Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer.

Introduction: Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods: Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results: Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2-18.8) for CPE and 10.3 months (95% CI 7.1-15.5; hazard ratio (HR) 0.62, 95% CI 0.25-1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07-0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8-61.9 months) for CPE compared to 17.2 months (95% CI 11.5-45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22-1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion: Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity.

A randomised open-label cross-over study of inhaler errors, preference and time to achieve correct inhaler use in patients with COPD or asthma: comparison of ELLIPTA with other inhaler devices.

Errors in the use of different inhalers were investigated in patients naive to the devices under investigation in a multicentre, single-visit, randomised, open-label, cross-over study. Patients with chronic obstructive pulmonary disease (COPD) or asthma were assigned to ELLIPTA vs DISKUS (Accuhaler), metered-dose inhaler (MDI) or Turbuhaler. Patients with COPD were also assigned to ELLIPTA vs Handihaler or Breezhaler. Patients demonstrated inhaler use after reading the patient information leaflet (PIL). A trained investigator assessed critical errors (i.e., those likely to result in the inhalation of significantly reduced, minimal or no medication). If the patient made errors, the investigator demonstrated the correct use of the inhaler, and the patient demonstrated inhaler use again. Fewer COPD patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS, 9/171 (5%) vs 75/171 (44%); MDI, 10/80 (13%) vs 48/80 (60%); Turbuhaler, 8/100 (8%) vs 44/100 (44%); Handihaler, 17/118 (14%) vs 57/118 (48%); Breezhaler, 13/98 (13%) vs 45/98 (46%; all P<0.001). Most patients (57-70%) made no errors using ELLIPTA and did not require investigator instruction. Instruction was required for DISKUS (65%), MDI (85%), Turbuhaler (71%), Handihaler (62%) and Breezhaler (56%). Fewer asthma patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS (3/70 (4%) vs 9/70 (13%), P=0.221); MDI (2/32 (6%) vs 8/32 (25%), P=0.074) and significantly fewer vs Turbuhaler (3/60 (5%) vs 20/60 (33%), P<0.001). More asthma and COPD patients preferred ELLIPTA over the other devices (all P⩽0.002). Significantly, fewer COPD patients using ELLIPTA made critical errors after reading the PIL vs other inhalers. More asthma and COPD patients preferred ELLIPTA over comparator inhalers.

Comparison of clinical outcome after first-line platinum-based chemotherapy in different types of KRAS mutated advanced non-small-cell lung cancer.

OBJECTIVES: As suggested by in-vitro data, we hypothesize that subtypes of KRAS mutated non-small cell lung cancer (NSCLC) respond differently to chemotherapy regimens. METHODS: Patients with advanced NSCLC and known KRAS mutation, treated with first-line platinum-based chemotherapy, were retrieved from hospital databases. PRIMARY OBJECTIVE: to investigate overall response rate (ORR), progression free survival (PFS) and overall survival (OS) between different types of platinum-based chemotherapy per type of KRAS mutation. RESULTS: 464 patients from 17 hospitals, treated between 2000 and 2013, were included. The majority of patients had stage IV disease (93%), had a history of smoking (98%) and known with an adenocarcinoma (91%). Most common types of KRAS mutation were G12C (46%), G12V (20%) and G12D (10%). Platinum was combined with pemetrexed (n=334), taxanes (n=68) or gemcitabine (n=62). Patients treated with taxanes had a significant improved ORR (50%) compared to pemetrexed (21%) or gemcitabine (25%; p<0.01). Patients treated with bevacizumab in addition to taxanes (n=38) had the highest ORR (62%). The PFS was significantly improved in patients treated with taxanes compared to pemetrexed (HR=0.72, p=0.02), but not OS (HR=0.87, p=0.41). In patients with G12V, significantly improved ORR (p<0.01) was observed for taxanes, but not PFS or OS. Patients with G12C or G12D mutation had comparable ORR, PFS and OS in all treatment groups. CONCLUSION: KRAS mutated NSCLC patients treated with taxane-based chemotherapy had best ORR. Response to chemotherapy regimens was different in types of KRAS mutation. Especially patients with G12V had better response to taxane treatment.

A randomised cross-over trial investigating the ease of use and preference of two dry powder inhalers in patients with asthma or chronic obstructive pulmonary disease.

OBJECTIVES: The objective of this randomised, cross-over study was to compare a new single-dose dry powder inhaler (Elpenhaler (EH)), with a widely used, multi-dose dry powder inhaler (Diskus (DK)) on critical errors, patient preference, and satisfaction with the inhalers. METHODS: First, patients read the instructions of one device, followed by a first inhalation attempt. Inhalation errors were assessed and if mistakes were made, correct inhaler use was demonstrated. Then patients had to demonstrate again and mistakes were registered. This was repeated up to four times. After completing the first device, the same procedure was started with the second inhaler. Primary outcome was the percentage of patients making at least one critical error after reading the insert. Secondary outcomes were inhaler preference and satisfaction with the inhalers. RESULTS: After reading the insert, 19 of 113 patients (17%) made at least one critical error with DK and 40 (35%) with EH (p = 0.001); 73% preferred the DK and 27% the EH (p < 0.001). The mean overall satisfaction score (1 = very satisfied; 5 = very dissatisfied) for DK was 1.59 and for EH 2.48 (p < 0.001). CONCLUSION: With DK fewer errors were made, more patients preferred DK over EH and patients were more satisfied with DK. This may enable DK to improve treatment outcomes more than EH.

Preference, satisfaction and errors with two dry powder inhalers in patients with COPD.

OBJECTIVE: To assess preference, satisfaction and critical errors with a novel, breath-actuated, multi-dose dry powder inhaler (DPI; Genuair®/Pressair™), versus a widely used, single-dose DPI (HandiHaler®) in patients with moderate-to-severe chronic obstructive pulmonary disease. METHODS: In this randomised, open-label, multicentre, cross-over study, patients (aged ≥ 40 years) inhaled placebo once daily through both inhalers for 2 weeks in addition to current medication. The primary end point was percentage of patients who preferred Genuair to HandiHaler. Overall patient satisfaction (5-point scale: 1 = very dissatisfied; 5 = very satisfied), critical errors and willingness to continue using each inhaler (0 = not willing; 100 = definitely willing) were assessed. RESULTS: Of 130 patients randomised, 105 were included in the intent-to-treat population (71.4% male; mean age 65.7 years). After 2 weeks, significantly more patients preferred Genuair than HandiHaler (79.1 vs 20.9%; p < 0.0001). Overall satisfaction scores (4.6 vs 3.8; p < 0.0001) and willingness to continue use scores (84.0 vs 62.5; p < 0.0001) were significantly higher with Genuair versus HandiHaler. Significantly fewer patients made ≥ 1 critical error with Genuair only compared with HandiHaler only (2.9 vs 19.0%; p < 0.0001). CONCLUSION: After 2 weeks' practice, patients preferred and were more willing to continue using Genuair than HandiHaler. Genuair was associated with higher patient satisfaction and fewer critical errors than HandiHaler.

Influence of introduction of positron emission tomography on adherence to mediastinal staging protocols and performance of mediastinoscopy.

PURPOSE: In this study, we investigated the impact of implementation of [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) in daily practice on adherence to mediastinal staging protocols and performance of mediastinoscopy in non-small-cell lung cancer (NSCLC) patients who are possible candidates for surgical resection. Institutional review board approval was obtained. PATIENTS AND METHODS: From a nonuniversity teaching hospital and three surrounding community hospitals in Eindhoven, the Netherlands, we studied data from 143 patients with NSCLC who underwent mediastinoscopy and/or thoracotomy in three consecutive periods (1, 0 to 9 months; 2, 10 to 18 months; and 3, 19 to 31 months) after introduction of PET. Mediastinoscopy was indicated in case of enlarged and/or PET-positive nodes. Adherence to these surgical mediastinal staging guidelines and the performance of PET and mediastinoscopy were investigated and compared between the three periods and with our previous study before introduction of PET. RESULTS AND CONCLUSION: Guidelines for indicating mediastinoscopy were adequately followed in significantly more instances after introduction of PET (80%), compared with the period before PET (66%). Optimal yield (lymph node stations 4, right and left, and 7) of mediastinoscopy (in 27% of patients) was not significantly different from the period before PET (39% of patients). Compared with the historical data, the percentage of positive mediastinoscopies increased from 15.5 to 17.6 (not significant). We found no significant differences between the three consecutive periods with regard to adequacy of indicating and performance of mediastinoscopy. After introduction of PET, adherence to staging guidelines with respect to mediastinoscopy improved. Although fewer mediastinoscopies had an optimal yield, more proved to be positive for metastases. Nevertheless, when a mediastinoscopy is indicated, surgeons must be encouraged to reach an optimal yield because PET positive nodes might be false negative. This occurred in 5% to 6% of all patients.