mely encouraging results from the interim analysis of the phase I/II

mely encouraging results from the interim analysis of the phase I/II nivolumab Darifenacin trial (CA209-040 trial) evaluating the efficacy of nivolumab in patients with hepatocellular carcinoma (HCC) were reported at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting Darifenacin held in Chicago from May 29 to June 2 Darifenacin Darifenacin 2015 [1]. HCC 33 (70%) had extrahepatic metastasis and six (13%) had vascular invasion. Thirty-two (68%) patients had previously been treated with sorafenib indicating that these patients had relatively advanced liver cancers. The results of an interim analysis performed on March 12 2015 after the treatment with the anti-PD-1 antibody showed that 17 patients remained on the study treatment while 30 patients terminated or discontinued the treatment because of disease progression (n=26) complete response (CR) Darifenacin (n=2) or adverse events (AE) (n=2 for elevated bilirubin or events unrelated to the study drug). According to the Common Terminology Criteria for Adverse Events (CTCAE) grading the only grade 4 AE was an elevated lipase level whereas grade 3 AEs included elevated liver enzymes [aspartate aminotransferase (AST) (11% n=5) and alanine aminotransferase (ALT) (9% n=4)]. None of the patients developed serious liver dysfunction or autoimmune disease. The overall objective response rate was 19% (n=8) including the two patients who achieved CR (5%). Disease control rates were 67% (n=28) for stable disease (SD) or better and 33% (n=14) for progressive disease (PD) indicating an extremely favorable study outcome (table ?(table11). Table 1 Best overall responses Waterfall plots revealed tumor size stabilization or reduction in 67% of the patient cohorts with HBV HCV and those without infection. Regarding the sturdiness of treatment responses the two patients with CR achieved this within three months of therapy and this was sustained for 12-18 months or longer. Another patient had SD until 11 months after the initiation of treatment and subsequently achieved a partial response (PR) to almost a CR at approximately 13 months. Patients with PR and SD had sustained disease and none of them had PD due to acquired tolerance. These outcomes show excellent durability of treatment using the anti-PD-1 antibody in HCC as observed in other types of cancer. A durable response is the most characteristic and favorable feature of the effect of immune checkpoint inhibitors. The two patients who achieved CR within three months maintained the response longer than 15 months despite cessation of anti-PD-1 antibody treatment within a few months of achieving CR. Similarly most patients with PR achieved this at ≤3 months except one patient who achieved PR at approximately four months. The ASCO report describes cases of the Darifenacin disappearance of bilobar multiple HCCs after six weeks of therapy accompanied by a drastic decline of alpha-fetoprotein level from 21 0 to 283 IU/mL. A reduction in tumor size from approximately 10 cm to nearly 2 cm was observed in one patient after 48 weeks revealing a durable response. Furthermore the overall survival rate was 62% at 12 months which is a highly promising outcome considering that the prognostic factors of tumors were poor in this patient cohort. In summary monotherapy Alcam with the anti-PD-1 antibody nivolumab had a manageable safety profile even in patients with HCC which was comparable with its safety profile in other types of cancer. It was also safe in patients with HBV and HCV contamination. The treatment showed a high response rate that was groundbreaking for an immunotherapy with longlasting durable responses. Durable responses were observed at all dose levels regardless of etiology (without contamination HBV and HCV cohorts). A phase I/II study with the growth cohorts of non-infected patients who are sorafenibnaive or -intolerant or have PD after sorafenib treatment (50 patients each) HCV-infected patients (n=50) and HBV-infected patients (n=50) was designed with a fixed dose of 3 mg/kg of nivolumab (total number of patients = 200). The trial is currently ongoing and the outcome is usually eagerly awaited. The immune checkpoint molecule PD-1 was first discovered by Prof. Tasuku Honjo of Kyoto University Graduate School of Medicine in 1992 [2 3 4 Ishida Honjo and colleagues later used mice lacking the PD-1 to show that this gene encodes a receptor that “applies the break to immune reaction” [2]. In 2000 the ligands of PD-1 (PD-L1 and PD-L2) were discovered by the Honjo group at Kyoto University in collaboration with the Genetics Institute in the United States. In 2002 Iwai et al. used a mouse model to show that inhibition of the conversation between PD-1 and its ligand markedly enhanced immunostimulation and.