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Objectives: Osimertinib is largely used as first-line therapy for metastatic epithelial growth factor receptor (EGFR) mutant lung cancers based on the FLAURA clinical trial. Real-world patient outcomes often differ from clinical trial outcomes. This study evaluated the efficacy of first-line osimertinib in patients treated in British Columbia (BC), Canada. Furthermore, we compared the outcomes of patients who would and would not have been eligible for the original FLAURA trial., Methods: Consecutive patients receiving first-line osimertinib for metastatic EGFR exon19 or L858R lung cancer were identified using the BC Cancer Pharmacy Database. Patient eligibility for the FLAURA clinical trial were retrospectively reviewed based on the following criteria: ECOG ≥ 2, symptomatic brain metastases or on steroids, hemoglobin < 90 g/L, platelets < 100x10 9 /L, or a creatinine clearance < 50 mL/min. mOS was assessed for the entire population and compared between patients who would have been eligible and ineligible for FLAURA., Results: From January 2020 to October 2021, 311 patients received first-line osimertinib; 44 % (137/311) were deemed FLAURA ineligible, predominantly due to low ECOG (n = 120). After a median follow-up of 26.5 months, the mOS for the entire cohort was 27.4 months (95 %CI 23.8-30.1). The mOS for ineligible patients was 18 months shorter than eligible patients (15.8 vs 34.2, p < 0.001). Ineligible patients had higher rates of de novo stage IV disease, higher rates of stage IVB disease, and more sites of disease than eligible patients., Conclusion: In this real-world population, nearly half of patients would have been ineligible for FLAURA. The mOS was one year shorter than reported in FLAURA. However, patients who would have been eligible for the FLAURA clinical trial had similar OS to patients enrolled in FLAURA. Trial ineligible patients had a higher burden of disease at baseline which may have led to inferior outcomes. Further research is needed to improve outcomes in these patients., Competing Interests: Declaration of competing interest JC Wells, M Mullin, and S Sun have no COIs to report. C Ho has received: Grants/Research funding - Astra Zeneca, Roche. Honoraria - Abbvie, Amgen, Astra Zeneca, Bayer, BMS, CADTH, Eisai, Jazz, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi. B Melosky has received speaker honoraria or attended advisory boards for Astra Zeneca, BMS, Merck, Roche, Pfizer, Takeda, Sanofi, EMD Serono, and Janssen J Laskin has received honoraria from Roche, Pfizer, Takeda and Lilly; she has also received research funding to her institution from Roche., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Adjuvant durvalumab after chemoradiotherapy (CRT) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). A post hoc exploratory analysis of PACIFIC revealed no OS benefit in the PD-L1 < 1% subgroup. This retrospective analysis assesses the real-world impact of durvalumab on OS according to PD-L1 tumor proportion score (TPS). Patients with stage III, unresectable NSCLC treated by CRT, with available PD-L1 TPS, from 1 March 2018 to 31 December 2020, at BC Cancer, British Columbia, Canada were included. Patients were divided into two groups, CRT + durvalumab and CRT alone. OS and PFS were analyzed in the PD-L1 ≥ 1% and <1% subgroups. A total of 134 patients were included in the CRT + durvalumab group and 117, in the CRT alone group. Median OS was 35.9 months in the CRT + durvalumab group and 27.4 months in the CRT alone group [HR 0.59 (95% CI 0.42-0.83), p = 0.003]. Durvalumab improved OS in the PD-L1 ≥ 1% [HR 0.53 (95% CI 0.34-0.81), p = 0.003, n = 175], but not in the <1% subgroup [HR 0.79 (95% CI 0.44-1.42), p = 0.4, n = 76]. This retrospective study demonstrates a statistically significant improvement in OS associated with durvalumab after CRT in PD-L1 ≥ 1%, but not PD-L1 < 1% NSCLC. Variables not accounted for may have biased the survival analysis. A prospective study would bring more insight.

(1) Background: Exon 20 insertion mutations (ex20ins) in EGFR and HER2 are uncommon driver mutations in non-small-cell lung cancer (NSCLC), with a poor prognosis and few targeted therapy options, and there are limited real-world data. Here, we report the clinicopathologic features and outcomes for patients with ex20ins NSCLC across British Columbia, Canada. (2) Methods: NSCLC patients with ex20ins in EGFR or HER2 were identified via tumour testing between 1 January 2016 and 31 December 2021 (n = 7233). Data were collected by chart review. Survival analyses were performed using the Kaplan-Meier method using the log-rank test. (3) Results: A total of 131 patients were identified. The median age was 66. Thirty-three percent of patients had brain metastases. For the EGFR cohort, the median OS was 18.6 months for patients who received any systemic therapy (ST) vs. 2.6 months for patients who did not ( p < 0.001). Median OS was similar for patients treated with ex20ins-specific tyrosine kinase inhibitors (TKIs) vs. other STs (18.6 vs. 15.9 months; p = 0.463). The median first-line PFS was 4.1 vs. 7.4 months for patients treated with a TKI vs. other ST ( p = 0.744). For the HER2 cohort, the median OS was 9.0 months for patients who received any ST vs. 4.9 months for patients who did not ( p = 0.015). The median OS was 23.0 months for patients treated with an ex20ins TKI vs. 5.6 months for patients who were not ( p = 0.019). The median first-line PFS was 5.4 vs. 2.1 months for patients treated with a TKI vs. other ST ( p = 0.343). (4) Conclusions: Overall survival was significantly longer among ex20ins patients who received any systemic therapy vs. those who did not. Overall survival was significantly better among HER2 ex20ins patients who received ex20ins-specific TKIs.

Aim: Report the final analysis from ASTRIS, the largest real-world study of second-/later-line osimertinib in advanced/metastatic EGFR T790M non-small-cell lung cancer (NSCLC). Methods: Patients with advanced/metastatic EGFR T790M NSCLC and prior EGFR-TKI treatment, received once-daily osimertinib 80 mg. Primary end point: overall survival (OS); secondary end points: progression-free survival (PFS), time-to-treatment discontinuation (TTD) and response rate. Safety was also recorded. Results: In 3014 patients, median OS: 22.8 months (21.6-23.8), median PFS: 11.1 months (11.0-12.0), median TTD: 13.5 months (12.6-13.9), and response rate: 57.3% (55.5-59.2). All end points reported with 95% CIs. Numerically longer median OS was observed in patients with baseline WHO performance status <2 versus 2 (24.0 vs 11.1 months) and those without versus with brain/leptomeningeal metastases (25.4 vs 18.0 months). No new safety signals were identified. Conclusion: Second-/later-line osimertinib demonstrated real-world clinical benefit and safety in advanced/metastatic EGFR T790M NSCLC. Clinical Trial Registration: NCT02474355 (ClinicalTrials.gov).

Background: non-small cell lung cancer (NSCLC) outcomes remain suboptimal for early-stage disease despite emerging advances in systemic therapy for the peri-operative period. Next-generation sequencing (NGS) identifies driver mutations for which targeted therapies have been developed that improve survival. The BC lung cancer screening program, which was initiated in May 2022, is expected to identify people with early and late stages of NSCLC. It is crucial to first understand the molecular epidemiology and patterns of time to initiate treatment across its five health authorities (HA) to optimize the delivery of care for NSCLC in BC. In this way, we may harness the benefits of targeted therapy for more people with NSCLC as novel advances in therapy continue to emerge. Objective: to compare (a) the frequency of actionable NSCLC molecular alterations among HAs and (b) the time to treatment initiation. Methods: a retrospective observational study was conducted with prospectively collected data from the BC CGL Database. Adults with late stage NSCLC who underwent targeted NGS were included for the time period from May 2020 to June 2021. Demographics, actionable molecular alterations, PDL-1 expression, and time to treatment across HAs were examined. Using appropriate statistical tests for comparison among HAs, p>0.05 was deemed significant. Results: 582 patients underwent NGS/IHC and analysis during the study period. The mean age was 71 (10.1), and 326 (56%) patients were female. A significantly higher proportion of all EGFRm+ were identified within Vancouver Coastal Health (VCHA) and Fraser Health Authority (FHA) compared to the other health authorities (p < 0.001). This also holds true for common sensitizing EGFRm+ alone (p < 0.001) and for sensitizing EGFRm+ when adjusted for females and smoker status (OR 0.75; 95% CI 0.62, 0.92; p = 0.005). Patients residing within the Northern, Interior, and Island HAs were less likely to receive treatment at the same rate as those in VCHA and FHA HAs. Conclusion: actionable NSCLC driver mutations are present in all regional HAs, with disparity noted in time to initiate treatment between HAs. This provides evidence for the importance of molecular testing for patients in all BC HAs to guide personalized and timely NSCLC treatment.

Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents ≈2%-10% of lung adenocarcinomas and has a reported incidence of ≈10%-30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions., Competing Interests: Disclosures JL reports receipt of honoraria for academic/accredited talks from Roche and AstraZeneca; membership of an advisory board and consultancy for AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, and Takeda; and receipt of research grants (funds to institution) from AstraZeneca, Roche, and Eli Lilly. SVL reports membership of an advisory board and consultancy for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, Celgene, G1 Therapeutics, Genentech/Roche, Guardant Health, Janssen, Eli Lilly, Loxo, MSD, Pfizer, PharmaMar, Regeneron, and Takeda; and receipt of research grants (funds to institution) from Alkermes, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Corvus, Genentech, Eli Lilly, Lycera, Merck, Merus, Molecular Partners, Pfizer, Rain, RAPT, Spectrum, and Turning Point Therapeutics. KT reports employment with Foundation Medicine; receipt of honoraria from BMS and Merck; and receipt of research grants from AstraZeneca. PC reports membership of an advisory board and consultancy for Roche, Pfizer, AstraZeneca, Novartis, Merck, Takeda, and Bristol-Myers Squibb; and receipt of honoraria from Boehringer Ingelheim, Roche, Pfizer, Novartis, Merck, Takeda, and AstraZeneca. JC reports consulting/advisory relationship with AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Novartis, MSD, Pfizer, Roche, and Takeda; and receipt of research funding from AstraZeneca, Boehringer Ingelheim, Pfizer, and Novartis. MRJ reports employment with QIAGEN Inc. AD reports receipt of honoraria from and membership of an advisory board for Ignyta/Genentech/Roche, Loxo/Bayer/Eli Lilly, Takeda, Ariad, Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, and AbbVie; associated research grants (funds to institution) from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, and PharmaMar; research grants from Foundation Medicine; royalties from Wolters Kluwer; CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, and Research to Practice; and other fees from Merck (food/beverage), Puma (food/beverage), Merus, and Boehringer Ingelheim. AC reports employment with Boehringer Ingelheim. SG reports employment with AstraZeneca as of 4 May 2020. FS reports employment with Boehringer Ingelheim RCV GmbH & Co KG. MD reports membership of an advisory council or committee for Roche, BMS, NanoString, MSD, AstraZeneca, Abbvie, Takeda, Boehringer Ingelheim, Blueprint, Merus, and Pfizer; consulting fees from Roche, BMS, MSD, AstraZeneca, Abbvie, Takeda, Boehringer Ingelheim, and Pfizer; and receipt of research grants from Novartis, NanoString, and Blueprint. The other authors have declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis., Patients and Methods: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points., Results: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm., Conclusions: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib., Clinical Trials Number: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981., Competing Interests: Disclosures VAP has declared honorarium from F Hoffman-La Roche; advisory or consultancy fees from Nektar Therapeutics, Astra Zeneca Pharmaceuticals, Arrys Therapeutics, Merck & Co, LOXO Oncology, Araxes Pharma, F. Hoffman–LaRoche Ltd, Janssen Research Foundation, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly & Co, Novartis Pharmaceuticals Corp., Takeda Pharmaceuticals, AbbVie, TRM Oncology, Tesaro, Exelixis, Gritstone, Leeds Biolabs, IDEAYA, Bolt Therapeutics, and G2 Innovation; and research funding from Eli Lilly & Co, Novartis, Merck, Astra Zeneca Pharmaceuticals, F Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, and Incyte. TSM has declared honoraria from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol-Myers Squibb, Celgene, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate, Hengrui Therapeutics, Ignyta, Incyte Corporation, InMed Medical Communication, IQVIA, Janssen, Loxo Oncology, Merck Serono, MSD, MORE Health, Novartis, OncoGenex Pharmaceuticals, OrigiMed, PeerVoice, Pfizer, PrIME Oncology, Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceutical, Takeda Pharmaceuticals HK, Vertex Pharmaceuticals, and Yuhan Corporation; advisory or consultancy fees from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol-Myers Squibb, Celgene, Cirina, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate, GeneDecode, Hengrui Therapeutics, Ignyta, Incyte Corporation, InMed Medical Communication, IQVIA, Janssen, Loxo-Oncology, Merck Serono, MSD, MORE Health, Novartis, OncoGenex Pharmaceuticals, OrigiMed, PeerVoice, Pfizer, PrIME Oncology, Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceutical, Takeda Pharmaceuticals HK, Vertex Pharmaceuticals, and Yuhan Corporation; leadership roles for AstraZeneca and Hutchison Chi-Med; research funding from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, MSD, Novartis, Pfizer, Roche, SFJ, and Xcovery; shareholdings in Hutchison Chi-Med, and Sanomics; stock options in Clearbridge BioMedics (now Biolidics), Loxo-Oncology, OrigiMed, and Virtus Medical Group; and officer or director for AstraZeneca, Hutchison Chi-Med (remunerated), American Society of Clinical Oncology (ASCO), Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), and International Association for the Study of Lung Cancer (IASLC; term ended on 30/4/19 [non-remunerated]). J-YH has declared honoraria from Roche, AstraZeneca, Bristol-Myers Squibb, MSD, and Takeda; advisory or consultancy fees from AstraZeneca, Bristol-Myers Squibb, MSD, Takeda, Pfizer, Novartis, and Lilly; research funding from Roche, Pfizer, Ono Pharmaceutical, and Takeda. M-JA has declared advisory or consultancy fees from AstraZeneca, MSD, Ono Pharmaceutical, and Lilly; and speaker fees from AstraZeneca, MSD, Ono Pharmaceutical, Lilly, Roche, Alpha Pharmaceutical, and Takeda. SSR has declared honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, and Tesaro; advisory or consultancy fees from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, and Tesaro; and research funding from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, and Takeda. SWK has declared advisory or consultancy fees from AstraZeneca; and research funding from AstraZeneca. FAS has declared advisory or consultancy fees from AstraZeneca; research funding from AstraZeneca; and shareholdings in AstraZeneca. JL has declared honoraria from Roche, AstraZeneca, and Pfizer; and research funding from Roche, Boehringer Ingelheim, Pfizer, and AstraZeneca. HA has declared honoraria from AstraZeneca, Chugai, Pfizer, and Boehringer Ingelheim; and advisory or consultancy fees from AstraZeneca and Pfizer. W-CS has declared travel, accommodation, or expenses from Bristol-Myers Squibb and Boehringer Ingelheim. TJ has declared advisory or consultancy fees from Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, and Pfizer. MS has declared honoraria from AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, Novartis, Celgene, Takeda, Lilly, Bristol-Myers Squibb, and MSD; advisory or consultancy fees from AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, Novartis, Celgene, Takeda, Lilly, Bristol-Myers Squibb, and MSD; and speaker fees from AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, Novartis, Celgene, Takeda, Lilly, Bristol-Myers Squibb, and MSD. Y-LW has declared honoraria from AstraZeneca, Roche, Eli Lilly, Pfizer, MSD, Bristol-Myers Squibb, and Boehringer Ingelheim; advisory or consultancy fees from AstraZeneca and Roche; and research funding from AstraZeneca and Roche. HM, MM, GL, and YR are employees of and have shareholdings in AstraZeneca. AD, YH, and WSMET have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum-pemetrexed according to the plasma T790M status., Methods: Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next-generation sequencing (NGS; Guardant360, Guardant Health)., Results: With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M-positive vs 39 mm for T790M-negative; P < .0001) and the presence of extrathoracic disease (58% for M1b-positive vs 39% for M0-1a-positive; P = .002). Progression-free survival (PFS) was prolonged in randomized patients (tissue T790M-positive) with a T790M-negative cobas plasma result in comparison with those with a T790M-positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum-pemetrexed groups (median, 5.6 vs 4.2 months)., Conclusions: PPA was similar between ddPCR and NGS assays; both were more sensitive than cobas plasma. All 3 test platforms are suitable for routine clinical practice. In patients with tissue T790M-positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden., (© 2019 American Cancer Society.)

Purpose: In the randomized phase IIb LUX-Lung 7 trial, afatinib significantly improved progression-free survival (PFS) and time-to-treatment failure vs gefitinib in patients with treatment-naïve epidermal growth factor receptor mutation-positive non-small cell lung cancer. We report post hoc analyses of tolerability-guided dose adjustment for afatinib and summarize the clinical characteristics of patients who continued afatinib/gefitinib beyond initial radiological progression in LUX-Lung 7., Methods: Patients received afatinib 40 mg/day or gefitinib 250 mg/day until investigator-assessed progression or beyond if beneficial. In case of selected treatment-related adverse events (TRAEs), the afatinib dose could be reduced by 10-mg decrements to minimum 20 mg (only dose interruptions were permitted with gefitinib)., Results: All randomized patients were treated (afatinib, n = 160; gefitinib, n = 159). Sixty-three patients had afatinib dose reduction (< 40 mg/day; 47 within first 6 months). Dose reduction decreased TRAE incidence/severity (before vs after; all grade/grade 3: 100.0%/63.5% vs 90.5%/23.8%). There was no evidence of significant difference in PFS for patients who received < 40 mg/day vs ≥ 40 mg/day for the first 6 months [median: 12.8 vs 11.0 months; hazard ratio 1.34 (95% confidence interval 0.90-2.00)]. Twenty-four and 26 patients continued afatinib and gefitinib, respectively, beyond progression in target lesions; median time from nadir of target lesion diameters to initial progression was 6.7 months and 5.6 months. Of these patients, ~ 70% had objective response or non-complete response/non-progressive disease in non-target lesions at initial progression., Conclusions: Protocol-defined dose adjustment of afatinib may allow patients to remain on treatment longer, maximizing clinical benefit even in the presence of radiological progression.

Objective: The Psychosocial Screen for Cancer (PSSCAN-R) questionnaire is a validated screening tool used to identify the psychosocial needs of patients with cancer. It assesses patients' perceived social supports and psychosocial needs, and the presence of symptoms of depression and anxiety. The study goals were to assess the prevalence and factors associated with distress in patients with newly diagnosed nonsmall cell lung cancer (NSCLC)., Methods: All patients with NSCLC referred to BC Cancer centers from 2011 to 2015, who completed a prospective PSSCAN-R questionnaire at the time of their first visit, were included in the study. Demographics and baseline disease characteristics were collected retrospectively. The chi-squared test, Fisher exact test, and logistical regression analysis were used to compare factors associated with the presence of distress based on sex, age, stage of disease, and performance status (PS)., Results: A total of 4281 NSCLC patients completed the PSSCAN-R questionnaire. Baseline characteristics: 70% were greater than or equal to 65, 50% female, 52% metastatic disease, 47% Eastern Cooperative Oncology Group (ECOG) greater than or equal to two. Patients who were female, less than 65, have metastatic disease and poor PS were more likely to report subclinical or clinical symptoms of anxiety. Symptoms of depression were associated with younger, female, poor PS patients, and social isolation., Conclusions: Newly diagnosed patients with NSCLC are likely to report clinical symptoms of anxiety and depression and have a high number of concerns in multiple psychosocial domains. Resource development for lung cancer patients should be based on their care needs with careful consideration of patients' age, gender, stage, and social situation to optimally support their psychosocial needs during treatment and follow-up., (© 2019 John Wiley & Sons, Ltd.)

The Personalized Onco-Genomics (POG) program at BC Cancer integrates whole-genome (DNA) and RNA sequencing into practice for metastatic malignancies. We examined the subgroup of patients with metastatic non-small-cell lung cancer (NSCLC) and report the prevalence of actionable targets, treatments, and outcomes. We identified patients who were enrolled in the POG program between 2012 and 2016 who had a tumor biopsy and blood samples with comprehensive DNA (80×, 40× normal) and RNA sequencing followed by in-depth bioinformatics to identify potential cancer drivers and actionable targets. In NSCLC cases, we compared the progression-free survival (PFS) of "POG-informed therapies" with the PFS of the last regimen prior to POG (PFS ratio). In 29 NSCLC cases, 11 were male (38%), the median age was 60.2 yr (range: 39.4-72.6), and histologies included were adenocarcinoma (93%) and squamous cell carcinoma (7%). Potential molecular targets (i.e., cancer drivers including TP53 mutations) were identified in 26 (90%), and 21 (72%) had actionable targets. Therapies based on standard-of-care mutation analysis, such as EGFR mutations, were not considered POG-informed therapies. Thirteen received POG-informed therapies, of which three had no therapy before POG; therefore a comparator PFS could not be obtained. Of 10 patients with POG-informed therapy, median PFS ratio was 0.94 (IQR 0.2-3.4). Three (30%) had a PFS ratio ≥1.3, and three (30%) had a PFS ratio ≥0.8 and <1.3. In this small cohort of NSCLC, 30% demonstrated longer PFS with POG-informed therapies. Larger studies will help clarify the role of whole-genome analysis in clinical practice., (© 2019 Tsang et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Little evidence has been generated for how best to manage patients with non-small-cell lung cancer (nsclc) presenting with rarer clinical scenarios, including oligometastases, oligoprogression, and pseudoprogression. In each of those scenarios, oncologists have to consider how best to balance efficacy with quality of life, while maximizing the duration of each line of therapy and ensuring that patients are still eligible for later options, including clinical trial enrolment., Methods: An expert panel was convened to define the clinical questions. Using case-based presentations, consensus practice recommendations for each clinical scenario were generated through focused, evidence-based discussions., Results: Treatment strategies and best-practice or consensus recommendations are presented, with areas of consensus and areas of uncertainty identified., Conclusions: In each situation, treatment has to be tailored to suit the individual patient, but with the intent of extending and maximizing the use of each line of treatment, while keeping treatment options in reserve for later lines of therapy. Patient participation in clinical trials examining these issues should be encouraged., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: SAL has received honoraria from Pfizer, AstraZeneca, Boehringer Ingelheim, and Novartis; SB has served on advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Eli Lilly, Novartis, Pfizer, and Roche, and has received research funding from AstraZeneca and Merck; NB has served on advisory boards for Amgen, AstraZeneca, Merck, Bayer, Boehringer Ingelheim, Bristol–Myers Squibb, Celgene, Eli Lilly, Novartis, Pfizer, Sanofi, and Roche; SB has received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Eisai, and Merck; PKC has served as an advisor for AstraZeneca, Boehringer Ingelheim, Hoffmann–La Roche, Pfizer, Novartis, Takeda, Eli Lilly, and Bristol–Myers Squibb, and has received research funding from Boehringer Ingelheim and Hoffmann–La Roche; PC has received grants for investigator-initiated research projects from AbbVie, Pfizer, and Sanofi–Aventis; DH has served on advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, and Merck, and has received honoraria from Pfizer; VH has participated on advisory boards for AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Merck, Pfizer, and Roche; RJ has served as an advisor or consultant for AstraZeneca/MedImmune, Bristol–Myers Squibb, Merck, Pfizer/emd Serono, and Roche, has received honoraria from AstraZeneca, Bristol–Myers Squibb, Merck, Pfizer/emd Serono, and Roche, and has received research funding from AstraZeneca, Bristol–Myers Squibb, and Merck; JL has received honoraria for talks from AstraZeneca, Boehringer Ingelheim, Pfizer, and Roche, and her institution has received grant funding for research trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Roche; in the last 2 years, NL has received honoraria for independent unrelated continuing medical education from AstraZeneca, Bristol–Myers Squibb, and Merck; DR has received honoraria and support from Accuray, BrainLab, Elekta, Pfizer/emd Serono, Siemens Healthineers, and Varian Medical Systems; JR has received speaker and advisory board fees and institutional research support for clinical trials funded by Astra-Zeneca, Bristol–Myers Squibb, Merck, Pfizer, and Roche; DJS has received honoraria (2015–2018) from Roche Canada, Boehringer Ingelheim Canada, Novartis Canada, Merck Canada, AstraZeneca Canada, Bristol–Myers Squibb Canada, Exactis Innovation, and Pfizer Canada, and has received institutional research support from Boehringer Ingelheim, AstraZeneca, Novartis, Bristol– Myers Squibb, and Celgene; MST has received honoraria from AstraZeneca, Bristol–Myers Squibb, Merck, and Roche/Ventana, and a research grant from Merck. The remaining authors have no conflicts to disclose.

Background: Resected NSCLC guidelines have varying recommendations on appropriate post-operative surveillance. There is general consensus that patients require follow-up with clinic visits and/or CT scans every 6 months for the first 2 years. This study evaluated compliance with surveillance guidelines and the impact on outcomes., Methods: The BC Cancer Agency (BCCA) provides cancer control for 4.6 million individuals. Inclusion criteria included referred patients from 2005 to 2010, resected stage Ib/II NSCLC, minimum 2 years follow-up at the BCCA, no prior cancer within 5 years. Retrospective chart review collected baseline parameters, follow up visits, CT imaging, recurrence and death., Results: 479 were referred and 263 were eligible. Baseline characteristics: median age 68, male 52%, current/former/never smoker 38/52/10%, stage Ib/II 51/49%, squamous/non 30%/70%. Adherence to visits and/or CT scans every 6 months in 2 years: clinic visits 77%, CT scans 35%, visit and/or CT 80%. Recurrence rate was 46% at 2 years. Surveillance below vs per/above guidelines; metastatic recurrence 57% vs 79% (p=0.28), curative intent treatment at recurrence 14% vs 9% (p=0.50), palliative systemic treatment given 14% vs 34% (p=0.42), DFS 66.6m vs 37.6m (p<0.001), OS 76.5m vs 37.7m (p<0.001)., Conclusions: Compliance with follow up recommendations for resected NSCLC was 80%. Guideline conformity did not increase the rate of curative treatment at recurrence nor did it increase the proportion of patients treated with palliative chemotherapy. Better adjuvant treatment and surveillance options are needed for resected NSCLC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data., Patients and Methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases., Results: Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib., Conclusion: In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib., Clinicaltrials.gov Identifier: NCT01466660., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Inhibitors of the programmed cell death 1 (PD-1) signaling axis have recently demonstrated efficacy and are rapidly being incorporated into the treatment of non-small cell lung cancers (NSCLCs). Despite clear benefits to certain patients, the association of these responses with a predictive biomarker remains uncertain. Several different biomarkers have been proposed, with differing results and conclusions. This study compares multiple methods of biomarker testing for treatment of NSCLCs with PD1-axis inhibitors. Tissue microarrays of matched primary and metastatic NSCLCs were used to compare four different PD-1 ligand (PD-L1) IHC techniques, as well as RNA ISH. Additional cases with whole genome and transcriptome data were assessed for molecular correlates of PD-L1 overexpression. Eighty cases were included in the IHC study. Multiple IHC methodologies showed a high rate of agreement (Kappa = 0.67). When calibrated to RNA expression, agreement improved significantly (Kappa = 0.90, p=0.0049). PD-L1 status of primary and metastatic tumors was discordant in 17 (22%) cases. This study suggests that different IHC methodologies for PD-L1 assessment provide slightly different results. There is significant discordance between the PD-L1 status of primary tumors and lymph node metastases. RNA ISH may be a useful adjunct to complement PD-L1 IHC testing., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2016 The Histochemical Society.)

Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting., Methods: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660., Findings: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure., Interpretation: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population., Funding: Boehringer Ingelheim., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: A nurse navigator (NN) pilot project for patients with lung cancer was implemented in British Columbia, a publicly funded health-care system. The purpose was to improve referral practices, timelines, and availability of molecular testing for patients with advanced non-small-cell lung cancer (NSCLC)., Methods: Patients with stage IIIB/IV NSCLC referred to the BC Cancer Agency, Vancouver, in 2011 and 2014, pre- and post-implementation of an NN, were included. Referral patterns, systemic therapy, radiotherapy (XRT) timelines, and molecular testing practices were compared., Results: The study included 408 patients: 212 in 2011 and 196 in 2014. Medical oncology (MO) end points comparing 2011 data with 2014 findings revealed that referral rates remained stable, and the proportion of patients who received systemic therapy increased from 57% to 69% (P = .05). Time from referral to MO consult was 18 days in 2011 versus 15.5 days in 2014 (P = .11); referral to systemic treatment was reduced from 48 to 38 days (P = .016). Comparison of molecular testing showed time between referral and the epidermal growth factor (EGFR) result was reduced from 34 days in 2011 to 20 days in 2014 (P < .001); rates of testing increased from 62% to 91%, respectively (P < .001); and EGFR mutation-positive rates were 19% versus 26%, respectively (P = .26). The radiation oncology (RO) end point results were as follows: 87% of patients were referred for RO consults in 2011 versus 80% in 2014 (P = .05), and the same proportion of patients received XRT (91% v 87%, respectively). Time from referral to RO consult decreased from 10 days in 2011 to 8 days in 2014 (P = .005); and referral to XRT in 2011 and 2014 was 18 days versus 11.5 days, respectively (P < .001)., Conclusion: Implementation of an NN was associated with reduced wait times and increased molecular testing, improving appropriate delivery of first-line targeted therapy. NN involvement facilitates correct allocation of physician and clinical resources., (Copyright © 2016 by American Society of Clinical Oncology.)

Over the past three decades, survival in advanced non-small-cell lung cancer (NSCLC) clinical trials has doubled with an increase in 1-year survival from 25% to 50 to 55%. This has been mainly attributed to improvements in systemic therapy. Although modern first-line chemotherapy regimens have more favorable toxicity profiles, a statistically significant improvement in overall survival has not been demonstrated in existing meta-analyses of second-generation versus third-generation combinations. Moreover, pivotal trials demonstrating statistically significant survival superiority of third-generation regimens are consistently not reproducible even for nonsquamous populations using pemetrexed-platinum combinations. As enhancement in the efficacy of first-line systemic therapy in patients without identifiable driver mutations is questionable, other factors are discussed that explain the doubling of 1-year survival reported in clinical trials. These factors include second-line or third-line therapy, maintenance chemotherapy, performance status selection, stage migration, sex migration, improved treatment of brain metastases, and better palliative care.

Aims: Systemic therapy in advanced non-small cell lung cancer (NSCLC) is the standard of care. The time of treatment administration has not been examined in the metastatic setting. A 'watch and wait' approach for the initiation of chemotherapy is sometimes used in clinical practice, either because of patient preference, presumed indolent disease behaviour, upfront radiotherapy or other interventions. We propose to evaluate the effect of a watch and wait approach on systemic treatment deliverability and patients' outcomes in a population-based study., Materials and Methods: A retrospective analysis of stage IIIB/IV NSCLC patients referred to medical oncology at the British Columbia Cancer Agency in 2009 was conducted. We defined the following: immediate chemotherapy (ICT) - chemotherapy ≤ 8 weeks from medical oncology consult; watch and wait chemotherapy (WWC) - initial observation with chemotherapy > 8 weeks from medical oncology consultation; watch and wait missed (WWM) - watch and wait patients who did not receive chemotherapy; best supportive care (BSC) - patients deemed chemotherapy ineligible. Statistical methods included Kaplan-Meier analysis, Log-rank tests and Cox proportional hazards modelling., Results: In total, 744 patients were seen by medical oncology; 355 (48%) received ICT, 173 (23%) watch and wait and 216 (29%) BSC. Of the 173 patients on a watch and wait approach, 42% missed an opportunity for chemotherapy due to poor performance status (50%), death (49%) and comorbidity (1%). The median overall survival was as follows: watch and wait 11.5 months, ICT 12.8 months and BSC 4.3 months (P < 0.0001). Controlling for confounding factors (age, gender, performance status), overall survival was longer in WWC (hazard ratio 0.73, confidence interval 0.81-1.07, P = 0.023) and lower in WWM (hazard ratio 1.68, 95% confidence interval 1.27-2.22, P < 0.0001), compared with ICT., Conclusions: A significant proportion of watch and wait patients never receive systemic therapy, predominantly due to a decline in performance status. Patients in the ICT group were younger, had a better performance status and had non-squamous histology compared with the watch and wait group. The overall survival was longer in the patients who received ICT versus watch and wait. The watch and wait strategy is associated with a high risk of missing the opportunity for any chemotherapy and should be judiciously implemented only in carefully selected patients., (Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.)

Aims: Platinum-based adjuvant chemotherapy is the standard of care for resected stage II non-small cell lung cancer (NSCLC). The purpose of this population-based study was to identify factors that predict for receiving adjuvant therapy and to assess the effect of delayed administration and dose reduction on survival., Materials and Methods: The British Columbia Cancer Agency provides cancer care to 4.6 million individuals across a large and varied geographical area. A retrospective review was conducted of all referred patients with resected stage II NSCLC between 2005 and 2010. Baseline characteristics, systemic therapy details and outcomes were recorded., Results: Of 258 stage II NSCLC patients, 158 received adjuvant chemotherapy (61%). No-adjuvant versus adjuvant population: men 52%/57%, median age 67/62, Eastern Cooperative Oncology Group (ECOG) ≤ 1 55%/75%, Charlson comorbidity score (CCS) ≤ 1 61%/74%, pneumonectomy 11%/26%. In patients who received chemotherapy, treatment details were: cisplatin/carboplatin based 81%/19%, median cycles delivered 4, median time from surgery to adjuvant chemotherapy 8 weeks, 72% received ≥ 80% (cisplatin < 256 mg/m(2) and carboplatin < AUC 19.2) total planned dose. On multivariate analysis younger age, better ECOG and pneumonectomy were predictive of adjuvant treatment. Overall survival of adjuvant-treated patients was inferior for those with CCS ≥ 2, age ≥ 70 and reduced dose intensity on multivariate analysis. The surgery to chemotherapy interval did not affect overall survival., Conclusions: Pneumonectomy and factors associated with better functional status predicted for receiving adjuvant chemotherapy. For patients who received adjuvant chemotherapy the total platinum dose given affected survival but time from surgery did not. A higher platinum dose delivery was important in maintaining the efficacy of adjuvant chemotherapy for resected stage II NSCLC in this retrospective population-based study., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Maintenance chemotherapy has been incorporated into treatment paradigms for advanced NSCLC. Eligibility criteria include stable disease/partial response and PS 0-1 after a first line platinum doublet. In practice, maintenance can be difficult to deliver due to patient factors and preferences. We propose to examine the proportion of patients eligible for maintenance and factors associated with the delivery of subsequent lines of chemotherapy., Methods: The BC Cancer Agency provides care to a population of 4.5 million. A retrospective review was conducted of all referred Stage IIIB/IV patients in 2009 who received first line systemic therapy. Baseline characteristics, PS and response after first line and subsequent systemic therapy details were recorded. Patients were deemed potentially maintenance eligible or not based on clinical trial criteria; however maintenance therapy was not delivered to these patients as it was not yet available., Results: 330 patients were identified; 98 were potentially maintenance eligible. The reason for maintenance ineligibility in n = 232; no upfront doublet (n = 41), PS ≥ 2 (n = 38), progressive disease (PD) (n = 53), PS ≥ 2 and PD (n = 62), PS ≥ 2 and unknown response (n = 35), PD and unknown PS (n = 3). Further chemotherapy (2nd line or beyond) was administered in maintenance eligible 68% vs ineligible 56%. Reasons for no further chemotherapy were predominantly decline in PS and brain metastasis. Median OS: 7 m for 1st line only versus 16.8m for ≥ 2 nd line (p < 0.001)., Conclusions: In our population based study, 30% of advanced NSCLC patients were eligible to receive maintenance chemotherapy based on the clinical trial criteria. Despite a good initial PS and disease control only 68% of maintenance eligible patients received subsequent therapy. A clear survival benefit was seen with ≥ 2 nd line treatment. Maintenance therapy or initiation of early second line therapy should be considered for advanced NSCLC patients to improve survival outcomes., (Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.)

Introduction: Chemotherapy improves overall survival (OS) in advanced non-small cell lung cancer (NSCLC), yet low rates of chemotherapy utilization have been observed. We sought to characterize the clinical effectiveness of chemotherapy in the general population by evaluating referral patterns, predictors of chemotherapy receipt and outcomes., Methods: All referred cases of stage IIIB/IV NSCLC in British Columbia from January 1 to December 31, 2009 were retrospectively reviewed. Patient demographics, tumor characteristics and treatments were extracted. OS was estimated using the Kaplan-Meier method. Cox Proportional Hazards modeling was used to control for confounding variables. Multiple logistic regression was used to assess factors that predicted for chemotherapy treatment., Results: 1373 patients were identified. Median age 70 years, 53% male, 37% ECOG ≥ 3., Histology: 34% non-squamous, 21% squamous and 46% NOS. 748 (54%) patients were assessed by medical oncology and 417 (30%) received chemotherapy. Predictors of chemotherapy treatment were younger age, ECOG 0-2, living in a rural area and not receiving radiotherapy. There was an improvement in OS in patients who received chemotherapy at 13.1 months versus best supportive care 5.4 months (p<0.0001). This remained statistically significant when controlling for ECOG, sex, age, histology (HR 0.68, CI 0.59-0.78)., Conclusions: In this population-based setting, 37% of patients had an ECOG ≥ 3 at the time of referral, 54% were assessed by a medical oncologist and only 30% received chemotherapy. This is despite the awareness that chemotherapy significantly improves survival. Strategies to optimize appropriate referral such that patients do not miss out on life-prolonging therapy should be evaluated., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Over the past decade, well tolerated second-line therapies for advanced non-small-cell lung cancer have been approved including erlotinib and pemetrexed in addition to docetaxel. We hypothesize that the introduction of less toxic chemotherapy has increased treatment of advanced non-small-cell lung cancer resulting in improved survival., Methods: The BC Cancer Agency provides cancer care to 4.5 million. A retrospective review was conducted of all referred Stage IIIB/IV patients in four 1-year time cohorts; C1 baseline (1998) and 6 months after the provincial approval of C2 docetaxel (2001), C3 erlotinib (2006), and C4 pemetrexed (2007)., Results: Two-thousand six-hundred and twenty-three patients were referred and 720 had systemic therapy. Characteristics: M/F 55%/45%, median age 67 (33-101), ECOG PS <=1/>=2/unknown 33%/56%/11%, squam/nonsquam/NOS 18%/41%/41%. More patients received first-line chemotherapy over time; 16%, 23%, 34%, and 33% C1-C4 respectively. In C1-C4 uptake of second line (21%, 27%, 37% and 55%) increased. Second-line docetaxel was frequently used in C2 (51%) but usage decreased in C4 to 7% versus erlotinib 50% and pemetrexed 26%. The median overall survival in the best supportive care group remained stable over time; however, increased use of systemic therapy was associated with improved survival C1 9.4 m versus C4 11.8 m (p = 0.023)., Conclusions: This population-based data set represents the trend of treatments over time at community and tertiary care cancer treatment sites. Over a 10-year period an increased proportion of patients were treated with first-line chemotherapy and an even greater number with second-/third-line treatment with an associated improvement in overall survival.

Introduction: Fluorescence in situ hybridization (FISH) is the standard procedure for the detection of anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement in non-small-cell lung carcinoma (NSCLC) but is expensive and time consuming. We tested three antibodies to ALK, using various detection systems, and hypothesized that ALK immunohistochemistry (IHC) may represent a cost-effective and efficient means of screening for ALK rearrangement in NSCLC., Methods: We screened 377 stage I or II NSCLC cases in a tissue microarray by FISH and IHC (5A4 [Leica Biosystems Newcastle Ltd, Newcastle upon Tyne, UYnited Kingdom] by Nichirei's N-Histofine ALK detection kit [Nichirei Biosciences inc., Tokyo, Japan], 5A4 by Novocastra with ADVANCE [Dako Canada inc., Burlington, Ontario, Canada], D5F3 by Cell Signaling Technology with ADVANCE [Cell Signalling Technologies inc., Danvers, MA], and DAKO clone ALK1 with FLEX [Dako Canada inc., Burlington, Ontario, Canada] and ADVANCE). IHC was scored as 0, 1+, 2+, or 3+. Possibly positive or positive cases were further analyzed by IHC and FISH on whole section., Results: Tissue microarray results were available on 377 cases by IHC and 273 cases by FISH. Eleven cases were positive or possibly positive by either IHC or FISH, and three cases were positive or possibly positive by both methods. Three cases were ALK-positive by FISH on whole section validation. There was no correlation between semiquantitative IHC score (1+, 2+, 3+) and ALK rearrangement by FISH. D5F3 (Cell Signaling by ADVANCE) and 5A4 (Novocastra by ADVANCE) showed the greatest combination of sensitivity (100%) and specificity (87.5% for 5A4 by Novocastra and 75% for D5F3 by Cell Signaling), and produced no false-negative results., Conclusions: IHC is a reliable screening tool for identification of ALK rearrangement in NSCLC and is antibody dependent. D5F3 (Cell Signaling) and 5A4 (Novocastra) can be used with FISH for identification of IHC-positive cases to reduce screening costs.

Introduction: The objectives of this study were to determine the frequency and prognostic significance of beta-catenin expression in a cohort of non-small cell lung cancer (NSCLC) patients., Methods: Tissue microarrays were constructed using clinically annotated formalin-fixed paraffin-embedded tumor samples from individuals diagnosed with NSCLC who underwent surgical resection with curative intent and had beta-catenin expression status determined by immunohistochemistry., Results: Negative beta-catenin expression was seen in 28% (103/370) of NSCLC cases and was prognostic of a reduced overall patient survival (P = .008) and also was significantly correlated with the presence of lymphatic invasion (P = .015). In multivariate analysis, the loss of beta-catenin expression retained independent prognostic significance and showed an adjusted hazard ratio of 3.18 (confidence interval, 1.46-6.91, P = .004) for reduced patient survival when adjusting for the presence of lymphatic invasion, tumor grade, nodal status, and tumor stage., Conclusions: Beta-catenin represents an important prognostic marker in individuals diagnosed with surgically resectable NSCLC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This open-label, phase II study evaluated the antitumor activity and safety of sunitinib monotherapy as maintenance treatment following first-line chemotherapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Following treatment with standard doublet chemotherapy (paclitaxel and carboplatin), patients received oral sunitinib (starting dose 50mg/day) in 6-week cycles (Schedule 4/2: 4 weeks on treatment, 2 weeks off treatment) until disease progression, unacceptable toxicity or withdrawal of consent. The primary endpoint was probability of survival at 1 year ≥55%. Of 84 patients who received first-line chemotherapy, 66 (79%) received sunitinib maintenance therapy (median sunitinib cycles started: 2 [range 1-20]). Probability of survival at 1 year was 40.5% (95% confidence interval [CI]: 29.8, 51.0). Median overall survival was 10.4 months (95% CI: 8.0, 12.2). The objective response rate was 27.4% (95% CI: 18.2, 38.2). The most frequently reported all-causality adverse events of any grade during sunitinib maintenance therapy were fatigue/asthenia (55%), diarrhea (36%), and nausea (32%). These data suggest that maintenance therapy may have value in NSCLC, although the primary endpoint of the study was not met., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Background: Results of two phase 3 trials have shown first-line bevacizumab in combination with chemotherapy improves clinical outcomes in patients with advanced or recurrent non-squamous non-small-cell lung cancer (NSCLC). The SAiL (MO19390) study was undertaken to assess the safety and efficacy of first-line bevacizumab combined with standard chemotherapy regimens in clinical practice., Methods: Between August, 2006, and June, 2008, patients with untreated locally advanced, metastatic, or recurrent non-squamous NSCLC were recruited to this open-label, single group, phase 4 study from centres in 40 countries. Eligible patients had histologically or cytologically documented inoperable, locally advanced, metastatic, or recurrent disease (stage IIIB-IV); an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, hepatic, and renal function. Patients received bevacizumab (7.5 or 15 mg/kg every 3 weeks) plus standard chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety; analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00451906., Findings: At the final data cutoff (July 24, 2009), an ITT population of 2212 patients was assessed. The incidence of clinically significant (grade > or = 3) adverse events of special interest was generally low; thromboembolism occurred in 172 (8%) patients, hypertension in 125 (6%), bleeding in 80 (4%), proteinuria in 67 (3%), and pulmonary haemorrhage in 15 (1%). 57 (3%) patients died because of these adverse events, with thromboembolism (26 patients, 1%) and bleeding (17, 1%) as the most common causes. The most common grade 3 or higher serious adverse events deemed by investigators to be associated with bevacizumab were pulmonary embolism (28 patients; 1%) and epistaxis, neutropenia, febrile neutropenia, and deep vein thrombosis (all of which occurred in 13 patients [1%]). Bevacizumab was temporarily interrupted after 28 (2%) of 1347 bleeding events and 72 (7%) of 1025 hypertension events, and permanently discontinued after 110 (8%) bleeding events and 40 (4%) hypertension events. No new safety signals were reported., Interpretation: Our results confirm the manageable safety profile of first-line bevacizumab in combination with various standard chemotherapy regimens for treatment of advanced non-squamous NSCLC., Funding: F Hoffmann-La Roche Ltd., (2010 Elsevier Ltd. All rights reserved.)

Purpose: Current chemotherapeutic regimens have only modest benefit for non-small cell lung cancer (NSCLC) patients. Cumulative toxicities/drug resistance limit chemotherapy given after the first-line regimen. For personalized chemotherapy, clinically relevant NSCLC models are needed for quickly predicting the most effective regimens for therapy with curative intent. In this study, first generation subrenal capsule xenografts of primary NSCLCs were examined for (a) determining responses to conventional chemotherapeutic regimens and (b) selecting regimens most effective for individual patients., Experimental Design: Pieces (1x3x3 mm(3)) of 32 nontreated, completely resected patients' NSCLCs were grafted under renal capsules of nonobese diabetic/severe combined immunodeficient mice and treated with (A) cisplatin+vinorelbine, (B) cisplatin+docetaxel, (C) cisplatin+gemcitabine, and positive responses (treated tumor area

Lung cancer is the leading cause of cancer death in men and women. In 2008, in the US > 200,000 patients were diagnosed with lung cancer and > 160,000 died from their disease. Over 80% of lung cancers are of the non-small cell type, for which chemotherapy has demonstrated modest survival benefits at all stages of disease. Agents that alter critical molecular cell growth pathways are a growing area of research and development including targeted therapies directed at the EGFR. Downstream effects of EGFR dimerization and activation include cell proliferation, differentiation and angiogenesis, key events in the malignant process. Two main classes of drugs have been developed, small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies directed against the extracellular domain of the receptor. This review discusses clinical studies with several new therapies and the plans for drug development.

Objective: We used a large patient population to identify immunohistochemical biomarkers to enable improved prognostication in patients with non-small cell lung carcinoma (NSCLC)., Methods: A tissue microarray was constructed using duplicate 0.6 mm cores of formalin-fixed paraffin-embedded tissue blocks from 609 patients with NSCLC. Immunohistochemical was used to detect 11 biomarkers including epidermal growth factor receptor, Her2, Her3, p53, p63, bcl-1, bcl-2, Thyroid transcription factor, carcinoembryonic antigen, chromogranin, and synaptophysin. A clinical database was generated prospectively at the time of tissue collection. Survival outcomes were obtained from a Provincial Cancer Registry database. Univariate and multivariate analyses were performed to look for a relationship between biomarker expression, smoking history, and survival., Results: Survival data for 535 cases were available. As of June 2005, 429 patients (80%) had died; of these 286 (54%) died of lung cancer, 117 (22%) died of other known causes, and for 26 (5%) the cause of death was not available. Univariate analysis revealed that bcl-2 (p = 0.007) was the only biomarker prognostic for improved overall survival (OS). bcl-2 (p = 0.021) and p63 (p = 0.025) were both found to be prognostic for improved disease-specific survival (DSS). Multivariate analysis (using age and biomarker expression) revealed that bcl-2 expression is prognostic for improved OS (p = 0.005) and DSS (p = 0.021)., Conclusions: Our results suggest that bcl-2 expression is prognostic for improved OS and DSS in NSCLC. Testing for bcl-2 expression in a prospective study will help to determine its clinical relevance in prognostication.

The existence of non-small cell lung carcinoma with neuroendocrine differentiation as a distinct entity and its relevance for prognostic and treatment purposes is controversial. This study assesses the frequency and biologic and prognostic significance of neuroendocrine (NE) expression of synaptophysin (SNP), chromogranin (Ch), and neural cell adhesion molecule (N-CAM) using tissue microarray (TMA) and immunohistochemistry. Six hundred nine nonsmall cell lung carcinomas (NSCLCs) were reviewed for subclassification. TMA blocks were made using duplicate 0.6-mm-diameter tissue cores and slides stained with SNP, Ch, and N-CAM. Immunoreactivity was considered if 1% or more of tumor cells were positive. Hematoxylin and eosin-stained sections were subclassified as: 243 adenocarcinoma (ACA), 272 squamous cell carcinoma (SCC), 35 large cell carcinoma, 32 non-small cell carcinoma NOS, and 6 other (carcinosarcoma, giant cell carcinoma). Positivity for either marker was identified in 13.6% of NSCLC (76/558). NSCLC showed reactivity for Ch in 0.4% of cases (2/524), for SNP in 7.5% of cases (39/521) and for N-CAM in 8.6% of cases (44/511), whereas only 0.2% of cases (1/517) showed coexpression of SNP and Ch and none of all 3 markers. The assessment of NE differentiation in NSCLC is unnecessary and expensive and is of no clinical or prognostic significance. SNP or N-CAM stains a small minority of NSCLC, whereas Ch immunoreactivity is less common. Positivity for any 2 NE markers is rare. SNP is more likely to be expressed in adenocarcinoma (P=0.01) and N-CAM in squamous-cell carcinoma (P=0.008). Otherwise there was no correlation between immunoreactivity and tumor morphology. Disease specific and overall survival is not influenced by NE differentiation and therefore non-small cell lung carcinoma with neuroendocrine differentiation should not be a subclass distinct from the other NSCLC.

Institutional series suggest specific subgroups of patients with non-small cell lung cancer (NSCLC); female, Asian, non-smokers, respond preferentially to gefitinib. Vancouver, BC, has a large Asian population and therefore is an ideal location to study this differential effect in a Western setting. We performed a retrospective analysis of patients treated with single agent gefitinib to determine if our experience reflects this observation. The pathology, radiology, laboratory investigations and clinical records of 61 patients treated with gefitinib at the BCCA between April 2002 and May 2004 were reviewed. Partial radiologic response was defined as per SWOG response criteria. Symptom responses were subjectively evaluated from chart review. Baseline characteristics at diagnosis; 62% Caucasian, 38% Asian, male 47%, smokers 67%, non-smokers 33%, ECOG 0/1 59%; tumor histology: 57% adenocarcinoma, 13% bronchoalveolar variant, 7% squamous, 23% other. Median treatment duration was 2 months. On radiologic review, 14 patients had a partial response, 25 had stable disease, 21 progressed, and 1 unknown. Twenty patients reported improved symptoms after>/=1 month, 23 had no change, 17 had symptom progression and 1 unknown. Toxicity was minimal; one patient had grade 3 hepatotoxicity that resolved with treatment cessation. Of the 14 radiological responders, 10 were Asian, 10 ECOG 0/1, 10 female, 8 non-smokers, 8 adenocarcinoma and 4 bronchoalveolar variant. At the BCCA, in a select number of patients with advanced NSCLC, gefitinib demonstrated radiologic evidence of anti-tumor activity and provided clinical benefit with minimal side effects. Most of the responders were patients of Asian ethnicity who had immigrated to Canada from China, Taiwan or Hong Kong. Our results suggest that the preferential response to gefitinib seen in the Asian population is preserved in a Western setting. The molecular basis of the improved response rate observed in the subset of female, Asian, non-smokers with adenocarcinoma or bronchoalveolar variant is currently being explored by gene sequencing studies at the British Columbia Cancer Agency Genome Science Centre.