Phase Ib and Expansion Study of Gemcitabine, Nab-Paclitaxel, and Ficlatuzumab in Patients With Metastatic Pancreatic Cancer.

BACKGROUND: In preclinical pancreatic ductal adenocarcinoma (PDAC) models, inhibition of hepatocyte growth factor (HGF) signaling using ficlatuzumab, a recombinant humanized anti-HGF antibody, and gemcitabine reduced tumor burden. METHODS: Patients with previously untreated metastatic PDAC enrolled in a phase Ib dose escalation study with 3 + 3 design of 2 dose cohorts of ficlatuzumab 10 and 20 mg/kg administered intravenously every other week with gemcitabine 1000 mg/m2 and albumin-bound paclitaxel 125 mg/m2 given 3 weeks on and 1 week off. This was followed by an expansion phase at the maximally tolerated dose of the combination. RESULTS: Twenty-six patients (sex, 12 male:14 female; median age, 68 years [range, 49-83 years]) were enrolled, 22 patients were evaluable. No dose-limiting toxicities were identified (N = 7 pts) and ficlatuzumab at 20 mg/kg was chosen as the maximum tolerated dose. Among the 21 patients treated at the MTD, best response by RECISTv1.1: 6 (29%) partial response, 12 (57%) stable disease, 1 (5%) progressive disease, and 2 (9%) not evaluable. Median progression-free survival and overall survival times were 11.0 months (95% CI, 7.6-11.4 months) and 16.2 months (95% CI, 9.1 months to not reached), respectively. Toxicities attributed to ficlatuzumab included hypoalbuminemia (grade 3, 16%; any grade, 52%) and edema (grade 3, 8%; any grade, 48%). Immunohistochemistry for c-Met pathway activation demonstrated higher tumor cell p-Met levels in patients who experienced response to therapy. CONCLUSION: In this phase Ib trial, ficlatuzumab, gemcitabine, and albumin-bound paclitaxel were associated with durable treatment responses and increased rates of hypoalbuminemia and edema.

County-Level Variation in Triple Guideline-Directed Medical Therapy in Heart Failure With Reduced Ejection Fraction.

Background: Current guidelines recommend simultaneous initiation of multidrug guideline-directed medical therapy classes for heart failure with reduced ejection fraction. Objectives: The purpose of this study was to evaluate county-level variation in use of triple guideline-directed medical therapy, defined as simultaneous prescription fills for beta-blockers, renin-angiotensin system inhibitors or angiotensin receptor neprilysin inhibitors, and mineralocorticoid receptor antagonists, in heart failure with reduced ejection fraction. Methods: We conducted a cohort study using Medicare Fee-for-Service claims data (parts A, B, and D between 2013 and 2019). Features of counties including area-level indicators of poverty, employment, and educational attainment and aggregated patient-level sociodemographic and medical history variables were compared by quintiles of triple therapy use. A multilevel logistic regression model was constructed to estimate the contextual effect of clustering by counties, which was expressed as a median OR. Results: 304,857 patients from 2,600 counties (83% of all U.S. counties) were included. The median for triple therapy use was 14.3% (IQR: 10.3%-18.8%) across included counties with a wide variation (range: 0%-54.5%). Compared to counties in the highest use quintile, counties in lowest triple therapy use quintile had worse area-level indicators of socioeconomic status (% unemployment 6.8% vs 6.2%). Counties in lowest quintile had higher proportion of Black patients (13.3% vs 5.7% in highest quintile) and patients with low-income subsidy (29.3% vs 25.8% in highest quintile). The median OR was 1.30 (95% CI: 1.28-1.33). Conclusions: We observed variation in triple therapy use across counties in the United States with suboptimal local use patterns correlating with indicators of socioeconomic disadvantage.

A Phase II Study of Ziv-Aflibercept in Patients With Advanced Extrapancreatic Neuroendocrine Tumors.

OBJECTIVES: Neuroendocrine tumors (NETs) are characterized by their expression of vascular endothelial growth factor (VEGF). This trial investigated the activity of Ziv-aflibercept, a recombinant protein that binds to and inhibits the activity of VEGF, in patients with advanced NETs (NCT01782443). METHODS: A single-arm, phase II trial enrolling patients with advanced, progressive extrapancreatic NET. Patients were treated with Ziv-aflibercept 4 mg/kg intravenously on day 1 and 15 of a 28-day cycle; the starting dose was reduced to 2 mg/kg on days 1 and 15 of a 28-day cycle because of hypertension-related events. The primary end point was progression-free survival. RESULTS: The trial enrolled 19 patients (13 male:6 female). Patients received a median of 7 cycles (range, 1-18 cycles). The median progression free survival was 11.8 months (95% confidence interval, 3.2-16.1 months), and the median overall survival was 36.4 months (95% confidence interval, 16.1-not reached). Best responses by Response Evaluation Criteria in Solid Tumors 1.1 are as follows: 1 (5%) partial response, 13 (68%) stable disease, 2 (10%) with progressive disease, and 3 (15%) unevaluable. Hypertension occurred in 18 patients (95%), including grade 3-4 hypertension in 12 patients (63%). CONCLUSIONS: Although the progression free survival is similar to other VEGF inhibitors in NET, toxicity may preclude further investigation.