Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012.

BACKGROUND: Second-line treatment options for advanced head and neck squamous cell carcinoma (HNSCC) are limited. The phase Ib KEYNOTE-012 study evaluated the safety and the efficacy of pembrolizumab for the treatment of HNSCC after long-term follow-up. METHODS: Multi-centre, non-randomised trial included two HNSCC cohorts (initial and expansion) in which 192 patients were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks (initial cohort; N = 60) or 200 mg every 3 weeks (expansion cohort; N = 132). Co-primary endpoints were safety and overall response rate (ORR; RECIST v1.1; central imaging vendor review). RESULTS: Median follow-up was 9 months (range, 0.2-32). Treatment-related adverse events (AEs) of any grade and grade 3/4 occurred in 123 (64%) and 24 (13%) patients, respectively. No deaths were attributed to treatment-related AEs. ORR was 18% (34/192; 95% CI, 13-24%). Median response duration was not reached (range, 2+ to 30+ months); 85% of responses lasted ≥6 months. Overall survival at 12 months was 38%. CONCLUSIONS: Some patients received 2 years of treatment and the responses were ongoing for more than 30 months; the durable anti-tumour activity and tolerable safety profile, observed with long-term follow-up, support the use of pembrolizumab as a treatment for recurrent/metastatic HNSCC.

Maintenance and inspection as risk factors in helicopter accidents: Analysis and recommendations.

In this work, we establish that maintenance and inspection are a risk factor in helicopter accidents. Between 2005 and 2015, flawed maintenance and inspection were causal factors in 14% to 21% of helicopter accidents in the U.S. civil fleet. For these maintenance-related accidents, we examined the incubation time from when the maintenance error was committed to the time when it resulted in an accident. We found a significant clustering of maintenance accidents within a short number of flight-hours after maintenance was performed. Of these accidents, 31% of these accidents occurred within the first 10 flight-hours. This is reminiscent of infant mortality in reliability engineering, and we characterized it as maintenance error infant mortality. The last quartile of maintenance-related accidents occurred after 60 flight-hours following maintenance and inspection. We then examined the "physics of failures" underlying maintenance-related accidents and analyzed the prevalence of different types of maintenance errors in helicopter accidents. We found, for instance, that the improper or incomplete (re)assembly or installation of a part category accounted for the majority of maintenance errors with 57% of such cases, and within this category, the incorrect torquing of the B-nut and incomplete assembly of critical linkages were the most prevalent maintenance errors. We also found that within the failure to perform a required preventive maintenance and inspection task category, the majority of the maintenance programs were not executed in compliance with federal regulations, nor with the manufacturer maintenance plan. Maintenance-related accidents are particularly hurtful for the rotorcraft community, and they can be eliminated. This is a reachable objective when technical competence meets organizational proficiency and the collective will of all the stakeholders in this community. We conclude with a set of recommendations based on our findings, which borrow from the ideas underlying the defense-in-depth safety principle to address this disquieting problem.