Virtual Library

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Abstract:
Molecular classification of lung cancer revealed that the most frequently mutated oncogene in lung cancer is the KRAS due to smoking and this molecular subclass is exclusively occur in the adenocarcinoma histologic variant and rarely in large cell variant. It also can be detected in the mixed histological variants like the adenosquamous subtype. The incidence of KRAS mutation in lung adenocarcinoma is 30% based on exon2 testing. (1) However, it is expected that similar to colorectal cancer, a complex RAS panel mutational analysis involving rare KRAS exon3 and 4 and NRAS exon2-4 could increase this figure significantly (probaly by 5-10%). Since RAS mutations are exclusive and do not occur together with other oncogenic driver mutations the complett RAS panel mutation determination could help to clearly define a large set of adenocarcinoma patents where further molecular analysis is not necessary. Analysis of two large patient cohort of lung adenocarcinoma and colorectal cancer (500 pt each) revealed that the alleic variations are highly similar in mutant KRAS exon2 in this two cancer types. The TGT (G-C) transversion in codon 12 was proved to be lung cancer specific while the GAC (G-D) codon 13 alteration was colorectal cancer specific. Since the RAS mutation in lung cancer is considered to be smoking-related, this highly similar allelic profile in colorectal cancer can be the molecular signature of smoking in this cancer type. Analysis of KRAS exon 2 aminoacid conversions by smoking status revealed that in non-smokers mutation is rare and if it occurs it is most frequently G12V unlike in smokers where G12C is the predominant. G12V-type patients may respond better to conventional chemoterapy (2). RAS mutant lung cancer patients are resistant to EGFR TKI inhibitors (1). EGFR protein expression is highly similar in KRAS mutant and wt lung adenocarcinoma but interestingly phosphorylated-EGFR is overexpressed in KRAS mutant tumors even overcoming EGFR mutated ones suggesting an aberrant RAS-driven signaling. (3) KRAS mutation in lung cancer is a poor prognostic factor. Analysis of the organ metastatic pattern of KRAS mutant lung adenocarcinoma revealed that brain and bone metastatic potential of these tumors are similar to KRASwt ones while these tumors tend to prefer pleural dissemination and liver. On the other hand, KRAS mutant lung adenocarcinoma is less likely give rise adrenal- or lung metastasis, a clearly indication a different biology as compared to KRASwt cancers. It is an important issue today the maintenance of the molecular profiles in metastases as compared to the primary tumor. This issue may be less sensitive in case of patients where surgical removal of the primary is impossible (a significant proportion of lung cancers) while can be more significant where only metastases are present in the patients. Analysis of the literature data indicates that the discrepancy rate of RAS mutation status in lymphatic metastases is low (below 10%), in case of visceral metastases increases to 14-24% range while is was reported to be the highest in bone metastasis (1). Lung cancer is reported to be a clonally heterogenous cancer and these alterations are most probably due to clonal variations during metastatic dissemination. With the advent of liquid biopsy technology monitorization of this process is now feasible using circulating DNA. A major issue clinically today is the development of resistance to target therapies. Both lung adenocarcinoma and colorectal cancer is treated by EGFR-targeted therapies where the molecular mechnisms of acquired resistance are now reported. It is interesting that in colorectal cancer patients the main cause of resistance to anti-EGFR antibody therapy is the emergence of RAS mutated clones in progressing tumors which were in minority in the primary. Although RAS mutation is equally frequent in lung adenocarcinoma, EGFR-TKI resistance is most frequently due to EGFR T790M mutation or HER2 amplification but no report on the emergence of RAS mutated clones.(4) In case of ALK mutated lung adenocarcinoma resistance to ALK inhibitors is mainly due to novel mutations in ALK. In a small proportion of cases KRAS amplification or NRAS mutation can be detected which suggest that in ALK-translocated lung cancer no minor RAS mutant clones are present in the tumors. (5) Check point inhibitor therapy is a new modality of lung cancer management targeting CTLA4, PD1 or PDL1 as targets on immune cells or cancer cells (PDL1). Although two drugs are registered in NSCLC, the significance of RAS mutations in this new modality is not known yet. In case of Nivolumab it is known that smokers are responding better to anti-PD1 therapy than nonsmokers suggesting that KRAS mutant tumors might be a better target but direct subgroup analysis is lacking. In case of Pembrolizumab even such an indirect data are missing therefore the question cannot be answered yet. The fact that EGFR mutant tumors are tend to respond less to anti-PD1 therapy suggest that beside PDL1 status molecular classification can also be a predictive factor for selecting patients for immunotherapy. (6) References 1.Tímár J: The clinical relevance of KRAS gene mutation in non-small-cell lung cancer. Curr Opin Oncol 26: 138-144, 2014 2. Cserepes M, Ostoros Gy, Lohinai Z, Rásó E, Barbai T, Tímár J, Rozsás A, Moldvay J, Kovalszky I, Fabián K, Gyulai M, Ghanim B, László V, Klikovits T, Hoda MA, Grusch M, Berger W, Klepetko W, Hegedűs B, Döme B: Subtype-specific KRAS mutations in advanced lung adenocarcinoma: A retrospective study of patients treated with platinum-based chemotherapy. Eur J Cancer 50: 1819-1828, 2014 3.Moldvay J, Barbai T, Bogos K, Piurko V, Fillinger J, Popper HH, Tímár J: EGFR autophosphorylation but not protein score correlates with histologic and molecular subtypes in lung adenocarcinoma. Diagn Mol Pathol 22: 204-209, 2013 4. Belchis DA, Tseng LH, Gmiadek T et. al. Heterogeneity of resistance mutations detectable by next-generation sequencing in TKI-treated lung adenocarcinoma. Oncotarget 2016 (in ress) 5. Dagogo-Jack I, Show AT. Crizotinib resistance: implications for therapeutic strategies. Ann Oncol 273:iii42-iii50,2016 6. El-Osta H, Shahid K, Mills GM, Peddi P. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer. Oncotarget 9:5101-5016,2016

Abstract:
TP53 mutations represent the commonest mutation seen in NSCLC. Over 50% of NSCLC tumours harbour a TP53 mutations. TP53 mutations in tobacco smokers are predominantly G-to-T transversions and deletions. In non-smokers, however, these alterations are rare. p53 is a stress response protein/transcription factor and is involved in cellular response to DNA damage induced by oxidative stress and external factors such as sunlight and radiation. Expression of p53 protein is largely controlled through degradation of the protein by the mouse double minute 2 (MDM2) E3 ligase and MDM4. Post-translational modification by various kinases/phosphatases and acetylases/deacetylases also regulates p53 activity. Amongst the various type of TP53 mutation that can occur, conformational TP53 mutations may contribute to the emergence of new functions leading to genomic instability, inhibition of apoptosis, cell migration, and drug resistance. These mutations may result in the binding and inactivation of p53-related proteins such as p63 and p73, or with other transcriptional factors resulting in modification of their activity and, hence, altered gene expression. Apart from the loss of tumour-suppressor functions, TP53 mutations may result in gain of function favouring cellular proliferation, inhibition of apoptosis, and genomic instability. As a result not all P53 mutations are the same with some more likely to affect the pathogenesis of NSCLC than others. Broadly speaking TP53 mutations may be divided into disruptive and non-disruptive cohorts. Many non-disruptive p53 mutations result in gain of function. In a recent series of 318 patients that included 125 with EGFR-mutations, non-disruptive TP53 mutations were associated with a poor prognosis. A recent study using an ELISA demonstrated p53 antibodies in 20.4% of lung cancer patients. A significant correlation between serum p53 antibodies and high levels of p53 expression in the corresponding tumour samples was seen. In NSCLC, the presence of p53 antibodies were significantly associated with poorly differentiated. High levels of p53 antibodies were also associated with high grade tumours, with squamous cell histology and with a poor prognosis in squamous cell carcinoma. Oncogenic KRAS mutations have been reported in up to 40% of adenocarcinomas and 5% of squamous cell carcinomas of the lung. These mutations are found largely in lung adenocarcinomas with solid growth patterns. While KRAS mutations are classically associated with a significant smoking history, they are also identified in a substantial proportion of never-­smokers. KRAS mutations are relatively mutually exclusive from EGFR, BRAF and ALK mutations/rearrangements but have considerable overlap with both P53 and PIK3CA mutations. The commonest mutation is in codon 12 but mutations in codon 13 and 61 are also been described. Substitutions in these residues result in constitutively elevated levels of Ras-GTP due to reduced intrinsic GTP hydrolysis and resistance to GTPase-activating proteins and hence activation of the Raf and phosphatidylinositol 3-kinase. Although controversy on the prognostic and predictive value of the presence of a KRAS mutation in a tumour exists, recent studies indicate that patients with KRAS mutations are resistant re chemotherapy and radiotherapy, with a lower objective response rate and worse progression free and overall survival rates. A number of recent studies have allowed us to gain novel insights into the role of KRAS in the pathogenesis of lung cancer, in particular adenocarcinoma of the lung. Increasing evidence indicates a role for chronic inflammation in the pathogenesis of lung cancer, an observation being exploited clinically through the use of immune checkpoint inhibitors such as pembrolizumab. A proportion of KRAS mutation positive tumours have been found to have a high tumour mutation burden that may indicate sensitivity to such agents. KRAS mutations have also been associated with tumour-infiltrating lymphocytes. Recent work has demonstrated that KRAS mutation in lung epithelial cells preferentially leads to recruitment of Th17 positive immune cells that produce IL-17, a cytokine that promotes inflammation. IL-17 induces tumorigenesis by recruiting GR1C CD11bC immune cells. Recent work has demonstrated that miRs may play a role in the regulation of KRAS. For example miR-31 has recently been reported to be over-expressed in lung adenocarcinoma and to correlate with worse survival. Using a transgenic mouse model that allows for lung-specific expression, induction of miR-31 results in lung hyperplasia, followed by adenoma formation and later the development of adenocarcinoma. Induced expression of miR-31 acts with mutant KRAS to accelerate lung tumourigenesis by down-regulating a number of negative regulators of RAS/MAPK signaling. The expression of mesothelin, a cell surface glycoprotein that may have a role in cell adhesion and metastases, is seen in several epithelial cancers and has recently been assessed in adenocarcinoma of the lung using immunohistochemistry. The intensity of staining and the percentage of cells expressing mesothelin in the report was blinded for molecular data and outcome. Mutations of EGFR, KRAS, BRAF, AKT1, PIK3CA and HER2 were assessed by pyrosequencing; HER2 amplification and ALK translocation were assessed by fluorescence in situ hybridization. Of the advanced lung adenocarcinomas, 53% expressed mesothelin to some degree. High mesothelin expression, defined as mesothelin positivity in more than 25% of cells, was found in 24% of patients. High mesothelin expression was associated with a worse survival (median 18.2 months vs. 32.9 months; P = 0.014) and with wild-type EGFR, and was strongly associated with mutant KRAS. The increased understanding of the tumour promoting activities of KRAS mutations, and the association with biomarkers, provides novel insights that will facilitate targeting of these tumours with novel agents in the future.

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Interest in adaptive design study methods stems from the principle that these methods hold promise for improving drug development compared to conventional study design (i.e., non-adaptive) methods. The theoretical advantages of adaptive designs are that (1) they provide similar information more efficiently by reducing sample size and total cost, (2) increase the likelihood of success on the study objective, treating more patients with more effective treatments or (3) lead to better improved appreciation of the effects of therapy such as dose-response relationship or subgroup effects, for example identifying efficacious drugs for specific subgroups of patients based on their biomarker profiles, which may also lead to more impactful subsequent studies). Adaptive designs use accumulating data to modify the ongoing trial without undermining the integrity and validity of the trial. They also hold the potential for shortening the time for drug development. Several aspects of these trials including the dose-finding scheme, interim analysis, adaptive randomization, biomarker-guided randomization, and seamless designs will be discussed. Many, but not all adaptive designs are devised under the Bayesian framework incorporating principles such as (I) obtaining the prior distribution; (II) collecting data to calculate the data likelihood; and then (III) computing the posterior distribution. The Bayesian framework provides an ideal statistical framework for adaptive trial designs (1, 2). Examples of trials conducted with adaptive designs include the BATTLE and BATTLE-2 trials and ISPY-2. The basic principle is that patients enrolling earlier in a trial are used to inform how subsequent patients are treated, thus improving the efficiency of the study; this means that fewer patients are required to achieve the same answers regarding safe dosing and/or efficacy. The BATTLE and BATTLE-2 trials are prime examples of this approach. Both trials have implemented adaptive randomization schemes to assign patients to the more efficacious treatments based on their biomarker-guided profiles, and use interim analyses to monitor the efficacy outcomes during the trial. The BATTLE trial (3, 4) enrolled patients with stage IV recurrent non-small cell lung cancer, employing a primary endpoint of eight-week disease control rate, as a binary outcome. Four targeted therapies, erlotinib, vandetanib, erlotinib plus bexarotene, and sorafenib, were evaluated, with one therapy targeting each one of four biomarker profiles and it used an adaptive randomization scheme to allocate patients to the different treatments; hence, patients had higher probabilities of being assigned to better treatments based on their biomarker profiles. The trial showed that adaptive design could work in a complex trial that assessed multiple drugs and biomarkers and required tissue collection and biomarker analysis. Based on the findings of the BATTLE trial, a follow-up BATTLE-2 trial (5) was started, that evaluated four treatment regimens, erlotinib, sorafenib, erlotinib + MK2206, and MK2206 + AZD6244, in a two-stage design with adaptive randomization. The first stage was completed with 200 patients. Biomarker selection was planned in 3 steps: training, testing and validation. In the training step, 10–15 potential prognostic and predictive markers were selected from the previous BATTLE experience, cell line data, and relevant literature information. In the testing step, the selected markers are tested using the data acquired from stage 1 of the BATTLE-2 trial. In the validation step, the markers selected in the first stage of the BATTLE-2 trial are used for adaptive randomization in the second stage of BATTLE-2. In BATTLE-2, we pre-specified an extremely limited set of markers and our intent was to use the first half of the study (200 patients) to conduct prospective testing of biomarkers/gene signatures. Predictive markers were to be used to guide patient assignments in the second half of the study. Although the design theoretically provided advantages, since clear predictive markers did not exist for any of the treatment Arms, activity was modest yielding no new predictive markers and not warranting further exploration. The ISPY-2 trial (6) is a multicenter phase II trial in the neoadjuvant setting for patients with breast cancer. The primary end point is pathologic complete response (PCR) at the time of surgery. The patient population is partitioned into ten subgroups depending on hormone-receptor (HR) status, HER2 status and Mamma Print signature. Experimental drugs are added to neoadjuvant therapy with the overall goal to prospectively learn as efficiently as possible which patients respond to each experimental treatment based on their biomarker profiles. Adaptive randomization with interim analysis is used within each biomarker subgroup, with the treatments that are performing better within a subgroup being assigned with greater probability to patients belonging to that subgroup. The phase II drug-screening stage is followed by a phase III confirmatory stage. The ISPY-2 trial has recently shown that two promising drugs improve response rates in specific biomarker subsets and has graduated these two drugs veliparib and neratinib for further development (7). The pharmaceutical industry and regulatory agencies are therefore very interested in adaptive designs because of their potential advantages and because they reflect medical practice in the real world. To recapitulate, incorporation of adaptive designs in carefully designed and executed trials can enhance drug development, provide greater benefit to the enrolled patients, and effectively address many research questions of interest. These designs require deep understanding of theoretical statistical methodology, extensive modeling with simulations, specialized software and robust databases. Continued implementation in trials with guidance from regulatory agencies and innovative methods will contribute towards progress in therapies. 1.Berry DA. Bayesian clinical trials. Nat Rev Drug Discov. 2006;5:27–36. 2.Lee JJ, Chu CT. Bayesian clinical trials in action. Stat Med. 2012;31:2955–2972. 3. Zhou X, Liu S, Kim ES, et al. Bayesian adaptive design for targeted therapy development in lung cancer-a step toward personalized medicine. Clin Trials. 2008;5:181–193. 4. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE Trial: Personalizing therapy for lung cancer. Cancer Discov. 2011;1:44–53. 5.Papadimitrakopoulou V, Lee JJ, Wistuba II et al. The BATTLE-2 Study: A Biomarker-integrated targeted therapy study in previously treated patients with advanced non-small cell lung cancer. J Clin Oncol Aug 1,2016 Epub ahead of print 6.Barker AD, Sigman CC, Kelloff GJ, et al. I-SPY 2: An adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther. 2009;86:97–100. 7.Quantum Leap. I-SPY 2 Trial graduates 2 new drugs. 2013 Available online:http://www.quantumleaphealth.org/spy-2-trial-graduates-2-new-drugs-press-release/

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Abstract:
The value of any treatment is determined by the magnitude of its clinical benefit (MCB) balanced against its cost. Whereas costs of procurement and out-of-pocket expenditures vary from country to country, the MCB, as derived from well-designed clinical trials, is a relative constant. Consequently, meaningful discussion of value and relative value are predicated on an understanding of the MCB. MCB in this context refers to the added benefit, usually compared to a control (the best current standard care). Until recently there was no standard tool for grading the MCB of cancer therapies, which may range from trivial (median progression-free survival advantage of only a few weeks) to substantial (improved long term survival). Recognising the importance of presenting clear and unbiased statements regarding the MCB from new therapeutic approaches derived from high quality clinical trials the European Society for Medical Oncology (ESMO) has developed a validated and reproducible tool to assess the MCB for cancer medicines, the ESMO MCB Scale (ESMO-MCBS). This tool uses a rational, structured and consistent approach to derive a relative ranking of the magnitude of clinically meaningful benefit that can be expected from a new anti-cancer treatment. The ESMO-MCBS is an important first step to the critical public policy issue of value in cancer care, helping to frame the appropriate use of limited public and personal resources to deliver cost effective and affordable cancer care. The ESMO-MCBS v1.0 [1]has been developed and validated for solid cancers. The tool is presented in two parts. Form 1 is used to evaluate adjuvant and other treatments with curative intent. Form 2 (a, b or c) is used to evaluate non-curative interventions, with form 2a for studies with OS as the primary outcome, form 2b for studies with PFS or TTP as primary outcomes, 2c for studies with QoL, toxicity or response rate as primary outcomes and for non-inferiority studies. Form 2a is prognostically sub-stratified for studies where the control arm produced OS greater or less than or equal to 1 year, and form 2b is stratified for studies where the control arm PFS is <6m or >6mth. Version 1.0 can be applied to comparative outcome studies evaluating the relative benefit of treatments using outcomes of survival, QoL, surrogate outcomes for survival or QoL (DFI, EFS, TTR, PFS and TTP) or treatment toxicity in solid cancers. Eligible studies can have either a randomised or comparative cohort design or a meta- analysis which report statistically significant benefit (P>0.05, upper limit of 95[th] percentile for HR <1) from any one, or more of the evaluated outcomes. For treatments with curative intent, the scale is graded A, B or C. Grades A and B represent a high level of clinical benefit . For cancers treated without curative intent, the scale is graded 5, 4, 3, 2, 1, where grades 5 and 4 represent a high level of proven clinical benefit. The scale incorporates a “dual rule” taking into account the variability of the estimated HR from a study, the lower limit of the 95% Confidence Interval (CI) for the HR is compared to specified threshold values; and second the observed absolute difference in treatment outcomes is compared to the minimum absolute gain considered as beneficial. Different candidate threshold values for HR and absolute gains for survival, DFS and PFS, adjusted to represent as accurately as possible the expert opinion of the oncology community, have been explored through extensive simulations. In all forms HR thresholds refer to the lower extreme of the 95% CI, analogous to the convention of evaluating null effect by the upper limit of the 95%CI <1. The performance of the evaluation rule based on the lower limit of the 95% CI of HR, was compared to the simpler rule of using a cut-off for the point estimate of HR, in conjunction with the additional rule on the minimum absolute gain in treatment outcome. The simulation results under different HR values and corresponding power, favoured the proposed approach to use the lower limit of the 95% CI which takes into account the variability of the estimate. The concern that small studies generate wider confidence intervals is real and justified, however in the ESMO-MCBS v1.0 all high grading scores in a non-curative setting incorporate both HR and absolute gain to mitigate against over valuing small studies with wide HR. This structured and disciplined approach to deriving estimates of clinically meaningful benefit from published data can be used in a range of settings: it can help public policy-makers advance “accountability for reasonableness” in resource allocation deliberations, contribute to formulation of clinical guidelines , in the clinic it can help clinicians to weigh the relative merits of competing relevant therapeutic options in situations in which there is no direct comparative data and grading may also be of benefit when explaining the relative merit of therapeutic options to patients and their families. Finally ESMO-MCBS may be of use to editors, peer reviewers and commentators in considering the clinical significance of research findings from randomised clinical studies, cohort studies and meta-analyses with statistically significant positive findings. Experience accrued in evaluating trials in the management of non small-cell lung cancer have been critical in the development process of v1.0, particularly with regard to the interpretation of PFS is studies with extensive crossover on progression that precludes meaningful OS survival results. In this cohort of studies, the inclusion of QoL evaluation was able to generate confirmatory secondary evidence to support the clinical significance of the PFS findings. The proliferation of new agents targeting NSCLC with specific mutations that have been approved on the basis if Phase I-II data have challenged the working group to expand the scope of the scale to include single arm studies. This new subscale will be among the amendments in the planned revision that is under development and scheduled for publication early next year. 1. Cherny NI, Sullivan R, Dafni U et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Annals of oncology 2015; 26: 1547-1573.

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Abstract:
With limited resources for health, Low and Middle Income Countries (LMICs) struggle to guarantee all members of their society toget cancer treatments, especially the innovative but expensive cancer medicines[1, 2]. Cancer is a leading cause of deathin Thailand, which is an upper-middle income country in South-East Asia. From 2003 to 2011, the mortality rate from cancer rose from 79 to 95 per100,000 populations. [3].Since the Thai health care reform in 2001[4, 5] several stakeholders have initiated policies andprogramsto facilitate access to medicines. The Thai NLEM is different from the one listed by WHO, due to the fact that WHO listed only the minimum required medicine, while the Thai list included an optimum list. At the present, the Thai NLEM has more than 700 items of active ingredients and 1000 dosage forms [6, 7]. When the NLEM was first introduced in 1981, only cost, safety, and efficacy were considered as criteria for inclusion whereas effectiveness was added to the list of criteria in 2004. Since 2008, economic evidence has become important for the Sub-committee of the NLEM to justify the new costly medicines such as type E2 to be included in the list of NLEM. As of 2009, the NLEM can be divided into six categories, which are A, B, C, D, E1, and E2. Type A: Basic medicines that every health facility must make available Type B: Alternative, second line medicines of those in category A Type C: Medicines prescribed only by specialists TypeD: Medicines used only for particular indications and diseases Type E1: Medicines used only for special or vertical programs Type E2: Medicines that are high costs but are important for particular groups of patients Heath Care Coverage for Thai residences are divided into 3 categories 1. Universal Coverage Scheme (UCS) Cover 75% of Thai population 2. Social Security Scheme (SSS) Cover 19%, Private sector employees, excluding dependants 3. Civil Servant Medical Benefit Scheme (CSMBS) Cover 9%, Government employees plus dependants (parents, spouse and up to two children age <20) The CSMBS has covered most of the cancer drugs including the expensive drugs, however UCS and SSS have covered only drugs listed in the NELM; thus there are unmet need for cancer patients with these two healthcare schemes. Thai government set up several policies to enable access to the cancer drugs such as Compulsory Licensing, Pooled purchasing (price negotiation), Special marketing arrangement (price negotiation), and E2 access program. Several pharmaceutical companies provide their own scheme for patients who are willing to pay for the drug by themselves (patient access program) Even with all the programs available, the problem of accessibility of costly anticancer drugs still persists. There should be more input into this problem. References 1. Kanavos P, Das P, Durairaj V, Laing R, Abegunde DO (2010) Options for financing and optimizing medicines in resource-poor countries World Health Organization. 2. American College of Physicians (2011) How can our Nation Conserve and Distribute Health Care Resources Effectively and Efficiently? Philadelphia: American College of Physicians. 3. MoharaA,YoungkongS,PérezVelascoR,WerayingyongP,PachaneeK,etal.(2012)UsinghealthtechnologyassessmentforinformingcoveragedecisionsinThailand.JComparEffectRes.1:137–146. 4. Damrongplasit K, Melnick GA (2009) Early results from Thailand's 30 Baht Health Reform: something to smile about. Health Aff (Millwood). 28: w457–466. doi: 10.1377/hlthaff.28.3.w457 PMID: 19336469 5. Towse A, Mills A, Tangcharoensathien V (2004) Learning from Thailand's health reforms. BMJ. 328: 103–105. PMID: 14715608 6. Yoongthong W, Hu S, Whitty JA, Wibulpolprasert S, Sukantho K, et al. (2012) National drug policies to local formulary decisions in Thailand, China, and Australia: drug listing changes and opportunities. Value Health. 15: s126–131. doi: 10.1016/j.jval.2011.11.003 PMID: 22265059 7. Turongkaravee S, Rattanavipapong W, Khampang R, Leelahavarong P, Teerawattananon Y, et al. (2012) Evaluation of high-cost medicine scheme (Category E2) under the 2008 National List of Essential Medicines. Nonthaburi: Health Intervention and Technology Assessment Program.

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Background:
The interaction of immune cells and cancer cells shapes the immunosuppressive tumor microenvironment. For successful cancer immunotherapy, comprehensive knowledge of anti-tumor immunity as a dynamic spacio-temporal process is required for each individual patient. To this end, we developed an "immunogram for the cancer-immunity cycle" using next-generation sequencing.

Methods:
Whole-exome sequencing and RNA-Seq were performed in 20 non-small cell lung cancer patients (12 adenocarcinoma, 7 squamous cell carcinoma, and 1 large cell neuroendocrine carcinoma). Mutated neoantigens and cancer-germline antigens expressed in the tumor were assessed for predicted binding to patients’ HLA molecules. The expression of genes related to cancer-immunity was assessed and normalized; immunogram was drawn in a radar chart composed of 8 axes reflecting 7 steps of cancer-immunity cycle.

Results:
Distinctive patterns of immunogram were observed in lung cancer patients: T-cell-rich and T-cell-poor. Patients with T-cell-rich pattern had gene signatures of abundant T cells, Tregs and MDSCs, checkpoint molecules and immune-inhibitory molecules in the tumor, suggesting the presence of counter regulatory immunosuppressive microenvironment. Unleashing of counter regulations, i.e. checkpoint inhibitors, may be indicated for these patients (Figure A). Immunogram of T-cell-poor phenotype reflected lack of anti-tumor immunity, inadequate DC activation, and insufficient antigen presentation in the tumor (Figure B). When the immunograms were overlaid within each tumor histology, no typical pattern was elucidated. Both T-cell-rich and T-cell-poor phenotypes were present in each histology, suggesting that histology cannot necessarily reflect the cancer-immunity status of the tumor (Figure C,D). These results were consistent with previous studies showing that clinical responses of checkpoint blockade were not easily predicted by the histology. Figure 1



Conclusion:
Utilizing the immunogram, the landscape of the tumor microenvironment in each patient can be appreciated. Immunogram for the cancer-immunity cycle can be used as an integrated biomarker and thus may become a helpful resource toward optimal personalized immunotherapy.

Background:
Recent evidence indicates that efficacy and durability of responses to immune checkpoint inhibitors in lung carcinomas correlate with increased nonsynonymous mutation (NSM) burden, putative neoantigen number, and in some tumor types, PD-L1 protein expression. In this study, we retrospectively analyzed the relationship of lung carcinoma mutation burden, PD-L1 expression and immune infiltrates with clinical response in patients receiving immune checkpoint blockade.

Methods:
Tumor nonsynonymous mutation data derived from clinical targeted next generation sequencing (309 genes) of lung carcinomas from 94 patients treated with immune checkpoint inhibitors was correlated with clinical outcomes, including durable clinical benefit (DCB; >6 months partial or stable response) and progression-free survival (PFS). PD-L1 immunohistochemistry (clone E1L3N, Cell Signaling Technology, Envision+ detection, Dako) was considered positive if ≥1% of tumor cells and/or tumor-infiltrating immune cells (IC) stained. PU.1, CD3, and FOXP3 immunohistochemistry was used to highlight tumor-associated macrophages and non-regulatory and regulatory T cell populations, which were manually quantified per mm[2].

Results:
The mean patient age was 62 years (range: 32-91 years). Lung tumor types included 69 adenocarcinomas, 11 squamous cell carcinomas, 5 small cell carcinomas, and 9 of other/combined histology. Therapies included PD1 inhibitors (82), a PD-L1 inhibitor (5) and multiple agents (7). Across all tumor types, patients with DCB had a significantly higher number of NSM (range: 1-42) than patients who showed no durable benefit (NDB) [DCB: 12; NDB: 8, p = 0.0027]. Patients with greater than the median number of NSM (9) had significantly longer PFS than those with ≤9 (p = 0.015). Increasing smoking history correlated with higher mutation load (p = 0.047) and patients with a longer smoking history tended to have longer PFS although this trend did not reach statistical significance (p = 0.07). Expression of PD-L1 in either tumor cells or ICs was not associated with NSM burden (p = 0.47) or PFS (p = 0.92). PD-L1 expression in the tumor microenvironment was associated with increased numbers of tumor-associated macrophages (p = 0.0002), and non-regulatory and regulatory T cells (p = 0.0038 and 0.01 respectively).

Conclusion:
The non-synonymous mutation burden in lung carcinoma as assessed by targeted next generation sequencing is associated with increased PFS and durable clinical benefit to immune checkpoint inhibitors. In this limited cohort, PD-L1 expression using clone E1L3N does not predict response to these therapies. We add to growing evidence that increased somatic mutations in carcinomas influence response to immune checkpoint blockade.

Background:
Immune checkpoint, PD-1, inhibitors, have been approved to treat advanced NSCLC patients without oncogenic driver in the second-line setting based on durable clinical benefit. It has been demonstrated that the overall mutational burden in tumor tissue was significantly associated with progression free survival (PFS) of advanced NSCLC patients treated with PD-1 inhibitor. However, tumor tissue may not be available from all patients at any time during PD-1 blockade therapy. Therefore, the purpose of this study was to explore the predictive value of mutation/neoantigen burden from ctDNA on efficacy of PD-1 inhibitors.

Methods:
We treated advanced NSCLC patients without oncogenic drivers with PD-1 inhibitor in the second or more line setting. The whole-exome of tumor tissues and ctDNA at baseline and ctDNA at every time of efficacy evaluation from these patients were sequenced by NGS. The hybrid-capture-enriched libraries were sequenced on the Illumina HiSeq 4000 platform with 75-base paired-end reads, sequencing depth was 300 for ctDNA whole-exome sequencing. We compared the results of whole-exome sequencing between patients who achieved objective response to PD-1 inhibitor and patients who experienced disease progression. Besides, we also compared the results of whole-exome sequencing between baseline ctDNA and ctDNA extracted at efficacy evaluation.

Results:
Up to now, a total of 23 patients treated with PD-1 inhibitor received efficacy evaluation at least once in this study. Of them, 4 patients achieved partial response (PR), 3 patients achieved stable disease (SD). Of 4 patients with PR, 3 patients were found to harbor high mutation burden (more than 400 nonsynonymous mutations) from ctDNA and only 1 patient harbored mutation burden of less than 100 from ctDNA at baseline. We found the mutation or neoantigen burden from ctDNA changed during PD-1 blockade therapy. The efficacy of PD-1 inhibitor appeared to be more significantly associated with neoantigen burden rather than mutation burden. Only one ctDNA sample was found positive for MSH6 mutation (C1337X) and all baseline ctDNA samples were negative for microsatellite instability (MSI) status.

Conclusion:
Evaluating nonsynonymous mutation burden/neoantigen burden from ctDNA was feasible in advanced NSCLC patients treated with PD-1 inhibitors. The predictive value of neoantigen burden from ctDNA on the efficacy of PD-1 inhibitor may be better than that of mutation burden in advanced NSCLC. It may not be feasible to determine the status of mismatch-repair deficiency and MSI using ctDNA samples in advanced NSCLC. An expanded study is ongoing. More details will be presented in the conference.

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Background:
Anti-PD1 (programmed cell death 1) therapeutic antibodies have recently become available as a promising option in the treatment of patients with NSCLC in Austria. Several clinical studies suggested PD-L1 (programmed cell death ligand 1) protein expression in tumor cells to be a useful prognostic biomarker using several antibodies and different cutoffs. We studied PD-L1 expression in our NSCLC patient cohort and compared the performance of different antibodies. Furthermore we aimed to investigate the value of PD-L1 expression as a biomarker in a subset of patients treated with Anti-PD1 immunotherapy.

Methods:
PD-L1-Imunohistochemistry (IHC) was performed in 437 lung cancer specimens (316 adenocarcinomas, 77 squamous cell carcinomas and 44 NSCLC NOS) using the clones SP263 (Ventana), 28.8 (Abcam) and EL1L3N (Cell Signaling) on the VENTANA IHC platform. The percentages of tumor cells (TC) with membranous staining were determined - irrelevant of staining intensity; TC-counts of less than 1 % were interpreted as negative. Staining with at least two of the antibodies was available in 378 specimens (SP263/28.8 in 320 and 28.8/E1L3N in 117). 60 specimens were stained with three antibodies. From 58 patients receiving Nivolumab clinical information about response to therapy was available.

Results:
PD-L1 was expressed in 244 specimens (54.84%). 112 (25.63%) showed TC counts ≥50%, and 132 (30.21%) were <50%. 193 (44.16%) were negative. SP263 showed stronger staining intensity than 28.8 and E1L3N. Differences in TC-percentage were seen in 67 of 378 specimens, with major changes in 16 specimens (negative to positive in 4 and <50% to ≥50% in 12 cases). Higher TC percentages were seen with SP263. In the 58 treated patients complete remission was seen in 6 (4 ≥50%, 2 negative), partial remission in 14 (10 ≥50%, 3 <50%, 1 negative), stable disease in 4 (2 <50%, 2 negative), paradox reaction in 7 (1 ≥50%, 3 <50%, 3 negative) and progressive disease in 27 (4 ≥50%, 14 <50%, 9 negative).

Conclusion:
PD-L1 is expressed in the majority of NSCLC patients. Despite minor differences in expression levels all three tests provided reliable results. Furthermore PD-L1-IHC showed to be a useful biomarker in NSCLC especially concerning the good response to Anti-PD1 therapy in tumors with PD-L1 expression ≥50%. However as some PD-L1 negative tumors also responded, negative test results cannot definitely exclude patients from immunotherapy.

Background:
Diverse factors have been associated with clinical benefit to PD-1 axis blockers in NSCLC including PD-L1 protein expression by immunohistochemistry and increased mutation load/predicted class-I neoantigens. However, the association and predictive value of the tumor genomic landscape, composition of the tumor immune microenvironment and T-cell function remain unclear.

Methods:
We performed whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) for T-cells in pre-treatment FFPE samples from 45 NSCLC patients treated with PD-1 axis blockers (alone or in combination) in our institution. Genomic analysis was used to evaluate the mutational load and predicted class-I neoantigens. Multiplexed QIF-based immunoprofiling was used to measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3+ cells) and T-cell activation (Granzyme-B in CD3+ cells). We studied the association between the tumor somatic mutations, predicted neoantigens, T-cell infiltration/function and clinical benefit /survival.

Results:
Increased mutational load was positively associated with predicted class-I neoantigens, variants in DNA-repair genes, smoking and absence of activating mutations in EGFR; but not associated with the level of CD3+ T-cells, T-cell proliferation (Ki-67 in CD3+ cells) and function (Granzyme-B in CD3+ cells). Increased mutations and candidate class-I neoantigens were significantly associated with response to therapy (P=0.02 and 0.03, respectively), but not with overall survival at 3-years (median cut-point, log rank P=0.92 and 0.80, respectively). Higher CD3 positivity was not associated with response to therapy (P=0.17), but was significantly associated with overall survival (median cut-point, log rank P=0.03). Regardless of the mutational load and candidate neoantigen content, elevated CD3 with low Ki-67/Granzyme-B in CD3 predicted longer survival after PD-1 axis blockade than high CD3/high Ki-67/Granzyme-B in CD3, or low T-lymphocyte infiltration.

Conclusion:
Increased somatic mutations are associated with smoking and response to PD-1 agents, but not with tumor T-cell infiltration/activation and overall survival. Regardless of the mutational load, increased T-cell infiltration using QIF is significantly associated with longer survival after PD-1 axis blockade in NSCLC. The subgroup of NSCLC with the highest potential of benefit to immune reinvigoration using PD-1 axis blockade comprise tumors with elevated lymphocyte infiltration but low in situ activation/proliferation.

Background:
Non-small cell lung cancer (NSCLC) make up the majority of all lung cancer cases and is associated with very poor prognosis. Immune checkpoint blockers have now been shown to induce unprecedented durable response in a fraction of NSCLC patients with pre-existing T cell infiltration within their tumor. However in order to improve their efficacies beyond this subset of patients, a detailed molecular characterization to identify factors associated with lack of T cell infiltration is needed. A recent analysis in metastatic melanoma identified Wnt/B-catenin pathway activation as a mechanism for lack of T cell infiltration. We pursued similar analyses of immunologic gene signatures and molecular associations in squamous cell lung cancer (SCC) and lung adenocarcinoma (LA).

Methods:
We analyzed RNAseq data from two lung cancer datasets of The Cancer Genome Atlas (TCGA) (N = 499 for SCC and N = 514 for LA). Samples were categorized into non-T cell inflamed and T cell-inflamed groups using unsupervised consensus clustering based on the expression of 160 immune-related genes. Ingenuity pathway analysis was utilized to identify molecular pathways activated in non-T cell-inflamed tumors.

Results:
A similar proportion of non-T cell-inflamed tumors were identified in the two cohorts (SCC: 34%; LA: 31%). 47% of the SCC tumors were identified as T cell-inflamed, as compared to 37% in LA. A positive correlation was observed between CD8A and PD-L1, IDO1, LAG3 and TIM3 (p<0.00001). Total of 1,216 genes are significantly up-regulated in non-T cell-inflamed SCC tumors and 596 in LA with at least 1.5-fold change and FDR-adjusted p<0.05. Among these, a total of 194 genes are up-regulated in both SCC and LA, with the rest being specific for each subtype (SCC: 84%; LA: 67%). Pathway analysis suggested 35 upstream regulators were activated in SCC and 32 in LA (activation z-score≥2.0). Among these, 10 upstream regulators are activated in both datasets (ATF4, CTNNB1, KAT6A, KLF4, MYC, NFE2L2, PI3K, SCAP, SP1, SREBF2). Finally, we performed the same gene expression analysis on RNAseq data from matched normal tissues (N = 51 for SCC and N = 59 for LA) and confirmed that the T-cell inflamed gene signature is a property of the tumor rather than normal lung tissue.

Conclusion:
Our analyses successfully identified genes and associated pathways that are enriched in NSCLC subtypes with no immune infiltration. Rational strategies to improve the efficacy of immune checkpoint blockers beyond the current subset of responders should be based on targeting these pathways.

Abstract not provided

Background:
Nivolumab was approved in Japan on December 17, 2015 for previously treated non-small cell lung cancer (NSCLC). The expression of programmed death-ligand 1 (PD-L1) in tumor tissue is considered a predictive factor for clinical response to nivolumab. However, in Japan, there are no commercially available diagnostic kits for evaluating PD-L1 expression. In addition, little is known regarding other predictive factors of response to nivolumab monotherapy in patients with NSCLC. Therefore, we examined the relationships between the response to nivolumab monotherapy and clinical parameters in patients with NSCLC.

Methods:
Between December 2015 and April 2016, we performed a retrospective analysis of 50 patients with NSCLC treated with nivolumab monotherapy (3 mg/kg, every 2 weeks) at our Institution in the clinical setting.

Results:
Baseline characteristics of patients who received nivolumab monotherapy were: median age, 65 years [range:39–76]; 60% male; 26% ECOG-PS 0, 64% ECOG-PS 1; 38% smoker; 58% stage Ⅳ disease, 22% postoperative recurrence; 80% non-squamous (SQ) NSCLC; 36% non-SQ NSCLC patients had active EGFR mutations; 20% second-line, 18% third-line. The objective response rate (ORR) for all patients treated with nivolumab monotherapy was 18% (95%CI 10–31). Univariate analysis revealed that predictive factors of response to nivolumab monotherapy were associated with “SQ”, “response to the treatment immediately before nivolumab monotherapy”, “therapeutic line of nivolumab (second-line and third-line treatment)” and “smoker” categories (Table 1). In the multivariate logistic regression analysis, the independent predictive factors were “SQ” (P = 0.0069) and “response to the treatment immediately before nivolumab monotherapy” (P < 0.0001) (Table 1). Figure 1



Conclusion:
“Response to the treatment immediately before nivolumab monotherapy”, other than “SQ” histology may be predictors of clinical response to nivolumab in patients with NSCLC.

Background:
Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade remains elusive. This study was sought to identify the potential biomarkers that predicted response to PD-1 blockade immunotherapy in lung adenocarcinoma.

Methods:
We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from cohorts of both lung adenocarcinoma public database including The Cancer Genome Atlas (TCGA), GEO repository (GSE72094) and Broad dataset, and clinical immunotherapeutic patients in our center. Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.

Results:
We observed distinct function of TP53 and KRAS mutation in regulating immune tumor microenvironment (TME). It is TP53 mutation but not KRAS mutation in lung adenocarcinoma that significantly increased expression of immune checkpoints, facilitated CD8+T cell infiltration and activated T-effector and interferon-γ (IFN-γ) signature. Interestingly, TP53 and KRAS co-mutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. More importantly, TP53 or KRAS mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell cycle regulating, DNA replication and damage repair. Finally, clinical immunotherapeutic data were further confirmed that TP53 or KRAS mutation lung adenocarcinoma patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 blockade immunotherapy. Figure 1



Conclusion:
This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding PD-1 blockade immunotherapy.

Background:
Immunotherapies that target PD-1/PD-L1 exploit the primary roles of cytotoxic agents in lung cancers. However, tyrosine kinase inhibitors (TKIs) are still considered to be the first choice in lung cancer patients with EGFR mutations. Although immunotherapies may be applied as second line or later therapeutic approaches in these patients, after acquisition of resistance to EGFR-TKIs, it is unclear if acquired resistance mechanisms alter PD-L1 expression status that is employed as an important predictive biomarker for PD-1/PD-L1 targeting agents.

Methods:
Lung cancer cell lines with EGFR mutations (HCC827, HCC4006, PC9, and H1975) and their isogenic descendants with acquired resistance to various EGFR-TKIs were examined in this study. The resistance mechanisms of descendants include T790M secondary mutation, MET gene amplification, epithelial to mesenchymal transition (EMT), and loss of amplified EGFR mutant allele. PD-L1 expression status was analyzed by immunohistochemistry (IHC) and immunoblotting. Effects of acquired resistance mechanisms on PD-L1 expression were also evaluated by shRNA mediated knockdown of candidate molecules, and co-localization analysis using fluorescent imaging. IFN-gamma was used to mimic immune cell attack. Published microarray data of cells with acquired resistance to EGFR-TKIs were also employed to evaluate our findings.

Results:
PD-L1 expression was upregulated in several resistant cells and correlated with EGFR activation. In addition, we found that the phosphorylation of EGFR tyrosine (Y) 992 site, but not Y845, Y1068, or Y1173, was correlated with increased expression of PD-L1. We also observed that TKI-resistant cells with marked E-cadherin downregulation (HCC4006 erlotinib resistant cells and H1975 osimertinib resistant cells), one of hallmarks of EMT, showed decreased expression of PD-L1. However, one cell line (853#10), displaying EMT-like phenotype but only slight E-cadherin downregulation, showed PD-L1 upregulation. Published microarray data from three TKI-resistant lines with EMT-like features also support the correlation of low E-cadherin and reduced PD-L1 expression. ShRNA mediated knockdown of E-cadherin decreased the expression of PD-L1 in parental cell lines. IFN-gamma treatment upregulated PD-L1 expression in both parental and in resistant cells with E-cadherin downregulation, however PD-L1 expression in resistant cells was still lower and localized mainly in the cytoplasm rather than the cell membrane.

Conclusion:
We observed a dramatic change of PD-L1 expression status in lung cancers with EGFR mutation after acquisition of resistance to EGFR-TKIs, depending on the resistance mechanisms. These results support the importance of re-biopsy after acquisition of resistance to EGFR-TKIs, not only for the resistance mechanisms but also for the evaluation of PD-L1 expression status.

Abstract not provided

Background:
Rab25, a member of Rab family of small GTPases, is associated with progression of various types of human cancer including lung cancer that is the leading cause of cancer-associated deaths around the globe.

Methods:
Figure 1In this study, we report the gene therapeutic effect of short hairpin Rab25 (shRab25) on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorgenesis in female A/J mice. Initially, Mice (six-week-old) were injected with single dose of NNK (2 mg/0.1 ml saline/mouse) by intraperitoneal injection to induce the tumor. 8 weeks later, shRab25 was delivered with GPT-SPE (glycerol propoxylate triacrylate (GPT) and spermine) complex into tobacco-induced lung cancer models through a nose-only inhalation system twice a week for 2 month.



Results:
Figure 1Remarkably, aerosol-delivered shRab25 significantly decreased the expression level of Rab25 and other prominent apoptosis related proteins in female A/J mice. The apoptosis in these mice were determined by detecting the expression level of Bcl-2, PCNA, Bax and further confirmed by TUNEL assay.



Conclusion:
Our results strongly confirm the tumorigenic role of Rab25 in tobacco carcinogen induced-lung cancer and hence demonstrate aerosol delivery of shRab25 as a therapeutic target for lung cancer treatment.

Background:
GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.

Methods:
A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).

Results:
165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.

Conclusion:
RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.

Abstract not provided

Background:
EGFR tyrosine kinase (TKI) showed better progression free survival (PFS) in EGFR-mutant non-small cell lung cancer (NSCLC), but the overall survival (OS) benefit were not clear so far. Treatment sequence may contribute to OS, but there are little data so far. We aimed to analyze the impact of treatment sequence of EGFR TKI and chemotherapy on outcomes in EGFR-mutant NSCLC.

Methods:
Among NSCLC patients who had EGFR exon 18–21 mutation test results between 2009 and 2014 at Seoul St. Mary’s Hospital, 114 patients who had recurrent or metastatic disease, EGFR mutation positive excluding T790M mutation, and received both EGFR tyrosine kinase inhibitor (TKI) and chemotherapy as the 1[st] or 2[nd] line of treatment were included. Patients were categorized into two groups according to the treatment sequence: 1[st] line EGFR TKI followed by chemotherapy (group A), 1[st] line chemotherapy followed by EGFR TKI (group B). The median follow-up duration was 64.6 (15.8–202.8) months.

Results:
Among total 114 patients, 69 patients received EGFR TKI first and then chemotherapy (group A), and the remaining 45 patients received vice versa (group B). Group A was younger (P = 0.029) and less frequently received platinum-doublet agents than Group B (P <0.001). Performance status and EGFR mutation status were not different. Overall response or disease control rate were significantly better for EGFR TKI comparing to chemotherapy regardless of treatment sequence. However, PFS on both treatment were longer in group B (P = 0.008), especially for patients with exon 19 deletion (P = 0.002). On multivariate analyses, performance status (P = 0.006 for PFS, P <0.001 for OS) and treatment sequence [hazard ratio (HR) = 0.027, P = 0.027 for PFS; HR = 0.64, P = 0.065 for OS] were related to prognosis.

Conclusion:
For exon 19 deletion subtype of EGFR-mutant NSCLC patients, the sequence of cytotoxic chemotherapy followed by EGFR TKI showed better PFS comparing with the reverse sequence, EGFR TKI followed by cytotoxic chemotherapy . We will present the data from larger cohorts the WCLC meeting.

Background:
AC0010 was designed specifically to inhibit EGFR active mutations and the T790M acquired resistant mutation. The purpose of the study is to determine the safety, antitumor activity and recommended phase II dose of AC0010 in T790M-postitive NSCLC patients after the first generation EGFR TKIs treatment.

Methods:
This is a dose escalation and expansion phase I/II study. Oral AC0010 was administered on a 28-day cycle with the starting dose at 50 mg BID. In any given dose cohort, if 1 out of 3 patients was evaluated as PR at the first cycle, and no DLT determined, up to 20 patients will be enrolled. Plasma samples were collected to evaluate pharmacokinetics of AC0010. T790M in biopsy samples was detected by a central laboratory. NCT02330367.

Results:
As of 10 Jul 2016, 136 patients have been treated across 7 cohorts (50, 100, 150, 200, 250, 300, and 350 mg BID). At the 30 Jun 2016 cutoff, 124 pts were evaluable. MTD has not been reached. The most common adverse events (AE) regardless of study drug relationship were diarrhea (38%), rash (26%) and ALT/AST elevation. Most AEs were grade 1 and 2. The most common Grade 3/4 drug-related AE was diarrhea (2%) rash (2%) and ALT/AST elevation (4%, 2%). All patients with AEs of the grade 3/4 were recovered after either stopped the treatment or reduced the dose. As of the cutoff date, there is no Grade 2,3 hyperglycemia, and grade 3 QTc prolongation. RECIST responses were observed at all dose levels except 50 mg BID. Amongst 124 evaluable patients in all cohorts, ORR (including unconfirmed responses) and disease control rate (DCR) was 44% and 85% respectively. In the dose cohorts between 150 mg BID and 300 mg BID (n=95 pts), the ORR and DCR were 51% and 89%. PK shows rapid absorption with a T~max~ of 2-4h and a median T1/2 of 8 h. At 300 mg BID, total 32 patients were treated and ORR and DCR are 53% and 90% respectively. Based on the efficacy, safety and PK results, the 300 mg BID was selected as RP2D. The phase II, AEGIS-1 study has started.The Phase II result will be presented.

Conclusion:
AC0010 shows a safe profile and antitumor activity against T790M mt NSCLC. Phase II, AEGIS-1 study is ongoing to evaluate therapeutic outcomes as a second line treatment for T790M positive NSCLC patients. Clinical trial information: NCT02330367

Background:
Approximately 10% of EGFR mutant NSCLCs have an in-frame insertion in exon 20 of EGFR resulting in innate resistance to 1[st] generation TKIs. The reported response rate of patients with EGFR exon 20 insertions to gefitinib and erlotinib is 5% with a median progression free survival of 1.5 months. It has been shown that exon 20 insertions stabilize the active conformation of EGFR and increase affinity to ATP over TKIs. We hypothesize that exon 20 insertions induce conformational changes to the drug binding pocket resulting in EGFR TKI resistance which can be overcome by covalently binding TKIs.

Methods:
Ba/F3 cells expressing 7 different clinically observed EGFR exon 20 insertion mutations spanning the helix (residues 763-766) and loop (residues 767-773) regions were generated and screened against 1[st], 2[nd], and 3[rd] generation EGFR inhibitors including erlotinib, gefitinib, afatinib, dacomitinib, neratinib, poziotinib, ibrutinib rocilentinib, EGF816, and osimertinib. Computational modeling was conducted to analyze the conformational changes and drug binding affinity.

Results:
In Ba/F3 cells with EGFR exon 20 insertions, most 1[st] and 3[rd] generation TKIs failed to inhibit growth of EGFR exon 20 insertions after residue 767 with IC~50 ~values above 100nM. However, poziotinib significantly inhibited cell growth of all EGFR exon 20 insertions tested across the helix and loop regions with an average IC~50~ value of 2.9nM, as compared to osimertinib and rocilentinib (IC~50~ values =103nM and 850nM, respectively). Further characterization using three-dimensional modeling revealed that exon 20 insertions induce conformational changes which cause a decreased affinity for 1[st] generation TKIs and steric hindrance of C797 reducing the ability of 3[rd] generation TKIs to covalently bind. A significant shift of the c-helix and p-loop result in a sterically hindered binding pocket. Therefore, the smaller, more flexible 1,2-dichloro-3-fluorobenzene terminal group of poziotinib can overcome the structural changes induced by the exon 20 insertions, whereas the ridged 1-methylindole terminal group of osimertinib cannot.

Conclusion:
EGFR exon 20 insertions induce a shift of the p-loop and c-helix resulting in steric hindrance of the binding pocket thereby preventing binding of 1[st] generation and 3[rd] generation EGFR inhibitors including rocilentinib and osimertinib. A smaller, more flexible inhibitor such as poziotinib can overcome the steric hindrance of the drug binding pocket. Currently, in vivo studies of the EGFR D770insNPG GEMM, and EGFR H773insNPH PDX model with poziotinib are underway, and a clinical trial testing poziotinib in EGFR exon 20 mutant NSCLC patients will begin enrollment this year.

Abstract not provided

Background:
MET alterations leading to exon 14 skipping occur in ~4% of non-squamous non‑small cell lung cancer (NSCLCs) and 20–30% of sarcomatoid lung carcinomas, resulting in MET activation and sensitivity to MET inhibitors in vitro.[1–4] Crizotinib, initially developed as a MET inhibitor, is currently approved for the treatment of ALK-rearranged and ROS1-rearranged advanced NSCLC. We present crizotinib antitumor activity and safety data in patients (pts) with MET exon 14-altered advanced NSCLC.

Methods:
Advanced NSCLC pts positive for MET exon 14-alteration status determined locally by molecular profiling were enrolled into an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195) and received crizotinib at a starting dose of 250 mg BID. Objective responses were assessed using RECIST v1.0.

Results:
As of the data cut-off of Feb 01, 2016, 21 pts with MET exon 14-altered NSCLC received crizotinib treatment (18 response-evaluable, 3 not yet evaluable). Median age was 68 y (range: 53−87). Tumor histology was: 76% adenocarcinoma, 14% sarcomatoid adenocarcinoma, 5% adenosquamous carcinoma, and 5% squamous cell carcinoma. Sixty-two percent (62%) of pts were former-smokers, 38% never-smokers, and there were no current smokers. Duration of treatment ranged from 0.2 to 12.2 mo, with 76% of pts (16/21) still ongoing. Five pts discontinued treatment (1 due to AE, 3 due to clinical or disease progression, and 1 preferred alternative treatment formulation). PRs were observed in 8 pts, for an objective response rate of 44% (95% CI: 22–69); 9 pts had stable disease. Median time to response was 7.8 weeks (range: 7.0–16.3), which was the approximate time of the scheduled first on treatment tumor scans for patients. Median progression-free survival could not be calculated. The most common (≥25%) treatment-related AEs (TRAEs) were edema (43%) diarrhea (33%), nausea (33%), vision disorder (33%), and vomiting (29%). Most TRAEs were grade 1/2 in severity and consistent with the known safety profile of crizotinib. Four grade 3 TRAEs (edema, bradycardia, anemia, and weight increased) and no grade 4 or 5 TRAEs were reported. Enrollment of pts with MET exon 14-altered NSCLC continues, and updated data will be available at the time of presentation.

Conclusion:
Crizotinib has clinically meaningful antitumor activity in pts with MET exon 14-altered advanced NSCLC. The drug has a tolerable AE profile, consistent with that previously reported for pts with ALK-rearranged or ROS1-rearranged advanced NSCLC. Further study of crizotinib in this pt population is warranted.

Background:
Lung-MAP (S1400), is a master protocol that incorporates genomic testing of tumors through a next generation sequencing (NGS) platform (Foundation Medicine) and biomarker-driven (matched) therapies for patients with squamous cell lung cancer (SCCA) after progression on first-line chemotherapy.

Methods:
The Lung-MAP trial, activated June 16, 2014, includes 3 matched- and 1 non-match study. Matched studies include: S1400B evaluating taselisib, a PI3K inhibitor, S1400C evaluating palbociclib, a CDK 4/6 inhibitor and, S1400D evaluating AZD4547, an FGFR inhibitor. The non-match study S1400I tests nivolumab + ipilimumab vs. nivolumab. Two studies have closed: S1400E evaluating rilotumumab an HGF monoclonal antibody + erlotinib closed 11/26/2014 and S1400A evaluating MEDI4736 in non-match pts, closed 12/18/2015.

Results:
From June 16, 2014 to June 15, 2016, 812 pts were screened and 292 pts registered to a study: 116 to S1400A, 27 to S1400B, 53 to S1400C, 32 to S1400D, 9 to S1400E and 55 to S1400I. Demographics: Screening was successful for 705 (87%) of screened eligible pts. Median age 67 (range 35-92); male 68%; ECOG PS 0-1 88%, PS 2 10%; Caucasian 85%, Black 9%, other 5%; never/former/current smokers 4%/58%/36%. Table 1 displays biomarker prevalence; 39% of pts matched; 33.9%, 4.8%, and 0.3% with 1, 2, and all 3 biomarkers, respectively. Tumor mutation burden (TMB) was available for 636 (90.4%) of eligible pts. The distribution of TMB is: 126 (19.8%) low (≤5 mutations Mb), 415 (65.1%) intermediate (6-19 mutations/Mb), and 96 (15.1%) high (≥20 mutations/Mb). The median TMB was 10.1.

Conclusion:
Genomic screening is feasible as part of this master protocol designed to expedite drug registration, confirm anticipated prevalence of targeted alterations in SCCA and reveal intermediate or high TMB in most (80.2%) pts. Treatment results are not yet available as patients continue to accrue. Clinical trial information: NCT02154490

Background:
Brain metastases develop in 25–40% of patients with NSCLC. Osimertinib is an oral, potent, irreversible EGFR-TKI, selective for both sensitising (EGFRm) and T790M resistance mutations. Preclinical and early clinical evidence support central nervous system (CNS) penetration and activity of osimertinib. Two Phase II studies (AURA extension [NCT01802632] and AURA2 [NCT02094261]) evaluating the efficacy and safety of osimertinib are ongoing. We present a pre planned subgroup analysis assessing pooled CNS response from these two studies; data cut-off (DCO) was 1 November 2015. An earlier pooled analysis from these two studies (1 May 2015 DCO) showed the objective response rate (ORR) in patients with CNS metastases was consistent with ORR in the overall patient population.

Methods:
Patients with advanced NSCLC who progressed following prior EGFR-TKI therapy with centrally-confirmed T790M positive status (cobas® EGFR Mutation Test) received osimertinib 80 mg once daily (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment. CNS efficacy was assessed in an evaluable for CNS response analysis set, which included patients with at least one measurable CNS lesion on baseline brain scan (RECIST v1.1) by blinded independent central neuroradiology review (BICR). Effect of prior radiotherapy on CNS response was assessed.

Results:
As of 1 November 2015, 50/192 patients with baseline brain scans had at least one measurable CNS lesion identified by BICR. Baseline demographics were broadly consistent with the overall patient population. Confirmed CNS ORR was 54% (27/50; 95% CI: 39%, 68%), with 12% complete CNS response (6/50 patients). The median CNS duration of response (22% maturity) was not reached (95% CI: not calculable [NC], NC). The estimated percentage of patients remaining in response at 9 months was 75% (95% CI: 53, 88). CNS disease control rate (DCR) was 92% (46/50; 95% CI: 81%, 98%). Median time to first response was 5.7 weeks (range: 5.6–6.6). Median best percentage change from baseline in CNS target lesion size was 53% (range: -100% – +80%). Median follow up for CNS progression-free survival (PFS) was 11 months; the median CNS PFS was not reached (95% CI: 7, NC). At 12 months, 56% (95% CI: 40%, 70%) of patients were estimated to remain on study, alive and CNS progression-free. CNS response was observed regardless of prior radiotherapy to the brain.

Conclusion:
Osimertinib demonstrates durable efficacy in patients with T790M NSCLC and measurable CNS metastases, with a CNS response rate of 54% and a DCR of 92%.

Abstract not provided

Background:
The identification and development of tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have revolutionized and greatly improved the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). Unfortunately, acquired resistance (AR) to these agents remains a major clinical problem hindering durable responses. Although significant work has been done to identify particular mechanisms of acquired resistance, little is known regarding the global mutational landscape of EGFR mutant tumors before therapy or at the manifestation of acquired resistance.

Methods:
Using specimens obtained in the IRB approved, Yale Lung Rebiopsy program, we completed whole exome sequencing of 15 EGFR mutant tumors with paired tissue obtained pre-treatment and at the time of AR to EGFR TKIs. An additional 5 unpaired AR samples were also analyzed. The mutational burden and copy number profile of the specimens were studied.

Results:
We found that the mutational burden of pre-treatment EGFR mutant tumors varies widely between tumors. TKI treatment, however, does not significantly alter the overall or non-synonymous mutation load at AR. Interestingly, EGFR[L858R]tumors had a significantly higher mutation burden at acquired resistance to EGFR TKIs than EGFR[Δ19] tumors. The higher mutation burden in EGFR[L858R] tumors compared to those harboring EGFR[Δ19 ]mutations was further confirmed through analysis of TCGA data. Recurrently altered genes shared in the pre- and AR specimens include TP53, EGFR and AKT1. Alterations in EGFR (T790M), MYCBP2, WHSC1L1, AXL, MET, HGF, MYC and NTRK1 were found at exclusively at AR.

Conclusion:
Collectively, these data provide valuable insight into the mutational landscape of EGFR mutant NSCLCs as they evolve on TKIs and identify potential resistance candidate genes for further investigation.

Background:
Brain metastasis in non-small cell lung cancer (NSCLC) develop in 20-40% of all patients and represent a major cause of NSCLC morbidity and mortality. The mechanisms driving metastatic potential across the blood-brain-barrier remain poorly understood.

Methods:
Affymetrix microarray was performed on RNA extracted from 75 pairs of snap-frozen primary lung adenocarcinoma and matched normal lung tissue. Changes in gene expression from the primary lung adenocarcinomas that did not ever metastasize to brain over up to 15 years of follow up were compared to the lung adenocarcinomas that ultimately seeded a brain metastasis. From these 75 patients, tissue from 5 paired snap-frozen brain metastases was also available and gene expression changes between the primary lung adenocarcinomas and matched brain metastases were investigated to identify genes and pathways of interest in the development of brain metastasis. Affymetrix Transcriptome Analysis Console software was used for data analysis and interpretation with fold changes >2.0 and p-value of <0.05 for significance.

Results:
From the 75 patients 20 (27%) ultimately developed a brain metastasis from their primary lung adenocarcinoma and 55 (73%) were followed long term without development of brain metastasis. Microarray identified 71 genes that were differentially expressed in lung adenocarcinomas that later produced brain metastasis. S100 calcium binding protein, RAP1GAP, GPR160, and immunoglobins were among the upregulated genes in primary lung adenocarcinomas that developed brain metastasis. Within the matched sets of brain metastasis, hierarchical clustering showed clear distinction in expression patterns comparing brain metastasis verses normal lung, as well as primary adenocarcinomas verses normal lung. 267 genes were identified to be significantly differentially expressed between paired brain metastasis and primary lung adenocarcinomas. Significant changes in focal adhesion, angiogenesis, matrix metalloproteinase pathways, and immunoglobulins were found in the brain metastasis compared with the paired primary lung tumor.

Conclusion:
This study represents the largest microarray analysis of snap frozen pairs of primary lung adenocarcinoma and brain metastasis to date. S100 calcium binding protein, RAP1GAP, GPR160 genes, immunoglobulins, and focal adhesion, angiogenesis, and matrix metalloproteinase pathways were among the upregulated genes in primary lung adenocarcinomas that developed brain metastasis.

Background:
There are still limited data on the extent of intratumoral heterogeneity of cancer gene mutations and genome-wide copy number aberrations between primary tumors and metastases in non-small cell lung cancers (NSCLC). Deconvolution of the intermixture of tumor and stromal components remains a major challenge for such analysis. To overcome these limitations, we applied a refined nuclei flow sorting approach on matched longitudinal biopsies (primary/metastasis) from pulmonary adenocarcinomas.

Methods:
Multiparameter Ploidy Profiling (MPP) comprises the isolation of nuclei from frozen or formalin-fixed and paraffin embedded (FFPE) tissues, followed by multiparameter flow sorting by DAPI for DNA content (ploidy) and TTF1 as a lineage marker to enrich for tumor cell nuclei. Homogenous TTF1 expression was ascertained by immunohistochemistry. Sorted populations were subjected to genomic profiling by high resolution aCGH and NGS with the Ion Torrent™ Comprehensive Cancer Panel. This approach allows for the detection of genome-wide copy number aberrations and provides all exon-coverage of 409 well-known cancer genes. Sequencing was performed with a mean depth of 965x.

Results:
MPP was successfully applied on 44 frozen or FFPE tissue specimens from 19 patients. Clonally unrelated secondary primaries were found in three patients, defined by the absence of both shared copy number (CN) transition and somatic mutations. The concordance rate between primary tumor and corresponding metastases was 65.2% and reached 85.5% for mutations and copy number amplifications/deletions in the top 12 affected genes (including CDKN2A, KRAS, ATM, KEAP1, EGFR and STK11). The correlation of the allele frequencies between primary tumors and metastases was linear (r=0.87, p<0.001), irrespective of the time interval between the tissue resections. Overall, ploidy was not different between primary tumors and metastases. Additionally, the metastases did not bear a higher burden of private events (CN transitions and somatic mutations) than the primary tumors.

Conclusion:
MPP is a powerful method to increase the precision of downstream analysis due to unprecedented purity of tumor DNA. Our data argue for a high concordance rate of mutations and CN transitions between primary tumors and their corresponding metastases. Intriguingly, the ploidy remains remarkably stable during progression even after long time-periods, which suggests chromosomal stability with a limited degree of macroevolutionary shifts over time and space. Taken together, our data suggest the presence of at least two evolutionary patterns: 1) early/branched and 2) late/linear progression, with a continuum from high to low genetic divergence of the primary tumor and metastases to their most recent common ancestor.

Background:
Evidence supports the existence of genomic discrepancy in multiple primary lung cancers (MPLC). This study identified genomic alterations of MPLC by targeted next-generation sequencing (NGS) and assessed whether inter-tumor heterogeneous somatic mutations could be detected in circulating tumor DNA (ctDNA).

Methods:
94 tumor samples originating from 45 clinically considered multiple primary lung cancer patients (including multiple solid tumors and multifocal tumors) were available for genomic alteration analysis (NCT02833467). DNA and RNA were extracted from fresh tumor tissue or formalin-fixed, paraffin-embedded tissue. 143 cancer-related genomic alterations including single nucleotide variations (SNVs), short insertions and deletions (InDels), copy number variations (CNVs) and gene rearrangements were identified by Oncomine Comprehensive Panel (OCP), Ion Torrent techniques. High frequency clinical relevant mutations (EGFR, KRAS, BRAF, PIK3CA) were identified in circulating tumor DNA by droplet digital PCR (ddPCR).

Results:
The median age of the patients was 61 years and 71% were female. 91% patients were stageⅠ. Molecular analysis performed with a good quality. One hundred and thirty-six mutations and twenty four fusions were detected. Alterations were found in 81 of the 94 lesions (86%), involving EGFR (50.0%), TP53(10.6%), KRAS (8.5%), BRAF (4.3%), ERBB2 (4.3%), PIK3CA(2.1%),PTEN(2.1%),ALK (2.1%),ROS1 (1.1%), RET (7.4%), NF2(2.1%), CDKN2A(2.1%), APC(5.3%), ATM(5.3%),etc. Forty-two (93.3%) patients harbored discordant gene distribution between multiple tumors. CNVs were much higher in patients with more than 2 lesions. Forty-eight lesions harbored detectable somatic mutations by ddPCR, in which 30(62.5%) lesions were identified positive in circulating tumor DNA. 76.9% (20/26) solid dominant lesions were positive, which is significantly higher than ground glass opacity(GGO) dominant lesions(45.5%, 10/22, p=0.037). Figure 1



Conclusion:
Targeted NGS by OCP is feasible to detect multiple mutations simultaneously in early stage multiple primary lung cancers. Circulating tumor DNA has the ability to detect discordant somatic mutations and may represent of the overall mutational load and inter-tumor heterogeneity in multiple solid lung tumors.

Abstract not provided

Background:
Morphological and genetic heterogeneity predict prognostics, impede continuous responses to systemic regimens and foster inevitable treatment failure. But how morphological and genetic features evolve in tumorigenesis still remains controversial.

Methods:
Single(n=1112) and multiple(n=91) primary adenocarcinoma patients receiving surgeries with specific prominent subtypes were screened. Six patients with mixed ground glass opacities and maximum cross-sections of primary tumors were randomly selected. Intra-tumoral regions with different subtypes and imaging densities related to relative distributions, were resected for target region sequencing and further molecular evolutionary analyses.

Results:
Clinical data revealed certain preferences of driver gene mutations and discrepant survival benefits. Driver gene heterogeneity was higher in multiple primary lung cancers(51.7%, 15/29) than single ones(1.4%, 1/70). Copy number alterations implied more consistence within the same subtype and tended to be higher in lepidic subtype. Somatic nucleotide variants revealed highest homogeneity between different regions within the same tumor lesion. Sequencing data indicated larger fractions of geographically ubiquitous mutations than pathologically ones, and higher mutation frequencies of shared mutations in the lepidic than acinar subtype. Phylogenetic trees exhibited higher geographically private mutation burdens of lepidic than acinar region in lesions with mixed subtypes; while in lesions with the same subtype, the central region bore higher mutation burdens than in the periphery, implying a linear accumulation of genetic mutations. Functional analyses of private mutations verified that lepidic subtypes promoted intracellular organism and structure development, promoting growth and proliferation. Acinar subtypes lead to metabolic and signaling transduction pathway. Preferences of divergent pathway alterations delineated branched evolutions from low to higher grade subtypes. Figure 1



Conclusion:
We propose a model that the same morphological subtype evolves with a linear accumulation and mixed subtypes in branched evolutionary trajectories with preferences to pathway alterations. Couple with relatively geological distributions of different subtypes, tumor microenvironment might contribute more to genetic instability and thus tumor evolutions.

Background:
Patient-derived tumor xenografts (PDXs) have high fidelity to their histological origins, and maintain the molecular heterogeneity and genetic aberrations of the donor patient tumors more faithfully than established in non-small cell lung cancer (NSCLC) cell lines. This study evaluated whether our panel of PDX models recapitulate known cancer-related gene mutations.

Methods:
Whole-exome sequencing was completed on 103 NSCLC PDX models, 47 adenocarcinoma (AdC) and 56 squamous (SqCC), with a mean coverage of 84x. After filtering for contaminating mouse reads, the exome data were aligned using the Burrows-Wheeler Aligner, processed using the standard GATK pipeline, and mutations were identified using MuTect. Additional filtering using dbSNP, ExAC and ESP was performed for cases without corresponding normal adjacent lung exome data (n = 80). The identified mutations were compared to 1260 frequently mutated cancer-related genes, which were compiled from a panel of cancer-related mutated genes (555) and a panel of lung cancer-specific mutated genes (1082).

Results:
High rates of somatic mutations were observed in both AdC (mean of 12.4 mutations/megabase) and SqCC (mean of 11.7 mutations/megabase) PDX models. Compared to the rates observed in primary lung cancers in The Cancer Genome Atlas studies (mean of 8.9 mutations/megabase in AdC; 8.1 mutations/megabase in SqCC), these values appear higher, but may be inflated due to the lack of data from corresponding normal tissues. AdC models had a total of 953 mutated genes (median: 57 genes/model; range: 5-307), while SqCC models were characterized by 1007 mutated genes (median: 55 genes/model; range: 21-354). Specific mutation frequencies were compared to those determined in a recent study involving genomic alterations in human primary lung AdC and SqCC (Nature Genetics 2016; 48; 607–616). This comparison, based on mutated genes common in both studies, demonstrated significant correlation of the frequencies in 791 genes in AdC (ρ=0.78; p<2.2×10[-16]), as well as in 799 genes in SqCC (ρ=0.73; p<2.2×10[-16]). Three genes that were reported as significantly mutated in both AdC and SqCC primaries, and had higher mutation frequencies in SqCC, were also observed to be higher in our SqCC PDX models (TP53: 48.9% in AdC vs. 55.4% in SqCC; CDKN2A: 4.3% vs. 7.1% and PIK3CA: 2.1% vs. 23.2%); however, the statistical significance of these differences needs to be tested.

Conclusion:
Mutation landscapes in cancer genes are recapitulated in AdC and SqCC PDX models. The fidelity of these landscapes in matched patient primary tumour samples is being investigated.

Background:
CT imaging is standard-of-care for surveillance following definitive lung cancer therapy but is complicated by difficulties in distinguishing recurrence from treatment-related fibrosis and inability to detect microscopic disease. CAPP-Seq is a novel blood-based assay that uses next-generating sequencing to quantitate circulating tumor DNA (ctDNA). We performed a prospective study to compare disease surveillance by CAPP-Seq to CT imaging after definitive treatment for localized lung cancer.

Methods:
We prospectively enrolled 34 patients treated definitively for non-metastatic primary lung cancer at Stanford University between June 2010 and September 2015. Our cohort included 22 (64.7%) patients with stage III, 6 (17.6%) patients with stage II and 6 (17.6%) patients with stage I disease. All patients received pre-treatment evaluation by thoracic CT and PET/CT scans as well as ctDNA quantitation by CAPP-Seq. Twenty-one (61.8%) patients were treated with conventionally fractionated radiotherapy, 8 (23.5%) with hypofractionated radiotherapy, 3 (8.8%) with surgery, and 2 (5.9%) with both surgery and radiotherapy. Twenty-five (73.5%) patients received platinum-based doublet chemotherapy. Following treatment completion, patients underwent disease surveillance by CT scans and CAPP-Seq every 3-6 months. CT scans were evaluated using RECIST v1.1. CAPP-Seq was performed at each time point as previously described (Newman et al, Nature Medicine 2015 and Nature Biotechnology 2016).

Results:
A total of 222 scans and 107 plasma samples were analyzed. Median follow-up time was 21.1 months and median overall survival was 30.0 months. Eighteen (52.9%) patients progressed based on RECIST criteria and CAPP-Seq detected ctDNA at or before the time of RECIST progression in all patients (18 of 18; 100%) with a lead-time of 121 +/- 39 days (mean +/- SEM). For 13 of 16 (81.3%) evaluable patients who progressed, ctDNA was detected at the first time-point after completion of all treatment (median 2 months post treatment), indicating detection of minimal residual disease. Two-year overall survival for patients with detectable post-treatment ctDNA was 25.3% versus 92.9% for those with no detectable post-treatment ctDNA (p=0.0003, HR=6.8, 95% CI=2.6-17.9). This difference remained significant in multivariate models controlling for stage, age, sex, and tumor volume (P=0.01).

Conclusion:
We found that noninvasive ctDNA profiling appears to be useful for evaluating response to lung cancer treatment. Quantitation of ctDNA allowed identification of minimal residual disease, which was strongly associated with outcome. These results suggest that ctDNA assessment after definitive intent treatment could potentially be used to guide risk-adapted treatment strategies for localized lung cancer.

Abstract not provided

Background:
Tumor-associated fibroblasts (TAFs) are increasingly regarded as essential co-conspirators for tumor progression in all solid tumors including non-small cell lung cancer. While most TAFs exhibit activation markers indicative of a myofibroblast-like phenotype, senescence markers have been reported in a growing list of selected cancer types only. However, the presence of senescent TAFs in lung cancer remains undefined. Assessing senescence in lung TAFs is important because previous studies have reported that senescent TAFs enhances tumor growth, which is in marked contrast with the widely accepted tumor-suppressive role of senescence in cancer cells.

Methods:
We examined common senescence markers in patient derived lung TAFs from the 3 major non-small cell lung cancer (NSCLC) subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Given the difficulties in gathering LCC-TAFs owing to the lower prevalence of LCC compared to the other subtypes, primary fibroblasts from 2 independent fibroblast collections were used. Senescence markers included senescence-associated beta-galactosidase, permanent growth arrest and spreading.

Results:
We found an enrichment of the myofibroblast-like phenotype in TAFs regardless their histologic subtype, yet senescence was observed in LCC-TAFs only regardless their neuroendocrine status. Likewise, co-culturing normal lung fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to induce senescence, and this induction was prevented in the presence of an antioxidant, indicating that it is mediated through oxidative stress. Remarkably, senescent fibroblasts provided growth and invasive advantages to LCC cells in culture and in vivo beyond those effects provided by control (non-senescent) fibroblasts.

Conclusion:
Our findings expand recent evidence that challenges the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless their histologic subtype. Of note, because LCC often distinguishes itself in the clinic by its aggressive nature, our findings support that senescent or senescent-like TAFs may contribute to the selective aggressive behavior of LCC tumors.

Background:
Next-generation sequencing techniques have allowed the discovery of driver mutations in non-small cell lung cancer (NSCLC) that can be translated into advances in cancer diagnosis and treatment. However, specific oncogenic alterations are still unknown in a high proportion of NSCLC patients, that therefore cannot benefit from targeted therapies. The challenge is to identify new genetic alterations that allow the use of molecular-targeted therapies. In previous studies from our group (Aramburu et al. BMC Genomics 2015), the analysis of tumor molecular profiles from patients with NSCLC allowed us to identify the DNA copy number amplification of YES1 kinase (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) as a prognostic marker in lung cancer. YES1 kinase is member of the Src family of non-receptor protein tyrosine kinases that are involved in the regulation of cell growth, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. The aim of this project is to evaluate if YES1 is a driver gene in NSCLC, and if targeting its activation may be a potential new therapeutic strategy.

Methods:
We first evaluated the prognostic role of YES1 protein expression in two independent series of 76 and 234 NSCLC patients, respectively. In both series, the multivariate analysis revealed that high YES1 expression is an independent poor prognostic factor for overall survival (CUN series HR: 3.416 [0.933-12.508]; MD Anderson series HR: 1.570 [1.032-2.391]). We next evaluated the effect of YES1 knockdown in 5 NSCLC cell lines with YES1 amplification and overexpression, and in 3 cell lines without YES1 amplification and with low protein expression. YES1 downregulation by two specific siRNAs decreased proliferation and cell survival only in those cells overexpressing YES1. Congruently, YES1 inhibition led to apoptosis only in those cells.

Results:
Consistent with these results, constitutive overexpression of YES1 in cells with low YES1 expression significantly enhanced cell proliferation. We next evaluated the effect of the multitarget Src kinase inhibitor dasatinib on the proliferation of NSCLC cell lines with high (8 cell lines) or low (4 cell lines) YES1 expression. Dasatinib dramatically inhibited proliferation in high YES1-expressing cell lines, whereas low YES1 cell lines were more resistant to dasatinib treatment (GI50s were four orders of magnitude higher in resistant cells).

Conclusion:
In conclusion, our results indicate that YES1 is a promising therapeutic target in NSCLC. Furthermore, amplification and high expression of YES1 may define a subset of patients who may potentially benefit from dasatinib treatment.

Background:
Akt2 (Protein Kinase B isoform 2) is an essential protein, which is involved in tumor cell proliferation, differentiation, motility, and cell death in non small cell lung cancer (NSCLC). Raf1 is also a key protein regulating the functions in NSCLC. However, the relationships between Akt2 and Raf1 are unknown. This study aimed to investigate the influence of Akt2 knockdown and its interaction with overexpression Raf-1 in non-small cell lung cancer cells.

Methods:
Small interfering RNA was used to knockdown Akt2 and lentivirus was introduced to overexpress Raf1 in H1299, A549, Sk-mes and H460 cell lines. Western blot was performed to investigate expression levels of relevant proteins in the pathway. Cell survival, proliferation and apoptosis were evaluated in vitro and vivo. Then we examined Akt2 and Raf1 expressions via immunohistochemistry (IHC) in 65 NSCLC patients.

Results:
Knockdown of Akt2 suppressed cell proliferation, arrested tumor cells in G0/G1 phase and induced apoptosis in all cell lines distinctively. Raf1 phosphorylation was also inhibited after Akt2 knockdown in the cell lines. When Raf1 overexpression combined with Akt2 knockdown in these cell lines, cell proliferation was enhanced, and apoptosis rates was decrease compared with Akt2 knockdown alone. These trends were also observed in vivo experiments. Furthermore, the downstream proteins of Raf1, such as MEK, ERK, p-MEK and p-ERK were observed decrease in Akt2 knockdown groups. Of all NSCLC specimens, Akt2(+)/Raf1(+) patients had the worst prognosis of 5-year overall survivals. Figure 1



Conclusion:
Our study demonstrates that knockdown of Akt2 suppresses tumorigenesis by attenuating cell proliferation, increasing apoptosis and interfering cell cycle in non-small cell lung cancer. Raf1 overexpression partly offsets these effects by enhancing cell proliferation, suppressing apoptosis and affecting downstream proteins. Thus, there may be existing Akt2/Raf1 pathway in NSCLC, which plays an important role in tumorigenesis.

Abstract not provided

Background:
Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, based on low intensity alternating electric fields delivered non-invasively using a portable, home use, medical device. In-vitro, human mesothelioma cells were found to be highly susceptible to TTFields. TTFields have been shown to extend survival of patients with glioblastoma when added to standard of care chemotherapy.

Methods:
The trial will accrue a total of 80 patients with unresectable, previously untreated mesothelioma. Patients are treated with TTFields in combination with pemetrexed and cisplatin or carboplatin. Continuous TTFields at 150 kHz for a minimum of 18 hours/day are applied to the thorax together with standard dosing of chemotherapy. Inclusion criteria include ECOG 0-1, pathological evidence mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients are followed q3 weeks (CT scan q6 weeks) until disease progression. The primary endpoint is overall survival (OS) and secondary endpoints are response rate, progression free survival (PFS) and treatment-emergent toxicity. This prospective, single arm study assumes that historical control has an exponential survival distribution and a median survival of 12.1 Months (Vogelzang et al.). The sample size provides 80% power with a two sided alpha of 0.05 to detect a Hazard Ratio of 0.67 for OS, compared to the historical data.

Results:
To date, 42 patients have been enrolled in the trial with an average follow up time of 11.5 months. Median age is 67±9 (range 43-78), 79% are male and 48% smokers. 14% (6 patients) have metastatic disease and 33% (14 patients) have an ECOG score of 1. Median survival has not been reached at this time. The 12-month survival rate is 79.7% (95% CI 57.2-91.2) and median PFS is 7.3 months (95% CI 5.6-NA). No device-related serious adverse events (AEs) have been reported to date. Expected TTFields-related dermatitis was reported in 55% (23 patients). Only 2 patients had grade 3 dermatitis. The following severe (grade 3-4) systemic AEs were reported: hematological (26%), hepatobiliary (2%), respiratory (2%).

Conclusion:
These interim results of the ongoing STELLAR study demonstrated no safety concerns for the combination of TTFields to the thorax together with standard chemotherapy for previously untreated mesothelioma patients. The 12-month survival rate was significantly higher, and PFS longer, than that of historical controls reported by Vogelzang et al. Final analysis of the study will be performed after enrollment and follow up of all 80 patients in the study are completed.

Background:
Standard first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin, yielding a median overall survival (OS) of only ~1 year, thus new approaches are required. As demonstrated by the bevacizumab MAPS study, inhibition of the VEGF pathway is of interest as a treatment approach for MPM. Nintedanib is an oral, triple angiokinase inhibitor of VEGFR, PDGFR and FGFR. This study will evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with advanced MPM.

Methods:
Patients with unresectable MPM (chemo-naïve, ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomised (1:1) to receive up to 6 cycles of pemetrexed (500 mg/m[2])/cisplatin (75 mg/m[2]) on Day 1 plus nintedanib (200 mg bid)/placebo on Days 2–21. Patients without disease progression received maintenance treatment with nintedanib/placebo. The primary endpoint was progression-free survival (PFS).

Results:
87 patients were randomised to receive pemetrexed/cisplatin, plus nintedanib/placebo. Patient characteristics were comparable between the groups. PFS was longer in the nintedanib vs the placebo arm, in both the overall study population and in epithelioid patients (Table 1). Preliminary OS data also favour nintedanib. All patients experienced at least one adverse event (AE, any grade), with 7% of patients in the nintedanib arm discontinuing due to AEs, vs 15% with placebo. Serious AEs occurred in 36% vs 42% of patients in the nintedanib and placebo arms, respectively. The most common ≥grade 3 AEs occurring in nintedanib vs placebo patients were neutropenia (34% vs 10%), ALT increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%).

Conclusion:
Nintedanib plus pemetrexed/cisplatin demonstrated clinical efficacy with improved PFS and a tolerable safety profile in patients with unresectable MPM. Based on these promising findings, this Phase II study was extended to a confirmatory Phase III trial, which is currently enrolling patients. Clinical trial identifier: NCT01907100.

Background:
Millions of people have been potentially exposed to asbestos, the primary cause of malignant mesothelioma (MM). Presently, no reliable biomarkers are available to identify among potentially exposed people, those individuals who have actually been exposed and who are at high risk of MM. High Mobility Group Box Protein-1 (HMGB1) is a key mediator of asbestos-induced inflammation and MM pathogenesis. Recently, HMGB1 hyper-acetylation has been functionally associated to its active release by inflammatory cells. Here, we compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls.

Methods:
We compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls. Previously proposed MM biomarkers fibulin-3, osteopontin, and mesothelin were also blindly measured in blood collected from participants to the study.

Results:
HMGB1 serum levels reliably distinguished asbestos-exposed individuals and MM patients from unexposed controls. Moreover, the levels of total and hyper-acetylated HMGB1 were significantly higher in MM patients compared to asbestos-exposed individuals, and did not vary with tumor stage, suggesting that early lesions are also associated to increased HMGB1 levels. At a cutoff value of 2.00 ng/mL, the sensitivity and specificity of hyper-acetylated serum HMGB1 in differentiating MM patients from asbestos-exposed individuals was 100%, outperforming, in parallel experiments, other previously proposed biomarkers: osteopontin, fibulin-3, and mesothelin. When comparing MM patients to patients with other non-MM cytologically benign or malignant pleural effusion, the combination of two biomarkers, HMGB1 and fibulin-3, provided the highest sensitivity and specificity in differentiating these two groups. Moreover, we found that HMGB1 drives MM development and sustains MM progression, and we demonstrated that targeting HMGB1 inhibits MM cell growth and motility in vitro, reduced tumor growth in vivo and prolonged survival.

Conclusion:
Despite the relatively small size of our cohorts, our results are of exceptional significance and clinical relevance as they provide the first biomarker of asbestos exposure and indicate that hyper-acetylated HMGB1 is a very sensitive and specific biomarker to differentiate MM patients from individuals occupationally exposed to asbestos and unexposed controls. Moreover, our results on HMGB1 inhibitors indicate that HMGB1 targeting hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.

Abstract not provided

Background:
A 6-microRNA signature (miR-Score, Kirschner et al 2015) was previously demonstrated to show high prognostic accuracy in a series of surgical specimens (with and without induction chemotherapy). In the present study we investigated these microRNAs in an independent cohort of MPM patients all treated with induction chemotherapy followed by extrapleural pneumonectomy (EPP). The main focus of the study was to evaluate the possible effects of induction chemotherapy on microRNA expression and to refine and validate the miR-Score for use in chemo-naïve diagnostic specimens.

Methods:
We identified a cohort of 120 MPM patients who received chemotherapy followed by EPP between 1999 and 2014 at University Hospital Zurich. At present microRNA analysis (RT-qPCR) has been carried out in 34 pairs of chemo-naïve (diagnostic biopsy) and chemo-treated (EPP) specimens. Paired-samples t-test was employed to determine differences in microRNA expression pre- and post-chemotherapy. Accuracy of the miR-Score in predicting a good prognosis (>20 months survival post-surgery) was evaluated by ROC curve analysis. In addition, binary logistic regression modelling was used to build a refined miR-Score.

Results:
Applying the miR-Score to chemo-naïve diagnostic specimens revealed an area under the ROC curve (AUC) of 0.65 (95% CI: 0.46-0.84), and the same analysis on the EPP specimens gave an AUC of 0.57 (95% CI: 0.37-0.77). Therefore, the accuracy of the miR-Score was lower than observed in the previous study. However, pairwise comparison of microRNA expression before and after chemotherapy showed that although not reaching statistical significance, the levels of several microRNAs were lower following induction chemotherapy. We next employed binary logistic regression modelling on microRNA levels in chemo-naïve tissue to determine whether a refined microRNA signature less susceptible to chemotherapy-induced changes could be created. A refined miR-Score consisting of miR-221 and miR-30e, the two microRNAs least affected by chemotherapy, achieved AUCs of 0.77 (95% CI: 0.61-0.94) and 0.80 (95% CI: 0.64-0.96) in diagnostic and EPP specimens, respectively. When applied to samples from the previous study, the refined score resulted in an AUC of 0.72 (95% CI: 0.54-0.90).

Conclusion:
This validation and refinement study has shown that the expression of several miR-Score microRNAs appears to be affected by standard chemotherapy. A refined miR-Score was generated which is less susceptible to the effect of chemotherapy and may have prognostic value when applied to diagnostic specimens. Further validation in additional paired samples and investigation of the effect of cisplatin, pemetrexed and gemcitabine on microRNA expression are ongoing.

Background:
Tumor volume has been reported to be a valuable prognosticator for malignant pleural mesothelioma (MPM) survival. We wanted to assess the precision of CT scan based preoperatively measured tumor volume when correlated to the actual resected tumor weight and tumor volume after pleurectomy/decortication.

Methods:
From 10/2012 – 06/2016 the tumor weight of surgery specimens was measured in 32 patients undergoing macroscopic complete resection by (extended) pleurectomy/decortication ((e)P/D). The median tumor weight of all patients was (n=32) 443g (95-783g). In all patients tumor volume was measured in the CT or PET-CT scans performed before surgery as described previously (Frauenfelder 2011). Tumor volume of the resected specimen was additionally measured in 21 patients. Relations between tumor weight, tumor volume at surgery, CT-volume, cT stage and pT stage were analyzed using Spearman rank correlation.

Results:
Median time between CT scan and surgery was 18 days (range 1-48). The analysis revealed a moderate correlation between CT tumor volume and weight (p=0.001, correlation coefficient 0.58, CT volume and tumor volume at surgery showed strong correlation (p=0.001, correlation coefficient 0.65). No significant correlation was observed between cT stage and tumor weight (p=0.1, correlation coefficient 0.31), but a moderate correlation between cT stage and CT volume (p=0.001, correlation coefficient 0.58) as well as specimen volume (p=0.008, correlation coefficient 0.58). There was a moderate correlation of tumor weight with pT stage (p=0.02, correlation coefficient 0.42), but no correlation of CT volume (p=0.1, correlation coefficient 0.31) as well as specimen volume with the pT stage (p=0.2, correlation coefficient 0.32). Figure 1



Conclusion:
The correlation between preoperatively assessed CT tumor volume and volume of the resected specimen showed a strong correlation. To assess the prognostic role of CT measured tumor volume a correlation to prognosis has to be performed before implementation as a new T-factor.

Abstract not provided

Background:
Malignant pleural mesothelioma (MPM) is an asbestos-related tumour with poor prognosis. Since MPM is diagnosed at advanced stage due to non-specific symptoms and investigations, it is thought that only an early diagnosis will improve patient’s outcome. Breathomics allows to detect volatile organic compounds (VOCs) in breath which can be used as non-invasive biomarkers. Although we were able to discriminate MPM patients from controls using ion mobility spectrometry breathomics, we were not able to identify specific VOCs. Therefore, we aimed to identify VOCs in the breath of MPM persons and persons at risk with gas chromatography-mass spectrometry (GC-MS).

Methods:
Fourteen MPM patients, eighteen asymptomatic asbestos-exposed individuals, 16 individuals with benign asbestos-related diseases and fourteen healthy non-exposed persons were included. After 2 hours of fasting, participants breathed tidally for 5 minutes through a mouthpiece connected to a VOC filter. Subsequently, a full vital capacity was captured in a Tedlar bag of which 500 ml was immediately transferred on a Tenax[GR]-column. Samples were thermally desorbed followed by GC-MS analysis (Agilent 6890A–Thermo Focus DSQII). VOCs were manually selected in the chromatogram and standardised to an internal standard (toluene-d8). Only VOCs with a S/N-ratio>10 were used. Using SPSSv23, significant differences were searched and ROC-curves for discriminating MPM from all control groups were constructed. VOCs which had an AUC~ROC~>0.80 are reported.

Results:
114 VOCs were selected of which 17 were significantly different between MPM patients and controls. Of these, 7 had AUC~ROC~>0.80 and are possible markers for MPM diagnosis.Figure 1



Conclusion:
The large discriminative power and good sensitivity and specificity imply the possibility to use breath analysis for MPM screening. Therefore, persons exposed to asbestos with a positive test should be considered for follow-up in a cost-effective way, decreasing the need for CT-scans and radiation exposure in low-risk persons. Further work includes combining models for discrimination and validating these findings.

Background:
Monoclonal Antibodies (mAbs) against the Epidermal Growth Factor Receptor (EGFR) in association with platinum-based doublet chemotherapy have emerged as a potential first-line treatment option for advanced non-small cell lung cancer (NSCLC). This study was conducted to systematically review available data and evaluate the efficacy and toxicity of anti-EGFR mAbs plus chemotherapy vs chemotherapy alone for advanced NSCLC.

Methods:
We carried out a search on network databases and oncology conference abstracts for studies between 1990 and January 2016. Only prospective randomized clinical trials were included. Primary endpoints were overall survival (OS) and toxicity frequency. Secondary endpoints were progression-free survival (PFS) and overall response rate (ORR). Subgroup analysis was performed assessing histological subtypes, EGFR protein expression by immunohistochemistry (IHC), EGFR gene copy number by fluorescence in-situ hybridization (FISH), EGFR mutation status, and smoking status.

Results:
Seven studies (2 with necitumumab and 5 with cetuximab) were included with 5,057 patients. Compared to chemotherapy alone, significant benefits were demonstrated by the addition of anti-EGFR mAb to chemotherapy in OS (HR 0.90; 95%CI 0.84-0.95), PFS (HR 0.93; 95%CI 0.87-0.98), and ORR (OR 1.27; 95%CI 1.06-1.51). In subgroup analyses, the association of anti-EGFR mAb was associated with improved OS among patients with squamous histology (HR 0.84; 95%CI 0.76-0.92), tumours with high EGFR expression by IHC (HR 0.83; 95%CI 0.70-0.98), and smokers (HR 0.87; 95%CI 0.79-0.96). Patients with squamous histology and high EGFR expression by IHC achieved the highest benefit with the association (HR 0.71; 95%CI 0.59-0.86). The OS with the association also seemed to be higher in EGFR FISH negative and in EGFR wild-type tumours, but without statistical significance. Chemotherapy plus anti-EGFR mAb caused more grade 3 or worse adverse events (OR 1.73; 95%CI 1.50-2.00), remarkedly these known to be associated with anti-EGFR therapy, such as acne-like rash (OR 34.13; 95%CI 16.40-71.00) and hypomagnesemia (OR 6.23; 95%CI 3.04-12.77).

Conclusion:
Anti-EGFR therapy plus platinum-based doublet chemotherapy as first-line treatment demonstrated significant efficacy benefits with acceptable toxicity for advanced NSCLC. This benefit is more expressive among squamous histology with high EGFR expression. EGFR protein expression by IHC seems to be a predictive marker for survival in the association group. Further research is needed to corroborate these findings.

Background:
SQUIRE (NCT00981058) demonstrated adding necitumumab (N) to gemcitabine/cisplatin (GC) improved survival in patients with Stage IV squamous NSCLC (SQ-NSCLC). Retrospective analysis revealed consistent treatment effect in favor of patients receiving N monotherapy as continuation after chemotherapy (CT) (GC+N continuation patients) versus continuation therapy-eligible GC arm patients (GC non-progressors). In the EU, N is approved for patients with EGFR-expressing tumors. We repeated the analysis in this patient population.

Methods:
Patients with Stage IV SQ-NSCLC were randomized 1:1 for ≤6 cycles of G (1250 mg/m[2] iv, Days [d] 1,8) and C (75 mg/m[2] iv, d1) either with or without N (800 mg iv, d1,8). Patients in GC+N without progression continued N until progressive disease (PD). SQUIRE included mandatory tissue collection. EGFR protein expression was assessed by IHC in a central lab (Dako EGFR PharmDx kit). Analyses were done in EGFR-expressing patients (EGFR >0). Patients who received ≥4 cycles of CT without PD were included. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan-Meier method. 95% CIs and hazard ratios estimated using stratified Cox proportional hazards model.

Results:
Of 1093 patients (ITT population), 982 patients (89.8%) had evaluable IHC assay results; 935/982 (95.2%) had EGFR>0. GC+N arm continuation therapy patients included 228 patients with EGFR>0 and 194 patients (EGFR>0) were GC arm non-progressors. Baseline characteristics were similar except gender (Males: 81% in GC+N vs 91% in GC arm). CT exposure was balanced. Median OS from randomization in GC+N vs GC was 16.1 vs 14.9 months; HR 0.76 (95% CI, 0.61, 0.95). Median PFS in GC+N vs GC was 7.4 vs 6.9 months; HR 0.81 (95% CI, 0.66, 1.00). Figure 1



Conclusion:
In patients with EGFR-expressing tumors, a consistent treatment effect in favor of GC+N continuation maintenance compared to GC non-progressors was observed, similar to ITT population with no unexpected increases in AEs.

Background:
Squamous cell carcinoma (SCC) of the lung is a genetically complex and difficult-to-treat cancer. In LUX-Lung 8, afatinib (40mg/day) significantly improved OS (median 7.9 vs 6.8 months, HR=0.81 [95% CI, 0.69‒0.95], p=0.008), PFS (2.6 vs 1.9 months, HR=0.81 [0.69‒0.96], p=0.010) and DCR versus erlotinib (150mg/day) in patients with relapsed/refractory SCC of the lung (n=795). Notably, 12-month (36 vs 28%; p=0.016) and 18-month survival (22 vs 14%; p=0.016) was significantly higher with afatinib than erlotinib, indicating that some patients derive prolonged benefit from afatinib. Here, we present post-hoc analysis of baseline characteristics and efficacy/safety of afatinib in long-term responders (treatment for ≥12 months). Hypothesis-generating analysis of archived tumor samples and blood serum was undertaken to identify possible molecular/clinical biomarkers.

Methods:
Tumor samples were retrospectively analyzed using FoundationOne[TM] next-generation sequencing (NGS); EGFR expression was determined by immunohistochemistry. Pre-treatment serum samples were analyzed with VeriStrat[®], a MALDI-TOF mass spectrometry test, and classified as VeriStrat-Good or VeriStrat-Poor-risk.

Results:
15/398 patients treated with afatinib were long-term responders. Median duration of treatment was 16.6 months (range: 12.3‒25.8). Patient characteristics were similar to the overall dataset (median age: 65 years [range: 54‒81]; male: 80.0%; Asian: 13.3%; ECOG 0/1: 40.0%/60.0%; best response to chemotherapy CR or PR/SD: 53.3%/46.7%; current and ex-smokers: 80.0%). Median PFS was 16.2 months (range: 2.8‒24.0); median OS was 23.1 months (range: 12.9‒31.5). The most common treatment-related AEs (all grade/grade 3) were: diarrhea (73.3%/6.7%); rash/acne (66.7%/6.7%); stomatitis (13%/7%). AEs generally occurred soon after treatment onset (median onset, days [range]: diarrhea 11 [5‒48]; rash/acne 17 [9‒107]; stomatitis 15 [11‒19]). Four patients required a dose reduction to 30mg/day due to treatment-related AEs (diarrhea, rash, stomatitis, diarrhea/rash). NGS was undertaken in 9 patients and details will be presented at the meeting. Genomic aberrations in the ErbB/FGF gene families were identified in 44.4%/55.6% of long-term responders (overall dataset: 29.4%/58.0%). Of 14 patients assessed by VeriStrat, 85.7% were VeriStrat-Good (overall dataset: 61.6%). Immunohistochemistry data was available for two patients; one overexpressed EGFR (≥10% positive cells; H-score ≥200)

Conclusion:
Baseline characteristics of long-term responders to afatinib were similar to the overall dataset. In this sub-group, afatinib conferred a survival benefit of nearly 2 years. Afatinib was well tolerated with predictable and transient AEs that occurred soon after treatment onset. The dataset was too small to identify any clear NGS/VeriStrat predictive signals. Further studies are required to predict long-term response to afatinib.

Abstract not provided

Background:
The irreversible ErbB family blocker afatinib and the reversible EGFR TKI gefitinib are approved for first-line treatment of advanced EGFRm+ NSCLC. This Phase IIb trial prospectively compared afatinib versus gefitinib in this setting.

Methods:
LUX-Lung 7 assessed afatinib (40 mg/day) versus gefitinib (250 mg/day) in treatment-naïve patients with stage IIIb/IV NSCLC harbouring a common EGFR mutation (Del19/L858R). Co-primary endpoints were PFS (independent review), time to treatment failure (TTF) and OS. Other endpoints included ORR and AEs. In case of grade ≥3/selected grade 2 drug-related AEs the afatinib dose could be reduced to 30 mg or 20 mg (minimum). The primary analysis of PFS/TTF was undertaken after ~250 PFS events. The primary OS analysis was planned after ~213 OS events and a follow-up period of ≥32 months.

Results:
319 patients were randomised (afatinib: 160; gefitinib: 159). At the time of primary analysis, PFS (HR [95% CI] 0.73 [0.57‒0.95], p=0.017), TTF (0.73 [0.58‒0.92], p=0.007) and ORR (70 vs 56%, p=0.008) were significantly improved with afatinib versus gefitinib. The most common grade ≥3 AEs were diarrhoea (13%) and rash/acne (9%) with afatinib and elevated ALT/AST (9%) with gefitinib. 42% of patients treated with afatinib had ≥1 dose reduction due to AEs; dose reductions were more common in females than males (77%/23%) and non-Asians than Asians (64%/36%). Dose reduction of afatinib did not negatively impact PFS (<40mg vs ≥40mg; HR [95% CI]: 1.34 [0.90‒2.00]) but reduced incidence and severity of drug-related grade ≥3 AEs. Treatment discontinuation due to drug-related AEs was the same in each arm (6%). The data cut-off for primary OS analysis occurred on 8 April 2016. At this time, median treatment duration (range) was 13.7 (0‒46.4) versus 11.5 (0.5‒48.7) months with afatinib and gefitinib. 25% (afatinib) and 13% (gefitinib) of patients received treatment for >24 months. 73% and 77% of patients in the afatinib and gefitinib arms had ≥1 subsequent systemic anti-cancer treatment, with 46% and 56% receiving a subsequent EGFR-TKI including osimertinib (14%)/olmutinib (14%). OS data, including subgroup analysis with respect to subsequent therapy will be presented at the meeting.

Conclusion:
Afatinib significantly improved PFS, TTF and ORR versus gefitinib in EGFRm+ NSCLC patients, with a manageable AE profile and few drug-related discontinuations. Dose adjustment of afatinib reduced drug-related AEs without compromising efficacy. Primary OS analysis will be reported.

Background:
Since the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) was launched in Japan, the survival periods of advanced/recurrent EGFR mutation positive (EGFR m+) non-small cell lung cancer (NSCLC) patients have been getting longer. However, clinical factors which contributed to the extension of survival periods of these patients remain unclear. We investigated overall survival, prognostic factors and treatments patterns of EGFR m+ NSCLC patients in real-world clinical practice.

Methods:
This is a multi-center, observational, retrospective study. Histologically or cytologically diagnosed EGFR m+ NSCLC patients who were started first-line treatment from 1/1/2008 to 31/12/2012 were enrolled. The primary objective was the estimated OS. The secondary objectives were to determine prognostic factors, real-world treatment patterns.

Results:
1,660 EGFR m+ NSCLC patients were enrolled from 17 hospitals in Japan (median age 67.0 years, female 64.8%, 38.9% had smoking history, ECOG-performance status 0, 1, 2, 3, 4 were 39.5%, 41.1%, 7.1%, 4.9%, 0.7%, respectively, adenocarcinoma 95.2%, 50.1% exon 19 deletion, 66.7% at stage IV). Median estimated OS was 29.7 months. Cox regression analysis revealed age, smoking history, performance status, histological diagnosis, EGFR mutation type and clinical stage were independently associated with OS. Five year survival rate of stage IV patients was 13.8%. The median number of treatment regimens was two. EGFR-TKI and platinum-doublet chemotherapy were most frequently used as first- and second-line treatments.

Conclusion:
Real world treatment of the large data-set of 1,660 EGFR m+ NSCLC patients was retrospectively investigated. Median OS was 29.7 months and EGFR-TKIs are major components of the treatment regimens for these patients in Japan. (NCT0247520)

Background:
In 2011, following gefitinib (IRESSA[®]) NDA voluntary withdrawal, US patients benefiting from gefitinib were eligible to continue gefitinib through the IRESSA Clinical Access Program (ICAP), an IRB-approved protocol. A subset of ICAP investigators subsequently collected additional retrospective data on their ICAP patients through another IRB-approved project (“chart-review subset”).

Methods:
For all enrolled ICAP patients, demographic and serious adverse event (SAE) reports were reviewed. All ICAP investigators were invited to participate in chart review; 47 accepted and collected data on patient/tumor characteristics and safety/tolerability of prolonged gefitinib therapy among their 79 ICAP patients.

Results:
Across 137 US sites, 191 patients enrolled in ICAP. As of September 2016, 75 (39%) remain on gefitinib; discontinuations were due to progression (36%), death (34%), AEs (13%), or other (17%). Sixty-four (34%) patients reported 162 SAEs; 5 (2.6%) patients had 12 SAEs considered to be gefitinib-related by investigators. The chart-review subset included 79 (41%) patients with median age of 69 years at ICAP enrollment, who were predominantly female (70%) and white (84%); 95% had a confirmed NSCLC diagnosis. Due to the evolving understanding of genetic mutations in NSCLC at the time of gefitinib initiation, the majority of patients (79%) never had EGFR sequencing performed. Although tissue is not available for EGFR status confirmation, we assume these patients are nearly exclusively EGFR mutation-positive. Median total length of gefitinib was 11.1 years (6.5-15.1; Table). Long-term gefitinib was well-tolerated; 5% discontinued due to a gefitinib-related AE. Ten-year survival rate from first-ever initiation of gefitinib was 86% and 15-year was 59%. Table. Gefitinib treatment patterns and tolerability among ICAP chart-review patients.

Abstract not provided

Background:
Trials of chemoradiotherapy for different tumors, including lung cancer, have shown a correlation between protocol deviations and adverse outcomes. Radiation quality assurance (RTQA) was mandated for all patients treated in the PROCLAIM (NCT00686959) trial evaluating two different chemoradiotherapy regimens.

Methods:
The study was open to accrual between 2008-2012. Planned chemoradiotherapy dose was 60-66 Gy in daily 2 Gy fractions. Quality was assessed through review of radiation treatment plans and monitoring of protocol violations. Review of the radiation plan was mandated for all patients; prior to radiation start for the first enrolled patient at each site. Real-time review was performed randomly in 20% of additional patients with nonreal-time review performed for the remainder. Parameters assessed for major violations per protocol included: <95% of planned total volume (PTV) received by 93% of prescribed dose; >1 cm[3] contiguous volume within or outside the PTV received >115% of prescribed dose; V~20~ (volume of lung receiving ≥20 Gy) >38%; and maximum point dose to spinal cord of >48 Gy. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kapan-Meier methodology and groups were compared by log-rank test and Cox proportional hazard modeling.

Results:
Of 598 patients randomized in 126 investigational sites, 554 received study assigned chemoradiotherapy. The median dose delivered was 66 Gy, with 92.6% of patients receiving planned chemoradiotherapy dose (60-66 Gy). A total of 40 patients, enrolled at twenty-eight sites had major RTQA violations. Seven sites enrolled ≥2 patients with major violations. Patients with major violations has a higher incidence of Stage IIIB disease (70.0% vs. 50.6%) and larger tumors (median planned PTV=653 vs. 523cc) than patients with no violations. Patients treated at sites with ≥2 patients with violations (n=86), had a lower median OS (median 21.1 vs. 29.8 months; HR 1.442) and median PFS (median 7.3 vs. 11.3 months; HR 1.345) than patients at sites where none had violations.

Conclusion:
Major chemoradiotherapy protocol violations were uncommon in the PROCLAIM study, which may be a reflection of the mandatory RTQA. Protocol violations were more frequent in patients with Stage IIIB and larger tumors, which generally require more complex chemoradiotherapy plans. The observation of discrepant outcomes at centres with multiple major RTQA violations is hypothesis-generating but should be interpreted with caution due to the small number of patients.

Background:
Anatomical change of tumor contour during radiotherapy contributes to target missing. Adaptation of tumor volume could however result in an increased incidence of recurrences in the area of target reduction. This study aims to investigate the incidence of failure of adaptive approach in evaluating the risk of local recurrence in the area excluded during replanning.

Methods:
In this prospective study, LA-NSCLC patients treated with concomitant chemoradiation underwent weekly chest-CT simulation during therapy. In case of tumor shrinkage, a new tumor volume (TV) was delineated and a new treatment plan outlined (replanning). Patterns of failure were classified as: in field (persistence or recurrence in TV post-replanning), marginal (recurrence in the area of initial TV excluded from the post-replanning TV) and out of field (recurrence outside of initial TV). Toxicity, OS, and PFS were reported.

Results:
A total of 217 NSCLC patients were treated in our centre from 2012 to 2014. In 50 cases a target volume reduction was recorded and replanning outlined. A mean initial and replanning CTV of 154.9cc and 90.7cc were reported with an average CTV shrinkage of 42% between simulation CT and replanning CT. With a median follow-up of 20.5 months, 30% of patients experienced local failure which was in field, marginal and out of filed in 20%, 6% and 4% of cases respectively. Acute G3 pulmonary and esophageal toxicity was reported in 2% and 4% of patients respectively. Figure 1 Figure 1: (A) Tumor volume delineation at first CT simulation; (B) the reduced target volume at replanning CT



Conclusion:
The possibility to reduce toxicity and the documented low rate of marginal failures makes the adaptive approach a modern option for future randomized studies. The best scenario to confirm tumor activity is its application in neoadjuvant chemoradiation trials.

Background:
Radiation (RT) associated cardiac injury in patients with lung cancer is of unclear significance. RTOG 0617 demonstrated reduced overall survival (OS) with dose-escalated RT for Stage III NSCLC, with higher heart doses predicting for worse OS. We assessed the impact of heart doses on toxicity and survival for patients enrolled on several prospective RT dose-escalation trials.

Methods:
From 1996-2009, 133 patients with Stage III NSCLC (ECOG PS 0-1) were treated on six prospective trials using induction/concurrent chemotherapy and dose-escalated conformal RT to 70-90 Gy. Broad clinical outcomes (e.g. OS) were prospectively assessed. RT plans were reviewed, cardiac structures were defined, and dose/volume metrics were computed. Patient records were retrospectively reviewed for post-RT symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, and pericarditis). Baseline cardiac risk was calculated using the World Health Organization / International Society of Hypertension (WHO/ISH) score. A competing risks model accounting for the risk of death was used for statistical analysis.

Results:
112 patients were included in the final analysis. Median f/u was 19 mo. (75 mo. for the 39 patients without documented progression). Median OS and PFS were 22 and 12 mo. Median prescribed RT dose was 74 Gy. 15 patients (13%) had symptomatic cardiac events (6 pericardial effusion, 5 myocardial infarction, 2 unstable angina, 2 pericarditis) at median 26 mo. post-RT (range, 7-68). On univariate analysis, Heart mean dose (p=0.001), Heart V5Gy (p<0.001), and Heart V30Gy (p=0.002) were associated with symptomatic cardiac events, whereas baseline WHO/ISH score (p=0.204) and coronary artery disease (p=0.109) were not. Heart doses were higher in patients with vs without events (mean 22Gy vs 11Gy, V5Gy 60% vs 35%, V30Gy 35% vs 14%). On multivariate pair analysis accounting for baseline risk, heart doses remained significant predictors of cardiac events (e.g. Heart mean dose, p=0.001, HR 1.05 / 1Gy). 2-year competing risk-adjusted rate of symptomatic cardiac events was 11.1% vs 1.5% for Heart mean dose ≥15Gy vs <15Gy (p=0.003, HR 6.7). 34 patients (30%) had asymptomatic pericardial effusions. There was no association between heart doses and OS.

Conclusion:
Clinically significant symptomatic cardiac events following high-dose thoracic RT for Stage III NSCLC occurred in 13% of patients at a median 2 years post-RT, with the rate appearing to be heart dose dependent. RT-associated cardiac toxicity in the definitive treatment of Stage III NSCLC may occur earlier than historically understood, and heart doses should be minimized. Supported in part by NIH grant CA69579.

Abstract not provided

Background:
Early attempts of stereotactic body radiation therapy (SBRT) of centrally located lung tumors resulted in high toxicity, questioning the utility of the method in this situation. Since then, different risk adapted fractionation schedules with acceptable toxic effects have been reported from various institutions. However, consensus on the tolerability of centrally located structures to high-fraction doses is still lacking and the clinical toxic effects in relation to dose to organs at risk (OAR) need to be evaluated.

Methods:
We here report a first toxicity analysis of the HILUS-trial – a prospective Nordic multicenter non-randomized phase II trial of SBRT to centrally located lung tumors. Patients with a centrally located tumor (defined as ≤1cm from the proximal bronchial tree) from either a primary non-small cell lung cancer (NSCLC) or a progressive metastasis from another solid tumor were eligible for the trial. Maximum tumor diameter was 5 cm. Patients receiving concomitant systemic anticancer therapy or with tumors reaching through the wall of a main bronchus were not eligible. All the patients were treated with 7Gyx8 and stratified to either arm A (=tumors close to a main bronchus) or arm B (=tumors close to a lobar bronchus). The aim was to include 30 patients in each arm. Follow-up was conducted every 3[rd] month during the first 2 years and thereafter every 6[th] month. The trial was approved by ethical committees in each country.

Results:
Seventy-four patients (42 in arm A and 31 in arm B) were included between 2011 and 2016. Sixty-five patients experienced side effects from the study treatment; the most common being grade 1-2 dyspnea, grade 1-2 cough and grade 1-2 fatigue. Twenty-one patients (28%) experienced grade 3-5 side effects (atrioventricular block, bleeding, dyspnea, empyema, fatigue, fever, fistula, lung infection, pain, pneumonitis, pneumothorax and ventricular arrhythmia). Seven patients (6 in group A and 1 in group B) may have suffered grade 5 side effects; six patients experienced lethal hemoptysis after a median of 15.5 months (2.5-21months) and one patient suffered from a lethal pneumonitis 5 months post study treatment. Grade 4-5 side effects occurred more frequently in group A than in group B (19% vs 3%). Further analyses of risk factors for serious toxicity in relation to dose-volume parameters and patient- and tumor characteristics will be presented.

Conclusion:
SBRT of centrally located tumors may be afflicted with high risk of serious toxicity and further evaluation of clinical and dose-volume dependent risk factors are highly warranted.

Background:
Stereotactic body radiation therapy (SBRT) has emerged as an effective treatment for early-stage lung cancer. Histologic subtyping in surgically resected lung adenocarcinomas is recognized as a prognostic factor, with the presence of solid or micropapillary patterns predicting poor outcomes. Herein, we describe outcomes following SBRT for early-stage lung adenocarcinoma by histologic subtype.

Methods:
We identified 119 consecutive patients (124 lesions) with stage I-IIA lung adenocarcinoma who were treated with definitive SBRT at our institution between August 2008 and August 2015 and had undergone core biopsy. Histologic subtyping was performed according to the 2015 WHO Classification. Thirty-seven tumors (30%) were of high risk subtype, defined as containing a component of solid and/or micropapillary pattern. Cumulative incidences of local, nodal, regional and distant failure were compared between high risk vs. non-high risk adenocarcinoma subtypes with Gray’s test, and multivariable-adjusted hazard ratios were estimated from propensity score-weighted Cox regression models.

Results:
Median follow-up for the entire cohort was 17 months and 21 months for surviving patients. The 1-year cumulative incidence of local, nodal, regional and distant failure, respectively, in high risk and non-high risk lesions were 7.3%, 14.8%, 4.0%, 22.7% and 2.7%, 2.6%, 1.2%, 3.6%. Hazard ratios for local, nodal, regional and distant failure, respectively, of high risk lesions compared to non-high risk were 16.8 (95% CI 3.5-81.4), 3.8 (95% CI 0.95-15.0), 20.9 (95% CI 2.3-192.3), 6.9 (95% CI 2.2-21.1). No significant difference was seen with regard to overall survival.

Conclusion:
Outcomes following SBRT for early-stage adenocarcinoma of the lung are highly correlated with histologic subtype, with micropapillary and solid tumors portending significantly higher rates of locoregional and metastatic progression. In this context, histologic subtype based on core biopsies is a novel prognostic factor and may have important implications for patient selection, adjuvant treatment, biopsy methods and clinical trial design.

Background:
Stereotactic Body Radiation Therapy (SBRT) is the standard of care for medically inoperable patients with early-stage non-small cell lung cancer (NSCLC). However, NSCLC is comprised of several histological subtypes and the impact of this heterogeneity on SBRT treatments has yet to be established.

Methods:
We analyzed 740 early-stage NSCLC patients treated definitively with SBRT from 2003 through 2015. We calculated cumulative incidence curves using the competing risk method and identified predictors of local failure using Fine and Gray regression.

Results:
Overall, 72 patients had a local failure with a cumulative incidence of local failure at three years of 11.8%. On univariate analysis, squamous histology, younger age, fewer medical comorbidities, higher BMI, higher PET SUV, central tumors and lower radiation dose were associated with an increased risk of local failure. On multivariable analysis, squamous histology (HR 2.4 p = 0.008) was the strongest predictor of local failure. Patients with squamous cancers fail SBRT at a significantly higher rate than those with adenocarcinomas or NSCLC-not otherwise specified, with three-year cumulative incidences of local failure of 18.9% (95% CI= 12.7-25.1%), 8.7% (95% CI= 4.6-12.8%), 4.1% (95% CI= 0-9.6%), respectively.

Conclusion:
Our results demonstrate an increased rate of local failure after SBRT in patients with squamous cell carcinoma. Standard approaches for radiotherapy that demonstrate efficacy for a population may not achieve optimal results for individual patients. Establishing the differential dose-responses of SBRT across histological groups is likely to improve efficacy and inform ongoing and future studies that aim to expand indications for SBRT.

Abstract not provided