Michael K. Palmer

Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With Advanced Lung Adenocarcinoma With EGFR Mutations

PURPOSEnPatient-reported symptoms and health-related quality of life (QoL) benefits were investigated in a randomized, phase III trial of afatinib or cisplatin/pemetrexed.nnnPATIENTS AND METHODSnThree hundred forty-five patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma were randomly assigned 2:1 to afatinib 40 mg per day or up to six cycles of cisplatin/pemetrexed. Lung cancer symptoms and health-related QoL were assessed every 21 days until progression using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 questionnaires. Analyses of cough, dyspnea, and pain were preplanned, including percentage of patients who improved on therapy, time to deterioration of symptoms, and change in symptoms over time.nnnRESULTSnQuestionnaire compliance was high. Compared with chemotherapy, afatinib significantly delayed the time to deterioration for cough (hazard ratio [HR], 0.60; 95% CI, 0.41 to 0.87; P = .007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 0.93; P = .015), but not pain (HR, 0.83; 95% CI, 0.62 to 1.10; P = .19). More patients on afatinib (64%) versus chemotherapy (50%) experienced improvements in dyspnea scores (P = .010). Differences in mean scores over time significantly favored afatinib over chemotherapy for cough (P < .001) and dyspnea (P < .001). Afatinib showed significantly better mean scores over time in global health status/QoL (P = .015) and physical (P < .001), role (P = .004), and cognitive (P = .007) functioning compared with chemotherapy. Fatigue and nausea were worse with chemotherapy, whereas diarrhea, dysphagia, and sore mouth were worse with afatinib (all P < .01).nnnCONCLUSIONnIn patients with lung adenocarcinoma with EGFR mutations, first-line afatinib was associated with better control of cough and dyspnea compared with chemotherapy, although diarrhea, dysphagia, and sore mouth were worse. Global health status/QoL was also improved over time with afatinib compared with chemotherapy.

Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1).

Background: Patient-reported symptom and health-related quality of life (HRQoL) benefit of afatinib, a novel, irreversible, ErbB Family Blocker, was investigated in a double-blind, randomized, phase IIb/III trial (LUX-Lung 1). Methods: Five hundred and eighty-five patients with lung adenocarcinoma (stage IIIb/IV), who had progressed after chemotherapy (1–2 lines) and at least 12 weeks of erlotinib or gefitinib, were randomized (2:1) to receive either afatinib plus best supportive care (BSC) or placebo plus BSC. Symptom and HRQoL benefit were measured using the lung cancer-specific European Organisation for Research and Treatment of Cancer (QLQ-C30/LC13) and EuroQol (EQ-5D) questionnaires. Non–small-cell lung cancer–related symptoms (cough, dyspnea, and pain) were prespecified using three preplanned analyses (percentage of patients improved/worsened/stable, change in scores over time, and time to deterioration of scores). Results: Compared with patients on placebo, a significantly higher proportion of afatinib-treated patients showed an improvement in cough (p < 0.0001), dyspnea (p = 0.006), and pain (p < 0.0001). Afatinib also significantly improved the mean scores over time for cough (p < 0.0001), dyspnea (p = 0.0161), and pain (p = 0.0056); significantly delayed the time to deterioration for cough (p < 0.001); and showed a trend in delaying dyspnea (p = 0.170) and pain (p = 0.287). Consistent with the adverse-event profile of afatinib, a significantly (p < 0.05) higher proportion of afatinib-treated patients showed worsening of diarrhea, sore mouth, dysphagia, and appetite scores. However, compared with placebo, afatinib significantly (p < 0.05) improved QoL assessed with the EQ-5D questionnaire and global health status/QoL, physical functioning, and fatigue, which were assessed with the European Organisation for Research and Treatment of Cancer questionnaires. Conclusion: In the LUX-Lung 1 trial, the addition of afatinib to BSC significantly improved non–small-cell lung cancer–related symptoms (cough, dyspnea, and pain), fatigue, physical functioning, and HRQoL and significantly delayed time to deterioration of cough.

Analysis of patient-reported outcomes from the LUME-Lung 1 trial: A randomised, double-blind, placebo-controlled, Phase III study of second-line nintedanib in patients with advanced non-small cell lung cancer

INTRODUCTIONnThe LUME-Lung 1 trial (NCT00805194; Study 1199.13) demonstrated a significant overall survival (OS) advantage for nintedanib plus docetaxel compared with placebo plus docetaxel as second-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and adenocarcinoma histology. Patient-reported outcomes (PROs) for symptoms and health-related quality of life (QoL) are reported here.nnnMETHODSnPROs were assessed at screening, on Day 1 of each 21-day treatment cycle, at the end of active treatment, and at the first follow-up visit. PRO instruments were the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 supplement, and the EuroQol disease-generic questionnaire (EQ-5D and EQ-VAS). Analyses of PRO items for lung cancer-specific symptoms of cough, dyspnoea and pain were prespecified.nnnRESULTSnRates of questionnaire completion were high. There was no significant difference in time to deterioration of global health status/QoL, or symptoms of cough, dyspnoea or pain, between the treatment groups for both the overall study population and the adenocarcinoma population. Time to deterioration of some gastrointestinal events was shorter with nintedanib versus placebo. Longitudinal analysis for the adenocarcinoma population showed comparable changes between the groups in symptom scores over time, with numerical differences in favour of nintedanib for cough and pain scales, and significant reductions in some pain items with nintedanib versus placebo. There was no statistically significant difference in EQ-5D or EQ-VAS between the groups.nnnCONCLUSIONnThe significant OS benefit observed with the addition of nintedanib to docetaxel therapy was achieved with no detrimental effect on patient self-reported QoL.

Symptom and Quality of Life Improvement in LUX-Lung 6: An Open-Label Phase III Study of Afatinib Versus Cisplatin/Gemcitabine in Asian Patients With EGFR Mutation-Positive Advanced Non–small-cell Lung Cancer

Introduction: In the phase III, LUX-Lung 6 trial, afatinib prolonged progression-free survival (PFS) versus cisplatin/gemcitabine in Asian patients with epidermal growth factor receptor (EGFR) mutation-positive non–small-cell lung cancer (NSCLC). This article provides detailed assessments of patient-reported outcomes (PROs), a LUX-Lung 6 secondary end point, and explores the relationship between PFS and health-related quality of life (QoL) in these patients. Methods: Patients (n = 364) were randomized (2:1) to oral afatinib (40u2009mg/day) or up to six cycles of cisplatin/gemcitabine (21-day cycle; cisplatin 75u2009mg/m2 [d1]; gemcitabine 1000u2009mg/m2 [d1,8]). QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and its lung cancer-specific module. The relationship between PFS (investigator assessment and independent review) and QoL was evaluated using analysis of covariance and a longitudinal model. Results: More patients treated with afatinib versus cisplatin/gemcitabine showed improvements in global health status/QoL (p < 0.0001) and physical (p < 0.0001), role (p = 0.013), and social (p < 0.001) functioning scales. Delayed symptom deterioration and better QoL over time was also observed with afatinib. QoL measured before tumor assessment was considerably poorer for patients with progression than those without progression, with significant differences in mean scores at multiple assessment time points. Results from the longitudinal analysis consistently demonstrated a significant negative impact of progression on QoL (p < 0.0001). Conclusion: Afatinib improved PFS and PROs versus chemotherapy in EGFR mutation-positive NSCLC patients. Progression was associated with statistically significant worsening in QoL measured before tumor assessment, underscoring the value of PFS as a clinically relevant end point.

Ewing's sarcoma, adjuvant chemotherapy and pathologic fracture.

Abstract Between 1970 and 1975, 19 patients under age 15 with Ewings sarcoma have been treated with adjuvant chemotherapy in addition to radiotherapy to the primary tumour. The chemotherapy regimen of vincristine and cyclophosphamide was not rigorously structured and evolved over the six years. The two most recent patients have also had adriamycin. The median survival of 45 months is statistically better than the 18 months experienced by the 31 children treated without adjuvant chemotherapy from 1956 to 1969 . Eight pathologic fractures have occurred in 6 of the 19 patients on adjuvant chemotherapy. Only one of the fractures was at diagnosis. The other 7 fractures occurred from 3 to 72 months following diagnosis with a median of 6 months. There were only 3 pathologic fractures in the 31 patients treated without adjuvant chemotherapy—two were at diagnosis and one was at a metastatic site. The increased risk of pathologic fractures appears to be related to the adjuvant chemotherapy.

Is progression-free survival associated with a better health-related quality of life in patients with lung cancer? Evidence from two randomised trials with afatinib

Objective Progression-free survival (PFS) is frequently used as an efficacy end point in oncology clinical trials. However, there is limited evidence to support a positive association between improvement in PFS and improvement in health-related quality of life (HRQoL). The association between PFS and HRQoL was evaluated in two randomised trials. Materials and methods Data from two randomised controlled trials in patients with non-small cell lung cancer (NSCLC; LUX-Lung 1 and LUX-Lung 3) were used to investigate HRQoL in patients to determine whether tumour progression is accompanied by worsening HRQoL. HRQoL was assessed using the cancer-specific European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30, the EuroQol EQ-5D overall utility and EuroQol EQ visual analogue scale. In both studies, progression was evaluated by independent review using RECIST criteria (primary end point) and also by investigator assessment. The relationship between tumour progression and HRQoL was evaluated using analysis of covariance and a longitudinal model. Results Compliance with HRQoL questionnaire completion was high. In both studies, patients with progression consistently experienced numerically poorer HRQoL at the time of progression than patients without progression. Differences in mean scores were statistically significant (p<0.05) between patients with and without progression at week 4 in all analyses in LUX-Lung 1 and at multiple time points in LUX-Lung 3. Results from the longitudinal analysis showed that progression (by independent review and investigator assessment) appears to have consistent negative impact on all three HRQoL measures (all p<0.0001). Conclusions Tumour progression in patients with NSCLC was associated with statistically significant worsening in HRQoL. These findings confirm the value of PFS as a patient-relevant end point.

Variability of low-density lipoprotein cholesterol response with different doses of atorvastatin, rosuvastatin, and simvastatin: results from VOYAGER.

AIMSnPatient response to statin treatment is individual and varied. As a consequence, when using a specific-dose approach, as recommended in the 2013 American College of Cardiology/American Heart Association guideline, there will be a range of reductions in the concentration of low-density lipoprotein cholesterol (LDL-C). The aim of this study was to use individual patient data from the VOYAGER meta-analysis to determine the extent of the variability in LDL-C reduction in response to treatment across the recommended doses of different statins.nnnMETHODS AND RESULTSnThe percentage change from baseline in LDL-C was calculated using individual subject data collected from 32 258 patients treated with atorvastatin 10-80 mg, rosuvastatin 5-40 mg, or simvastatin 10-80 mg. The percentage change in LDL-C for each patient was then used to generate waterfall plots that demonstrated the extent of the variability in response to treatment at all doses of the three statins. The standard deviation of LDL-C reduction for all statins and doses ranged from 12.8 to 17.9%. The percentage of patients experiencing a suboptimal response (<30% reduction in LDL-C) ranged from 5.3 to 53.3%.nnnCONCLUSIONnThese results indicate that there is considerable individual variation in the LDL-C reduction at all doses of simvastatin, atorvastatin, and rosuvastatin.

A VOYAGER Meta-Analysis of the Impact of Statin Therapy on Low-Density Lipoprotein Cholesterol and Triglyceride Levels in Patients With Hypertriglyceridemia.

Elevated triglyceride (TG) levels are associated with increased cardiovascular disease risk. In patients with mild-to-moderate hypertriglyceridemia, defined by the European Atherosclerosis Society Consensus Panel as a TG level of 177 to 885 mg/dl (2.0 to 10.0 mmol/L), low-density lipoprotein cholesterol (LDL-C) reduction remains the primary treatment goal. Using data from the indiVidual patient meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin and simvastatin (VOYAGER) meta-analysis, we analyzed LDL-C and TG reductions in patients with baseline TG ≥177 mg/dl (≥2.0 mmol/L). Least squares mean percentage change from baseline in LDL-C and TG was compared using 15,800 patient exposures to rosuvastatin 5 to 40 mg, atorvastatin 10 to 80 mg, and simvastatin 10 to 80 mg in patients with baseline TG ≥177 mg/dl (≥2.0 mmol/L). Comparisons were made using mixed-effects models with data only from studies directly comparing treatments by randomized design. Mean LDL-C reductions ranged from -26.9% to -55.5%. Rosuvastatin 10 to 40 mg resulted in significantly greater LDL-C reductions than equal or double doses of atorvastatin and simvastatin (p <0.05). Mean TG reductions ranged from -15.1% to -31.3%. Rosuvastatin 10 mg resulted in significantly greater TG reductions than atorvastatin 10 mg (p <0.05). Rosuvastatin 20 and 40 mg resulted in TG reductions similar to those with equal doses of atorvastatin. Rosuvastatin 10 to 40 mg resulted in significantly greater TG reductions than equal or double doses of simvastatin (p <0.05). In conclusion, in patients with hypertriglyceridemia, LDL-C reduction was substantial and dependent on the choice and dose of statin. TG reduction was numerically less than for LDL-C, and additional TG-lowering therapy may be considered to further reduce residual cardiovascular risk.

Doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in LDL-C and non-HDL-C: Results from the VOYAGER meta-analysis:

Background Achieving the greatest reduction in atherogenic lipoproteins requires the optimum dose and potency of statin. Using data from the VOYAGER meta-analysis, we determined doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). Methods Least squares mean percentage change in LDL-C and non-HDL-C was calculated using 38,052 patient exposures to rosuvastatin 5–40u2009mg, atorvastatin 10–80u2009mg and simvastatin 10–80u2009mg. Equipotent doses were estimated by linear interpolation between actual adjacent doses. Results Rosuvastatin 5u2009mg reduced LDL-C by 39% and non-HDL-C by 35%. Equivalent reductions in LDL-C required atorvastatin 15u2009mg or simvastatin 39u2009mg. Equivalent reductions in non-HDL-C required atorvastatin 14 mg or simvastatin 42u2009mg. Rosuvastatin 10u2009mg reduced LDL-C by 44% and non-HDL-C by 40%. Equivalent reductions in LDL-C required atorvastatin 29 mg or simvastatin 72u2009mg. Equivalent reductions in non-HDL-C required atorvastatin 27 mg or simvastatin 77u2009mg. Rosuvastatin 20u2009mg reduced LDL-C by 50% and non-HDL-C by 45%. Equivalent reductions in LDL-C and non-HDL-C required atorvastatin 70 mg and atorvastatin 62u2009mg, respectively, and were not achieved with the maximum 80u2009mg dose of simvastatin. Rosuvastatin 40u2009mg reduced LDL-C by 55% and non-HDL-C by 50%. Comparable reductions were not achieved with the maximum 80u2009mg doses of atorvastatin or simvastatin. Conclusions Regarding reductions in LDL-C and non-HDL-C, each rosuvastatin dose is equivalent to doses 3–3.5 times higher for atorvastatin and 7–8 times higher for simvastatin.

To what extent do high-intensity statins reduce low-density lipoprotein cholesterol in each of the four statin benefit groups identified by the 2013 American College of Cardiology/American Heart Association guidelines? A VOYAGER meta-analysis

BACKGROUNDnThe 2013 American College of Cardiology and American Heart Association (ACC/AHA) guidelines identify four patient groups who benefit from moderate- or high-intensity statin treatment; those with: 1) atherosclerotic cardiovascular disease (ASCVD); 2) low-density lipoprotein cholesterol (LDL-C) ≥190xa0mg/dl; 3) diabetes; or 4) a 10-year ASCVD risk ≥7.5%. High-intensity statins, anticipated to reduce LDL-C byxa0≥50%, were identified as rosuvastatin 20-40xa0mg and atorvastatin 40-80xa0mg.nnnMETHODS AND RESULTSnIndividual patient data (32,258) from the VOYAGER database of 37 studies were used to calculate least-squares mean (LSM) percentage change in LDL-C during 8496 patient exposures to rosuvastatin 20-40xa0mg, and atorvastatin 40-80xa0mg in the four patient benefit groups. LSM percentage reductions in LDL-C with rosuvastatin 20 and 40xa0mg were greater than with atorvastatin 40xa0mg, overall and in each statin benefit group, and with rosuvastatin 40xa0mg were greater than with atorvastatin 80xa0mg overall and in three of the four benefit groups (all pxa0<xa00.05). For example, in the ASCVD group, 40%, 59%, 57% and 71% of patients treated with atorvastatin 40xa0mg, atorvastatin 80xa0mg, rosuvastatin 20xa0mg and rosuvastatin 40xa0mg, respectively, had a ≥50% reduction in LDL-C.nnnCONCLUSIONSnThe choice and dose of statin have an impact both on the percentage LDL-C reduction and achievement of ≥50% reduction in LDL-C, overall and within each of the four statin benefit groups outlined by the 2013 ACC/AHA guidelines. This may be of importance for clinicians in their choice of treatment for individual patients.