crolibulin (EPC2407) / Immune Pharma - LARVOL DELTA

Overall survival results from the phase 2 NIVOFGFR2 study of first-line nivolumab plus CAPOX in patients with FGFR2-positive, PD-L1-positive metastatic gastric cancer. (ASCO 2024) - P2 | " In this single-arm, multi-center, phase 2 study, eligible patients had metastatic untreated HER2-negative gastric adenocarcinoma, and their PD-L1 expression (CPS≥5; DAKO 28-8) and FGFR2 status (moderate (2+) and strong (3+) membranous staining in more than 1% of tumor cells; Abсam EPR24075-418) were centrally confirmed by IHC. Patients were treated with nivolumab 360 mg in combination with capecitabine and oxaliplatin every 3 weeks till disease progression or unacceptable toxicity... Despite the modest efficacy of nivolumab with CAPOX in the first-line setting, a favorable median OS was observed, possibly attributable to the incorporation of ramucirumab with paclitaxel in the second-line treatment of FGFR2-positive, PD-L1-positive metastatic gastric cancer."

Clinical • IO biomarker • Metastases • P2 data • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2 • HER-2 • PD-L1

Novel 4-Aryl-4H-chromene derivative displayed excellent in vivo anti-glioblastoma efficacy as the microtubule-targeting agent. (PubMed, Eur J Med Chem) - "In this study, a series of novel 4-Aryl-4H-chromene derivatives (D1-D31) were designed and synthesized by integrating quinoline heterocycle to crolibulin template molecule based on the strategy of molecular hybridization...Compound D19 was verified as the microtubule-targeting agent through downregulating tubulin related genes of U87 cells, destroying the cytoskeleton of tubulins and interacting with the colchicine-binding site to inhibit the polymerization of tubulins by transcriptome analysis, immune-fluorescence staining, microtubule dynamics and EBI competition assays as well as molecular docking simulations...Significantly, compound D19 dose-dependently inhibited the tumor growth of orthotopic glioma xenografts model (GL261-Luc) and effectively prolonged the survival time of mice, which were extremely better than those of positive drug temozolomide (TMZ)...Furthermore, the results of in silico simulation studies and P-gp transwell assays verified the positive..."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Efficacy and safety of nivolumab and CapeOX in patients with previously untreated FGFR2-positive, PD-L1-positive advanced gastric cancer: A single-arm, multicenter, phase 2 study NIVOFGFR2. (ASCO-GI 2024) - P2 | " In this single-arm, multi-center, phase 2 study, eligible patients had metastatic untreated HER2-negative gastric adenocarcinoma with centrally confirmed expression of PD-L1 (CPS≥5; DAKO 28-8) and FGFR2 (moderate (2+) and strong (3+) membranous staining in more than 1% of tumor cells; Abсam EPR24075-418). Patients received nivolumab 360 mg with CapeOX (capecitabine and oxaliplatin) every 3 weeks... An interim analysis demonstrates modest efficacy and an acceptable safety profile of nivolumab in combination with chemotherapy in patients with FGFR2-positive, PD-L1-positive metastatic GC. Further follow-up is ongoing. 1."

Clinical • IO biomarker • Metastases • P2 data • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2 • HER-2 • PD-L1

Expression and amplification of FGFR2 in gastric cancer: a comparative study (ECP 2023) - "Conclusion EPR24075-418 assay showed the best results among others in FGFR2 immunohistochemical evaluation: concordance with FISH was 100% in 3+ cases. Due to high FGFR2 heterogeneity in tumor, both primary tumor and metastasis must be stained by immunohistochemistry or when it is not possible more material of primary tumor should be evaluated."

Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2

Study of FGFR2 status in gastric cancer by immunohistochemistry and fluorescent in situ hybridization (PubMed, Arkh Patol) - "Clone EPR24075-418 showed the best result in assessing the expression of FGFR2: the correlation with FISH results in reaction 3+ was 100%. Due to the high heterogeneity of FGFR2 expression, it is recommended to either examine the material of the primary tumor and metastasis, or evaluate a large volume of the primary tumor."

Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2

Agreement between FGFR2 immunohistochemistry assays and fluorescence in situ hybridization (FISH) in metastatic gastric cancer: A comparison study. (ASCO-GI 2023) - " Pairwise comparison of 4 tests based on the same patient population was performed: 3 IHC assays [Abcam clone EPR24075-418, R&D clone 98706, Santa Cruz clone C-8] and one FISH test... Among patients who were negative by FISH, 86%-93% of the patients were negative by IHC assay (Abcam). Among patients who were positive by FISH, 75-80% of them were positive by IHC. FISH should not be recommended as a substitute for a FGFR2 IHC assay due to high probability of false negative prediction as a result of intratumoral heterogeneity and low PCC."

Metastases • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2

Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin. (PubMed, Sci Rep) - P1 | "The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. These findings are suggestive of cell swelling and decreased tumor perfusion 2-3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents."

Clinical • Journal • P1 data • Oncology • Solid Tumor

Molecular mechanism of crolibulin in complex with tubulin provides a rationale for drug design. (PubMed, Biochem Biophys Res Commun) - "Here we report a 2.5 Å crystal structure of tubulin complexed with crolibulin. This complex structure reveals the interactions between crolibulin and tubulin, helps explain the results of the structure-activity-relationship (SAR) studies and provides a solid structural basis for the design and development of new 4-Aryl-4H-chromenes derivatives as MTAs."

Journal