Clinical definition of acquired resistance to immunotherapy in patients with metastatic non-small-cell lung cancer.

Acquired resistance (AR) to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade is frequent in non-small-cell lung cancer (NSCLC), occurring in a majority of initial responders. Patients with AR may have unique properties of persistent antitumor immunity that could be re-harnessed by investigational immunotherapies. The absence of a consistent clinical definition of AR to PD-(L)1 blockade and lack of uniform criteria for ensuing enrollment in clinical trials remains a major barrier to progress; such clinical definitions have advanced biologic and therapeutic discovery. We examine the considerations and potential controversies in developing a patient-level definition of AR in NSCLC treated with PD-(L)1 blockade. Taking into account the specifics of NSCLC biology and corresponding treatment strategies, we propose a practical, clinical definition of AR to PD-(L)1 blockade for use in clinical reports and prospective clinical trials. Patients should meet the following criteria: received treatment that includes PD-(L)1 blockade; experienced objective response on PD-(L)1 blockade (inclusion of a subset of stable disease will require future investigation); have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody in patients not exposed to anti-PD-(L)1 in 6 months.

Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial.

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).

Uptake of a 21-gene expression assay in breast cancer practice: views of academic and community-based oncologists.

PURPOSE: Advances in personalized medicine have produced novel tests and treatment options for women with breast cancer. Relatively little is known about the process by which such tests are adopted into oncology practice. The objectives of the present study were to understand the experiences of medical oncologists with multigene expression profile (gep) tests, including their adoption into practice in early-stage breast cancer, and the perceptions of the oncologists about the influence of test results on treatment decision-making. METHODS: We conducted a qualitative descriptive study involving interviews with medical oncologists from academic and community cancer centres or hospitals in 8 communities in Ontario. A 21-gene breast cancer assay was used as the example of gep testing. Qualitative analytic techniques were used to identify the main themes. RESULTS: Of 28 oncologists who were approached, 21 (75%) participated in the study [median age: 43 years; 12 women (57%)]. Awareness and knowledge of gep testing were derived from several sources: international scientific meetings, participation in clinical studies, discussions with respected colleagues, and manufacturer-sponsored meetings. Oncologists observed that incorporating gep testing into their clinical practice resulted in several changes, including longer consultation times, second visits, and taking steps to minimize treatment delays. Oncologists expressed divergent opinions about the strength of evidence and added value of gep testing in guiding treatment decisions. CONCLUSIONS: Incorporation of gep testing into clinical practice in early-stage breast cancer required oncologists to make changes to their usual routines. The opinions of oncologists about the quality of evidence underpinning the test affected how much weight they gave to test results in treatment decision-making.

Improving molecular testing and personalized medicine in non-small-cell lung cancer in Ontario.

BACKGROUND: Although molecular testing has become standard in managing advanced nonsquamous non-small-cell lung cancer (nsclc), most patients undergo minimally invasive procedures, and the diagnostic tumour specimens available for testing are usually limited. A knowledge translation initiative to educate diagnostic specialists about sampling techniques and laboratory processes was undertaken to improve the uptake and application of molecular testing in advanced lung cancer. METHODS: A multidisciplinary panel of physician experts including pathologists, respirologists, interventional thoracic radiologists, thoracic surgeons, medical oncologists, and radiation oncologists developed a specialty-specific education program, adapting international clinical guidelines to the local Ontario context. Expert recommendations from the program are reported here. RESULTS: Panel experts agreed that specialists procuring samples for lung cancer diagnosis should choose biopsy techniques that maximize tumour cellularity, and that conservation strategies to maximize tissue for molecular testing should be used in tissue processing. The timeliness of molecular reporting can be improved by pathologist-initiated reflex testing upon confirmation of nonsquamous nsclc and by prompt transportation of specimens to designated molecular diagnostic centres. To coordinate timely molecular testing and optimal treatment, collaboration and communication between all clinicians involved in diagnosing patients with advanced lung cancer are mandatory. CONCLUSIONS: Knowledge transfer to diagnostic lung cancer specialists could potentially improve molecular testing and treatment for advanced lung cancer patients.

Approach to biomarker testing: perspectives from various specialties.

BACKGROUND: Despite its importance for patient outcomes, biomarker testing for lung cancer is not uniformly integrated into the Canadian health care system. To better understand current practice patterns for lung cancer biomarker testing, we assessed physician perspectives by specialty and region. METHODS: A national survey of Canadian lung cancer specialists was conducted to understand their perspectives on biomarker testing in lung cancer. The 11-item survey assessed the current practice and challenges of testing. The survey was sent to 375 specialists. RESULTS: The overall response rate for the survey was 36%. Nearly all specialists reported that knowing tumour genotyping results affects patient outcome and influences the treatment decision. Medical oncologists most commonly initiated molecular testing; however, most respondents suggested a shared model involving medical oncologists and pathologists. More than half of all responding specialists had the perception that fewer than 25% of test results are available for first-line treatment decisions. Identified barriers to routine testing for all lung cancer patients included cost, lack of funding, tissue availability, and sample quality. CONCLUSIONS: There was clear agreement that biomarker testing is important in determining appropriate treatment for patients. There is a need for general consensus on who should initiate molecular testing. Clear clinical guidance for pathologists has to be established for molecular testing, including defining the population to be tested, the timing of testing, and the tests to be performed. Testing could be facilitated by including more information on diagnostic sample requisitions, such as clinical suspicion of primary lung cancer, cancer history, and other samples already collected.

Estimation of drug cost avoidance and pathology cost avoidance through participation in NCIC Clinical Trials Group phase III clinical trials in Canada.

BACKGROUND: Cost avoidance occurs when, because of provision of a drug therapy [drug cost avoidance (dca)] or a pathology test [pathology cost avoidance (pca)] during trial participation, health care payers need not pay for standard treatments or testing. The aim of our study was to estimate the total dca and pca for Canadian patients enrolled in relevant phase iii trials conducted by the ncic Clinical Trials Group. METHODS: Phase iii trials that had completed accrual and resulted in dca or pca were identified. The pca was calculated based on the number of patients screened and the test cost. The dca was estimated based on patients randomized, the protocol dosing regimen, drug cost, median dose intensity, and median duration of therapy. Costs are presented in Canadian dollars. No adjustment was made for inflation. RESULTS: From 1999 to 2011, 4 trials (1479 patients) resulted in pca and 17 trials (3195 patients) resulted in dca. The total pca was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). The total dca was estimated at $27,952,512, of which targeted therapy constituted 43% (five trials). The combined pca and dca was $32,147,361. CONCLUSIONS: Over the study period, trials conducted by the ncic Clinical Trials Group resulted in total cost avoidance (pca and dca) of approximately $7,518 per patient. Although not all trials lead to cost avoidance, such savings should be taken account when the financial impact of conducting clinical research is being considered.

Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer.

BACKGROUND: Testing for EGFR mutations and ALK rearrangement has become standard in managing advanced nonsmall-cell lung cancer (NSCLC). However, many institutions in Europe, North America and other world regions continue to face a common challenge of facilitating timely molecular testing with rapid result turnaround time. We assessed the prevalence of biomarker testing for advanced NSCLC patients and whether testing affected the timeliness of treatment decisions. METHODS: We conducted a retrospective chart review of a random sample of one-quarter of all patients with advanced NSCLC referred to the Princess Margaret Cancer Centre from 1 April 2010 to 31 March 2013. RESULTS: Of 300 patients reviewed, 175 seen by medical oncology had nonsquamous NSCLC, 72% of whom had biomarker testing carried out. Patients tested for biomarkers were more likely to be female (47% versus 21%, P = 0.002), Asian (27% versus 6%, P = 0.005) and never smokers (42% versus 8%, P < 0.0001). Only 21% of patients with biomarker testing had results available at their initial oncology consultation. This group had a shorter median time from consultation to treatment decision (0 versus 22 days, P = 0.0008) and time to treatment start (16 versus 29, P = 0.004). Thirteen percent underwent repeat biopsy for molecular testing after the initial consultation. Of those with positive EGFR or ALK results, 19% started chemotherapy before biomarker results became available. CONCLUSIONS: Awaiting biomarker testing results can delay treatment decisions and treatment initiation for patients with advanced NSCLC. This may be avoided by incorporating reflex biomarker testing into diagnostic algorithms for NSCLC at the level of the pathologist, and further education of specialists involved in obtaining diagnostic cancer specimens to ensure they are sufficient for molecular testing.

Management of egfr tki-induced dermatologic adverse events.

Targeting the epidermal growth factor receptor (egfr) pathway has become standard practice for the treatment of advanced non-small-cell lung cancer. Compared with chemotherapy, egfr tyrosine kinase inhibitors (tkis) have been associated with improved efficacy in patients with an EGFR mutation. Together with the increase in efficacy comes an adverse event (ae) profile different from that of chemotherapy. That profile includes three of the most commonly occurring dermatologic aes: acneiform rash, stomatitis, and paronychia. Currently, no randomized clinical trials have evaluated the treatments for the dermatologic aes that patients experience when taking egfr tkis. Based on the expert opinion of the authors, some basic strategies have been developed to manage those key dermatologic aes. Those strategies have the potential to improve patient quality of life and compliance and to prevent inappropriate dose reductions.

A population-based study of the epidemiology of pancreatic cancer: a brief report.

OBJECTIVE: Administrative data are used to describe the pancreatic cancer (pcc) population. The analysis examines demographic details, incidence, site, survival, and factors influencing mortality in a cohort of individuals diagnosed with pcc. METHODS: Incident cases of pcc diagnosed in Ontario between 1 January 2004 and 31 December 2011 were extracted from the Ontario Cancer Registry. They were linked by encrypted health card number to several administrative databases to obtain demographic and mortality information. Descriptive, bivariate, and survival analyses were conducted. RESULTS: During the period of interest, 9221 new cases of pcc (4548 in men, 4673 in women) were diagnosed, for an age-adjusted standardized annual incidence in the range of 8.6-9.5 per 100,000 population. Mean age at diagnosis was 70.3 ± 12.5 years (standard deviation). Five-year survival was 7.2% (12.8% for those <60 years of age and 3.6% for those >80 years of age). Survival varied by sex, older age, rural residence, lower income, site of involvement in the pancreas, and presence of comorbidity. CONCLUSIONS: The mortality rate in pcc is exceptionally high. With an increasing incidence and a mortality positively associated with age, additional support will be needed for this highly fatal disease as demographics in Ontario continue to trend toward a higher proportion of older individuals.

A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer.

BACKGROUND: This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC). METHODS: This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients. RESULTS: The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months. CONCLUSION: Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.

Patients' perceptions of gene expression profiling in breast cancer treatment decisions.

INTRODUCTION: Determining the likely benefit of adjuvant chemotherapy for early-stage breast cancer patients depends on estimating baseline recurrence risk. Gene expression profile (gep) testing of tumours informs risk prediction, but evidence of its clinical utility is limited. We explored patient perceptions of gep testing and the impact of those perceptions on chemotherapy decisions. METHODS: We conducted one focus group (n = 4) and individual interviews (n = 24) with patients who used gep testing, recruited through clinics at two hospitals in Ontario. Data were analyzed using content analysis and constant comparison techniques. RESULTS: Patients' understanding of gep testing was variable, and misapprehensions were common. Patients valued the test because it provided them with certainty amidst confusion, with options and a sense of empowerment, and with personalized, authoritative information. They commonly believed that the test was better and fundamentally different from other clinical tests, attributing to it unique power and truth-value. This kind of "magical thinking" was derived from an amplified perception of the test's validity and patients' need for reassurance about their treatment choices. Despite misperceptions or magical thinking, gep was widely considered to be the deciding factor in treatment decisions. CONCLUSIONS: Patients tend to overestimate the truth-value of gep testing based on misperceptions of its validity. Our results identify a need to better support patient understanding of the test and its limitations. Findings illustrate the deep emotional investment patients make in gep test results and the impact of that investment on their treatment decisions.

Access to personalized medicine: factors influencing the use and value of gene expression profiling in breast cancer treatment.

UNLABELLED: Genomic information is increasingly being used to personalize health care. One example is gene expression profiling (gep) tests, which estimate recurrence risk to inform chemotherapy decisions in breast cancer. Recently, gep tests were publicly funded in Ontario. We explored the perceived utility of gep tests, focusing on the factors influencing their use and value in treatment decision-making by patients and oncologists. METHODS: We conducted interviews with oncologists (n = 14) and interviews and a focus group with early-stage breast cancer patients (n = 28) who underwent gep testing. Both groups were recruited through oncology clinics in Ontario. Data were analyzed using the content analysis and constant comparison techniques. RESULTS: Narratives from patients and oncologists provided insights into various factors facilitating and restricting access to gep. First, oncologists are positioned as gatekeepers of gep, providing access in medically appropriate cases. However, varying perceptions of appropriateness led to perceived inequities in access and negative impacts on the doctor-patient relationship. Second, media attention facilitated patient awareness of gep, but also complicated gatekeeping. Third, the dedicated administration attached to gep was burdensome and led to long waits for results and also to increased patient anxiety and delayed treatment. Collectively, because of barriers to access, those factors inadvertently heightened the perceived value of gep for patients relative to other prognostic indicators. CONCLUSIONS: Our study delineates the factors facilitating and restricting access to gep, and highlights the roles of media and organization of services in the perceived value and utilization of gep. The results identify a need for administrative changes and practice guidelines to support streamlined and standardized use of gep tests.

Population-based utilization of radiation therapy by a Canadian breast cancer cohort.

We examined trends in radiation therapy (rt) utilization by a population-based breast cancer cohort in Ontario. The provincial cancer registry provided a breast cancer cohort based on diagnosis dates from April 1, 2005, to March 31, 2010. Staging information was also available. The cohort was then linked, by encrypted health card number, to linkable administrative datasets, including rt utilization. The average age in the identified female breast cancer cohort (n = 39,656) was 61.6 ± 14.0 years. Almost two thirds of the patients (n = 25,225) received rt, and staging information was available for 22,988 patients (9541 stage i, 8516 stage ii, 4050 stage iii, and 881 stage iv). The average number of rt courses received by the patients was 1.4 ± 0.7 for stage i, 1.8 ± 1.1 for stage ii, 2.5 ± 1.3 for stage iii, and 2.8 ± 2.4 for stage iv. The ratio of conventional rt to intensity-modulated rt was 70.9%:16.6% for stage i, 71.6%:11.3% for stage ii, 74.6%:4.6% for stage iii, and 89.6%:2.2% for stage iv. From 2005 to 2010, almost two thirds of a Canadian female breast cancer cohort received rt, and the average number of courses increased with disease severity. A similar trend was observed with the type of rt (use of conventional rt increased with disease severity). The next step is to apply unit costs to the number of fractions and to obtain rt planning and radiation therapist times.

Health system costs for stage-specific breast cancer: a population-based approach.

OBJECTIVE: The objective of the present analysis was to determine the publicly funded health care costs associated with the care of breast cancer (bca) patients by disease stage. METHODS: Incident cases of female invasive bca (2005-2009) were extracted from the Ontario Cancer Registry and linked to administrative datasets from the publicly funded system. The type and use of health care services were stratified by disease stage over the first 2 years after diagnosis. Mean costs and costs by type of clinical resource used in the care of bca patients were compared with costs for a matched control group. The attributable cost for the 2-year time horizon was determined in 2008 Canadian dollars. RESULTS: This cohort study involved 39,655 patients with bca and 190,520 control subjects. The average age in those groups was 61.1 and 60.9 years respectively. Most bca patients were classified as either stage i (34.4%) or stage ii (31.8%). Of the bca cohort, 8% died within the first 2 years after diagnosis. The overall mean cost per bca case from a public payer perspective in the first 2 years after diagnosis was $41,686. Over the 2-year time horizon, the mean cost increased by stage: i, $29,938; ii, $46,893; iii, $65,369; and iv, $66,627. The attributable cost of bca was $31,732. Cost drivers were cancer clinic visits, physician billings, and hospitalizations. CONCLUSIONS: Costs of care increased by stage of bca. Cost drivers were cancer clinic visits, physician billings, and hospitalizations. These data will assist planning and decision-making for the use of limited health care resources.

Pathologist-initiated reflex testing for biomarkers in non-small-cell lung cancer: expert consensus on the rationale and considerations for implementation.

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice.

A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours.

BACKGROUND: To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin. METHODS: Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations. RESULTS: Eighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ≥ 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted. CONCLUSION: The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.

Population-based home care services in breast cancer: utilization and costs.

OBJECTIVE: To determine utilization and costs of home care services (hcs) for individuals with a diagnosis of breast cancer (bc). METHODS: Incident cases of invasive bc in women were extracted from the Ontario Cancer Registry (2005-2009) and linked with other Ontario health care administrative databases. Control patients were selected from the population of women never diagnosed with any type of cancer. The types and proportions of hcs used were determined and stratified by disease stage. Attributable home care utilization and costs for bc patients were determined. Factors associated with hcs costs were assessed using regression analysis. RESULTS: Among the 39,656 bc and 198,280 control patients identified (median age: 61.6 years for both), 75.4% of bc patients used hcs (62.1% stage i; 85.7% stage ii; 94.6% stage iii; 79.1% stage iv) compared with 14.6% of control patients. The number of hcs used per patient-year were significantly higher for the bc patients than for the control patients (14.97 vs. 6.13, p < 0.01), resulting in higher costs per patient-year ($1,210 vs. $325; $885 attributable cost to bc, p < 0.01). The number of hcs utilized and the associated costs increased as the bc stage increased. In contrast, hcs costs decreased as income increased and as previous health care exposure decreased. INTERPRETATION: Patients with bc used twice as many hcs, resulting in costs that were almost 4 times those observed in a matched control group. Less than an additional $1000 per bc patient per year were spent on hcs utilization in the study population.

Bleeding events in bevacizumab-treated cancer patients who received full-dose anticoagulation and remained on study.

BACKGROUND: Bevacizumab provides clinical benefit in multiple solid tumours, but is associated with some increase in bleeding risk. Thrombotic events necessitating therapeutic anticoagulation (TA) are common in cancer. This report describes the safety of concurrent bevacizumab and TA in three large placebo-controlled clinical studies. METHODS: Study 1 (metastatic colorectal cancer (mCRC)), study 2 (mCRC), and study 3 (advanced non-small cell lung cancer) were blinded phase III studies. Eligibility criteria excluded patients on TA. Patients on protocol treatment who developed thrombotic events requiring TA were permitted to continue bevacizumab or placebo under specified conditions. Adverse events in patients who received bevacizumab and TA concurrently were assessed using the NCI-CTCAE scale. RESULTS: While experience is limited, venous thrombotic events were the most common reason for TA initiation in the three studies. Severe bleeding event rates for patients receiving TA in the bevacizumab-treated groups were similar in frequency to the placebo groups, ranging from 0 to 8% or 0 to 67 events per 100 patient-years. No severe pulmonary bleeding was reported in any of the TA-treated populations. CONCLUSIONS: These data suggest that bevacizumab did not increase the risk of severe bleeding in cancer patients who received TA.

Biomarkers of clinical benefit for anti-epidermal growth factor receptor agents in patients with non-small-cell lung cancer.

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.

An economic analysis of the INTEREST trial, a randomized trial of docetaxel versus gefitinib as second-/third-line therapy in advanced non-small-cell lung cancer.

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.