CD26 is a transmembrane glycoprotein with dipeptidyl peptidase IV activity that is overexpressed in malignant pleural mesothelioma (MPM). We performed a phase I study to determine the maximum tolerated dose, pharmacokinetics, and antitumor activity of YS110, a monoclonal antibody to CD26, in Japanese patients with MPM intolerant of or refractory to prior standard therapies.The study was designed as an open-label, 3 + 3 dose-escalation, phase I trial. Patients were sequentially assigned to three dosing cohorts (2, 4, or 6 mg/kg). Each 6-week treatment cycle consisted of YS110 administration weekly for 5 weeks followed by a 1-week rest period. Treatment was continued until disease progression, death, or intolerable toxicity. Corticosteroid, antihistamine, and acetaminophen administration before each infusion was adopted to limit infusion-related reactions (IRRs).Nine Japanese patients (seven men and two women, mean age of 62.2 years), three in each dosing cohort, were enrolled in the study. No patient developed a dose-limiting toxicity. Adverse events of grade 3 or 4 developed in seven patients, with the most common such event being a decreased lymphocyte count. Two patients had mild or moderate IRRs. The serum concentration of YS110 increased in a dose-dependent manner. Among seven patients evaluable for tumor response, four showed stable disease and one achieved a partial response.YS110 showed promising antitumor efficacy and was generally well tolerated in Japanese patients with advanced MPM at doses of up to 6 mg/kg. YS110 will be tested at 6 mg/kg in a subsequent phase II study.
Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With <i>NTRK</i> Fusion-Positive Solid Tumors
9089 Background: Most of targetable gene alterations are found only in 1-5% of non-small cell lung cancer (NSCLC) cases. Large scale screening systems for these rare populations are necessary for the development of molecular targeted therapies. Thus, a nationwide lung cancer genomic screening project in Japan (LC-SCRUM-Japan) has been operated since February 2013. Methods: Non-squamous NSCLCs without EGFR mutations were eligible for inclusion in this study. The tumors were analyzed for ALK/RET/ROS1 fusions using RT-PCR, and detected fusions were confirmed by FISH. Since March 2015, this nationwide project has been amended to an academic-industrial collaboration project with 14 pharmaceutical companies, and the samples were further subjected to a next-generation sequencing (NGS) system, Oncomine Comprehensive Assay, enabling the simultaneous analysis of 143 cancer-related genes. Results: As of December 31, 2015, 195 institutions across Japan were participating and 2161 patients had been enrolled. Among 1988 available samples, including 497 for the NGS analysis, ALK/RET/ROS1 fusions were detected in 37 (2%)/51 (3%)/86 (4%), respectively. The NGS analysis also showed that 269 cases (54%) had targetable gene alterations, including 82 KRAS mutations (17%), 36 ERBB2 mutations (7%), 28 BRAF mutations (6%), 22 PIK3CA mutations (4%), 6 NRAS mutations (1%), 6 MAP2K1 mutations (1%) and 2 FGFR2 fusions (0.4%). MET/ERBB2/FGFR1 amplifications were also detected by the NGS in 13 (3%)/11 (2%)/3 (1%) cases, respectively. Through this screening, the preplanned numbers of patient with RET and ROS1 fusions (n = 19 and 26, respectively) were successfully enrolled in clinical trials of vandetanib (LURET study in Japan) and of crizotinib (OO12-01 study in East Asia), respectively. Three patients with ERBB2 alterations and 2 with MET amplifications were also enrolled in genotype-matched ongoing trials. Conclusions: This nationwide screening system enables efficiently and successfully detecting various targetable gene alterations in NSCLC, thereby contributing to promote cancer precision medicine through the development of targeted therapies.
Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With <i>NTRK</i> Fusion-Positive Solid Tumors
Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With <i>NTRK</i> Fusion-Positive Solid Tumors
