancer Sept.2023). In a Phase 2 study (NCT04731467) 31 patients with advanced/metastatic PDAC progressed after 1st line therapy, were randomized for CM24 (20mg/kg q2wk), nivo (240mg/kg q2wk) and liposomal irinotecan, 5 fluorouracil and leucovorin (Nal-IRI/5FU/LV, q2wk) treatment (experimental arm) vs Nal-IRI/5FU/LV only (control arm). Interim analysis of the data showed Median OS for the experimental arm was 7.72m (95% CI: 4.00-8.11) vs. 5.62m (95% 3.22 -7.89) for the control arm (HR: 0.74; 95% CI: 0.31-1.77). Median PFS for the experimental group was 3.8m (95% 1.8-5.0) vs. 1.9m (95% 0.9, 3.6) for the control arm (HR 0.72; 95% CI: 0.33-1.60) (ASCO2024-LBA4143). Here we present a subgroup analysis evaluating serum MPO as a potential biomarker for CM24-based therapy. Methods: Patients were randomized as described above. Pre-dose serum samples were collected from 30 out of 31 pts and serum MPO levels were evaluated using ELISA (Cayman), where the measured mean serum MPO in healthy subjects (n=30) was 53 +/-7[SE]. NET-induced blood coagulation was tested using platelet aggregation assay. Results: Mean pre-dose MPO level in patients (n=30) was 359 +/- 46 [SE] and was selected as a threshold for biomarker analysis. OS for patients with MPO levels below the threshold (n=9/16) was 8.1 mo in the experimental arm (HR 0.34; (95% CI: 0.099-1.149)) vs 4.5mo in the control (n=9/15). PFS for patients with MPO levels below the threshold was 4.2mo in the experimental arm vs. 1.7 mo in the control (HR 0.24 (95% CI: 0.20-1.59)). NET-associated blood coagulation and the inhibitory effect of CM24 were tested in vitro. NETs induced platelet aggregation in a dose-dependent manner, and CM24 significantly reduced it (50-70% reduction, p value < 0.0001) at NET levels related to the selected biomarker range (MPO<357) but was less effective at higher NET levels (MPO>500), which relate to MPO above the threshold. These results are in line with the proposed CM24 MoA, affecting NET-related cancer complications. Conclusions: Exploratory biomarker analysis suggests serum MPO as a potential predictive biomarker for CM24-based therapy showing prolonged median OS, PFS and 66% reduction in risk of death vs control in PDAC patients with MPO levels below threshold compared to interim analysis that estimated OS and PFS risk reduction of 26% and 28%, respectively. These findings will be further evaluated in upcoming clinical studies. Citation Format: Teresa Macarulla, Michael Cecchini, Rocio Garcia-Carbonero, Talia Golan, Ruth Perets, Erkut Borazanci, Manuel Pedegral, Mariano Ponz-Sarvisé, Mohammed Najeeb Al Hallak, Shubham Pant, Valentina Boni, Omar Saavedra, María José de Miguel-Luken, Alexis D. Leal, Andrés J. Muñoz Martín, Tamara Sauri-Nadal, Michael Schickler, Hava Ben David, Hadas Reuveni. Exploratory biomarker evaluation of the randomized Phase 2 cohort of CM24 in combination with nivolumab and chemotherapy in advanced/metastatic pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C005.
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