CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumour-dependent irAE profiles may be identified as data emerge from ICI trials.

Background:Obtaining tissue for pancreatic carcinoma diagnosis and biomarker assessment to aid drug development is challenging. Circulating tumour cells (CTCs) may represent a potential biomarker to address these unmet needs. We compared prospectively the utility of two platforms for CTC enumeration and characterisation in pancreatic cancer patients in a pilot exploratory study.Patients and methods:Blood samples were obtained prospectively from 54 consenting patients and analysed by CellSearch and isolation by size of epithelial tumour cells (ISET). CellSearch exploits immunomagnetic capture of CTCs-expressing epithelial markers, whereas ISET is a marker independent, blood filtration device. Circulating tumour cell expression of epithelial and mesenchymal markers was assessed to explore any discrepancy in CTC number between the two platforms.Results:ISET detected CTCs in more patients than CellSearch (93% vs 40%) and in higher numbers (median CTCs/7.5 ml, 9 (range 0–240) vs 0 (range 0–144)). Heterogeneity observed for epithelial cell adhesion molecule, pan-cytokeratin (CK), E-Cadherin, Vimentin and CK 7 expression in CTCs may account for discrepancy in CTC number between platforms.Conclusion:ISET detects more CTCs than CellSearch and offers flexible CTC characterisation with potential to investigate CTC biology and develop biomarkers for pancreatic cancer patient management.

Background: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. Methods: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. Results: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5-11.0) and 1 year OS was 43% (95% CI 40-47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS.

The development of the cytotoxic T-lymphocyte-associated protein 4 inhibitor ipilimumab and its approval in 2011 for the treatment of metastatic melanoma has heralded a new era in immuno-oncology. Subsequently, novel agents against the programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis have shown significant activity in melanoma and a variety of other tumor types. Pembrolizumab was the first anti-PD-1 antibody to be approved by the US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma with disease progression following ipilimumab, and if BRAFV600 mutation positive, a BRAF inhibitor. Pembrolizumab has also received breakthrough status for the treatment of EGFR mutation-negative, ALK rearrangement-negative non-small cell lung cancer (NSCLC) that has progressed on or following platinum-based chemotherapy. There remain a number of pivotal trials in progress to further evaluate the optimal use of pembrolizumab alone and in combination for melanoma, NSCLC, and other tumor types. In this article, we review the efficacy and toxicity profile of pembrolizumab and evaluate its future development.

The incidence of melanoma is increasing worldwide. Advances in targeted agents and immunotherapy have improved outcomes in metastatic disease, but biomarkers are required to optimize treatment. We determined the prevalence of circulating tumor cells (CTCs) and explored their utility as prognostic and pharmacodynamic biomarkers. A total of 101 patients with metastatic cutaneous melanoma were recruited prospectively. CTC number was determined using the CellSearch platform and melanoma kits in samples taken at baseline and serially during treatment. CTC numbers ranged between 0 and 36 per 7.5 ml blood; 26% of patients had ≥ 2 CTCs. Baseline CTC number was prognostic for median overall survival (OS) in univariate analysis (2.6 vs. 7.2 months (P<0.011) for patients with ≥ 2 CTCs vs. <2 CTCs, respectively). In multivariate analysis, CTC number was an independent prognostic biomarker of OS (hazard ratio (HR) 2.403, 95% confidence interval (CI) 1.303-4.430, P=0.005). Patients receiving treatment in whom CTC number remained ≥ 2 CTCs during treatment had shorter median OS than those who maintained<2 CTCs (7 vs. 10 months, HR 0.34, 95% CI 0.14-0.81, log-rank test P=0.015). In conclusion, CTC number in metastatic cutaneous melanoma patients is prognostic for OS with a cutoff of 2 CTCs per 7.5 ml blood. CTC number measured before and throughout treatment provided additional prognostic information. Larger studies are warranted to confirm CTC biomarker utility in melanoma patients.

Prostate cancer is a leading cause of cancer-related death in men worldwide. Aberrant signaling in the androgen pathway is critical in the development and progression of prostate cancer. Despite ongoing reliance on androgen receptor (AR) signaling in castrate resistant disease, in addition to the development of potent androgen targeting drugs, patients invariably develop treatment resistance. Interactions between the AR and PI3K pathways may be a mechanism of treatment resistance and inhibitors of this pathway have been developed with variable success. Herein we outline the role of the PI3K pathway in prostate cancer and, in particular, its association with androgen receptor signaling in the pathogenesis and evolution of prostate cancer, as well as a review of the clinical utility of PI3K targeting.

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Ipilimumab produces durable responses in some metastatic melanoma patients. Neutrophil, platelet, and eosinophil to lymphocyte ratios (NLR, PLR, and ELR) may be associated with the immune response in cancer thereby acting as biomarkers of toxicity and efficacy in ipilimumab‐treated patients. Data were collected on clinical characteristics and lactate dehydrogenase (LDH), NLR, PLR, and ELR at baseline, post cycle 2 and at the end of treatment for 183 patients treated with ipilimumab between 2008 and 2015 at the Princess Margaret Cancer Centre. Associations between clinical characteristics, LDH, NLR, PLR, and ELR with toxicity or survival outcomes of progression‐free (PFS) and overall survival (OS) were assessed using univariable and multivariable analysis. Prognostic models of outcome at each time point were determined. Of the 183 patients included, the median age was 58, 85% had M1c disease, 58% were performance status 1, and 64% received ipilimumab as second line therapy. Median follow up was 7.5 months (range: 0.3–49.5), median PFS was 2.8 months (95% confidence intervals (CI): 2.8–3.2), and median OS was 9.6 months (95% CI: 7.9–13.2). Prognostic factors for OS by multivariable analysis were LDH and NLR at all‐time points. Prognostic models using LDH (× 2 upper limit of normal) and NLR 4) differentiated patients into high, moderate, and low risk of death prior to or on ipilimumab treatment (P < 0.0001 for each model). No factors were associated with toxicity. Prognostic models based on NLR and LDH values at baseline and on treatment differentiate patients into good, intermediate, and poor prognostic groups and may be relevant in patient management.