Highlights of This Issue

Abstract

Lee and colleagues examined serial measurements of cholesterol, triglycerides, and glucose from patients randomized to interferon or temsirolimus in the Global Advanced Renal Cell Carcinoma Phase III Trial. Temsirolimus treatment was associated with larger mean increases in cholesterol (1.02 mmol/L; P < 0.0001), triglycerides (0.32 mmol/L; P = 0.0008), and glucose (1.28 mmol/L; P < 0.0001) compared with interferon, and improved survival (OS: HR 0.76, P = 0.02; PFS: HR = 0.70; P = 0.001). Cholesterol increase is a potential predictor for temsirolimus efficacy; these data have important implications for the design of other mTOR inhibitor studies.Erythropoiesis-stimulating agents (ESA) are widely used in treatment of myelodysplastic syndromes (MDS). Their efficacy is variable, and clinical parameters may only partially predict response. To refine prediction of response, Spinelli and colleagues set up a cytofluorimetric assay to evaluate in vitro activation of the erythropoietin signaling pathway in primary MDS marrow cell subpopulations. Erythropoietin in vitro was able to phosphorylate STAT5 in erythroid progenitors of MDS. This activation was significantly weaker than in progenitors from normal marrows, but correlated with clinical response. This test successfully identifies, prior to therapy, MDS patients who will respond to ESAs, thus avoiding noneffective treatments.GDC-0973 is a potent and selective MEK1 inhibitor currently in clinical trials. Wong and colleagues designed a series of preclinical studies to characterize GDC-0973 tumor disposition and pharmacodynamics in preclinical melanoma tumor models. PK–PD modeling was used to integrate preclinical and limited early clinical data in order to identify a minimum target plasma concentration in patients. Prospective predictions of active doses compared well with clinical responses. This work illustrates how PK–PD modeling can be used to improve the predictive value of preclinical data in the phase I setting.Demetri and colleagues present the complete longitudinal analyses, including final overall survival (OS), from the randomized, placebo-controlled, phase III study that led to regulatory approval of sunitinib for the treatment of patients with advanced imatinib-resistant/intolerant gastrointestinal stromal tumor. The confounding effect of the study's crossover design (allowing placebotreated patients to receive sunitinib upon disease progression) on OS was demonstrated: Conventional analyses resulted in biased comparisons favoring the control arm, despite a statistically significant difference in time to tumor progression. However, rank-preserving structural failure-time analysis modeling the absence of crossover estimated a substantial OS benefit for sunitinib versus placebo.