Bin Yao

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m 2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m 2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

OBJECTIVE: To investigate whether long-term optimal glycemic control can be achieved without medication by transient continuous subcutaneous insulin infusion (CSII) and the possible mechanisms responsible for this remission. RESEARCH DESIGN AND METHODS: Newly diagnosed type 2 diabetic patients (n = 138, fasting glucose >11.1mmol/l) were hospitalized and treated with CSII for 2 weeks. Intravenous glucose tolerance tests (IVGTTs) were performed, and blood glucose, HbA(1c), lipid profiles, proinsulin, insulin, and C-peptide were measured before and after CSII. Patients were followed longitudinally on diet alone after withdrawal of insulin. RESULTS: Optimal glycemic control was achieved within 6.3 +/- 3.9 days by CSII in 126 patients. The remission rates (percentages maintaining near euglycemia) at the third, sixth, twelfth, and twenty-fourth month were 72.6, 67.0, 47.1, and 42.3%, respectively. Patients who maintained glycemic control >12 months (remission group) had greater recovery of beta-cell function than those who did not (nonremission group) when assessed immediately after CSII. Homeostasis model assessment of beta-cell function (HOMA-B) and the area under the curve (AUC) of insulin during IVGTT were higher in the remission group (145.4 +/- 89.6 vs. 78.5 +/- 68.5, P = 0.002, and 1,423.4 +/- 523.2 vs. 1,159.5 +/- 476.8 pmol x l(-1) x min(-1), P = 0.044). Change in acute insulin response was also greater in the remission group than that in the nonremission group (621.8 +/- 430.4 vs. 387.3 +/- 428.8 pmol x l(-1) x min(-1), P = 0.033). CONCLUSIONS: Short-term intensive insulin therapy can induce long-term glycemic control in newly diagnosed type 2 diabetic patients with severe hyperglycemia. The improvement of beta-cell function, especially the restoration of first-phase insulin secretion, could be responsible for the remission.

To investigate the effect of antidiabetic agents on nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM), 75 patients with T2DM and NAFLD under inadequate glycemic control by metformin were randomized (1:1:1) to receive add-on liraglutide, sitagliptin, or insulin glargine in this 26-week trial. The primary endpoint was the change in intrahepatic lipid (IHL) from baseline to week 26 as quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF). Secondary endpoints included changes in abdominal adiposity (subcutaneous adipose tissue [SAT] and visceral adipose tissue [VAT]), glycated hemoglobin, and body weight from baseline to week 26. We analysed data from intent-to-treat population. MRI-PDFF, VAT, and weight decreased significantly with liraglutide (15.4% ± 5.6% to 12.5% ± 6.4%, P < 0.001; 171.4 ± 27.8 to 150.5 ± 30.8, P = 0.003; 86.6 ± 12.9 kg to 82.9 ± 11.1 kg, P = 0.005, respectively) and sitagliptin (15.5% ± 5.6% to 11.7% ± 5.0%, P = 0.001; 153.4 ± 31.5 to 139.8 ± 27.3, P = 0.027; 88.2 ± 13.6 kg to 86.5 ± 13.2 kg, P = 0.005, respectively). No significant change in MRI-PDFF, VAT, or body weight was observed with insulin glargine. SAT decreased significantly in the liraglutide group (239.9 ± 69.0 to 211.3 ± 76.1; P = 0.020) but not in the sitagliptin and insulin glargine groups. Changes from baseline in MRI-PDFF, VAT, and body weight were significantly greater with liraglutide than insulin glargine but did not differ significantly between liraglutide and sitagliptin. Conclusion: Combined with metformin, both liraglutide and sitagliptin, but not insulin glargine, reduced body weight, IHL, and VAT in addition to improving glycemic control in patients with T2DM and NAFLD.

PURPOSE: We evaluated whether motesanib (a selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) combined with carboplatin/paclitaxel improved overall survival (OS) versus chemotherapy alone in patients with nonsquamous non-small-cell lung cancer (NSCLC) and in the subset of patients with adenocarcinoma. PATIENTS AND METHODS: Patients with stage IIIB/IV or recurrent nonsquamous NSCLC (no prior systemic therapy for advanced disease) were randomly assigned 1:1 to carboplatin (area under the curve, 6 mg/ml · min) and paclitaxel (200 mg/m(2)) intravenously for up to six 3-week cycles plus either motesanib 125 mg (arm A) or placebo (arm B) once daily orally. OS was the primary end point. Secondary end points included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and association between placental growth factor (PLGF) change and OS. RESULTS: A total of 1,090 patients with nonsquamous NSCLC were randomly assigned (arms A/B, n = 541 of 549); of those, 890 had adenocarcinoma (n = 448 of 442). Median OS in arms A and B was 13.0 and 11.0 months, respectively (hazard ratio [HR], 0.90; 95% CI, 0.78 to 1.04; P = .14); median OS for the adenocarcinoma subset was 13.5 and 11.0 months, respectively (HR, 0.88; 95% CI, 0.75 to 1.03; P = .11). In descriptive analyses (arms A v B), median PFS was 5.6 months versus 5.4 months (P = < .001); ORR was 40% versus 26% (P < .001). There was no association between PLGF change and OS in arm A. The incidence of grade ≥ 3 AEs (arms A and B, 73% and 59%, respectively) and grade 5 AEs (14% and 9%, respectively) was higher with motesanib treatment. CONCLUSION: Motesanib plus carboplatin/paclitaxel did not significantly improve OS over carboplatin/paclitaxel alone in patients with advanced nonsquamous NSCLC or in the adenocarcinoma subset.