Nikolaos Diamantis

Antibody-drug conjugates—an emerging class of cancer treatment

Antibody-drug conjugates (ADCs) are an emerging novel class of anticancer treatment agents that combines the selectivity of targeted treatment with the cytotoxic potency of chemotherapy drugs. New linker technology associated with novel highly potent cytotoxic payloads has permitted the development of more effective and safe ADCs. In recent years, two ADCs have been licensed, T-DM1 and brentuximab vedotin, and are already establishing their place in cancer treatment. A plethora of ADCs are being investigated in phases I and II trials, emerging data of which appears promising. As we deepen our understanding of what makes a successful ADC, an increasing number of ADCs will likely become viable treatment options as single agents or in combination with chemotherapy. This review will present the philosophy underlying ADCs, their main characteristics and current research developments with a focus on ADCs in solid tumours.

A study of 1088 consecutive cases of electrolyte abnormalities in oncology phase I trials

Background The incidence and clinical significance of electrolyte abnormalities (EAs) in phase I clinical trials are unknown. The objective of this study is to evaluate the incidence and severity of EAs, graded according to CTCAE, v4.03, to identify variables associated with EAs and their prognostic significance in a phase I population. Methods A retrospective chart review was performed of 1088 cases in 82 phase I clinical trials consecutively treated from 2011 to 2015 at the Drug Development Unit of the Royal Marsden Hospital. Cox regression analysis was performed to examine the relationship between overall survival (OS) and baseline characteristics, treating the occurrence of grade III/IV EAs as a time-varying covariate. Results The most common emergent EAs (all grades) were as follows: hyponatraemia 62%, hypokalaemia 40%, hypophosphataemia 32%, hypomagnesaemia 17% and hypocalcaemia 12%. Grade III/IV EAs occurred in 19% of cases. Grade III/IV EAs occurred during the dose-limiting toxicity window in 8.46% of cases. Diarrhoea was associated with hypomagnesaemia at all grades (p < 0.001), hyponatraemia at all grades (p = 0.006) and with G3/G4 hypokalaemia (p = 0.02). Baseline hypoalbuminaemia and hyponatraemia were associated with a higher risk of developing other EAs during the trial in the univariate analysis. Patients who developed grade III/IV EAs during follow-up had an inferior median OS (26 weeks vs 37 weeks, hazard ratio = 1.61; p < 0.001). Conclusion This is the first study to demonstrate the clinical significance of baseline hypoalbuminaemia and hyponatraemia, which are predictors of development of other EAs in phase I patients. Grade III/IV EAs are adverse prognostic factors of OS independent of serum albumin levels.