Adopting otitis media practice guidelines increases adherence within a large primary care network.

AIM: Unnecessary antibiotic prescriptions to treat otitis media (OM) contribute to adverse drug reactions, increased cost and antibiotic resistance. Clinical care guidelines can help promote consistent treatment of conditions such as OM. This study evaluates adherence before and after implementation of an institutional guideline for the diagnosis and treatment of paediatric OM. METHODS: A retrospective chart review was performed to collect encounter information for paediatric patients seen within a primary care clinic network and diagnosed with OM before and after full implementation of a clinical care guideline. Patient cohorts from 2013 and 2016 were compared to determine which factors, including age, symptoms and diagnosis, were associated with treatment guideline adherence. RESULTS: Comparison of encounters from 2013 (n = 418) to 2016 (n = 635) revealed a significant difference in adherence to the 2013 Michigan Medicine Otitis Media Guideline. Overall adherence increased from 61.2% in 2013 to 70.6% in 2016 (χ2  = 9.85, P < 0.0017). Antibiotic use for acute OM decreased from 99.7% in 2013 to 96.7% in 2016 (χ2  = 10.04, P = 0.0015). Antibiotic prescriptions for OM with effusion decreased significantly from 42.9% in 2013 to 17.4% in 2016 (χ2  = 11.93, P < 0.0006). CONCLUSION: Implementation of an institutional OM clinical practice guideline contributed to a significant increase in overall treatment adherence of OM for paediatric patients between the 2013 and 2016 cohorts. The number of antibiotic prescriptions for paediatric patients diagnosed with acute OM or OM with effusion significantly decreased from 2013 to 2016.

Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma.

LESSONS LEARNED: The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. ENMD-2076 showed a favorable toxicity profile. The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent. Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components. BACKGROUND: Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor. METHODS: Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 or Lansky 70-100, and adequate organ function were eligible. Patients were prescribed ENMD-2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one-sided alternative of 15%. Secondary endpoints included 6-month progression-free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study. RESULTS: Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug-related serious adverse event was hypertension in three patients. Three deaths were reported on-study-two due to disease progression and one due to pulmonary embolism not related to ENMD-2076. CONCLUSION: The study provided no rationale for further studying ENMD-2076 as a single agent in FLC.

Genomic Characterization of ERBB2-Driven Biliary Cancer and a Case of Response to Ado-Trastuzumab Emtansine.

PURPOSE: Biliary tract cancers (BTCs), which include intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (EHC), and gallbladder cancer (GBC), have limited treatment options. We sought to comprehensively examine the clinical and molecular characteristics of BTCs with amplification or mutation of ERBB2. METHODS: Demographic, outcome, and treatment response data were collected for patients with ERBB2-altered BTC identified by next-generation sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets from 2014 to 2018. RESULTS: A total of 517 patients with BTC underwent next-generation sequencing (ICC, n = 313; EHC, n = 93; GBC, n = 111). Twenty-eight patients (5.4%) had ERBB2 alterations, including 2.7% with ERBB2 gene amplification, 2.3% with ERBB2 mutation, and 0.4% with concurrent amplification and mutation. The prevalence of ERBB2 gene alterations was significantly higher in GBC (12.6%) than in ICC (2.2%) and EHC (7.5%; P < .001). In ERBB2-amplified tumors, the median fold change was 6.4 (range, 2.1 to 19.7), while in ERBB2-mutant tumors, the most frequent mutated domain was the extracellular domain (32%), with all mutations in this region involving the S310 codon. Frequent co-altered genes in this cohort were TP53 (54%), PIK3CA (21%), and CDKN2A (18%); KRAS amplification/mutation was found in 7% of patients. One patient with ERBB2-amplified EHC who enrolled in a basket trial (ClinicalTrials.gov identifier: NCT02675829) had a partial response to the human epidermal growth factor receptor 2-targeted antibody-drug conjugate ado-trastuzumab emtansine. CONCLUSION: ERBB2 alterations are present in 5.4% of BTCs. When present, the degree of ERBB2 gene amplification is often high, and S310 codon mutations are the most common hotspot. These features, along with the presented case, support further development of human epidermal growth factor receptor 2-targeted therapy in ERBB2-mutant and/or -amplified BTC.

Binimetinib plus Gemcitabine and Cisplatin Phase I/II Trial in Patients with Advanced Biliary Cancers.

PURPOSE: Mutations in the RAS/RAF/MEK/ERK signaling pathway are commonly found in biliary tract cancer (BTC). Binimetinib, a selective inhibitor of MEK1/2, has single-agent activity. Preclinical data support binimetinib combination with chemotherapy, when given in an interrupted dosing schedule.Patients and Methods: A phase I/II trial evaluated binimetinib in combination with gemcitabine and cisplatin in patients with untreated advanced BTC. The primary endpoints were to determine the MTD (phase I), and PFS 6 and RR (phase II). Tumor tissue for targeted gene sequencing and blood samples for peripheral blood pERK expression were evaluated. Patients received oral binimetinib twice daily with gemcitabine and cisplatin on day 8 and 15 of a 21-day cycle. Binimetinib was held for 2 days prior to and on day of each chemotherapy treatment. RESULTS: Twelve patients enrolled in the phase I showed the MTD of binimetinib at 45 mg orally twice daily with gemcitabine 800 and cisplatin 20 mg/m2. Twenty-nine patients were treated in the phase II. Six patients treated at MTD in phase I were evaluable as part of phase II. PFS 6 months was 54% and RR was 36%. Median overall survival was 13.3 months (95% CI, 9.8-16.5). MSK-IMPACT 410-gene panel showed aberrations in the RAS-RAF-MEK-ERK pathway and mutations in PIK3CA, AKT2, PIK3CG, BRAF, and MAP3K1 in responding patients. CONCLUSIONS: Binimetinib with gemcitabine and cisplatin did not show an improvement in PFS 6 and RR. Molecular profiling may help select patients who may benefit from this triplet therapy, which is not planned at this time.