Osteoporosis in adult males is an underrecognized problem. Patients with haemophilia have several predisposing factors for developing decreased bone mineral density (BMD) including prolonged periods of immobility, reduced weight bearing and co-morbidities associated with bone loss. To establish prevalence and risk factors associated with decreased BMD in patients with haemophilia. Adults with moderate or severe haemophilia A or B underwent dual-energy X-ray absorptiometry (DXA). BMD was correlated to laboratory values, joint mobility measurements and physical activity questionnaires. Thirty patients completed evaluations. The median age was 41.5 years (range 18-61). Median lowest T-score by DXA was )1.7 (range: )5.8 to +0.6), with the femoral neck being the site of the lowest T-scores. Based on World Health Organization criteria, 70% of patients had decreased BMD. Twenty-seven per cent of the participants (n = 8) had osteoporosis and 43% (n = 13) had osteopenia. Variables associated with increased bone loss included lower serum 25-hydroxyvitamin D levels (P = 0.03), lower body mass index (P = 0.047), lower activity scores (P = 0.02), decreased joint range of motion (P = 0.046), HIV (P = 0.03), HCV (P = 0.02), history of inhibitor (P = 0.01) and age (P = 0.03). Adults with haemophilia are at increased risk for developing osteoporosis. A history of HCV and HIV infections, decreased joint range-of-motion, decreased activity levels, history of an inhibitor and low body weight predict bone loss and suggest a population to target for screening. A high prevalence of vitamin D insufficiency was observed. Future studies should investigate interventions, including vitamin D supplementation, to prevent bone loss and fractures for this at-risk population.

IMPORTANCE Erlotinib is a standard first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) with erlotinib is approximately 10 months. OBJECTIVE To determine whether adding bevacizumab to erlotinib treatment results in superior progression-free survival compared with erlotinib alone. DESIGN, SETTING, AND PARTICIPANTS This phase 2 randomized clinical trial compared erlotinib plus bevacizumab with erlotinib alone in EGFR-mutant NSCLC. The trial was conducted in 17 US academic and community medical centers among 88 patients with EGFR exon 19 deletion or exon 21 L858R mutation based on local testing and stage 4 NSCLC who were eligible for bevacizumab. Patients were enrolled between November 2, 2012, and August 22, 2016, and followed up for a median (range) of 33 (0.7-62.5) months. Data were analyzed on August 28, 2018, and included data from November 2, 2012, to August 20, 2018. INTERVENTIONS Patients were randomized with equal allocation to 150 mg of oral erlotinib daily alone or with 15 mg/kg of intravenous bevacizumab every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent. MAIN OUTCOMES AND MEASURES The primary outcome was PFS as assessed by the investigator; secondary outcomes were objective response rate (ORR), adverse events, and overall survival (OS). Analysis was designed to detect a hazard ratio (HR) of 0.667 for PFS (an improvement from a median PFS of 10 to 15 months). RESULTS Among 88 patients enrolled, the median (range) age was 63 (31-84) years; 62 patients (70%) were female; 75 (85%) were white, 8 (9%) were African American, 3 (3%) were Asian, and for 2 (2%), data on race were not available. Forty-eight patients (55%) were never smokers, 45 patients (51%) were of Eastern Cooperative Oncology Group performance status 1, and 59 patients (67%) had EGFR exon 19 deletion. Compared with erlotinib, the combination did not result in a significant difference in PFS (HR, 0.81; 95% CI, 0.50-1.31; P = .39; median PFS 17.9 [combination] and 13.5 months [erlotinib]), ORR (81% vs 83%; P = .81), and OS (HR, 1.41; 95% CI, 0.71-2.81; P = .33; median OS, 32.4 months [combination] and 50.6 months [erlotinib]). Adverse events of grade 3 or higher observed in 5 or more patients in the combination and erlotinib arms were skin eruption in 11 (26%) vs 7 (16%) patients, diarrhea in 4 (9%) vs 6 (13%) patients, hypertension in 17 (40%) vs 9 (20%) patients, and proteinuria in 5 (12%) vs 0 (0%) patients. CONCLUSIONS AND RELEVANCE Erlotinib plus bevacizumab compared with erlotinib did not result in a significant improvement in PFS in EGFR-mutant NSCLC. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01532089.

Summary Background Erlotinib is approved for the treatment of all patients with advanced non-small cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We tested the efficacy of cabozantinib and the combination of erlotinib plus cabozantinib, as compared with erlotinib, in patients with EGFR wild-type NSCLC. Methods In this three arm, randomised phase 2 study, the primary endpoint was to compare progression-free survival (PFS) of patients treated with cabozantinib versus erlotinib alone, and the combination of erlotinib plus cabozantinib versus erlotinib alone. Patients were eligible if they had received 1–2 previous treatments for advanced non-squamous EGFR wild-type NSCLC. Patients were stratified by performance status and line of therapy, then randomised using permuted blocks within strata to receive open label oral daily dosing of erlotinib (150 mg), cabozantinib (60 mg), or erlotinib (150 mg) and cabozantinib (40 mg). Imaging was performed every 8 weeks. At the time of radiographic progression, there was optional crossover for patients in either single agent arm to receive combination therapy. The comparison between erlotinib and each of the arms was powered (91%) to detect a PFS hazard ratio (HR) of 0.5 (1-sided p-value 0.10-level). Secondary objectives were overall survival (OS), radiographic response by RECIST version 1.1 and description of adverse events by CTCAE version 4.0. This trial is registered with ClinicalTrials.gov, number NCT01708954. Findings At complete enrollment, we randomised 125 patients (42 assigned to erlotinib, 40 assigned to cabozantinib, 43 assigned to the combination), of which 111 (89%) were eligible and received treatment per protocol were included in the primary analysis (38, 38, and 35 patients on erlotinib, cabozantinib, and combination, respectively). Compared to erlotinib alone (median 1.8 months), PFS was significantly improved in the cabozantinib arm (4.3 months, HR 0.39, 1-sided p=0.0003, 80% CI 0.27–0.55) and also in the erlotinib plus cabozantinib arm (4.7 months, HR 0.37, 1-sided p=0.0003, 80% CI 0.25–0.53). The safety analysis population included all patients who received study therapy regardless of eligibility. The most common grade 3 or 4 adverse events were diarrhea (3 [8%] in the erlotinib group vs 3 [8%] in the cabozantinib group vs 11 [28%] in the erlotinib and cabozantinib group), hypertension (none vs 10 [25%] vs 1 [3%]), fatigue (5 [13%] vs 6 [15%] vs 6 [15%]), oral mucositis (none vs 4 [10%] vs 1 [3%]), and thromboembolic event (none vs 3 [8%] vs 2 [5%]). Adverse events that were grade 3 or worse occurred in 13 (33%) patients in the erlotinib group, in 28 (70%) patients in the cabozantinib group, and in 28 (72%) patients in the erlotinib and cabozantinib group. One death of respiratory failure occurred in the cabozantinib group, deemed possibly related to either drug or diseas...

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