Irinotecan is a topoisomerase inhibitor, widely used in treatment of malignancies including pancreatic ductal adenocarcinoma (PDAC) as part of the FOLFIRINOX regimen prescribed as a first‐line treatment in several countries. However, irinotecan has not been successfully introduced as a second‐line treatment for pancreatic cancer and few randomized clinical studies have evaluated its added value. Efficacy of liposomal irinotecan (nal‐IRI) combined with 5‐fluorouracil and leucovorin (5‐FU/LV) was reported in the phase III NAPOLI‐1 trial in metastatic PDAC following failure of gemcitabine‐based therapy. Several features of nal‐IRI pharmacokinetics (PK) could result in better outcomes versus nonliposomal irinotecan. Irinotecan is a prodrug that is converted to active SN‐38 by carboxylesterase enzymes and inactivated by cytochrome P450 3A4/3A5. SN‐38 is inactivated by UGT1A1 enzymes. Individual variations in their expression and activity could influence enhanced localized irinotecan activity and toxicity. Liposomal irinotecan exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. Liposomal irinotecan also has a longer half‐life and higher area under the concentration‐time curve (0–∞) than nonliposomal irinotecan, as the liposomal formulation protects cargo from premature metabolism in the plasma. This results in irinotecan activation in tumor tissue, leading to enhanced cytotoxicity. Importantly, despite the longer exposure, overall toxicity for nal‐IRI is no worse than nonliposomal irinotecan. Liposomal irinotecan exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. Liposomal irinotecan is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors, and small‐cell lung cancer.

Nivolumab is a human monoclonal antibody against the immune checkpoint receptor programmed death‐1, inhibiting binding to programmed death‐ligand 1 or 2 (PD‐L1 or PD‐L2). This phase 2 study evaluated the efficacy and safety of nivolumab in patients with advanced/recurrent uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma (STS). Patients received nivolumab 240 mg at 2‐week intervals. Primary endpoint was objective response rate; secondary endpoints included overall survival, progression‐free survival, and safety. PD‐L1 expression and microsatellite‐instability (MSI) status were analyzed as potential efficacy biomarkers. Objective response rate was 25%, 23%, and 0% in patients with cervical cancer (n = 20), corpus cancer (n = 22), and STS (n = 21), respectively. The lower 80% confidence intervals of objective response rates in patients with cervical or corpus cancer exceeded the threshold rate (5%); the primary endpoint was met in cervical and corpus cancer, but not in STS. Median progression‐free survival was 5.6, 3.4, and 1.4 months, and 6‐month overall survival was 84%, 73%, and 86% in cervical cancer, corpus cancer, and STS, respectively. The objective response rate was higher in patients with cervical cancer with PD‐L1‐positive (n = 5/15; 33%) versus PD‐L1‐negative (n = 0/5; 0%) tumors. The two patients with corpus cancer classified as MSI‐high responded; the six patients classified as microsatellite stable did not respond. Overall, nivolumab showed acceptable toxicity in all cohorts, with evidence of clinical activity in uterine cervical or corpus cancer, but not in STS. PD‐L1 expression in cervical cancer and MSI‐high in corpus cancer may predict clinical activity of nivolumab in these cancers.

Purpose: This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53-MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers. Experimental Design: Initial dosing regimens were: 1A (Day 1; 21-day cycle; dose 12.5-350 mg); 2A (Days 1-14; 28-day cycle; dose 1-20 mg). Alternative regimens included 1B (Days 1 and 8; 28-day cycle) and 2C (Days 1-7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLTs) during Cycle 1. Results: Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced Grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10.3% (95% CI, 2.2-27.4) in solid tumors and 4.2% (95% CI, 0.1-21.1), 20% (95% CI, 4.3-48.1), or 22.2% (95% CI, 8.6-42.3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively. Conclusions: A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies.

The aim of the study was to evaluate the efficacy and safety of nivolumab combined with ipilimumab in treatment-naïve Japanese patients with advanced melanoma. In this multicentre, single-arm study, treatment-naïve Japanese patients with unresectable stage III/IV or recurrent melanoma received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses, followed by biweekly doses of nivolumab (3 mg/kg). The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included overall survival (OS), progression-free survival (PFS), disease control rate and safety. The subtypes of the thirty patients enrolled were: 12, mucosal; eight, non-acral cutaneous; seven, acral; two, uveal and one, unknown primary melanoma. The ORR was 43.3% (95% confidence interval [CI]: 25.5, 62.6) with central and local assessment. The centrally and locally assessed disease control rate (95% CI) were 73.3% (54.1, 87.7) and 86.7% (69.3, 96.2), respectively. At the median follow-up period of 14.1 months (range 5.2-27.7), median OS and centrally assessed PFS were not reached. OS (95% CI) at 6, 12, 18 and 24 months was 93.3% (75.9, 98.3), 83.3% (64.5, 92.7), 72.9% (50.0, 86.5) and 65.6% (40.4, 82.2), respectively. Treatment-related adverse events (AEs) occurred in all patients. Grade III-IV and serious AEs occurred, mostly during the combination phase, in 23 (76.7%) and 20 (66.7%) patients, respectively. No treatment-related deaths occurred. This study confirmed the efficacy and safety of nivolumab plus ipilimumab in treatment-naïve Japanese patients with advanced melanoma including rare subtypes. Incidence rates for grade III-IV AEs were high but manageable with appropriate medical attention and treatment. JapicCTI-152869.

MicroRNAs (miRNAs) are involved in virtually all biological processes, including stem cell maintenance, differentiation, and development. The dysregulation of miRNAs is associated with many human diseases including cancer. We have identified a set of miRNAs differentially expressed between human breast cancer stem cells (CSCs) and non-tumorigenic cancer cells. In addition, these miRNAs are similarly upregulated or downregulated in normal mammary stem/progenitor cells. In this review, we mainly describe the miRNAs that are dysregulated in human breast CSCs directly isolated from clinical specimens. The miRNAs and their clusters, such as the miR-200 clusters, miR-183 cluster, miR-221-222 cluster, let-7, miR-142 and miR-214, target the genes and pathways important for stem cell maintenance, such as the self-renewal gene BMI1, apoptosis, Wnt signaling, Notch signaling, and epithelial-to-mesenchymal transition. In addition, the current evidence shows that metastatic breast CSCs acquire a phenotype that is different from the CSCs in a primary site. Thus, clarifying the miRNA regulation of the metastatic breast CSCs will further advance our understanding of the roles of human breast CSCs in tumor progression.