Clinical trial designs for evaluating and exploiting cancer evolution.

The evolution of drug-resistant cell subpopulations causes cancer treatment failure. Current preclinical evidence shows that it is possible to model herding of clonal evolution and collateral sensitivity where an initial treatment could favourably influence the response to a subsequent one. Novel therapy strategies exploiting this understanding are being considered, and clinical trial designs for steering cancer evolution are needed. Furthermore, preclinical evidence suggests that different subsets of drug-sensitive and resistant clones could compete between themselves for nutrients/blood supply, and clones that populate a tumour do so at the expense of other clones. Treatment paradigms based on this clinical application of exploiting cell-cell competition include intermittent dosing regimens or cycling different treatments before progression. This will require clinical trial designs different from the conventional practice of evaluating responses to individual therapy regimens. Next-generation sequencing to assess clonal dynamics longitudinally will improve current radiological assessment of clinical response/resistance and be incorporated into trials exploiting evolution. Furthermore, if understood, clonal evolution can be used to therapeutic advantage, improving patient outcomes based on a new generation of clinical trials.

Building on the anti-PD1/PD-L1 backbone: combination immunotherapy for cancer.

Introduction: Immunotherapy has revolutionized the treatment of cancer. Given this growing success, at the same time, there are significant limitations and unanswered questions concerning response rates, duration of therapy, why some patients respond and others do not, and if combining different immune-agents would overcome this lack of response, increase the chance of success and postpone acquired resistance. Areas covered: The comprehension of how to properly modulate the immune pathways, the molecular and the immunological bases of the disease, will be fundamental to guide the development of therapeutic interventions and combinations that will be more suitable for treatment of cancer patients. In this review, we discuss the strategies of immunotherapy combinations in order to develop more effective immunotherapy programs, with a particular focus on melanoma and renal cancer patients, as well as the combination of immunotherapy and chemotherapy. Expert Opinion: Given the complexity of immune activation, combinatorial approaches are needed, and due to the considerable variability in tumor biology across patients and tumor types, patient selection and biomarkers need to be further explored. In summary, combined therapies have shown promising success, but additional and continuous research to identify the safety, efficacy, optimal combination, dosage and timing are still required.

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.