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M. Boyer

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    ED 13 - The EGF Receptor and Targeting T790M (ID 13)

    • Event: WCLC 2015
    • Type: Education Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 4
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      ED13.01 - Biological Background and Controversies (ID 1824)

      14:20 - 14:40  |  Author(s): B.J. Solomon

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The ability to identify and therapeutically target specific mutations (typically exon 19 deletions and L858R) in the Epidermal Growth Factor Receptor (EGFR) gene marked the beginning of personalized medicine for NSCLC. Phase III clinical trials with the EGFR tyrosine kinase inhibitors gefitinib, erlotinib and afatinib demonstrated superiority of these agents over chemotherapy establishing these agents as standard therapy for EGFR mutation positive NSCLC. However, resistance to therapy invariably occurs through multiple, heterogeneous mechanisms of which a secondary gatekeeper mutation in EGFR, T790M, is the most frequent, being identified in 50-60% of patients at the time ofprogression after initial EGFR TKI. EGFR T790M is thought to result in resistance by increasing the affinity for ATP rather than simple stearic hinderance. Recently novel irreversible inhibitors, structurally distinct to earlier generation compounds, have been developed that inhibit T790M while having relatively less potency against wildtype EGFR including rocelitnib (C01686) and AZD9291. Phase I/II studies have demonstrated responses to rocilitinib (CO1686) and AZD9291 in about 60% of patients with T790M positive disease. Preliminary data indicates the degree of response may correlate with the allelic frequency of T790, with greater degrees of responses in patients with higher proportions of T790M. Resistance to these compounds has been described clinically and includes loss of T790M, small cell transformation as well asdevelopment of tertiary mutations C7957 (resistance to AZD9291).

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      ED13.02 - Detecting T790M in Blood and Tumor (ID 1825)

      14:40 - 15:00  |  Author(s): D.L. Aisner

      • Abstract
      • Presentation

      Abstract:
      Recent advances in targeted therapies and the molecular analysis of tumor samples have led to recommendations that EGFR mutation testing be implemented as standard of care in non-small cell lung cancer (NSCLC) of non-squamous type. This is in large part because of substantial benefits provided to patients treated with EGFR tyrosine kinase inhibitor (TKI) therapy, particularly those patients whose tumors are positive for activating, sensitizing mutations in EGFR. Despite these benefits, resistance to EGFR TKIs inevitably develops in all cases. The most common molecular mechanism of acquired resistance in this setting, occurring in approximately 50% of cases, is the evolution of a secondary ‘gatekeeper’ mutation which results in p.T790M (T790M). This acquired mutation results in a reduction in affinity of EGFR for the TKIs, while preserving catalytic function of the tyrosine kinase domain, The testing for T790M at the time of progression on TKI has emerged as an important clinical practice, as new-in-class EGFR TKIs demonstrate activity against this subset of resistant tumors. Because T790M initially emerges as a sub-clonal event, technical elements involved in its detection become paramount. Most importantly, achieving a high technical sensitivity to allow for detection of a sub-clonal (low alleleic frequency) phenomenon is critical for assays designed to detect this mutation. Sanger sequencing, for example, lacks the technical sensitivity to adequately identify low variant frequency events, and therefore alternate mechanisms of testing are required. Additional factors requiring major consideration in detection of T790M include potential sampling bias (particularly for the small biopsies or fine needle aspirates that are typically acquired), heterogeneity between multiple progressing lesions, cellular components of post-treatment biopsies, and technical ability to perform tumor enrichment to enhance detection. Genomic alterations resulting in T790M are uncommonly detected prior to TKI therapy, likely owing to the technical sensitivity of assays used to query for the presence of this alteration. Studies employing extraordinarily sensitive assays have demonstrated the presence of T790M as a subclonal event prior to TKI therapy in many tumors. Thus clonal selection under the pressure of TKI is a major mechanism allowing this alteration to be identified in the setting of progression on targeted therapy using less analytically sensitive assays. The secondary implication of this finding is that assays employed for detection of T790M must be adequately sensitive, but not over-sensitive to allow for the appropriate identification of what can best be considered the dominant mechanism of resistance. Others have postulated that highly sensitive detection of T790M prior to therapy could be used to determine a combination therapy approach which effectively prevents the evolutionary advantages of this sub-clone. In the uncommon instance that this alteration is identified at a high level pre-TKI therapy using standard assay approaches (<5% of cases), it can be associated with a germline alteration leading to a genetic predisposition for lung cancer. Recently, there has been great interest in the potential to monitor for the emergence of T790M alterations in the periphery, either via circulating tumor cells or circulating cell-free DNA. This approach is particularly attractive as it reduces requirements for invasive tissue sampling and can allow for a continuous monitoring approach. While the technical elements of liquid biopsy testing have been diversely applied, with very little in the way of consensus on methodology, numerous studies have demonstrated the promise of liquid biopsy approaches for both primary mutation detection as well as evaluation for T790M. In some cases, peripheral detection of T790M was demonstrated substantially before radiographic evidence of progression, a key proof-of-principle that such monitoring could be utilized as an effective approach for disease monitoring. Similar approaches for chimerism analysis or BCR-ABL1 transcript monitoring in the setting of bone marrow transplant or TKI therapy for chronic myelogenous leukemia, respectively, have been very successful. Major challenges still exist for both tissue-based and peripheral blood-based detection of T790M. Determination of the ideal level of assay technical sensitivity required for prediction of response to T790M-directed therapies will be a critical component to the implementation of these drugs in the clinic. In addition, for tissue biopsies, techniques to enhance the tumor cellularity of tested material and to avoid sample bias will need to be further refined. Liquid biopsy techniques, though demonstrating extraordinary promise, are widely divergent in terms of methodologies employed, and further study in this technological space is needed. 1. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clinical cancer research : an official journal of the American Association for Cancer Research 2011;17:1169-1180. 2. Inukai M, Toyooka S, Ito S, et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 2006;66:7854-7858. 3. Kim Y, Ko J, Cui Z, et al. The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol Cancer Ther 2012;11:784-791. 4. Majem M, Remon J. Tumor heterogeneity: evolution through space and time in EGFR mutant non small cell lung cancer patients. Transl Lung Cancer Res 2013;2:226-237. 5. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nature medicine 2014;20:548-554. 6. Oxnard GR, Paweletz CP, Kuang Y, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clinical cancer research : an official journal of the American Association for Cancer Research 2014;20:1698-1705. 7. Paweletz CP, Janne PA. Monitoring cancer through the blood. Cancer 2014;120:3859-3861. 8. Sorensen BS, Wu L, Wei W, et al. Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib. Cancer 2014;120:3896-3901. 9. Tartarone A, Lerose R. Clinical approaches to treat patients with non-small cell lung cancer and epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance. Ther Adv Respir Dis 2015. 10. Watanabe M, Kawaguchi T, Isa SI, et al. Ultra-Sensitive Detection of the Pretreatment EGFR T790M Mutation in Non-Small Cell Lung Cancer Patients with an EGFR-Activating Mutation Using Droplet Digital PCR. Clinical cancer research : an official journal of the American Association for Cancer Research 2015.

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      ED13.03 - How to Make the Best Use of 'Old' Drugs (ID 1826)

      15:00 - 15:20  |  Author(s): G.R. Oxnard

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Acquired resistance to initial EGFR TKI invariably develops in patients with EGFR-mutant lung cancer after a median of 9-14 months. Though acquired EGFR resistance in NSCLC is a clinical condition that is treated and studied worldwide, there has until recently been a paucity of prospective data describing the best practices for managing these patients. In 2014, the first phase III trial studying EGFR-mutant lung cancer with acquired resistance was reported. Presented at ESMO 2014, the IMPRESS trial established platinum doublet chemotherapy as the standard second-line therapy for these patients, with no benefit to additionally continuing EGFR TKI at progression. And yet, even with standard second-line therapy established, there remain questions regarding how to manage patients with progressive disease (PD) on EGFR TKI, questions that will likely grow even more complex should newer agents reach the market. One way of framing this question is to consider the tools we have for managing acquired EGFR resistance, and then to consider how to best utilize them. The following outline provides a brief summary of therapeutic strategies that will be discussed further at WCLC 2015. · Continued TKI after PD - Feasible for a median of 3 months, especially in those with slow or asymptomatic PD (Lo et al, Cancer, 2015; Park et al, ESMO, 2014) · Retreatment with TKI after PD on chemo - 25% RR on a prospective phase II study of 20 patients, but responses were brief with a 3.4 month median PFS (Oh et al, Lung Cancer, 2012) · Afatinib – Limited activity in LUX-Lung 1 trial with 7% RR and 3 month median PFS (Miller et al, Lancet Oncol, 2010) · Afatinib / cetuximab – 29% RR and 4.7 month median PFS, with responses seen regardless of T790M status (Janjigian et al, Cancer Disc, 2014) · Cytotoxic chemotherapy – Cisplatin /pemetrexed has a 34% RR and 5.4 month median PFS after PD on gefitinib (Mok et al, ESMO, 2014) · Erlotinib & bevacizumab – May delay development of PD, but no prospective data for treatment of resistance (Seto et al, Lancet Oncol, 2014) · Erlotinib & crizotinib – Hypothetical option for MET-mediated resistance but requires dose reduction of both (Ou et al, ASCO, 2012) · Nivolumab – 82 patients with prior TKI and chemo treated on CheckMate 057, and there was no OS benefit seen compared to docetaxel (HR 1.18) (Paz-Arez, ASCO, 2015) · Erlotinib & nivolumab – 3 of 20 patients responded (15%) in the phase I study (Rizvi et al, ASCO, 2014) · Brain radiation – For CNS-only progression, radiation followed by restarting TKI can gain additional months of PFS (Weickhardt et al, JTO, 2012) · SBRT or surgical resection – An approach that is hypothesized to debulk a single resistant clone, thus delaying clinical resistance and prolonging the progression-free period (Weickhardt et al, JTO, 2012; Yu et al, JTO, 2013)

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      ED13.04 - 3rd Generation EGFR TKI (ID 1827)

      15:20 - 15:40  |  Author(s): K. Park

      • Abstract
      • Presentation

      Abstract:
      The introduction of EGFR TKIs has dramatically changed the natural history of advanced and/or metastatic NSCLC. The objective response rates of 50 to 70% are achieved and overall survival has improved from 4-5 months to over 30 months in EGFRm(+) NSCLC patients. However, unfortunately the patients are not cured of the disease and after a median PFS of 9 to 13 months, the disease comes back eventually with the emergence of acquired resistance(AR) to EGFR TKIs. Mechanisms of AR include target gene modification, activation of bypass tracks or histologic transformation, etc. In approximately 60% of patients, the mechanism of resistance is due to the acquisition of a gatekeeper T790M EGFR mutation. This T790M mutation leads to an enhanced affinity for ATP, thus reducing the ability of ATP-competitive reversible EGFR tyrosine kinase inhibitors, including gefitinib and erlotinib, to bind to the tyrosine kinase domain of EGFR. One strategy to overcome this mechanism of resistance mediated by target gene modification is through the use of more potent, novel, next-generation inhibitors. The ‘2[nd]-generation’ irreversible EGFR inhibitors such as afatinib and dacomitinib, covalent inhibitors of HER family kinases, showed preclinical activity against T790M in vitro. Both agents demonstrated excellent clinical activities in EGFR TKI-naïve patients with EGFR-mutant NSCLC in terms of response rate and progression-free survival as compared to cytotoxic chemotherapy. However, the results of treatment in patients with EGFR-mutant lung cancer who progress on an EGFR TKI are quite disappointing. Studies of afatinib monotherapy among patients with acquired resistance to erlotinib or gefitinib showed a response rate of only 7-8% and a progression-free survival of 3 to 4 months. This result may be due to the fact that physiologic doses of current generation irreversible EGFR TKIs do not fully inhibit EGFR T790M and dose escalation of 2[nd]-generation EGFR inhibitors is limited by on-target inhibition of wild-type EGFR, which leads to EGFR-mediated toxicity (skin rash and diarrhea). The so-called ‘3[rd]-generation’ EGFR TKIs are pyrimidine-based irreversible inhibitors and has mutant-specific activity including T790M mutation while sparing wild-type EGFR. There are several 3[rd]-generation EGFR TKIs under development, e.g., AZD 9291, CO-1686(Rociletinib), HM61713, ASP8273, EGF816, to name a few. The early clinical trials of the 3[rd]-generation EGFR TKIs have demonstrated a promising efficacy in patients with advanced EGFR-mutated NSCLC who have progressed on prior EGFR TKI therapy, including cohorts of patients with EGFR T790M-mutated NSCLC. For CO-1686, the reported overall response rate in the phase 1 study was 59%(27/46) in patients with centrally confirmed EGFR T790M-containing tumors. Median progression-free survival was 13.1 months. Likewise, initial results from the phase I trial of AZD9291 demonstrated a response rate of 61%(78/127) in patients with EGFR T790M positive tumors with median PFS of 9.6 months. Both AZD9291 and CO-1686 have recently been granted Breakthrough Therapy designation by the US FDA based upon results from early clinical studies. Early phase I/II results of HM61713 also showed encouraging anti-tumor activity with objective response rate of 55%(34/62) in T790M positive Korean NSCLC patients and global phase II trial is planned to launch. The early results of EGF816 and ASP8273, another irreversible 3[rd]-generation EGFR TKIs under clinical development, were recently reported and both agents demonstrated encouraging response rates of 50-60% in T790M(+) NSCLC patients after progression on a 1[st] or 2[nd] generation EGFR TKIs. Further studies are ongoing and mature results are awaited. In brief, many of the 3[rd] generation EGFR TKIs currently at various stages of development look so promising with encouraging clinical activities for T790M(+) NSCLC patients esp. in terms of response rate. In general these newer generation EGFR TKIs also have much better toxicity profiles as they spare the wild-type EGFR, e.g., less skin rash, diarrhea or paronychia compared with the 1[st]- or 2[nd]-generation EGFR TKIs though the toxicity profiles are slightly differerent one from another at some aspects. Since the follow-up is rather short we need longer follow up to confirm survival benefits. We certainly have made a significant progress in the management of advanced NSCLC with AR to EGFR TKIs, however, there are still several issues to be investigated to further improve the treatment outcomes, e.g., optimal timing and/or sequence of the 3[rd] generation EGFR TKIs, how to delay or prevent the emergence of resistance to 3[rd] generation agents, CNS progression, management of non-T790M-dependent AR to EGFR TKIs, etc. References Cong CR and Jänne PA. The quest to overcome esistance to EGFR-targeted therapies in cancer. Nat Med. 2013;19(11):1389-1400 Lovly CM and Shaw AT. Molecular Pathways: Resistance to Kinase Inhibitors and Implications for Therapeutic Strategies. Clin Cancer Res. 2014;20(9):2249–56. Jänne PA et al. AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer, N Engl J Med. 2015 Apr 30;372(18):1689-99. Sequist LV et al. Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer, N Engl J Med. 2015 Apr 30;372(18):1700-9. Park K et al. Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI). PASCO 2015 #8084 Tan D S-W et al. First-in-human phase I study of EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor, in advanced non-small cell lung cancer (NSCLC) harboring T790M. PASCO 2015 #8013 Goto Y et al. ASP8273, a mutant-selective irreversible EGFR inhibitor in patients (pts) with NSCLC harboring EGFR activating mutations: Preliminary results of first-in-human phase I study in Japan. PASCO 2015 #8014T

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Author of

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    MINI 05 - EGFR Mutant Lung Cancer 1 (ID 103)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI05.08 - Comparison of the Efficacy of Dacomitinib v Erlotinib for NSCLC Pts with Del 19/L858R (ID 775)

      17:25 - 17:30  |  Author(s): M. Boyer

      • Abstract
      • Presentation
      • Slides

      Background:
      To date there have been limited randomized comparisons of EGFR tyrosine kinase inhibitors (TKI) in EGFR mutant NSCLC. Dacomitinib is a potent, irreversible EGFR inhibitor that demonstrated robust activity in a phase 2 study for patients with common activating EGFR mutations. Additionally, preclinical data suggests greater activity in patients with common EGFR activating mutations in exon 19 or 21. ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) each compared the clinical activity of dacomitinib (D) versus erlotinib (E) in advanced NSCLC including patients with common activating EGFR mutations; pooled results are presented.

      Methods:
      Patients (pts) with locally advanced/metastatic NSCLC were randomized following progression with 1 or 2 prior chemotherapy regimens to treatment with dacomitinib (D) (45 mg PO QD) or erlotinib (E) (150 mg PO QD). The Phase 2 study (A7471028) was open label while the Phase 3 ARCHER 1009 study was double-blind and double dummy. Archived tumor tissue, ECOG performance status (PS) of 0-2, adequate organ function and informed consent were required. Results of the two studies were previously reported individually. Analyses were performed by pooling patients with common EGFR activating mutations from both studies to compare efficacy of D versus E.

      Results:
      121 patients with any EGFR mutation were enrolled into the two studies with 1 patient randomized but not treated; 101 (53 on D) pts had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median PFS was 14.6 months (95%CI 9.0–18.2) for D and 9.6 months (95%CI 7.4–12.7) for E and unstratified HR 0.717 (95%CI 0.458–1.124) with 1-sided p=0.073. The median OS was 26.6 months (95%CI 21.6–41.5) for D and 23.2 months (95%CI 16.0–31.8) for E and unstratified HR 0.737 (95%CI 0.431–1.259) with 1-sided p=0.132. The corresponding pooled analyses were conducted separately in exon 19 and exon 21. The adverse-event profile did not differ between the activating mutation subset and the overall population. Figure 1



      Conclusion:
      Dacomitinib may be associated with an improved PFS and OS compared to Erlotinib in patients with exon 19/21 EGFR mutations. A prospective P3 study comparing D to another EGFR TKI in 1L EGFR mutated NSCLC is ongoing to verify these observations (NCT01774721).

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    MINI 28 - Psychological Impact of Lung Cancer and its Treatment (ID 150)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Palliative and Supportive Care
    • Presentations: 1
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      MINI28.01 - The Impact of Physical Activity on Fatigue and Quality of Life in Lung Cancer Patients: A Randomized Controlled Trial (RCT) (ID 3173)

      16:45 - 16:50  |  Author(s): M. Boyer

      • Abstract
      • Presentation
      • Slides

      Background:
      Physical activity (PA) has been shown to improve fatigue and quality of life (QOL) in a range of cancer populations. Little research has been done in the advanced lung cancer setting. This RCT evaluated a 2-month PA intervention in patients with unresectable lung cancer.

      Methods:
      Participants were stratified (disease stage, performance status [PS] 0-1 vs 2, centre) and randomized (1:1) to usual care (UC) (general nutrition and PA education materials) or UC plus 2-month program of supervised weekly PA and behaviour change sessions and home-based PA. Assessments were completed at baseline, 2, 4 and 6 months. The primary endpoint was fatigue (FACT-F subscale) at 2-months. Secondary endpoints included: QOL, functional abilities, physical fitness, activity (accelerometers), mood, dyspnea, survival and blood results. Intention-to-treat analysis using linear mixed models was done.

      Results:
      111 patients were randomized: male 55%, median age 62 (35-80); 95% NSCLC, 5% SCLC; 95% Stage IV. At baseline 77% were on active treatment. Baseline characteristics, including PA levels, comorbidities and Glasgow Prognostic Score (GPS) were well balanced between groups. Attrition was 22, 36 and 50% at 2, 4 and 6 months respectively; no difference between groups. Adherence to intervention sessions: behavioral 77%, PA 69%. There were no significant differences in fatigue, QOL, symptoms, mood, distress, sleep, dyspnea, activities of daily living, GPS between the groups at 2, 4 or 6 months. Patients over report PA levels compared to accelerometer data. Using accelerometer data, PA only increased in the PA group from 0 – 2 months, but the difference in PA between groups was not significant. Median survival (months): PA 13.7 vs UC 12.6 (p= 0.76): 38 participants remain alive.

      PA n=55 UC n=56 p-value
      FACT-F Fatigue: 0 2 4 6 38.4 37.5 39.6 36.6 36.3 36.3 35.4 34.5 0.61 0.10 0.44
      EORTC Global QOL 0 2 4 6 63.8 63.2 64.2 60.8 58.9 64.3 60.2 54.2 0.81 0.45 0.26
      Performance Status 0 2 4 6 0.8 0.8 0.8 0.7 0.9 1.0 1.0 1.2 0.30 0.16 0.01


      Conclusion:
      Adherence to the 8-week intervention was good but did not increase PA levels compared to education materials alone. No difference was seen in fatigue, QOL, symptom control or functional status.

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    ORAL 01 - Chemotherapy Developments for Lung Cancer (ID 88)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL01.04 - Discussant for ORAL01.01, ORAL01.02, ORAL01.03 (ID 3289)

      11:18 - 11:28  |  Author(s): M. Boyer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      P2.03-030 - Adjuvant Radiation Therapy Improves Survival in Pathological Stage IIIA N2 Non-Small Cell Lung Cancer Patients Staged with PET (ID 2556)

      09:30 - 09:30  |  Author(s): M. Boyer

      • Abstract
      • Slides

      Background:
      Recent studies suggest a possible survival benefit associated with adjuvant radiation therapy (ART) following curative surgery for patients with pathological stage IIIA N2 (pN2) Non Small-cell Lung cancer (NSCLC) but there is no randomized data. Lack of survival benefit observed in some of the studies could be due to some of these patients harbouring unexpected distant metastases. 18-FDG Positron Emission Tomography (PET) scanning has been shown to upstage 24% of patients with stage III NSCLC. We hypothesized that survival benefit may become apparent by excluding patients with unexpected distant metastases who would not benefit from ART with the use of PET staging. The objective of this study is to evaluate whether ART improves overall survival in pN2 NSCLC patients staged with PET.

      Methods:
      Patients with stage IIIA pN2 NSCLC who underwent pre-operative PET staging and curative surgery in a tertiary thoracic oncology facility between January 1995 and June 2014 were identified from a prospectively collected database. 388 patients fit the selection criteria of which 219 patients (57%) received ART (≥ 45Gy). The impact of ART on survival was analysed using the Kaplan-Meier method.

      Results:
      Median follow up duration was 24 months. 29% of the patients had pneumonectomies. 30 day post-operative mortality was 1.8%. Conformal radiotherapy was used in all patients. 195 patients (51%) received systemic chemotherapy (33% induction, 67% adjuvant). The use of chemotherapy was uncommon in the earlier part of the study. Median age was 65 years (range 29-85 years). The most common histopathology was adenocarcinoma (55%). Patient characteristics, type of resection, complete resection rate, and histopathology subtypes were similar between the group which received ART (219 patients) and the group which did not receive ART (162 patients) but more patients in the ART group received chemotherapy (60% vs.38%). ART group did significantly better in terms of median, 2-year and 5-year Overall Survival (OS) compared to No ART group (median survival 29 months vs. 20 months respectively, 2-year OS 57% vs. 44% respectively, 5-year OS 30% vs.16% respectively, Hazard Ratio 0.62 95% Confidence Interval 0.49 – 0.79; p <0.0001)

      Conclusion:
      Adjuvant Radiation Therapy improved overall survival in pathological stage IIIA N2 NSCLC patients staged with PET in this series. This is consistent with the growing evidence supporting the use of ART in the modern era. Tri-modality therapy in a large number of patients may have contributed to the superior result in the ART group.

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