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Background: Economic evaluations are an integral component of many clinical trials. Costs used in those analyses are based on the prices of branded drugs when they first enter the market. The effect of genericization on the cost-effectiveness (ce) or cost-utility (cu) of an intervention is unknown because economic analyses are rarely updated using the costs of generic drugs., Methods: We re-examined the ce or cu of regimens previously evaluated in Canadian Cancer Trials Group (cctg) studies that included prospective economic evaluations and where genericization has occurred or is anticipated in Canada. We incorporated the new costs of generic drugs to characterize changes in ce or cu. We also determined acceptable cost levels of generic drugs that would make regimens reimbursable in a publicly funded health care system., Results: The four randomized controlled trials included (representing 1979 patients) were cctg br.10 (early lung cancer, adjuvant vinorelbine-cisplatin vs. observation, n = 172), cctg br.21 (metastatic lung cancer, erlotinib vs. placebo, n = 731), cctg co.17 (metastatic colon cancer, cetuximab vs. best supportive care, n = 557), and cctg ly.12 (relapsed or refractory lymphoma, gemcitabine-dexamethasone-cisplatin vs. cytarabine-dexamethasone-cisplatin, n = 619). Since the initial publication of those trials, the genericization of vinorelbine, erlotinib, cetuximab, and cisplatin has taken place or is expected in Canada. Costs of generics improved the ces and cus of treatment significantly. For example, genericization of erlotinib ($1460.25 per 30 days) resulted in an incremental cost-effectiveness ratio (icer) of $45,746 per life-year gained compared with $94,638 for branded erlotinib. Likewise, genericization of cetuximab ($275.80 per 100 mg) produced an icer of $261,126 per quality-adjusted life-year (qaly) gained compared with $299,613 for branded cetuximab. Decreases in the cost of generic cetuximab to $129.39 and $63.51 would further improve the icer to $150,000 and $100,000 per QALY respectively., Conclusions: Genericization of a costly oncology drug can modify the ce and cu of a regimen significantly. Failure to revisit economic analyses with the costs of generics could be a missed opportunity for funding bodies to optimize value-based allocation of health care resources. At current levels, the costs of generics might not be sufficiently low to sustain publicly funded health care systems., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

Background: Afatinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (egfr tki), is approved for first-line therapy in advanced EGFR mutation-positive non-small-cell lung cancer (nsclc) and has previously demonstrated activity after failure of chemotherapy and reversible egfr tkis, with improved response and progression-free survival, compared with placebo. Outcomes in pretreated patients with advanced nsclc receiving afatinib through a Canadian special access program (sap) are reported here., Methods: Patients with nsclc progressing after at least 1 line of chemotherapy and an egfr tki were eligible to enrol in the sap. Characteristics of patients from the two largest accruing Canadian centres were retrospectively reviewed, including demographics, disease and treatment data, and patient outcomes., Results: The 53 patients who received afatinib (57% women, 51% never-smokers, 26% of East Asian ethnicity, and 66% with adenocarcinoma) had a median age of 59 years. EGFR mutations were documented in 25%, and EGFR wild-type in 8%. All patients had received prior egfr tki treatment, with 42% achieving a response. Patients took afatinib for a median of 2 months (range: 0-26 months); 17% required 1 or more dose reductions. Of 47 evaluable patients receiving afatinib, 10 experienced tumour shrinkage, and 11, stable disease. Median survival from afatinib initiation was 5 months (95% confidence interval: 2 months to 8 months). Grade 3 or greater diarrhea, rash, paronychia, and stomatitis were seen in 9%, 11%, 6%, and 4% of patients respectively., Conclusions: In an unselected population of pretreated patients with advanced nsclc after tki failure, median survival with afatinib therapy was 5 months. Through a sap, afatinib demonstrated activity in clinical practice, with manageable toxicity., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have no relevant conflicts.

Background: Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy., Patients and Methods: In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS)., Results: Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%-49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18-37) and median overall survival was 22.1 months (95% CI 17.1-27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%-71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%-36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths., Conclusions: Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%., Clinical Trial Name and Number: KEYNOTE-001 (ClinicalTrials.gov, NCT01295827)., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Women with early-stage breast cancer, of whom only 15% will experience a recurrence, are often conflicted or uncertain about taking chemotherapy. Gene expression profiling (GEP) of tumours informs risk prediction, potentially affecting treatment decisions. We examined whether receiving a GEP test score reduces decisional conflict in chemotherapy treatment decision making., Methods: A general population sample of 200 women completed the decisional conflict scale (DCS) at baseline (no GEP test score scenario) and after (scenario with GEP test score added) completing a discrete choice experiment survey for early-stage breast cancer chemotherapy. We scaled the 16-item DCS total scores and subscores from 0 to 100 and calculated means, standard deviations and change in scores, with significance (p < 0.05) based on matched pairs t-tests., Results: We identified five respondent subgroups based on preferred treatment option; almost 40% did not change their chemotherapy decision after receiving GEP testing information. Total score and all subscores (uncertainty, informed, values clarity, support, and effective decision) decreased significantly in the respondent subgroup who were unsure about taking chemotherapy initially but changed to no chemotherapy (n =33). In the subgroup of respondents (n = 25) who chose chemotherapy initially but changed to unsure, effective decision subscore increased significantly. In the overall sample, changes in total and all subscores were non-significant., Conclusions: GEP testing adds value for women initially unsure about chemotherapy treatment with a decrease in decisional conflict. However, for women who are confident about their treatment decisions, GEP testing may not add value. Decisions to request GEP testing should be personalised based on patient preferences., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non-small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit., Methods: We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review., Results: Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all the patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months. The median duration of progression-free survival was 3.7 months, and the median duration of overall survival was 12.0 months. PD-L1 expression in at least 50% of tumor cells was selected as the cutoff from the training group. Among patients with a proportion score of at least 50% in the validation group, the response rate was 45.2%. Among all the patients with a proportion score of at least 50%, median progression-free survival was 6.3 months; median overall survival was not reached., Conclusions: Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab. (Funded by Merck; KEYNOTE-001 ClinicalTrials.gov number, NCT01295827.).

Background: In evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC), overall survival (OS) as an endpoint seems to be of limited use because of a high level of treatment crossover for ethical reasons. A more efficient and useful indicator for assessing efficacy is needed., Methods and Findings: We identified 18 phase 3 trials in the literature investigating EGFR-tyrosine kinase inhibitor (TKIs) or ALK-TKIs, now approved for use to treat NSCLC, compared with standard cytotoxic chemotherapy (eight trials were performed in molecularly selected patients and ten using an "all-comer" design). Receiver operating characteristic analysis was used to identify the best threshold by which to divide the groups. Although trials enrolling molecularly selected patients and all-comer trials had similar OS-hazard ratios (OS-HRs) (0.99 vs. 1.04), the former exhibited greater progression-free survival-hazard ratios (PFS-HR) (mean, 0.40 vs. 1.01; P<0.01). A PFS-HR of 0.60 successfully distinguished between the two types of trials (sensitivity 100%, specificity 100%). The odds ratio for overall response was higher in trials with molecularly selected patients than in all-comer trials (mean: 6.10 vs. 1.64; P<0.01). An odds ratio of 3.40 for response afforded a sensitivity of 88% and a specificity of 90%., Conclusion: The notably enhanced PFS benefit was quite specific to trials with molecularly selected patients. A PFS-HR cutoff of ∼0.6 may help detect clinical benefit of molecular targeted agents in which OS is of limited use, although desired threshold might differ in an individual trial.

Purpose: Panobinostat is a potent oral pan-deacetylase inhibitor with promising clinical activity in hematologic malignancies. Panobinostat was shown to inhibit CYP2D6 activity in vitro; thus understanding the magnitude of the potential clinical inhibition of panobinostat on co-medications that are CYP2D6 substrates becomes important., Methods: This study evaluated the effects of co-administration of panobinostat with a sensitive CYP2D6 substrate, dextromethorphan (DM), in patients with advanced cancer who have functional CYP2D6 genes. Patients received 60 mg DM alone on day 1, panobinostat at 20 mg alone on days 3 and 5, and both agents on day 8. Plasma concentrations of DM and its metabolite dextrorphan (DX) were determined by liquid chromatography-tandem mass spectrometry following serial blood collections on day 1 (DM alone) and day 8 (in combination with panobinostat)., Results: Panobinostat increased DM exposure by 64 % [geometric mean ratio (GMR), 1.64 (90 % confidence interval (CI), 1.17-2.31)] and DX exposure by 29 % (GMR, 1.29 [90 % CI, 1.10-1.51]). These results indicated that panobinostat weakly inhibited a sensitive CYP2D6 substrate in cancer patients by increasing DM exposure by less than twofold., Conclusion: Safety monitoring of sensitive CYP2D6 substrates with narrow therapeutic index is recommended when co-administering with panobinostat in future clinical practice.

Introduction: Malignant mesothelioma (MM) is an aggressive disease with limited therapeutic options. In preclinical models, vascular endothelial growth factor (VEGF) stimulates MM proliferation. In MM patients, higher plasma VEGF levels correlate inversely with survival. Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors-1, -2, and -3., Methods: We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed MM who had received ≤1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily., Results: Fifty-one patients enrolled at 9 centers; 50 were evaluable for response. Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR+SD) was higher at the 45 mg cediranib dose level (67% vs. 34%, p=0.04). Median progression-free survival was 1.8 months (95% CI 0.1, 14.2); median overall survival (OS) was 4.4 months (95% CI 0.9, 41.7). The 1-year survival rate was 15%. Grade 3/4 toxicities were more frequent in the 45 mg dose level group (87% vs. 43%, p=0.002). These included fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy. Median OS was superior in patients who developed ≥grade 3 hypertension (8.5 vs. 4.1 months, p=0.024)., Conclusion: This trial did not meet its pre-specified response endpoint. A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The INTEREST (IRESSA NSCLC Trial Evaluating Response and Survival against Taxotere) trial compared gefitinib with docetaxel (Taxotere) in pretreated advanced non-small-cell lung cancer (NSCLC). Noninferiority for overall survival was concluded. Gefitinib had a better toxicity profile and greater improvements in quality of life (QoL). We undertook a cost-consequence analysis to estimate the direct medical costs of gefitinib compared with docetaxel., Patients and Methods: Summary data from INTEREST were used to derive resource utilization and direct costs from treatment start until drug discontinuation. Costs for treatment, adverse events, outpatient visits and investigations were calculated. Mean total cost-per-patient-per-arm was determined, and incremental cost was calculated. Utility values were generated from Functional Assessment of Cancer Therapy - Lung scores and compared between arms., Results: Incremental mean overall cost per patient for gefitinib over docetaxel was CAD $5161. Drug was the major contributor to overall cost in both arms. Longer mean duration of gefitinib therapy (134 versus 91 days) contributed to the incremental cost difference. The cost per 21-day cycle was similar in both arms ($1963 docetaxel, $2095 gefitinib)., Conclusion: The modest increase in cost associated with gefitinib supports its use as an alternative to docetaxel as second-line treatment of advanced NSCLC, particularly given the improvements in QoL, patient preference for oral therapy and better toxicity profile with gefitinib.

Non-small-cell lung cancer (NSCLC) remains by far the major cause of cancer-related death in the Western world in both men and women. The majority of patients will be diagnosed with metastatic disease, and chemotherapy doublets remain the cornerstone of treatment for these patients. However, chemotherapy has a minimal impact on long-term survival and prognosis remains poor for these patients. Further improvement in treatment is likely to require incorporation of novel targeted therapies. Among these agents, inhibitors of the epidermal growth factor receptor (EGFR) have demonstrated significant activity in the first-, second- or third-line treatment of NSCLC. The purpose of current paper is to present the evidence for using several proposed molecular biomarkers as a tool for selection of NSCLC patients for anti-EGFR treatment. According to current data, EGFR mutation status appears to be the strongest predictor for the selection of NSCLC patients to first-line treatment with EGFR tyrosine kinase inhibitors vs chemotherapy. Use of other biomarkers remains investigational.

Background: : Treatment of elderly patients with stage III NSCLC is controversial. Limited data exist, as the elderly are underrepresented in clinical trials., Methods: : After ethics approval, we performed a retrospective review of 1372 stage III NSCLC patients treated at our institution during the period 1997-2007. Patients with malignant effusions and microscopic N2 discovered only postoperatively were excluded, leaving 740 who were classified by treatment plan: palliative (palliative chemotherapy or radiation [≤40 Gy]); nonsurgical multimodality (>40 Gy radiation ± chemotherapy); or surgical multimodality (chemotherapy, radiation, and surgery). Demographics, treatment, toxicity, and survival were analyzed by age, 0 to 65 years, n = 384; 66 to 75 years, n = 256; 76+ years, n = 100, and compared using log-rank, univariate, and multivariate statistical tests., Results: : Patients older than 65 years were more likely to have poor performance status (p < 0.0001), multiple comorbidities (p < 0.0001), and to receive palliative therapy only (p < 0.0001). Older and younger patients treated with curative intent with nonsurgical bimodality therapy or trimodality therapy including surgery had similar rates of grade 3/4 toxicity (0-65 years, 39%; 66-75 years, 43%; 76+ years, 5%; p = 0.18) and toxic death (0-65 years, 4%; 66-75 years, 4%; 76+ years, 0%; p = 0.76). Survival was worse with increasing age (p < 0.0001), likely due to greater use of palliative treatment in the elderly. When survival was analyzed for patients treated with curative intent, there was no difference between age groups for nonsurgical (p = 0.32) or surgical (p = 0.53) therapy., Conclusion: : In select fit elderly patients, combined modality therapy is tolerable and is associated with survival similar to that of younger patients.

Vascular disrupting agents (VDAs) are an exciting new group of targeted therapies under active clinical research in many solid tumors, in particular, lung cancer. Small-molecule VDAs are the focus of current clinical research, and consist of the flavonoids and the tubulin-binding agents. Toxicities of single-agent VDAs are characterized by acute, transient, and generally noncumulative side effects including headaches, nausea and vomiting, tumor pain, hypertension, and tachycardia. Flavonoid agents can also cause infusion site pain, visual disturbances, electrocardiac abnormalities, and symptoms consistent with an acute release of serotonin. Tubulin-binding agents can result in cardiac ischemia, abdominal pain, neuromotor abnormalities and cerebellar ataxia, and acute hemodynamic changes. Clinical trials investigating VDAs in combination with traditional chemotherapy have also shown the potential for significant pharmacologic and adverse toxicity interactions. Further research will need to focus on pharmacokinetic and pharmacodynamic parameters to optimize dosing schedules, determine effective combinations with chemotherapy, and minimize toxicities associated with VDAs.

Purpose: Significant advances in the systemic management of metastatic non-small cell lung cancer (NSCLC) have occurred over the past decade, with options now including multiple lines of chemotherapy, epidermal growth factor receptor inhibitors, and antiangiogenic agents. Improvements in overall survival have been demonstrated in randomized controlled trials comparing these newer agents with best supportive care or standard therapy. This study examined uptake of these therapies in general practice and their impact on survival., Methods: This retrospective cohort study compared demographic, treatment, and survival data among 987 patients diagnosed with stage IV NSCLC at two institutions in 1998, 2003, and 2008. Cohorts were selected based on intervals when doublet chemotherapy, second-line chemotherapy, and targeted agents were incorporated into the standard treatment regimen., Results: The proportion of patients receiving systemic therapy increased over time (20% in 1998, 42% in 2008). Overall survival improved significantly across cohorts (p < .001), with 2-year survival rates of 0.3% in 1998, 4% in 2003, and 15% in 2008. In a multivariate survival analysis, the 2003 and 2008 cohorts were independently associated with longer survival, as was the use of one or more lines of systemic therapy. Elderly patients (aged ≥70 years) were also more likely to receive systemic therapy over time, with longer overall survival (p < .001)., Conclusion: Over the past decade, there has been an increasing use of systemic therapy in stage IV NSCLC patients, including the elderly. This has been associated with significantly longer overall survival.

Background: Bevacizumab, the anti-vascular endothelial growth factor agent, provides clinical benefit when combined with platinum-based chemotherapy in first-line advanced non-small-cell lung cancer. We report the final overall survival (OS) analysis from the phase III AVAiL trial. Patients and methods: Patients (n = 1043) received cisplatin 80 mg/m² and gemcitabine 1250 mg/m² for up to six cycles plus bevacizumab 7.5 mg/kg (n = 345), bevacizumab 15 mg/kg (n = 351) or placebo (n = 347) every 3 weeks until progression. Primary end point was progression-free survival (PFS); OS was a secondary end point. Results: Significant PFS prolongation with bevacizumab compared with placebo was maintained with longer followup {hazard ratio (HR) [95% confidence interval (CI)] 0.75 (0.64-0.87), P = 0.0003 and 0.85 (0.73-1.00), P = 0.0456} for the 7.5 and 15 mg/kg groups, respectively. Median OS was >13 months in all treatment groups; nevertheless, OS was not significantly increased with bevacizumab [HR (95% CI) 0.93 (0.78-1.11), P = 0.420 and 1.03 (0.86-1.23), P = 0.761] for the 7.5 and 15 mg/kg groups, respectively, versus placebo. Most patients (∼62%) received multiple lines of poststudy treatment. Updated safety results are consistent with those previously reported. Conclusions: Final analysis of AVAiL confirms the efficacy of bevacizumab when combined with cisplatin- gemcitabine. The PFS benefit did not translate into a significant OS benefit, possibly due to high use of efficacious second-line therapies. [ABSTRACT FROM AUTHOR]