Phase II study of afatinib plus pembrolizumab in patients with squamous cell carcinoma of the lung following progression during or after first-line chemotherapy (LUX-Lung-IO).

INTRODUCTION: Afatinib and pembrolizumab have separately shown survival benefit in patients with squamous cell carcinoma (SqCC) of the lung, and there is biological rationale for concurrent inhibition of the programmed death ligand-1 and epidermal growth factor receptor (EGFR) pathways in this patient population. MATERIALS AND METHODS: This open-label, single-arm study enrolled patients with SqCC of the lung who had progressed during/after first-line chemotherapy and comprised two parts: a safety run-in to establish the recommended phase II dose (RP2D; afatinib 40 mg or 30 mg once daily with pembrolizumab 200 mg every 3 weeks); and the main part assessing efficacy and safety of the RP2D. The primary endpoint was objective response rate (ORR); secondary endpoints included the RP2D, progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-four patients were treated in the safety run-in (afatinib 40 mg/30 mg cohorts: n = 12/12). Median age was 63.5 years; 79.2% of patients were male. All patients discontinued afatinib and pembrolizumab, most commonly due to disease progression (58.3% and 75.0%, respectively) or adverse events (AEs; 37.5% and 25.0%, respectively). The study was discontinued early after completion of the safety run-in, and no patients entered the main part. ORR was 12.5%; median PFS and OS were 13.1 and 29.3 weeks, respectively. All patients had ≥ 1 drug-related AE (grade ≥ 3: 45.8%). CONCLUSION: While there were no new or unexpected safety findings, exploratory analysis of antitumor activity indicated limited efficacy with afatinib plus pembrolizumab in patients with SqCC of the lung who had progressed during/after first-line chemotherapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT03157089.

Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY Extension study.

BACKGROUND: The CLARITY and CLARITY Extension studies demonstrated that treatment of relapsing-remitting multiple sclerosis (RRMS) with cladribine tablets (CT) results in significant clinical improvements, compared with placebo. This paper presents the key magnetic resonance imaging (MRI) findings from the CLARITY Extension study. METHODS: Patients who received a cumulative dose of either CT 3.5 or 5.25 mg/kg in CLARITY were rerandomized to either placebo or CT 3.5 mg/kg in CLARITY Extension. Patients from the arm that received placebo in CLARITY were assigned to CT 3.5 mg/kg. MRI assessments were carried out when patients entered CLARITY Extension and after Weeks 24, 48, 72 and 96, and in a supplemental follow-up period. RESULTS: At CLARITY Extension baseline, patients who received placebo during CLARITY had more T1 gadolinium-enhanced (Gd+) lesions than patients who received CT during CLARITY. These patients, who were then exposed to cladribine 3.5 mg/kg during the extension, experienced a 90.4% relative reduction (median difference -0.33, 97.5% confidence interval -0.33-0.00; p < 0.001) in T1 Gd+ lesions at the end of the extension compared with the end of CLARITY. Overall, the majority of patients in each treatment group remained free from T1 Gd+ lesions throughout CLARITY Extension. However, a small proportion of patients who were treated with cladribine in CLARITY and received placebo in CLARITY Extension showed evidence of increased MRI activity, and this was associated with a prolonged treatment gap between CLARITY and CLARITY Extension. CONCLUSION: A 2-year treatment with CT 3.5 mg/kg has a durable effect on MRI outcomes in the majority of patients, an effect that was sustained in patients who were not retreated in the subsequent 2 years after initial treatment. ClinicalTrials.gov identifier: NCT00641537.

Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.

BACKGROUND: In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To assess the safety and efficacy of cladribine treatment in a 2-year Extension study. METHODS: In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained. RESULTS: A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0-1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension. CONCLUSION: Cladribine tablets treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.

Estimation of discrete survival function for error-prone diagnostic tests.

The product limit or Kaplan-Meier (KM) estimator is commonly used to estimate the survival function in the presence of incomplete time to event. Application of this method assumes inherently that the occurrence of an event is known with certainty. However, the clinical diagnosis of an event is often subject to misclassification due to assay error or adjudication error, by which the event is assessed with some uncertainty. In the presence of such errors, the true distribution of the time to first event would not be estimated accurately using the KM method. We develop a method to estimate the true survival distribution by incorporating negative predictive values and positive predictive values, into a KM-like method of estimation. This allows us to quantify the bias in the KM survival estimates due to the presence of misclassified events in the observed data. We present an unbiased estimator of the true survival function and its variance. Asymptotic properties of the proposed estimators are provided, and these properties are examined through simulations. We demonstrate our methods using data from the Viral Resistance to Antiviral Therapy of Hepatitis C study.

Technical factors associated with anastomotic leak after Roux-en-Y gastric bypass.

BACKGROUND: Anastomotic leak is one of the most serious complications after Roux-en-Y gastric bypass (RYGB). Our objective was to examine the relationship between technical factors and incidence of clinically relevant anastomotic leak after RYGB in longitudinal assessment of bariatric surgery (LABS). The setting of the study was 11 bariatric centers in the United States, university, and private practice. METHODS: Patient characteristics, technical factors of surgery, and postoperative outcomes were assessed by trained researchers using standardized protocols. Correlation of surgical factors of patients undergoing RYGB (n = 4444) with the incidence of postoperative anastomotic leak was assessed by univariate χ(2) analysis. RESULTS: Forty-four participants (1.0%, 95% CI .7%-1.3%) experienced a clinically relevant anastomotic leak. Of these, 39 (89%) underwent abdominal reoperation and 3 (7%) died. Technical factors associated with anastomotic leak were open surgery (P<.0001), revision surgery (P<.0001), and use of an abdominal drain (P = .02). Provocative leak testing, method of gastrojejunostomy, and use of fibrin sealant were not associated with anastomotic leak. CONCLUSIONS: Anastomotic leak after RYGB was rare (1.0%). Most cases required reintervention; however, the majority (93%) recovered from this event. Open surgery, revision surgery, and routine drain placement were associated with increased leak rate. Some of these findings may be due to differences in preoperative patient risk.

Effect of steady-state faldaprevir on the pharmacokinetics of steady-state methadone and buprenorphine-naloxone in subjects receiving stable addiction management therapy.

The effects of steady-state faldaprevir on the safety, pharmacokinetics, and pharmacodynamics of steady-state methadone and buprenorphine-naloxone were assessed in 34 healthy male and female subjects receiving stable addiction management therapy. Subjects continued receiving a stable oral dose of either methadone (up to a maximum dose of 180 mg per day) or buprenorphine-naloxone (up to a maximum dose of 24 mg-6 mg per day) and also received oral faldaprevir (240 mg) once daily (QD) for 8 days following a 480-mg loading dose. Serial blood samples were taken for pharmacokinetic analysis. The pharmacodynamics of the opioid maintenance regimens were evaluated by the objective and subjective opioid withdrawal scales. Coadministration of faldaprevir with methadone or buprenorphine-naloxone resulted in geometric mean ratios for the steady-state area under the concentration-time curve from 0 to 24 h (AUC(0-24,ss)), the steady-state maximum concentration of the drug in plasma (C(max,ss)), and the steady-state concentration of the drug in plasma at 24 h (C(24,ss)) of 0.92 to 1.18 for (R)-methadone, (S)-methadone, buprenorphine, norbuprenorphine, and naloxone, with 90% confidence intervals including, or very close to including, 1.00 (no effect), suggesting a limited overall effect of faldaprevir. Although individual data showed moderate variability in the exposures between subjects and treatments, there was no evidence of symptoms of opiate overdose or withdrawal either during the coadministration of faldaprevir with methadone or buprenorphine-naloxone or after faldaprevir dosing was stopped. Similar faldaprevir exposures were observed in the methadone- and buprenorphine-naloxone-treated subjects. In conclusion, faldaprevir at 240 mg QD can be coadministered with methadone or buprenorphine-naloxone without dose adjustment, although given the relatively narrow therapeutic windows of these agents, monitoring for opiate overdose and withdrawal may still be appropriate. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637922.).

Longitudinal Assessment of Bariatric Surgery (LABS): retention strategy and results at 24 months.

BACKGROUND: Retaining participants in observational longitudinal studies after bariatric surgery is difficult yet critical because the retention rate affects interpretation and generalizability of results. Strategies for keeping participants involved in such studies are not commonly published. The objective of this study was to review LABS retention strategies and present the 24-month retention data. METHODS: The LABS Consortium monitors an observational cohort study of 2458 adults enrolled before bariatric surgery at 10 centers within the United States (LABS-2). To maximize data completeness, the investigators developed retention strategies, including flexible scheduling, a call protocol, reminder letters, abbreviated visit options, honoraria, travel reimbursement, providing research progress reports, laboratory results, newsletters, study website, and retention surveys. Strategies for locating participants included frequent updates of contact information, sending registered letters, and searching medical and public records. RESULTS: At 12 and 24 months, 2426 and 2405 participants remained active, with vital status known for 98.7% and 97.3% and weight obtained for 95.2% and 92.2%, respectively. There were 148 missed visits (6.2%) at 24 months primarily because of inability to contact the participant. Only 15 (0.6%) active participants at 24 months missed all follow-up visits. Although 42 participants could not be located or contacted at 6 months, data were obtained for 23 (54.7%) of them at 12 months, and of the 52 participants who could not be located or contacted at 12 months, data were obtained for 18 (34.6%) at 24 months. CONCLUSION: Longitudinal studies provide the ability to evaluate long-term effects of bariatric surgical procedures. The retention achieved in LABS is superior to that of many published reports but requires extensive effort and resources. This report identifies useful retention strategies. Further research is needed to identify the efficacy and cost-effectiveness of specific retention strategies.

Prevalence of adverse intraoperative events during obesity surgery and their sequelae.

BACKGROUND: Adverse intraoperative events (AIEs) during surgery are a well-known entity. A better understanding of the incidence of AIEs and their relationship with outcomes is helpful for surgeon preparation and preoperative patient counseling. The goals of this study are to describe the incidence of AIEs during bariatric surgery and examine their impact on major adverse complications. STUDY DESIGN: The study included 5,882 subjects who had bariatric surgery in the Longitudinal Assessment of Bariatric Surgery study between March 2005 and April 2009. Prospectively collected AIEs included organ injuries, anesthesia-related events, anastomotic revisions, and equipment failure. The relationship between AIEs and a composite end point of 30-day major adverse complications (ie, death, venous thromboembolism, percutaneous, endoscopic, or operative reintervention and failure to be discharged from the hospital within 30 days from surgery) was evaluated using a multivariable relative risk model adjusting for factors known to influence their risk. RESULTS: There were 1,608 laparoscopic adjusted gastric banding, 3,770 laparoscopic Roux-en-Y gastric bypass operations, and 504 open Roux-en-Y gastric bypass operations. Adverse intraoperative events occurred in 5% of the overall sample and were most frequent during open Roux-en-Y gastric bypass (7.3%), followed by laparoscopic Roux-en-Y gastric bypass (5.5%) and laparoscopic adjusted gastric banding (3%). The rate of composite end point was 8.8% in the AIE group compared with 3.9% among those without an AIE (p < 0.001). Multivariable analysis revealed that patients with an AIE were at 90% greater risk of composite complication than those without an event (relative risk = 1.90; 95% CI, 1.26-2.88; p = 0.002), independent of the type of procedure (open or laparoscopic). CONCLUSIONS: Incidence of an AIE is not infrequent during bariatric surgery and is associated with much higher risk of major complication. Additional study is needed to assess the association between specific AIEs and short-term complications.