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Zolbetuximab is a chimeric monoclonal antibody that targets claudin-18.2, a candidate biomarker in patients with advanced gastric/gastroesophageal cancer. This nonrandomized phase 1 study (NCT03528629) enrolled previously treated Japanese patients with claudin-18.2-positive locally advanced/metastatic gastric/gastroesophageal cancer in 2 parts: Safety (Arms A and B, n=3 each) and Expansion (n=12). Patients received zolbetuximab i.v. 800 mg/m

PDF file - 6669K, Antitumor activities of ASP3026 in hEML4-ALK transgenic mice.

Activation of anaplastic lymphoma receptor tyrosine kinase (ALK) is involved in the pathogenesis of several carcinomas, including non–small cell lung cancer (NSCLC). Echinoderm microtubule–associated protein like 4 (EML4)-ALK, which is derived from the rearrangement of ALK and EML4 genes, has been validated as a therapeutic target in a subset of patients with NSCLC. Here, we investigated the effects of ASP3026, a novel small-molecule ALK inhibitor, against ALK-driven NSCLC. ASP3026 inhibited ALK activity in an ATP-competitive manner and had an inhibitory spectrum that differed from that of crizotinib, a dual ALK/MET inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, orally administered ASP3026 was well absorbed in tumor tissues, reaching concentrations >10-fold higher than those in plasma, and induced tumor regression with a wide therapeutic margin between efficacious and toxic doses. In the same mouse model, ASP3026 enhanced the antitumor activities of paclitaxel and pemetrexed without affecting body weight. ASP3026 also showed potent antitumor activities, including tumor shrinkage to a nondetectable level, in hEML4-ALK transgenic mice and prolonged survival in mice with intrapleural NCI-H2228 xenografts. In an intrahepatic xenograft model using NCI-H2228 cells, ASP3026 induced continuous tumor regression, whereas mice treated with crizotinib showed tumor relapse after an initial response. Finally, ASP3026 exhibited potent antitumor activity against cells expressing EML4-ALK with a mutation in the gatekeeper position (L1196M) that confers crizotinib resistance. Taken together, these findings indicate that ASP3026 has potential efficacy for NSCLC and is expected to improve the therapeutic outcomes of patients with cancer with ALK abnormality. Mol Cancer Ther; 13(2); 329–40. ©2014 AACR.

PDF file - 64K, Inhibition of ALK phosphorylation and signal transduction in NCI-H2228 cells by ASP3026.

PDF file - 82K, Inhibitory activity of ASP3026 and crizotinib against various TKs.

PDF file - 445K, Growth of H2228-luc cells directly inoculated into the pleural cavity of NOD/SCID mice.

PDF file - 56K, Pharmacokinetic parameters of ASP3026 after 5-day repeated oral dosing of ASP3026 in NOD/SCID mice xenografted with NCI-H2228 cells.

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Supplementary Data from MK-2206, an Allosteric Akt Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted Drugs In vitro and In vivo

466 Background: CLDN18.2, a targetable biomarker, is a tight junction protein normally confined to gastric mucosa of healthy tissue and often retained in G/GEJa. Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates cancer cell death via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Phase 2 FAST study results showed prolonged survival with zolbetuximab+EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in CLDN18.2-positive G/GEJa. In ILUSTRO Cohort 2, confirmed partial responses (PRs) and stable disease (SD) were previously reported in 63.2% and 10.5%, respectively, of patients (pts) treated with zolbetuximab+mFOLFOX6 (modified 5-FU, folinic acid, oxaliplatin). Here is an analysis of CLDN18.2 expression and exploratory biomarkers from 2 studies of zolbetuximab alone or with mFOLFOX6 in G/GEJa. Methods: Data are from phase 1 (NCT03528629) and phase 2 (NCT03505320, ILUSTRO Cohorts 1 and 2) studies. Pts with CLDN18.2-positive locally advanced/metastatic G/GEJa received zolbetuximab alone (phase 1 [ineligible for SOC], n = 18; phase 2 Cohort 1 [≥3rd-line], n = 30) or with mFOLFOX6 (phase 2 Cohort 2 [1st-line], n = 21). Archival (any time before treatment), baseline (during screening or ≤3 months before first study treatment), and on-treatment (Cycle 3) tumor samples were collected when possible. CLDN18.2 expression and immune cell populations were assessed by IHC. Blood samples collected longitudinally while on treatment (phase 2 study) were analyzed for ADCC activity (ex vivo cell-based assay), circulating tumor antigens, and circulating tumor DNA (ctDNA). Results: Of 416 screened pts in both studies, 26.2% (n = 109), 9.6% (n = 40), and 36.1% (n = 150) had tumors that were CLDN18.2-positive in 1%–49%, 50%–74%, and ≥75% of tumor cells ( = strong to moderate staining intensity), respectively; 28.1% (n = 117) were CLDN18.2-negative (0/1+). Analysis of pre- and on-treatment tissue samples (n = 8 matched pairs) with zolbetuximab alone showed an increased trend in immune cell infiltration, with CD8+ T cells and CD163+ cells showing the most consistent trend. A trend of increased on-treatment vs baseline ADCC activity was observed in PBMCs collected from pts treated with zolbetuximab alone and with mFOLFOX6. Rapid and deep decreases in circulating tumor antigens (in pts with elevated antigen levels) and ctDNA were observed with best overall responses of both PR and SD. Conclusions: CLDN18.2 is a high-prevalence biomarker in G/GEJa. Treatment with zolbetuximab is associated with tumor and peripheral biomarker changes related to its proposed mechanism of action. Clinical responses observed in pts treated with zolbetuximab and mFOLFOX6 are associated with correlative biomarkers of activity including rapid deep molecular responses (ctDNA). Clinical trial information: NCT03528629 .