Virtual Library

Abstract not provided

Abstract:
The 2015 WHO Classification of Neuroendocrine Tumors Elisabeth Brambilla, Professor of Pathology, Department of Pathology; CHU Grenoble INSERM U 1209; Institute of Advanced Biosciences; University Grenoble Alpes; France Neuroendocrine lung tumors were considered as separate entities in the previous WHO classification 2004: the carcinoid tumors, small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) were grouped separately. However, in the current WHO 2015 classification, they are grouped together [1]. They are listed in the order of their frequency with SCLC first as it is the most common. SCLC (15% of lung tumors) is a malignant epithelial tumor which consist of densely packed small cells with scant cytoplasm, finely dispersed granular chromatin and absent or inconspicuous nucleoli. In contrast LCNEC is made of large cells and should show both neuroendocrine morphology (rosettes, palisades) and immunohistochemical neuroendocrine markers (at least one). Both SCLC and LCNEC can be pure or combined with NSCLC components but keep their diagnostic priority (SCLC-or LCNEC- combined). Carcinoid tumors are neuroendocrine malignancies accounting for <1% of all lung cancer, divided in two categories with highly different frequencies, the typical and atypical carcinoid, the last being extremely rare. Typical carcinoids are carcinoid tumors with <2mm[2] and lacking necrosis. They measure ≥0.5 cm in size. Atypical carcinoids are carcinoid tumors with 2-10 mitoses per 2mm[2] and/or foci of necrosis. Despite the grouping of these tumors together, it is clear that the carcinoids have major clinical, epidemiologic, histologic and genetic differences compared to the high grade SCLC and LCNEC. Carcinoid patients are significantly younger, have a better prognosis and lack the strong association with smoking that applies for SCLC and LCNEC. Also compared to carcinoid tumors, SCLC and LCNEC have much higher mitotic rates (more than 11 per 2mm[2]), more necrosis and can show combinations with other lung cancer types including adenocarcinoma or squamous cell carcinoma, which testify of a common progenitor cell derivation, not shared by carcinoid which is never mixed with a non-neuroendocrine (NE) tumor type. Carcinoid tumors also have very few genetic abnormalities compared to SCLC and LCNEC which show the highest rate of mutations per megabase among all cancer[3,4,5] . While in many cases, SCLC and carcinoid tumors can be diagnosed on good quality tumor material with a high quality H&E stained section and in well preserved cytological samples, immunohistochemistry (IH)/neuroendocrine markers can be very helpful in diagnosing pulmonary NE tumors especially in small biopsies with crushed artefact. Endocrine morphology and neuroendocrine IH markers are both required for the diagnosis of LCNEC. The cases with one missing (endocrine morphology or NE markers) are considered as large cell carcinoma in the absence of other differentiation marker on resection specimens, and as non-small cell lung carcinoma on small samples (cytology or biopsy) Mitotic counts are still retained to differentiate typical carcinoids (less than 2 mitoses per mm[2]) from atypical carcinoids (2 to 10 per 2mm[2]) and from high grade NE tumors SCLC and LCNEC (more than 11 mitoses per 2 mm[2 ], for being more reproducible than KI-67 evaluation. The role of Ki-67 is mainly to separate the high grade SCLC (more than 50%) and LCNEC (more than 40%) from the carcinoid tumors (from 1 to 15%) especially in small biopsies with crushed and/or necrotic tumor cells. It is recommended to avoid the diagnosis of SCLC or LCNEC for tumors with less than 50% and 40% MIB1/KI67 index respectively. Data are conflicting regarding the use of KI-67 in separating typical from atypical carcinoid tumors, so it is not recommended in this setting. Careful counting of mitoses is essential as it is the most important histologic criteria for separating typical from atypical carcinoid and the carcinoids from the high grade SCLC and LCNEC. Due to recognition of the potential overlap in the morphology of LCNEC and basaloid squamous cell carcinoma, it can be helpful to confirm negative squamous markers (i.e. p40) in TTF-1 negative tumors that otherwise meet criteria for LCNEC. Many recent progress have been made on the comprehensive genomic profiles of SCLC [3,4 ], LCNEC [5] and carcinoids [6]. Although sharing NE features, these 3 tumors group show substantial and significant differences.Recent comprehensive genomic analyses have established the genomic profile of SCLC [3,6.] Their unique and remarkable characteristic is the universal bi-allelic alteration of both TP53 and RB1 gene (100% for P53 and 93% for RB1) by different alterations of each of the 4 alleles: non synonymous mutations, damaging mutations by complex genomic rearrangements. Locally clustered mutations, indicative of functional selection, occurred on CREBBP (15%) and EP300 (13%) genes, inactivating their histone acetylase functions. Notch family genes inactivating their protein functions occurred in 25% of SCLC [4]. Notch is considered as a master regulator of NE differentiation. LCNEC genomics share characteristic features with SCLC for a part of LCNEC (SCLC-like LCNEC) or with AD /SQC for another part (about 25%). Mutations pattern and frequency of combined cases imply a considerable plasticity of theses tumours which might represent an evolutionary trunk branching SCLC to NSCLC. Carcinoid is a unique example of a tumor driven entirely by chromatin modifiers and remodeling genes, which are not mutant in SCLC. In summary, 51% of carcinoid carried mutations in chromatin remodeling genes. In addition, the eukaryotic translation initiation factor (EIF1AX) was mutated in 9% of cases, genes of the E3 ubiquitin ligases system were mutated or rearranged in 18%. Altogether 73% of carcinoids have driver genes that are candidates for targeted therapy [6.] New evidence is provided that carcinoid is not an early progenitor of high grade NE tumors SCLC and LCNEC. References: 1. Travis WD, Brambilla E, Burke A, Marx A, Nicholson A. WHO Classification of the Tumours of the Lung, Pleura, Thymus and Heart. 4th Edition. Lyon: IARC Press; 2015. 2. Clinical Lung Cancer Genome Project (CLCGP), Network Genomic Medicine (NGM). A genomics-based classification of human lung tumors. Sci Transl Med. 2013;5(209):209ra153. doi:10.1126/scitranslmed.3006802. 3. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44(10):1104-1110. doi:10.1038/ng.2396. 4. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47-53. doi:10.1038/nature14664. 5. Fernandez-Cuesta L, Peifer M, George J, et al. Genomic Characterization of Large-Cell Neuroendocrine Lung Tumors. J Thorac Oncol. 2015;10(9 - WCLC 2015 Abstracts: PDF Only):S185. doi:10.1097/01.JTO.0000473439.77589.a7. 6. Fernandez-Cuesta L, Peifer M, Lu X, et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun. 2014;5:3518. doi:10.1038/ncomms4518.

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Abstract:
The definition of staging in Lung Cancer is the determination of the anatomic extent of three tumor components: the primary tumor (T), the lymph nodes (N), and the metastases (M). Their accurate evaluation allows grouping patients in stages that is one, and perhaps the single most important, of several prognostic factors that guide the appropriate treatment option(s) to offer the patient. The clinical classification cTNM (Pre-treatment clinical classification), is based on evidence acquired before treatment The pathological classification pTNM (Post-surgical histopathological classification), is based on the evidence acquired before treatment, supplemented or modified by the additional evidence acquired from surgery and from pathological examination. A minimum number of tests is not required to define the extent of the disease, but it’s very clear that as more exhaustive the explorations more accurate and precise the staging will be. This may be strongly affected by the availability of physical and human resources, multidisciplinary work and adherence to clinical practice guidelines. After the changes proposed by the new IASLC-ATS-ERS lung adenocarcinoma classification and the IASLC proposals for revision of the T, N and M descriptors and stage groupings in the forthcoming (Eighth) edition of the TNM Classification for Lung Cancer, we must incorporate this new information into our clinical practice. (1, 2) The changes that The IASLC Staging Committee recommends for the T, N and M components and the resulting new stage grouping and their survival are summarized in table 1 and figure 1. The main changes in T components are the relevance of the size of the tumor for each cm, grouping of the involvement of the main bronchus or partial and total atelectasis or pneumonitis as a T2 descriptor and the reclassification of diaphragm invasion as T4. (3) N component remains without changes. (4) In M component a new M1b category includes patients with a single metastatic lesion in a single organ site and a new M1c category was introduce for patients with multiple lesions in a single organ or multiple lesions in multiple organs. (5) Some new stage groupings are proposed. The new size cut points of T1-N0-M0 tumors has been assigned to stage IA1, IA2, and IA3. The new stage IIIC (T3 and T4-N3-M0) reflects their worse outcome. Finally, stage IV disease has been divided into IVA (M1a, M1b) and IVB (M1c). The new IVA stage grouping should be used in trials analyzing patients with oligo-metastasis or pleural or pericardial disease. (2) For the newly described types of adenocarcinoma of the lung, The IASLC recommends incorporating the coding of AIS as Tis (AIS) and of MIA as T1mi into the traditional TNM classification. For part-solid tumors, the size of the invasive component should be used to assign a T category, but the whole tumor size should also be recorded. However, the measurements will be influenced by a number of observer-dependent and technical factors. It is important to perform the measurements for clinical staging on contiguous thin CT sections reconstructed with a high-resolution algorithm with multiplanar reconstruction. (6) For pathologic staging, attention should be given to the assessment of invasive and lepidic components. It can be helpful to correlate microscopic findings with measurements made on gross examination, particularly in inflated specimens or with CT findings. Patients who present with more than one pulmonary site of lung cancer may represent different patterns of disease as synchronous primary lung cancers, those with a separate solid tumor nodule(s) (intrapulmonary metastases), multifocal lung cancer presenting as multiple nodules with ground glass/lepidic features, and diffuse pneumonic-type adenocarcinoma. It is proposed that the T category of patients presenting ground glass/lepidic (GG/L) tumors be classified using the T category of the highest T lesion and in parentheses either the number of GG/L tumors or simply m for multiple (#/m). A single N and M category is assigned for all GG/L tumors combined. (7) Both clinical information (the presence of additional lesions identified by imaging) and the pathologic information (from resected lesions) should be used to determine the TNM classification. Lesions smaller than 5 mm or AAH are not counted. The pneumonic type of adenocarcinoma should be classified according to the size of the area of lung involved, or as T4 or M1a in the case of involvement of more than one lobe (i.e., either ipsilateral or contralateral). A single N and M category is assigned. In patients with separate tumor nodules (intrapulmonary metastases), it is proposed that the seventh edition classification of same-lobe nodules as T3, same side (different lobe) nodules as T4, and other-side nodules as M1a be carried forward. (8) It is easier to establish that two pulmonary foci of cancer are separate primary tumors than that they are metastatic from one another. Few features are sufficiently reliable by themselves, such as different histologic type and differences by a comprehensive histologic assessment of resected specimens or by matching breakpoints by DNA sequencing. Most criteria can be suggestive, but are associated with potential misclassification. These include biomarker patterns, imaging characteristics, and the presence or absence of nodal involvement. The fact that generally only biopsy specimens are available at the time of clinical decision making further adds to the uncertainty and difficulty of the assessment. A constellation of factors is better than any single factor; it is best to make a determination of separate primary versus metastatic lesions through a collective judgment of a multidisciplinary tumor board after taking into account all of the available information. (9) Synchronous primary cancers are classified with a T, N, and M category for each tumor; separate tumor nodules result in a T3, T4, or M1a category depending on the separate nodule’s location relative to the primary tumor. (10) Despite these proposals of staging, there will always be areas of difficulty and tumors that are challenging to classify. The prognostic value of clinical and pathological TNM staging in patients with SCLC was also confirmed, and the continued usage is recommended for SCLC in relation to proposed changes to T, N, and M descriptors for NSCLC in the eighth edition. (11) Table 1 Descriptors and T and M categories in the seventh edition and as proposed for the eighth edition. Figure 1 *Where there is a change, the resultant stage groupings proposed for the eighth edition are in bold, and the stage in the seventh edition is given in parenthesis. Figure 1 Overall survival by clinical and pathological stage according to the proposed eighth edition groupings using the entire database available for the eighth edition. Figure 2References: 1. Travis WD, et al. The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol. 2011;6: 244–285. 2. Goldstraw P et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer Journal of Thoracic Oncology, Vol. 11, Issue 1, p39–51 3. Rami-Porta R et al. The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology, Vol. 10, Issue 7, p990–1003 4. Asamura H et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 8th Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology, Vol. 10, Issue 12, p1675–1684 5. Eberhardt W E.et al. The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. Journal of Thoracic Oncology, Vol. 10, Issue 11, p1515–1522 6. Travis WD, et al. The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. Journal of Thoracic Oncology, Vol. 11, Issue 8, p1204–1223 7. Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification. Journal of Thoracic Oncology, Vol. 11, Issue 5, p666–680 8. Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology, Vol. 11, Issue 5, p681–692 9. Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology, Vol. 11, Issue 5, p651–665 10. Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. Journal of Thoracic Oncology, Vol. 11, Issue 5, p639–650 11. Nicholson AG et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the Clinical and Pathologic Staging of Small Cell Lung Cancer in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology, Vol. 11, Issue 3, p300–311

Abstract:
Malignant pleural mesothelioma (MPM) is a highly lethal malignancy arising from the serosal lining of the pleural cavity [1]. In up to 80% of patients, asbestos is considered to contribute to the development of this tumor within about 20 to 40 years of exposure time [2]. The incidence of MPM is expected to increase dramatically over the next few decades. It has been estimated that 250 000 people will die of MPM in Europe in the next three decades, and 2500–3000 new cases are diagnosed each year in the USA [3]. The macroscopic appearance of MPM depends on disease stage. In early stage MPM, the cancer presents as multiple small nodules on the surface of both pleural linings. In advanced stages, the multiple small nodules form a tumor plate which surrounds the lung like a cage and in most cases invades the lung parenchyma, diaphragm and pericardium [4]. The establishment of the pathological diagnosis of MPM and the classification in three main histological subtypes (namely epitheloid, biphasic and sarcomatoid) is important and has an impact on therapy and prognosis. Epitheloid MPM is more therapy responsive and associated with better outcome compared to biphasic and sarcomatoid histotypes. Other very important simple prognostic factors for MPM are disease stage and lymph node involvement. Therefore an adequate staging of MPM patients is crucial for therapy decision-making. The currently widely used staging system is the one according to International Mesothelioma Interest Group (IMIG) established in 1996 [5]. Based on the TNM (tumor-node-metastasis) system for malignant tumors, this staging system describes: the extent and size of the primary tumor, lymph node involvement and distant metastases. By the different TNM descriptors, MPM can be classified and summarized in four different tumor stages (IMIG I-IV). Patients suffering from stage I-III are considered for surgery within multimodality protocols, while palliative systemic or local treatment is indicated for stage IV in accordance with the current classification. Butchart et al. [6]proposed in 1976 an alternative staging system, referred to as the Butchart Staging. Contrary to the IMIG system (based on lung cancer staging) the Butchart system is particularly set up for MPM. Therefore, several differences between both staging systems exist. However, the IMIG in collaboration with the International Association for the Study of Lung Cancer (IASLC) have proposed a new T, N and M descriptors for in the forthcoming 8[th] edition of the TNM classification for MPM with significant changes to the 7[th] TNM edition and proposals have been very recently published [7-9]. With regard to the T descriptor, a fusion of both, clinical and pathological T1a and T1b into a T1 was recommended [7]. Regarding the N descriptor, a summary of the clinical and pathological N1 and N2 categories into a single category with the classification into ipsilateral, intrathoracic nodal metastases (N1) was proposed [8]. No changes have been recommended for the M descriptor in the 8[th] edition of the TNM [9]. In this presentation, 4 patient cases of different stages of MPM patients will be presented and the newly proposed TNM descriptors and IMIG staging will be applied. Cases and changes in the staging system will be discussed together with the attending audience in an interactive manner. After the presentation, the participants will be able to understand and practically apply the forthcoming changes in the TNM system for staging of MPM patients. 1. Whitaker, D., J.M. Papadimitriou, and M.N. Walters, The mesothelium and its reactions: a review. Crit Rev Toxicol, 1982. 10(2): p. 81-144. 2. Lanphear, B.P. and C.R. Buncher, Latent period for malignant mesothelioma of occupational origin. J Occup Med, 1992. 34(7): p. 718-21. 3. Peto, J., et al., The European mesothelioma epidemic. Br J Cancer, 1999. 79(3-4): p. 666-72. 4. Rudd, R.M., Malignant mesothelioma. Br Med Bull, 2010. 93: p. 105-23. 5. Rusch, V.W., A proposed new international TNM staging system for malignant pleural mesothelioma from the International Mesothelioma Interest Group. Lung Cancer, 1996. 14(1): p. 1-12. 6. Butchart, E.G., et al., Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thorax, 1976. 31(1): p. 15-24. 7. Nowak, A.K., et al., The IASLC Mesothelioma Staging Project: Proposals for Revisions of the T descriptors in the forthcoming Eighth edition of the TNM classification for pleural mesothelioma. J Thorac Oncol, 2016. 8. Rice, D., et al., The IASLC Mesothelioma Staging Project: Proposals for Revisions of the N Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma. J Thorac Oncol, 2016. 9. Rusch, V.W., et al., The IASLC Mesothelioma Staging Project: Proposals for the M Descriptors and for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Mesothelioma. J Thorac Oncol, 2016.

Abstract not provided

Abstract not provided

Abstract not provided

Background:
Based on two single-arm, multicentre, phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]), the FDA approved the ALK inhibitor alectinib for use in ALK+ NSCLC patients after prior crizotinib. Alectinib was well tolerated in both phase II studies and showed efficacy against both systemic and central nervous system (CNS) disease, the latter being a common progression site in ALK+ NSCLC. This analysis uses pooled data from the latest cut-offs (22 Jan 2016 for NP28761; 1 Feb 2016 for NP28673) to examine the long-term CNS efficacy of alectinib.

Methods:
Both studies enrolled crizotinib-refractory patients ≥18 years with ECOG PS 0–2 and locally advanced or metastatic ALK+ NSCLC (confirmed by FDA-approved test). CNS metastases were permitted if asymptomatic. Patients received 600mg oral alectinib BID. The primary endpoint in both studies was objective response rate (ORR) by independent review committee; secondary CNS endpoints included CNS ORR, CNS duration of response (DoR), and CNS disease control rate (DCR). CNS response and progression were determined by RECIST v1.1. All patients had baseline imaging to assess CNS metastases, with further imaging every 6 or 8 weeks for NP28761 and NP28673, respectively.

Results:
The overall pooled analysis population comprised 225 patients (n=87 from NP28761; n=138 from NP28673); median follow-up for this updated analysis was 18.8 (0.6–29.7) months (>6 months additional follow-up). At baseline, 50 patients had measurable and 86 had non-measurable CNS disease; together, these groups comprised 136 patients, 60% of the overall pooled population. Seventy percent of patients had prior CNS radiotherapy; 58% of these completed radiotherapy >6 months before study entry. Updated CNS data are shown in the Table and are consistent with systemic results.

	Measurable CNS disease at baseline (n=50)	Measurable and non-measurable CNS disease at baseline (n=136)
CNS ORR, n (%) [95% CI]	32 (64.0) [49.2–77.1]	60* (44.1) [35.6–52.9]
Complete response (CR), n (%)	11 (22.0)	39* (28.7)
CNS DCR, n (%) [95% CI]	45 (90.0) [78.2–96.7]	117 (86.0) [79.1–91.4]
Median CNS DoR, months [95% CI] Patients with event, n (%)	11.1 [7.6–NE] 18 (56.3)	13.8 [11.0–21.5] 32 (53.3)
* N.B. Non-measurable disease response can only be classified as CR, non-CR/non-progressive disease (PD) or PD

Conclusion:
This updated pooled analysis with mature data confirms that alectinib can provide long-term control of CNS metastases in ALK+ NSCLC, with a high CR rate.

Background:
Alectinib, a CNS-active and highly selective ALK inhibitor, has efficacy in patients with ALK-positive NSCLC with and without previous crizotinib treatment. Updated efficacy and safety from the alectinib phase 2 North American NP28761 study (NCT01871805) of patients with ALK-positive NSCLC previously treated with crizotinib, with 15 months’ additional follow-up from the primary analysis and 9 months’ additional follow-up from the previous analysis are presented.

Methods:
Patients ≥18 years old with ALK-positive NSCLC (FDA-approved FISH test), disease progression following crizotinib, and ECOG PS ≤2 were enrolled. Patients received oral alectinib (600mg) twice daily until progression, death or withdrawal. Primary endpoint: overall response rate (ORR) by independent review committee (IRC; RECIST v1.1.) Secondary endpoints: investigator-assessed ORR; progression-free survival (PFS); overall survival (OS), CNS ORR (CORR); disease control rate (DCR); safety.

Results:
At the updated cut-off (22 January 2016) an additional 15 months' follow-up from the primary analysis, 87 patients were enrolled. Median follow-up: 17.0 months (range 1.1–28.6). ORR in the response evaluable population (REP; n=67) by IRC: 52.2% (95% CI 39.7–64.6), median duration of response: 14.9 months. Median PFS and OS: 8.0 and 22.7 months, respectively. Table 1 presents other efficacy endpoints. Grade ≥3 AEs were reported in 41% of the safety population (n=87); most common: elevated levels of blood creatine phosphokinase (8%), alanine aminotransferase (6%), aspartate aminotransferase (5%). Two patients withdrew due to AEs; 28% had AEs leading to dose modification/interruption. Mean dose intensity was 92.0%.

IRC REP Responders, n CR, n (%) PR, n (%) SD, n (%) PD, n (%) Missing/NE, n (%) DCR, % (95% CI)	n=67[*] 35 0 (0) 35 (52.2) 18 (26.9) 11 (16.4) 3 (4.5) 79.1 (67.4,88.1)
Investigator REP Responders, n ORR, % (95% CI)	n=87 [46[†]] 52.9 (41.9, 63.7)
Measurable baseline CNS lesions (IRC)‖ Responders, n CORR, % (95% CI) Measurable/non-measurable baseline CNS lesions (IRC) Responders CORR,[‖] % (95% CI)	n=16 12[‡] 75.0 (47.6, 92.7) n=52 21[§] 40.4 (27.0, 54.9)

*n=20 did not have measurable disease per IRC and were not included in the IRC REP; [†]2 CR;[ ‡]4 CR;[ §]13 CR; [‖]non-measurable disease classified as CR, non-CR/non-PD or PD; NE=not evaluable/estimable

Conclusion:
Alectinib demonstrated durable responses, encouraging OS findings, good tolerability and an acceptable safety profile consistent with previous reports in this update of the NP28761 study with extended follow-up.

Background:
ALK inhibitors are the standard treatment for ALK+ NSCLC and the comparison between 2 ALK inhibitors will be valuable in determining therapeutic strategy for ALK+ NSCLC patients (pts). We conducted the randomized open-label Phase III trial designed to prove the superior PFS of ALC to CRZ in ALK-inhibitor naïve ALK+ NSCLC.

Methods:
ALK+ NSCLC pts were randomized 1:1 either to receive ALC (300 mg b.i.d.) or CRZ (250 mg b.i.d.) and stratified by ECOG PS (0/1 vs 2), treatment line (1[st] vs 2[nd]), and clinical stage (IIIB/IV vs recurrence). Primary endpoint was PFS according to the blinded independent review board. Secondary endpoints included overall survival, objective response rate, and safety. Under an assumption of expected hazard ratio (HR) of 0.643, 164 events were required to have 80% power with 2-sided alpha of 0.05. Three interim analyses (IA) for early stopping due to efficacy were planned after 33%, 50%, and 75% of required PFS events occurred.

Results:
207 pts were enrolled at 41 centers in Japan between November 2013 and August 2015. Independent data monitoring committee recommended the release of study data because the superiority in PFS had been demonstrated for ALC based on second IA. The PFS HR of ALC arm to CRZ arm was 0.34 (99.6826% CI: 0.17-0.70, stratified log-rank p<0.0001). Median PFS was not reached (95% CI: 20.3-Not Reached (NR)) in ALC arm while it was 10.2 months (95%CI: 8.2-12.0) in CRZ arm. ALC demonstrated favorable result of PFS in each sub-group for instance, treatment line (1[st] line: HR = 0.30, ALC: NR vs CRZ: 10.2 months, 2[nd] line: HR = 0.39, ALC: 20.3 months vs CRZ: 8.2 months), brain metastases at baseline (yes: HR = 0.08, ALC: NR vs CRZ: 10.2 months, no: HR = 0.39, ALC: 20.3 moths vs CRZ: 10.0 months) and clinical stage (stage IIIb/IV: HR = 0.31 ALC: 20.3 months vs CRZ: 8.3 months, recurrence: HR = 0.49, ALC: NR vs CRZ: 11.6 months). Grade 3-4 AEs (ALC: 26% vs CRZ: 52%), discontinuation of study drug due to AEs (ALC: 9% vs CRZ: 20%) and dose interruptions due to AEs (ALC: 29% vs CRZ: 74%) occurred with lower rate in the ALC arm. There were no treatment-related deaths in either arm.

Conclusion:
ALC demonstrated prolonged PFS compared with CRZ in all sub-groups with a favorable AE profile representing a potential new standard treatment for 1[st] line ALK+ NSCLC pts.

Abstract not provided

Background:
ROS1 rearrangements are present in the tumors of 1-2% of patients with lung adenocarcinoma (LAD). This patient subgroup is characterized by non-smoking history and younger than average age compared to the overall NSCLC population. In a phase I trial the ALK/ROS1/MET inhibitor crizotinib has shown to be highly effective in these patients (NCT00585195). EUCROSS is a prospective phase II trial of the Lung Cancer Group Cologne in collaboration with the Spanish Lung Cancer Group to evaluate crizotinib in ROS1-positive LAD. Here, we present preliminary data on efficacy and safety.

Methods:
Patients with advanced LAD harboring ROS1 rearrangements as confirmed by central FISH were eligible for the trial irrespectively of the number of prior treatment lines. Patients received treatment with crizotinib 250 mg BID - doses were adapted for management of AEs. Trial design: Fleming’s single stage phase II design. Primary endpoint: ORR (95% CI, H~0~: ORR≤20% vs. H~1~: ORR>20%). Secondary endpoints: a.o. PFS, OS and safety. All efficacy endpoints were assessed by investigator’s RECIST v1.1 and will be analyzed by IRB at a later stage. Baseline tumor tissue was analyzed by DNA-sequencing to identify the translocation Partners of ROS1, to validate FISH results and to identify additional biomarkers for prediction of response. Data-cut off for this report was March 2016.

Results:
In total, 34 patients were enrolled in EUCROSS at the time of data cut-off. Twenty-nine patients were eligible for efficacy assessment. Tumor tissue of 20 of these patients was suitable for further sequencing - 18 were sequenced positive for ROS1 fusion. The fusion partners involved were CD74 (N=9;50%), EZR (N=4;22%), SCL34A2 (N=3;17%), TPM3 and SDC4(N=1;6% each). The investigator assessed ORR was 69% (95% CI, 49.1-84.3) in the overall trial population and 83% (95% CI, 67.7-94.2) in the ROS1-positive by sequencing population (N=18;P=0.324 for difference of ORR). Three patients (10.3%;95% CI, 3.6-26.4) exhibited primary progression, two of them were sequenced ROS1-negative. All patients were included in the safety population (N=34). Most common AEs irrespectively of relatedness or grade were visual disorders (N=16;48%), edema (N=14;41%), diarrhea (N=13;38%) and bradycardia (N=11;32%).

Conclusion:
Crizotinib is a highly effective and safe treatment in the subset of ROS1 rearranged NSCLC patients as determined by FISH and DNA-sequencing. Although, the number of patients with tissue available for sequencing was low at the time of data cut-off, sensitivity and specificity support sequencing as the potential new gold-standard for the identification of clinically relevant ROS1 gene-rearrangements.

Background:
Crizotinib is an orally active inhibitor of receptor tyrosine kinases effective in NSCLC with ALK rearrangement. Recent data showed that this agent is dramatically effective in patients with ROS1 rearrangement and at least in some patients with MET deregulation, particularly individuals with exon 14 skipping mutations or with high levels of MET amplification.

Methods:
The METROS trial is a multicenter prospective phase II study designed to assess the efficacy and safety and tolerability of Crizotinib in pretreated metastatic NSCLC with MET amplification or MET exon 14 mutation or ROS1 rearrangement. The co-primary end-point was response rate to crizotinib in two cohorts of patients: cohort A) ROS1+: patients with ROS1 rearrangement; B) MET+: patients with MET amplification defined as ratio MET/CEP7 >2.2 on FISH testing or MET exon 14 skipping mutations. Eligible patients were treated with with crizotinib at the standard dose of 250 mg BID p.o.

Results:
At the time of the present analysis, preliminary data on the MET cohort are available. A total of 249 patients were screened and 18 resulted as MET+ (12 amplified and 6 mutated). Among them, 10 patients (9 amplified and 1 mutated) were included onto the study and received at least one dose of crizotinib, 6 patients were not eligibible beacause of not progressing to front line therapy, whereas 2 patients did not received crizotinib due to rapidly progressive disease. Characteristics of enrolled patients were: median age 68 years (range 39-77); male/female 8/2; ECOG PS 0/1/2: 6/3/1. In 8 cases crizotinib was offered as second-line therapy. All but one patients were current or past smokers. According to RECIST criteria, 2 partial responses and 4 stable disease were so far documented, with an overall disease control rate of 60%. Three patients are still on treatment. Therapy was generally well tolerated, with only 1 patient delaying therapy due to adverse events. Enrollment is still ongoing.

Conclusion:
Preliminary analysis of the METROS trial supports the potential efficacy of crizotinib in patients with MET deregulation, with a favorable toxicity profile. Updated results including median progression-free survival and survival were will be presented at the meeting.

Background:
ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC.

Methods:
We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization (FISH). ROS1 immunohistochemistry (IHC) and next-generation sequencing (NGS) was performed in available tumor samples. Ceritinib 750mg was administered once daily and the primary endpoint was objective response rate (ORR) by central independent radiologic review. The secondary endpoints included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), toxicity and concordance between FISH and IHC. ROS1 fusion partners were identified with the use of next-generation sequencing (NGS) in available tumor samples.

Results:
Between June 7, 2013, and February 1, 2016, a total of 404 patients underwent ROS1 prescreening, and 32 ROS1+ (by FISH) patients were enrolled. All patients except two (who did not respond to ceritinib) were crizotinib naïve. The median age of all patients was 62 years, and there were 24 females (75%). The majority of patients (84%) were never smokers, and all had adenocarcinoma histology. The median number of previous treatments before study enrollment was 3 (range, 2-7) and 17 (53%) patients had received three or more lines of chemotherapy. At the time of the data cut-off (April 18, 2016), the median follow-up was 7.5 months, and 15 (47%) patients had discontinued treatment. Of the 32 patients enrolled, 28 patients were evaluable for response by independent radiologic review. ORR was 63% (95% CI, 45.7-79.3), with 1 complete response and 19 partial responses. The median duration of response was 10.0 months (range, 0.4+-18.4+). Among 11 tumors that were tested by NGS, we identified 7 ROS1 fusion partners including ROS1-CD74, ROS1-SLC34A2, and ROS1-EZR. The median progression-free survival was 19.3 months (95% CI, 7.2-not reached), with 17 (53%) patients still in follow-up for progression. The median overall survival was not reached at the time of the data cut-off. Of 5 patients with retrospectively confirmed brain metastases, intracranial disease control was reported in 4 patients (80%). Gastrointestinal adverse events (vomiting, nausea, diarrhea) mostly grade 1-2, were the most frequent adverse events (80%); these events were manageable.

Conclusion:
Ceritinib demonstrated potent clinical activity in patients with advanced, ROS1-rearranged NSCLC, who received at least one prior line of platinum-based chemotherapy. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which ceritinib is highly active (ClinicalTrials.gov number, NCT01964157).

Abstract not provided

Background:
Drug resistance emergence is a daunting obstacle that limits long-term outcome benefits in precision cancer therapy. Mechanism of the initial emergence of molecular tumor resistance is still not fully understood. Recently, we identified an early precision drug escape mechanism with adaptive tumor cellular reprogramming emerging within days after drug initiation. Here we present a mass spectrometry imaging (MSI) approach to profile the biomolecular changes emerging within residual drug resistant tumor cells under precision ALK inhibitor (ALK-i) treatment.

Methods:
EML4-ALK fusion (ALK+) H3122 lung adenocarcinoma xenograft as well as an ALK+ patient biopsy-derived cell line (Ma-ALK001.S) were adopted for the MSI studies. MSI was carried out on FFPE tissues to compare peptide profiles between control tumors and 7- and 14-day ALK-i treated tumors using a histology guided mass spectrometry approach. Additionally, frozen control and ALK-i treated tumors were subjected to full section MSI to determine the ALK-i drug distribution as well as the changing landscape of lipids and metabolites. In parallel, Ma-ALK001.S cell line was treated with alectinib (ALK-i) in culture with samples collected at 0 hr, 8 hr, 3 days, 7 days, and 14 days. Cells were subjected to both MALDI-MS profiling analysis and Laser Ablation Electrospray Ionization (LAESI)-MS analysis. Statistical analyses were performed using MarkerLynx and SCiLS.

Results:
ALK+ H3122 lung adenocarcinoma murine xenograft model in vivo under treatment with/without ALK-i TAE684 was used in MSI studies at treatment day 0, day 7 and day 14, during tumor response. Pairwise and 3-way Wilcoxon rank sum tests were carried out and a Bonferroni correction applied. The greatest number of significant peaks were observed between day 0 and day 14 (677). Pairwise linear discriminant analysis classification algorithm models were generated resulting in over 94% classification accuracy in all comparison. Direct MS/MS fragmentation revealed that ALK-i was detected within the frozen ALK-i dosed tumors in early drug-escape. Several lipids were identified to expression landscape changes emerging under ALK-i. Biomolecular (peptides, lipids, and metabolites) profiling of Ma-ALK001.S cell line using combined MALDI and LAESI MSI analysis was successful, which provided novel insights into the early mechanisms of molecular drug resistance emergence.

Conclusion:
MSI allowed for direct in situ determination of the evolving expression landscape of biomolecules in ALK+ lung cancer under ALK-i precision therapy. These results provide a rationale to advance our MSI profiling studies for biomarkers discovery to gain deeper insights into molecular mechanisms of adaptive precision drug resistance emergence.

Background:
ALK rearrangement, most commonly EML4-ALK, is detected in approximately 3–7% of non-small cell lung cancer (NSCLC). Crizotinib, an ALK tyrosine kinase inhibitor (TKI), shows dramatic clinical efficacy in ALK-rearranged NSCLC patients. However, almost all patients acquire resistance after only 1 to 2 years. A variety of mechanisms, including ALK-secondary mutations, ALK amplification, and activation of alternative pathway, have been reported to mediate acquired resistance to crizotinib. While epithelial–mesenchymal transition (EMT) was recently reported to be associated with resistance to crizotinib in EML4-ALK lung cancer cells in vitro, the underlying mechanism has not been defined and no optimal therapy to overcome EMT-associated resistance has been identified.

Methods:
We continuously gave crizotinib treatment to SCID mice inoculated with EML4-ALK lung cancer cell line A925L into thoracic cavity and established crizotinib resistant A925LCR cells. After the limiting dilution of A925LCR cells, we obtained several single cell clones. The effects of the HDAC inhibitor quisinostat on the EMT state and the growth of the cells were examined in vitro and in vivo.

Results:
We found that some clones acquired EMT phenotypes, such as spindle shape morphology, expression of EMT-related proteins, and increased cell motility. Interestingly, Histone deacetylase (HDAC) inhibitor, quisinostat, induced mesenchymal-epithelial transition (MET) of A925LCR clones in vitro. Quisinostat reduced ZEB1 expression, induced MET, and thus restored sensitivity to crizotinib. Knockdown of ZEB1 expression in the A925LCR clones by si-RNA also induced MET and restored sensitivity to crizotinib, suggesting that quisinostat-induced MET depends on ZEB-1 suppression. MicroRNA profile analysis revealed that the A925LCR clones expressed significantly lower levels of miR-200 family including miR-200c which targets ZEB1, compared with parental A925L cells. Furthermore, quisinostat recovered miR-200c expression and antago-miR-200c abrogated quisinostat-induced MET in the A925LCR clone cells. These results indicate that quisinostat induced MET by up-regulating miR-200c expression which target ZEB1 and thereby re-sensitizing to crizotinib. In a pleural carcinomatosis model with A925LCR clone cells, quisinostat induced MET and caused remarkable tumor regression during the subsequent crizotinib re-challenge. Furthermore, we analyzed tumor tissue obtained at autopsy from an ALK-rearranged NSCLC patient who acquired resistance to crizotinib. We found that EMT was induced in both primary and metastasis lesions after crizotinib treatment, indicating that EMT is associated with crizotinib resistance in clinical therapy.

Conclusion:
Our findings suggest that EMT is possibly occurred in acquired resistance to crizotinib and intermittent use of HDAC inhibitor could be a novel therapeutic strategy for overcoming EMT-associated crizotinib-resistance in EML4-ALK lung cancer.

Background:
Patients with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) NSCLC often become resistant to tyrosine kinase inhibitor (TKI) therapy; central nervous system (CNS) relapse is common. Lorlatinib is a selective brain-penetrant ALK/ROS1 TKI, active against most known resistance mutations.

Methods:
In Ph I of the ongoing Ph I/II study NCT01970865, patients had ALK+ or ROS1+ NSCLC ± brain metastases and were treatment naïve or had disease progression after ≥1 TKIs. Patients received lorlatinib on day –7 and then once or twice daily from day 1. Primary objective was identification of MTD and recommended Ph II dose (RP2D). Other objectives were safety and efficacy by RECIST v1.1 including intracranial activity.

Results:
Of 54 patients treated in Ph I (cutoff Jan 15, 2016), 41 were ALK+, 12 ROS1+, and 1 had mutation status unconfirmed for ALK+ or ROS1+. Patients were heavily pretreated: 27 had received ≥2 prior TKIs and 20 had 1 prior TKI; 39 patients had CNS metastases at baseline. Patients were treated across 10 dose levels (total daily dose of 10–200 mg). Response rates were:

	N	CR	PR	uCR	uPR	Overall RR (CR + PR)
		n (%)
ORR in ALK+ and ROS1+	53	3(6)	22(42)	-	1(2)	25(47)
ORR in ALK+ with 1 prior TKI	14	1(7)	7(50)	-	-	8(57)
ORR in ALK+ with ≥2 prior TKI	26	2(8)	9(34)	-	1(4)	11(42)
IC ORR (target + non-target lesions) in ALK+ and ROS+	39	10(26)	4(10)	1(3)	2(5)	14(36)
IC ORR (target lesions) in ALK+ and ROS+	23	7(30	4(17)	-	2(9)	11(47)
ORR, objective response rate; IC ORR, intracranial objective response rate; CR, complete response; PR, partial response; RR, response rate; u, unconfirmed

Median duration of response was 10.5 months (95% CI 2.9– not reached [NR]) and 12.4 months (95% CI 6.5–NR) for ALK+ and ALK+/ROS1+ pts, respectively. 26 patients remain on treatment. The most common treatment-related adverse events (TRAEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade ≥3 TRAE. No patient discontinued due to a TRAE. Analyses of ALK resistance mutations in archival tumor tissue and plasma circulating free DNA collected before lorlatinib treatment are ongoing.

Conclusion:
Lorlatinib was well tolerated and demonstrated durable responses, including intracranial responses, in ALK+ and ROS1+ NSCLC, most of whom had CNS metastases and ≥1 prior TKIs. The RP2D was identified as 100 mg once daily. Ph II is ongoing.

Abstract not provided

Background:
Non-invasive genotyping of NSCLC patients by circulating tumor (ct)DNA is a promising alternative to tissue biopsies. However, ctDNA EGFR analysis remains challenging in patients with intrathoracic disease, with a reported 26-57% T790M mutation detection rate in plasma (Karlovich et al., Clin Cancer Res 2016; Wakelee et al., ASCO 2016). We investigated whether a mutation enrichment NGS could improve mutation detection in plasma and urine from TIGER-X, a phase 1/2 study of rociletinib in patients with EGFR mutation-positive advanced NSCLC.

Methods:
The therascreen (Qiagen) or cobas (Roche) EGFR test was used for EGFR T790M analysis in tumor biopsies. Urine and plasma were analyzed by trovera mutation enrichment NGS assay (Trovagene).

Results:
Of 174 matched tissue, plasma and urine specimens, 145 (83.3%) were T790M+ by central tissue testing, 142 (81.6%) were T790M+ by plasma, and 139 (79.9%) were T790M+ by urine. Urine and plasma combined identified 165 cases (94.8%) as T790M+. Of 25 cases positive by ctDNA but negative/inadequate by tissue, 16 were double-positive in plasma and urine, unlikely to be false positive (Figure 1). T790M detection rate was higher for extrathoracic (n=119) vs intrathoracic (n=55) disease in plasma (87.4% vs 69.1%, p=0.006) but not urine (81.5% vs 76.4%, p=0.42). Combination of urine and plasma identified T790M in 92.7% of intrathoracic and 95.8% of extrathoracic cases (p=0.47). In T790M+ patients, objective response rate was similar whether T790M mutation was identified by tissue, plasma or urine: 37.4%, 33.1% and 36.6%, respectively. 4 of 9 patients T790M+ by urine but negative by tissue responded, and 2 of 8 patients T790M+ by plasma but negative by tissue responded.

Conclusion:
Mutation enrichment NGS testing by urine and plasma combined identified 94.8% of T790M+ cases. Combination of urine and plasma may be considered before tissue testing in EGFR TKI resistant NSCLC, including patients without extrathoracic metastases. Figure 1

Background:
Treatment in non-small cell lung cancer is quickly evolving and new agents make it to the routine practice at a rapid pace. Whether outcome and PRO data generated in clinical trials with often narrow inclusion and exclusion criteria will hold up in the routine practice is of high interest, especially due to the increasing costs of new drugs. Therefore registry data are of ever increasing importance to patients, physicians and reimbursement institutions.

Methods:
Therefore, we have started a prospective, clinical registry for patients with metastatic non-small cell lung cancer. The purpose of CRISP is to set up a national clinical research platform to document representative data on molecular testing, sequences of systemic therapies and other treatment modalities, course of disease in patients with advanced or metastatic NSCLC in Germany not amenable to curative treatment. A particular focus is on molecular biomarker testing of patients before the start of first-line treatment. The data shall be used to assess the current state of care and to develop recommendations concerning topics that could be improved. PRO assessment will provide large-scale data on quality of life and anxiety/depression for real-life patients in routine practice. In addition, two questionnaires (concerning individual quality of life and patient-caregiver communication) will be validated in German patients with metastatic NSCLC. Furthermore CRISP will set up a decentral tissue annotation for future collaborative, investigational scientific biomarker testing.

Results:
This study will be carried out in up to 150 representative cancer centers in all therapeutic sectors in Germany. More than 8000 patients will be recruited and followed up to a maximum of 3 years, respectively until death. The first patients have been included as of December 2015. As of yet, 82 centers have been initiated, 211 patients have been recruited. Preliminary data will be presented at the meeting in terms of molecular test rates, demographic data as well as treatment stratification in the 1[st] line setting.

Conclusion:
The registry CRISP will be the first to present representative real life data, covering all treatment settings of patients with NSCLC in Germany. ClinicalTrials.gov Identifier: NCT02622581 CRISP is supported by Grants from AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, and Pfizer Pharma GmbH.

Background:
AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib, a T790M directed EGFR-TKI, vs platinum-based doublet chemotherapy in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on previous EGFR-TKI therapy. Concordance between plasma and tissue testing, and efficacy outcomes by baseline plasma T790M status, were evaluated.

Methods:
Eligible patients were randomised 2:1 to osimertinib 80 mg orally once daily or platinum-pemetrexed (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5) every three weeks for up to six cycles. Patients were tumour tissue T790M-positive (by cobas[®] EGFR Mutation Test v2) from a biopsy after disease progression prior to study entry. Blood samples were taken at baseline for retrospective analysis of T790M mutation status by plasma ctDNA using the cobas[®] EGFR Mutation Test v2.

Results:
Concordance data are reported in the table. Within the intent-to-treat (ITT) population (n=419), patients plasma T790M-positive and randomised to treatment (n=172) had markedly improved progression-free survival (PFS) by investigator assessment (IA) with osimertinib vs platinum-pemetrexed: hazard ratio 0.42 (95% CI: 0.29, 0.61); median 8.2 vs 4.2 months. Objective response rate (ORR) by IA was also distinctly improved with osimertinib vs platinum-pemetrexed: 77% vs 39% (odds ratio 4.96 [95% CI: 2.49, 10.15]; p<0.001). This is consistent with the ITT population: PFS hazard ratio 0.30 (95% CI: 0.23, 0.41); p<0.001 (median 10.1 vs 4.4 months); ORR 71% vs 31% (odds ratio 5.39 [95% CI: 3.47, 8.48]; p<0.001). Figure 1



Conclusion:
In plasma T790M-positive patients the clinical benefit of osimertinib was superior to platinum-pemetrexed, consistent with the ITT T790M-positive population selected by tumour tissue test. PFS with osimertinib was similar regardless of selection by tissue or plasma T790M-positive status. Based on these, and AURA Phase II data, routine biopsy testing is recommended for patients with a plasma T790M-negative test where feasible.

Abstract not provided

Background:
The association between depth of response to EGFR TKI and prognosis of EGFR-mutated NSCLC remains unclear. We aimed to assess the correlation between maximal tumor shrinkage and survival in patients treated with gefitinib and afatinib.

Methods:
Patients with advanced EGFR-mutated NSCLC enrolled in first-line gefitinib and afatinib clinical trials between 2005 and 2014 at the National Taiwan University Hospital were reviewed. Patients who had at least one measurable target lesion that shrank during treatment were included. Overall survival (OS) was defined as time from date of enrollment to death or May 30[th], 2016. Correlation between tumor shrinkage and OS was analyzed by Pearson correlation coefficient and Kaplan-Meier method. The influence of high maximal tumor shrinkage (defined as ≥50% tumor shrinkage), age, gender, types of EGFR mutation, central nervous system (CNS) involvement at diagnosis, CNS as site of progression, first-line EGFR TKI (gefitinib or afatinib), and subsequent treatments (chemotherapy, third-generation TKI) on OS was evaluated by a multivariate Cox proportional hazard model.

Results:
A total of 189 trial patients were screened and 91 patients were eligible for analysis (gefitinib n=42, afatinib n=49). The median maximal tumor shrinkage during first-line EGFR TKI treatment was 53% (interquartile range 30.5%). Maximal tumor shrinkage did not correlate with OS in all patients (R[2]=0.0225, p=0.169), and either the gefitinib (R[2]=0.0036, p=0.689) or afatinib (R[2]=0.0625, p=0.085) group (Fig.1A). High maximal tumor shrinkage also did not significantly affect OS (HR 0.86, 95% CI 0.54-1.40, p=0.564) (Fig. 1B). In multivariate analysis, CNS as site of progression (HR 2.96, 95% CI 1.39-6.29, p=0.005) and first-line afatinib (HR 0.51, 95% CI 0.29-0.91, p=0.022) were the only factors that significantly influenced OS.Figure 1



Conclusion:
The depth of response to first-line gefitinib and afatinib was not predictive of OS in patients with EGFR-mutated NSCLC.

Background:
DpR, defined as maximum tumor shrinkage, has emerged as a potential predictor for long-term treatment outcome across multiple tumors, including NSCLC treated with immunotherapy or targeted therapy. This exploratory analysis evaluated whether DpR correlated with survival in patients with advanced NSCLC treated with platinum-doublet chemotherapy in a phase III randomized clinical trial.

Methods:
Patients received first-line nab-paclitaxel 100 mg/m[2] weekly or paclitaxel 200 mg/m[2] q3w, both + carboplatin AUC 6 q3w. The current analysis evaluated DpR as best percent change from baseline in total target lesion length during treatment. For patients with tumor shrinkage, data were grouped into quartiles based on maximum percent shrinkage from baseline (Q1: > 0%-≤ 25%; Q2: > 25%-≤ 50%; Q3: > 50%-≤ 75%, Q4: > 75%) and compared with data from patients with no change or tumor growth (NC/G).

Results:
Tumor measurement by independent review (baseline and postbaseline) was evaluable in 959 patients pooled across treatments. The median (Figure) and 1-year OS increased with each quartile vs NC/G (NC/G: 4.8 months and 17%; Q1: 10.4 months and 44%; Q2: 14.5 months and 62%; Q3: 19.3 months and 71%; Q4: 23.5 months and 70%) with HRs for OS vs NC/G of 0.42 for Q1 (95% CI, 0.33-0.53; P < 0.0001), 0.28 for Q2 (0.22-0.36; P < 0.0001), 0.23 for Q3 (0.16-0.31; P < 0.0001), and 0.19 for Q4 (0.11-0.33; P < 0.0001), respectively. Similar findings were observed for all quartiles vs NC/G for age (≥ 70 and < 70 years) and histology (squamous and nonsquamous) in subset analyses (P < 0.05 for all comparisons).

Conclusion:
DpR was associated with increased OS in patients with advanced NSCLC receiving first-line platinum-based doublet chemotherapy, regardless of age or histology. These findings underscore the importance of evaluating quality of treatment response in this patient population.Figure 1

Background:
Circulating tumor cells (CTCs) have been reported prognostic and predictive in non-small cell lung cancer (NSCLC) and a few of other cancer types. In 1[st] line setting, whether EPCAM[+]CK[+]CD45[-] CTC and/or stem cell-like cKIT[+]EPCAM[+ ]CK[+]CD45[-] CTC enumeration and dynamic changes can be prognostic and/or predictive to standard chemotherapy need further investigation in Chinese patients with NSCLC.

Methods:
A prospective study on the CTC enumeration in advanced NSCLC with 1st line chemotherapy (POLICE) was started by China Thoracic Oncology Group (CTONG). Patients with NSCLC naïve for systemic regimens were enrolled since August 2013. CTCs were detected by Cell Search Platform and identified as positive for EPCAM[+]CK[+]CD45[-] phenotype. CD117 (cKIT) marker was added to test the frequency of stem cell-like cKIT[+]EPCAM[+]CK[+]CD45[- ]CTCs. Primary endpoints were CTC counts and its correlation with first line therapy.

Results:
Totally 180 patients were enrolled. In 174 case total CTC and cKIT[+]CTC positive (cutoff >=1) rates were 38.5% (67/172) vs 14.3% (24/168), 21.8% (31/142) vs 6.3% (9/142), 13.7% (13/95) vs 6.4% (6/94) and 40.4% (38/94) vs 15.0% (13/93) at time-points of baseline, after first-cycle-chemo, after four-cycles-chemo and disease progression. At time immediately after first-cycle-chemo, patients in CTC=0 group got statistically higher ORR (29.0% VS 7.1%, P=0.017) and DCR (74.2% VS 42.9%, P=0.002) than in CTC>=1 group. At time after four-cycles-chemo, patients in CTC=0 group got statistically higher DCR (88.3% VS 58.3%, P=0.026) than in CTC>=1 group. At time either after first-cycle-chemo or after four-cycles-chemo, patients in CTC>=1 group got worse PFS (5.7m VS 4.0m, P=0.025; 6.3m VS 4.0m, P=0.001 ) than in CTC=0 group. At time after first-cycle-chemo, patients in groups cKIT[+]CTC>=1 and cKIT[-]CTC>=1 got worse PFSs (3.1m vs 4.0m vs 5.7m, P=0.001) and worse DCRs (44.4% vs 42.1% vs 73.9%, P=0.009) than in CTC=0 group. For 142 patients categorized into three groups of dynamic CTC decrease (17), CTC unchanged (82), and CTC increase (43), there were significant differences in terms of DCR (71.8% vs 71.6% vs 33.3%, P=0.018) and PFS (5.2m vs 5.6m vs 3.1m, P=0.037).

Conclusion:
In first line setting of advanced NSCLC, at time-points after first-cycle-chemo other than baseline, total CTC or cKIT[+]CTC counts could be predictive for worse DCR or PFS. CTC increase from baseline to after-first-cycle-chemo might be a strong signal for the inefficacy of first line chemotherapy in the NSCLC patients.

Abstract not provided

Background:
Genotyping cell free circulating DNA (cfDNA) is a non-invasive method of detecting EGFR mutations (EGFRmu) in plasma and may provide an option to identify patients who progress while treated with EGFR TKIs. The aim of our study was to monitor plasma EGFRmu and identify dynamic case specific changes in plasma EGFRmu during routine treatment of advanced EGFRmu NSCLC patients.

Methods:
Plasma was collected from patients with advanced EGFRmu NSCLC treated with first- or second-generation EGFR TKIs. Plasma EGFRmu were dynamically monitored consecutively at every scheduled visit. Cobas EGFR Mutation Test v1 and v2 (Roche, USA) was used to detect 42 mutations at EGFR gene in exons 18 to 21. Liquid biopsy progression (LBP) was determined as reappearance of EGFRmu in plasma after negativisation during treatment or increase of EGFRmu levels expressed by semi-quantitative index (SQI). Radiologic progression was determined in accordance with RECIST1.1 criteria.

Results:
From May 2014, 23 patients were treated with EGFR TKIs for advanced EGFRmu NSCLC; 20/23 had detectable activating mutations in plasma before any treatment and were therefore included in our analysis. Dynamic changes of plasma EGFRmu during 1[st] line EGFR TKI treatment are shown in Figure 1. Eight patients (40%) experienced RECIST 1.1 progression while on treatment, whereas one patient was inevaluable. In 4/8 patients (50%) LBP appeared at the same time as radiologic progression, in 3/8 patients (37%) LBP appeared before radiologic progression (8w, 14w, 20w before, respectively) and in 1 patient (12%) radiologic progression appeared 6w before LBP. Among patients who did not experience radiologic progression yet, some dynamic changes in cfDNA were also observed, but alterations in the SQI values were much smaller. Figure 1



Conclusion:
Monitoring EGFR mutations in plasma is a feasible and less invasive method in routine clinical practice and could be used as a predictive marker of progression on treatment with EGFR TKIs.

Background:
NSCLC patients with activating mutations of the EGFR initially respond well to TKIs, but about half such patients develop TKI resistance through acquisition of a secondary T790M mutation. Whereas next-generation EGFR-TKIs have been developed to overcome T790M-mediated resistance, performance of a second tumor biopsy to assess T790M mutation status can be problematic.

Methods:
We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation–positive patients with acquired EGFR-TKI resistance.

Results:
A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M.

Conclusion:
Noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment.

Background:
EGFR T790M mutation occurs in about half of EGFR mutated NSCLC patients with acquired EGFR-TKI resistance. It is currently unknown if switching therapy to a third generation anti-EGFR TKI based on circulating tumor DNA at first detection with urine is superior to switching therapy based on radiographic progression. Herein we demonstrate the identification of T790M in urine months before radiographic progression, patient responses when treated with an anti-EGFR third generation TKIs, clinical cutoffs that may be predictive of benefit, and a novel clinical trial to consider for treatment selection.

Methods:
From 2014 to 2016 a total of 42 patients with EGFR activating mutations were followed at UCSD Moores Cancer Center through multiple lines of therapy. 34 patients had serial urine collection every 4-6wks from time of first visit. Clinical progression was assessed with CT imaging performed every two months.

Results:
Among the 42 patients, 35 patients had metastatic disease (6 with intrathoracic M1a disease and 29 with distant metastasis M1b). Urine volume ranged from 30-100ml. Average time from first line TKI start to urine T790M was 15.7mos (CI 9.6-25.6), time from TKI start to radiographic progression was 21.9mos (CI 10.7-27.0), and time from urine T790M to radiographic progression was 3.6mos (CI 0.9-6.8). All patients with >30 copies/10[5] genome equivalents (GEq) of urine T790M had response to third generation TKIs. In patients who had urine EGFR T790M from 10-30 copies/10[5] GEq, three serial measurements in the 10-30 range predicted response. EGFR T790M copies of less than 10 copies/10[5] GEq did not predict response to third generation inhibitors.

Conclusion:
EGFR T790M can be identified in urine before radiographic progression and quantitative cut-offs can be predictive of response. We are testing this prospectively in a clinical trial with serial ctDNA analyses obtained for resistance monitoring for up to 24 months on first line TKI therapy. Patients who have urine detection of T790M (>30 copies or three serial collections with 10-30 copies/10[5] GEq) at 12 months and before progression are randomized to second line third generation TKI therapy or continuation of the first line therapy until progression. Patients with undetectable urinary T790M or <10 copies/10[5] GEq will continue on the first line therapy past 12 months until progression. Overall survival, progression free survival, and time to progression will be compared between cohorts to validate the early detection of T790M by urine ctDNA and understand the impact of an early switch in therapy based on ctDNA analyses.

Abstract not provided

Abstract:
Background Malignant pleural mesothelioma (MPM) is an aggressive cancer of the lining of the chest wall and lung, its aetiology lies in asbestos exposure. With over 2,500 people diagnosed each year, the UK has the highest incidence of mesothelioma in the world. Chemotherapy is an established treatment for MPM but response rates are variable, evidence is lacking in new drug therapies and mortality remains high (in the UK half of patients die within 8.5 months of diagnosis) (Maggioni 2016, HSCIC 2015). Surgery is therefore an important option. Very little robust, randomised controlled trial evidence (RCT) exists regarding surgical interventions for mesothelioma and many studies are observational (Cao et al 2014). This has prompted global variations in surgical approaches (Mclean 2013). Extended Pleurectomy Decortication (EPD) is a surgery for patients considered to have resectable MPM. EPD involves the removal of the lining of the chest wall, lining of the lung, with the sac of the heart and / or diaphragm (as required to achieve complete tumour removal) but leaving the lung in-situ. However, evidence on survival or symptom improvement benefits of this surgery is limited (Cao et al 2014, Teh et al 2011). Challenges in surgical research are the lack of clinical trials and few patients choosing to enter RCTs for surgery (Treasure & Morton, 2012, Horton 1996). Potential explanations for this include restrictive trial regulation, patients declining randomisation, and difficulties in recruitment practice such as presenting trial arm options neutrally (Treasure & Morton 2012). The Mesothelioma and Radical Surgery 2 (MARS 2) Trial, a UK based study, will evaluate whether EPD can improve the length and / or quality of life in patients with surgically treatable disease and its cost-effectiveness. It will randomise participants to chemotherapy or chemotherapy plus surgery. The feasibility stage has demonstrated the ability to recruit and randomise to this study and the plan is to proceed to full trial. This paper presents findings from a nested qualitative patient experience sub-study within MARS 2 that investigated patient experience of the study interventions. It more specifically identifies the support and information needs for people regarding i) the interventions (surgery and chemotherapy) and ii) trial recruitment, consent and participation. This paper focuses on the findings related to support needs of the trial interventions. A summary of results will be provided along with reflections on the implications for future practice. Methods An in-depth longitudinal qualitative study with interviews of 16 participants randomised to chemotherapy (n=8) and chemotherapy + surgery (n=8). Interviews were conducted after randomisation (but before surgery in the surgical cohort). Surgical patients had an additional interview post-surgery. Framework analysis methods were used (Ritchie and Lewis, 2014). Follow-up interviews were at 6 and 12 months post-randomisation. This paper presents findings up to and including the 6 months follow-up. Results Participants reported being well informed about their illness, but had struggled to absorb and understand the extent of information delivered at diagnosis. This was influenced by the range of significant subjects that were covered in a number of consultations with different healthcare staff providing distinct specialist services. The topics discussed included diagnostic information about mesothelioma, treatment options and consequences, trials processes and logistics, and legal and financial information regarding classification of MPM as an industrial disease. Despite feeling well informed about their treatment some participants reported not being prepared for the full extent of the problems they experienced. Both chemotherapy and surgery were challenging treatments although they were associated with different physical effects. Adverse consequences of treatment were described including neutropenic sepsis and dehydration post chemotherapy, and bleeding, prolonged pneumothorax and infection post-surgery. For most participants pain and breathlessness were experienced post-surgery while nausea, anorexia, taste changes and constipation were associated with chemotherapy. Fatigue that impacted on daily living was experienced by both groups. Interventions to manage the consequences of treatment were recounted; some had been recommended by healthcare staff while others had been developed by patients from their own initiative. Participants reported struggling to cope with the effect of treatment whilst trying to deal with the broader context of coming to terms with their illness. Uncertainty was expressed in relation to treatment plans (exacerbated by the logistics surrounding participation in a clinical trial), severity and duration of side effects, rehabilitation and recovery and treatment outcomes. Participants employed a number of strategies to help with coping. These included ‘playing things down’, ‘weighing the balance’, ‘managing expectations’, ‘taking control’ ‘manning up’ and ‘trust in the doctor and/or treatment’. Many of these strategies facilitated staying positive, maintaining hope and finding comfort which was important to participants. Family members played a key role in coping. A diverse range of healthcare staff provided information, advice and practical interventions across the care pathway from community, surgical, respiratory and oncology services. Discussion Patient’s perspectives on the experience of receiving radical surgery and/or chemotherapy for mesothelioma were identified by the study. This provided valuable insights into their impact on patient’s feelings about their illness and treatment and how they coped with the challenges they were presented with. Multiple sources of uncertainty were expressed by participants. The contribution of healthcare staff to supporting coping and providing information and advice was appraised positively by participants. However, we identified that fragmentation could occur due to the diverse services involved in providing care with no single point of contact or co-ordination. Conclusion Understanding the patient’s perspective of the challenges associated with treatment, alongside their strategies for coping, provides insights for the services that can support patients undergoing arduous treatments for mesothelioma. The study reveals ways to facilitate strategies to help patients manage the condition, as well as treatment side-effects. Interventions to reduce uncertainty have been identified as a priority for service improvement.

Abstract:
Lung cancer is the commonest cancer worldwide with 1.6 million people diagnosed each year. People with lung cancer experience a high level of supportive care needs and many of these needs are unmet. Systematic supportive care is therefore vital in this patient group. Patient Reported Outcome Measures (PROMs) can be used to identify the supportive care needs of people with lung cancer and the collection of PROMs data is reported to have a number of positive effects on patient outcomes. Enhancing the utility of PROMs within clinical practice is the use of health technologies that have the ability to collect PROM data remotely from patients in their own homes and send this information in ‘real time’ immediately to relevant health/social care professionals for subsequent intervention. The Advanced Symptom Management System is one of the most evolved remote patient monitoring systems in cancer care. This presentation will initially focus on remote patient monitoring within the context of lung cancer before considering the implications for the future and the ultimate vision of connected health for all.

Abstract:
Introduction Systemic therapy (ST) with chemotherapy (Cht), targeted agents or immunotherapy (IT) represents the mainstay therapy for patients with advanced lung cancer; while adjuvant systemic therapy is recommended in a majority of patients with operable and locally advanced disease. The goal of ST is to prolong life without compromising quality of life (QoL). Despite the ability of ST to prolong life or even cure patients, QoL and life span might be compromised due treatment toxicity. In addition, uncontrolled adverse events (AEs) might lead to treatment interruption or discontinuation. Therefore, effective management of adverse events of anti-cancer drugs, the so-called “supportive care to systemic therapy” is extremely important for a true benefit, i.e. treatment effectiveness in a routine practice. During the last decade several improvements in prevention, treatment and amelioration of ST AEs been achieved. To implement them in everyday clinic practice a good understanding of adverse events, supportive care measures and professional skills of all team members are needed. Registered nurses, specialized in the oncology, the so called “oncology nurses” are key providers of supportive care in everyday clinical practice. Supportive care for prevention and treatment of adverse events Chemotherapy-induced nausea and vomiting (CINV) has been a priority in the supportive care of cancer patients ever since the first use of Cht (1). The introduction of 5-HT3 and NK1 antagonists into anti-emetic therapy resulted in much better control of CINV in lung cancer patients receiving highly emetogenic, platinum-based therapy. With proper use of available drugs complete control of vomiting could be achieved in up to 90% of these patients. However, despite the efficacy of new anti-emetic therapies a proper us of anti-emetics and other preventive measures are vital. Chemotherapy-induced neutropenia with febrile neutropenia (FN) as its ultimate and most serious complication are often observed in patients receiving Cht. The risk of FN can be predicted by assessing patient characteristics and mylotoxicity of the Cht regimen; and granulocyte-colony-stimulating factors (G-CSF) can be used to prevent it (2). Even thought, most of the regimens for lung cancer do not classify to high, i.e. more than 20% risk of febrile neutropenia, the primary prophylaxis with G-CSF is often necessary due to high comorbidity index, poor PS or extensive disease often present in lung cancer patients. In case of FN, a risk-base approach provided by MASCC helps us to decide which patients need hospitalization and which can be treated by antimicrobial therapy at home (3). Oral mucositis and diarrhea related to mucosal damage are frequent complications of Cht as well as targeted therapy with TKIs that can significantly affect patient’s QoL and the ability to deliver full doses and complete therapy. Oral care protocols are essential components in prevention and treatment of stomatitis, while intensive local therapy protocols with antibiotics, anesthetics and/or corticosteroids help to ameliorative symptoms (4). Diarrhea is quite common in lung cancer patients receiving Cht with an even higher occurrence in patients treated with TKIs (5). It could be life threatening in elderly, fragile patients and in patients with concurrent neutropenia, thus requiring a rapid and effective control. When dietary strategy does not work, or when patients present with severe grade 3/4 diarrhea pharmacologic intervention with loperamide or even somatostatin analogues should be initiated quickly. Skin changes (rash, dry skin, paronychia) are the most frequent AEs associated with targeted therapy for lung cancer next to diarrhea. Even though, they are usually mild or moderate they hava negative impact on patient’s QoL and might lead to dose modifications or even discontinuation. Prophylactic measures with regular use of moisturizing products, sunshine protection and careful skin hygiene are necessary. In case of severe but still localized changes topical corticosteroids/antibiotics are indicated while a severe and prolonged toxicity usually requires TKIs dose interruptions (6). Fatigue is a common symptom reported in up to 80% of LC patients. In most cases it is impossible to distinguish to what extend it is the adverse event of ST and to what of disease. It is increasingly reported in patients receiving targeted therapy or immunotherapy, and major improvements in recognition and treatment of fatigue have been achieved recently (7). Immunotherapy with checkpoint inhibitors (CPIs) represents a novel approach. By breaking of immune self-tolerance it might lead to autoimmune/inflammatory adverse events, designated as immune-related adverse events (irAEs), mainly including rash, diarrhea, hepatitis and endocrinopathies (8). Although most of irAEs are of low grade, some of them progress rapidly and prompt medical attention with treatment interruption and the administration of glucocorticoids is critical. Implications for nursing Oncology nurses should have in-depth knowledge on adverse events of systemic therapy and must be familiar with the supportive care protocols. Nursing interventions for prevention and treatment of particular adverse events are presented in Table 1. Oncology nurses play a key role in continuous education of patients, their families and caregivers on adverse events. They are valuable members of the multidisciplinary team performing ongoing assessment of AEs and monitoring of patients and actively discussing potential solutions and improvements with other team members, thus providing a high-quality patient-centered care. Figure 1

Background:
The eighth edition of lung TNM does not change any N descriptors, but it suggests some potential changes that might be used in the next edition. In fact, N2 would be divided into three groups: pN2a1 (skip lymph-node involvement), pN2a2 (single mediastinal station with hilar involvement) and pN2b (multiple mediastinal involvement). The aim of this study was to verify the value of this classification proposal analyzing our recent surgical experience.

Methods:
We retrospectively selected all patients treated with lobectomy, bilobectomy or pneumonectomy for T1/T2 N2 NSCLC (VII TNM edition) in the period between 2006 and 2010. We excluded all patients who underwent any kind of extended resection and who had another active tumor at the time of operation. A systematic lymph-node dissection was always carried out according to the IASLC guidelines. All patients were then restaged according to the new IASLC proposal. Overall Survival (OS), Disease Free Interval (DFI) and most important variables were analyzed.

Results:
Among 248 surgically treated pN2 patients, 108 entered our inclusion criteria. Pathology report showed a majority of T2 tumors (67,6%) and in almost half of cases an adenocarcinoma (50,9%); a mean number of 16,4 (DS 7,8) lymph-nodes were resected (5,8 (DS 2,9) from the hilum and 10,6 (DS 5,9) from the mediastinum). After restaging all cases with the new IASLC proposal we observed: 30 (27,8%) pN2a1; 57 (52,8%) pN2a2 and 21 (19,4%) pN2b. With a median follow up of 93 months, the median overall survival of the entire cohort was 27 months. pN2a1 had a significant better overall survival compared with the other two groups (p=0,020); conversely no statistically significant difference was found in OS between pN2a2 and pN2b. 1, 3 and 5-year survival for pN2a1, pN2a2 and pN2b were 90%, 81% and 71%; 53%, 37% and 24%; 45%, 26% and 19% respectively. Concurrently DFI was significantly better for pN2a1 (p=0,025). At univariate survival analysis age>65 years, more than 4 positive lymph nodes and postoperative complications were statistically significant variables. At the multivariate analysis only age and the number of positive lymphnodes were independent prognostic factors of a worse survival.

Conclusion:
Our experience partially validate the new proposal of IASLC of N2 staging. Patients with skip lymph-node metastasis (pN2a1) have a statistically significant better prognosis. Concurrently we observed and confirmed the important prognostic value of the number of the involved lymph-node, which should be considered as well in the next editions of the lung cancer staging system.

Background:
Stage IIIB non-small cell lung cancer (NSCLC) is a heterogeneous patient group, including T4N2 and T1-4N3 NSCLC. Traditionally, treatment for stage IIIB consists in definitive chemoradiation. Surgical treatment for stage IIIB NSCLC is used anecdotally in highly selected patients. Here, we studied patient outcome who underwent surgical resection as part of multimodality treatment for stage IIIB NSCLC.

Methods:
All patients from a single institution who underwent surgery for stage IIIB between 2000 and 2015 were included. Surgical candidates were selected on a case-by-case basis during multidisciplinary tumorboard conference. In general, N2-N3 diseases are not considered an absolute contraindication to surgery if lymph node involvement is limited to a non-bulky single site, the tumor is deemed completely resectable without major morbidity and the patient will tolerate multimodality treatment. Mediastinal staging comprised cervical mediastinoscopy, positron emission tomography coupled with CT from 2005 and endobronchial ultrasound guided fine-needle aspiration from 2011. Charts were retrospectively reviewed and data analyzed. Survival was calculated from the date of surgery until last follow-up. Univariate and multivariate analysis were performed to identify prognostic factors.

Results:
From 2000 to 2015, 5416 patients underwent lung resection for NSCLC in our center. Sixty patients (1%) underwent surgery for stage IIIB NSCLC. Forty-three were males (72%). Median age was 58 years (from 22 to 79). Thirty-two patients had T4N2 NSCLC involving the carina (n=16, 50%), superior vena cava (n=4, 12%), carina and superior vena cava (n=5, 16%), left atrium (n=5, 16%), pulmonary artery (n=1, 3%) and spine (n=1, 3%). Twenty-eight patients had N3-disease, involving supraclavicular (n=14, 50%) or contralateral mediastinal lymph nodes (n=14, 50%). Pneumonectomy was performed in 27 patients (45%). Twenty-nine patients (48%) had induction therapy, consisting in chemotherapy alone for all patients. Adjuvant therapy was administered to 52 patients (87%) and consisted mostly of chemoradiation (n=35, 67%). Complete resection (R0) was performed in 55 patients (92%). Post-operative mortality was 3% (n=2). Three- and 5-year overall survivals were 51% and 39%, respectively. Median survival was 40 months. Median follow-up was 17 months. Results of the multivariate analysis identified incomplete resection (p=0.008) and absence of adjuvant treatment (p=0.032) as prognostic factors for poor survival.

Conclusion:
An excellent 5-year survival of 39% was achieved in highly selected patients with stage IIIB NSCLC and treated with multimodality including surgery. Patients with stage IIIB NSCLC should therefore be discussed in a multidisciplinary setting, including thoracic surgeons.

Background:
Adjuvant chemotherapy is the standard of care for completely resected stage II-IIIa non-small cell lung cancer (NSCLC). A few trials suggest that neoadjuvant chemotherapy is a promising strategy for resectable NSCLC. Indirect comparison meta-analysis of adjuvant versus neoadjuvant therapy showed no difference in survival. This study was conducted to determine the difference of disease-free survival(DFS) between adjuvant chemotherapy and neoadjuvant chemotherapy among patients with resectable NSCLC.

Methods:
Patients with clinical stage IB-IIIA NSCLC were eligible. Patients were randomly assigned to 3 cycles adjuvant DC (Docetaxel: 75mg/m2, Carboplatin:AUC=5 on day 1, every 3wk) after completely resection (lobectomy or pneomonectomy with mediastinal lymphnode dissection, or 3 cycles neoadjuvant DC at the same schedule followed by surgery 3-6 wk after chemotherapy. The primary end point was 3 years DFS; secondary end points were 3ys and 5ys Overall Survival(OS) and Safety. Planned sample size is 410. The trail was early closed because slowly accrued.

Results:
Between March 2006 and May 2011,198 patients from 8 Institute were randomized to neoadjuvant arm (97 cases) or adjuvant arm (101 cases). The median age was 58, male accounted for 80.3%, Adenocarcinoma 48.5%, stage Ib, II a, II b and IIIa were 32.5%, 12.2%, 28.4% and 26.9% respectively. Two arms were balanced. 100% cases received neoadjuvant chemotherapy and 87.4% finished the planned adjuvant chemotherapy. No unexpected toxicities were seen and 41.2% of patients experienced grade 3-4 neutropenia. In neoadjuvant arm, the ORR was 34% and 12.4% patients developed PD. No difference in postoperative complication was found between two arms. Survival analysis show in Table 1.Figure 1



Conclusion:
Adjuvant or neo-adjuvant chemotherapy with docetaxel plus carboplatin in resectable clinical stage IB-IIIA NSCLC are feasible and safe. The final results showed no difference in 3ys DFS and OS between two arms. Long term survival in Adjuvant arm show the tendency of superior to neoadjuvant arm.

Abstract not provided

Background:
Tumor hypoxia is an adverse prognostic factor in many cancers. Hypoxia tracer [18]F-FAZA provides a non-invasive method of hypoxia imaging. This study aims to evaluate the feasibility and potential benefits of using FAZA-PET scans to assess NSCLC tumor hypoxia.

Methods:
The initial 17 patients of an ongoing study with stage II–III NSCLC have been analyzed prospectively by imaging with FAZA-PET before initiation of a radical course of radiotherapy. The hypoxic volume (HV) was defined as all voxels within the tumor with standard uptake value (SUV) more than 1.2 times the aorta SUVmean. The Tmax/Bmean ratio (T/B) was defined as maximum tumor SUV divided by aorta SUVmean. The hypoxic fraction (HF) was determined by dividing the HV by the entire gross tumor volume. Spearman correlation and Fisher’s test were used to explore potential correlations among several variables.

Results:
Median primary and nodal FAZA SUVmax were 1.7 (range: 1.0-3.8) and 1.7 (range: 1.0–3.3). Median primary and nodal T/B ratios were 1.4 (range: 1.0–2.5) and 1.3 (range: 1.0–2.2). Median primary and nodal HF were 3.9% (range: 0.0-38.2%) and 0.6% (range: 0.0-50.7%). The median time from diagnostic FDG PET to study FAZA PET scans was 28 days (range: 1–63). Median primary and nodal FDG SUVmax were 13.5 (range: 5.1–32.2) and 8.3 (range: 2.3–15.7). Larger primary tumor volume is correlated with higher FAZA-T/B (p=0.01) and higher HF (p=0.01). Primary tumors with higher T/B also had higher HF (p<0.0001). The same correlations also apply to nodal disease. Nodal FAZA SUVmax is correlated with primary FAZA SUVmax (p<0.0001). When comparing FAZA-PET with FDG-PET, nodal FDG SUVmax is correlated with nodal FAZA T/B (p=0.01) and nodal FAZA HF (p=0.01), which was not observed for primary disease. For each patient, the nodal station with the highest FAZA SUVmax correlates with the highest FDG SUVmax (p=0.02).

Conclusion:
Imaging intra-lesional hypoxia in NSCLC primary and nodal tumors is feasible and can be achieved with FAZA-PET. Larger tumor volume is correlated with higher T/B and HF in both primary and nodal masses. In the nodal volume only, higher FDG activity is correlated with higher FAZA T/B and higher HF. Ongoing trial accrual and follow-up of our patient cohort will provide more information with regards to the imaging and clinical value of FAZA-PET. This study may eventually lead to using FAZA-PET as a guiding tool to escalate dose to the hypoxic region of the tumor.

Background:
An increasing body of (pre)clinical evidence has suggested that metformin has an anticancer effect. The aim of this study was to investigate whether the use of metformin during concurrent chemoradiotherapy (cCRT) for locally advanced non-small cell lung cancer (NSCLC) improved treatment outcome.

Methods:
A total of 682 patients were included in this retrospective cohort study (59 metformin users, 623 control patients). All received cCRT in one of three participating radiation oncology departments in the Netherlands between January 2008 and January 2013. Primary endpoint was locoregional recurrence free survival (LRFS), secondary endpoints were overall survival (OS), progression-free survival (PFS) and distant metastasis free survival (DMFS)

Results:
No significant differences in LRFS or OS were found. Metformin use was associated with an improved DMFS (74% versus 53% at 2 years; p = 0.01) and PFS (58% versus 37% at 2 years and a median PFS of 41 months versus 15 months; p = 0.01). In a multivariate cox-regression analysis, the use of metformin was a statistically significant independent variable for DMFS and PFS (p = 0.02 and 0.03).

Conclusion:
Metformin use during cCRT is associated with an improved DMFS and PFS for locally advanced NSCLC patients, suggesting that metformin may be a valuable treatment addition in these patients. Evidently, our results merit to be verified in a prospective trial.

Background:
RTOG 0617 recommended 60Gy as the standard dose for unresectable stage Ⅲ non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT) Is the conclusion true? The phase I/II trial to determine the feasibility and effects of individual isotoxic radiation dose escalation in unresectable stage Ⅲ NSCLC treated with CCRT based on bilateral lung V20 and advanced technologies was studied.

Methods:
Consecutive patients with unresectable stage III NSCLC were entered in cohorts of eight from March 2006 to May 2009. Patients were assigned to receive concurrent administration of late course accelerated hyperfrationation (LCAHF) intensity modulated radiotherapy (IMRT) and chemotherapy. Isotoxic dose escalation was based on V20 and advanced  technologies including PET-CT, single-photon emission computed tomography (SPECT) and LCAHF IMRT. PET-CT was used to delineate the gross tumor volume. SPECT lung perfusion was applied to define different functional lung regions, which was used to optimize the IMRT plans. Patients with a V20 of 27% as a base level were enrolled into the first cohort. From the second cohort, the V20 further increased to 30%, 33%, 35%, 37%, and so on. The criteria for cessation of dose escalation was defined as more than 25% of patients in the cohort experienced dose limiting toxicity (DLT). To test the power of escalation dose, patients with total radiation dose over 66Gy would be assigned to the higher dose group (HD), while the other patients would be assigned to the standard dose one (SD).

Results:
Forty patients were enrolled. The maximum tolerated value of V20 was 37% in this study. Nineteen patients entered SD group, while twenty-one in HD. The overall response rate was as high as 80%. Follow-up for all patients ranged from 1 to 112 months with survival patients from 101 to 112 months. The median overall and progression free survivals were 25.0 and 13.0 months, respectively. 1-, 3-, 5- and 8-year overall survival (OS) rates were 72.5%, 22.5%, 17.5%, and 10.0%, respectively. Patients with stage Ⅲa achieved a longer median OS than those of stage Ⅲb (31 vs. 21 months, P=0.029). Especially, patients received HD radiotherapy got a significant better OS and local recurrence free survival than those in SD (27, 23 vs. 16, 19 months, P = 0.053, 0.037) without increasing severe toxicity.

Conclusion:
The protocol is feasible and effective. In the future, the radiation dose escalation for unresectable stage Ⅲ NSCLC treated with CCRT should be focused on toxicity control and advanced technology application.

Abstract not provided

Background:
EGFR exon 20 insertion mutations (EGFRex20ins) comprise a subset of EGFR activating alterations relatively insensitive to 1[st] and 2[nd] generation EGFR-TKIs. Comprehensive genomic profiling (CGP) integrated with PDX modeling may identify new EGFR-inhibition strategies for EGFRex20ins.

Methods:
EGFRex20ins and co-occurring genomic alterations were identified by hybrid-capture based CGP performed on 14,483 consecutive FFPE lung cancer specimens to a mean coverage depth of >650X for 236 or 315 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. An EGFRex20ins(N771_P772>SVDNP)/EGFR-amplified tumor (24 copies) from this cohort was implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice for tumor growth inhibition studies (TGI) with vehicle, erlotinib (50 mg/kg PO daily), osimertinib (25 mg/kg PO daily), and osimertinib (25 mg/kg PO daily) plus cetuximab (10 mg/kg IV, 2x/week) administered for 21 days.

Results:
CGP identified 263/14,483 cases (1.8%) with EGFRex20ins, which represent 12% (263/2,251) of EGFR activating mutations in this series. 90% (237/263) were NSCLC-adenocarcinoma, 9% (23/263) were NSCLC-NOS, and 1% (2/263) were sarcomatoid carcinoma. Over 60 unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%); 6% (15/263) harbored EGFR A763_Y764insFQEA, an EGFRex20ins typically sensitive to erlotinib. Among EGFRex20ins cases, EGFR-amplification occurred in 22% (57/263). Putative co-occurring driver alterations including EGFR (ex19del and L858R), Her2, MET and KRAS tended to be mutually exclusive, occurring only in 5% (12/263) of cases. The most common co-occurring alterations affected TP53 (56%), CDKN2A (22%), CDKN2B (16%), NKX2-1 (14%) and RB1 (11%). Average tumor mutation burden was low (mean 4.3 mutations/Mb, range 0-40.3 mutations/Mb). Clinical outcomes to 1st and 2nd generation EGFR-TKIs were obtained for a subset of cases with various EGFRex20ins, and 0/6 patients had responses. However, robust TGI was observed with combination osimertinib and cetuximab in a highly EGFR-amplified PDX model with a conserved EGFRex20ins (N771_P772>SVDNP) not associated with response to earlier generation EGFR-TKI, and was superior to vehicle, erlotinib or osimertinib alone (D21 mean tumor size 70 mm[3] vs. 1000, 800, 225 mm[3] respectively; p-values all <0.001).

Conclusion:
Diverse EGFRex20ins were detected in 12% of EGFR-mut NSCLC. Available clinical outcomes data demonstrated lack of response to 1[st] and 2[nd] generation EGFR-TKIs. Identification of co-occurring EGFR-amplification in 22% of cases led to testing of a dual EGFR blockade strategy with an EGFR monoclonal antibody and osimertinib, which demonstrated exceptional tumor growth inhibition in an EGFRex20ins PDX minimally responsive to erlotinib. These findings can rapidly be translated into an ongoing clinical trial of osimertinib and necitumumab.

Background:
Lung adenocarcinoma (LADC) driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Understanding the genetic factors underlying such LADC is required to elucidate disease etiology and to identify effective methods of prevention.

Methods:
We investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma　and 15,158 controls.

Results:
Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2, HLA-class II), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA-class II at 6p21.32 and 6p21.1 (FOXP4) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma (Shiraishi et al., Nature Communications, 2016, in press).

Conclusion:
This study indicates that multiple genetic factors, including an immunologic one, underlie the risk of lung adenocarcinomas with EGFR mutations.

Background:
Preclinical studies provide insights to therapy mechanisms of resistance that are not feasible with clinical studies. We investigated the signaling pathways that could be involved in adaptive resistance to gefitinib and/or osimertinib in EGFR mutant cells.

Methods:
We performed several laboratory methods to examine the signaling pathways involved in EGFR mutations. Signal transduction pathway analysis was designed using the Ingenuity Pathway Analysis (IPA) software (https://www.ingenuity.com/) Figure 1



Results:
Pathways mediating EGFR mutations are: i) ERK1/2 via Ras and MEK1/2 ii) AKT via PI3K and iii) STAT3 via JAK (Figure). By Western blot analysis, phosphorylation of Tyr705 on STAT3 was noted after 2 hours of gefitinib or osimertinib treatment in PC9 and H1975 EGFR mutant cells. Unexpectedly, YAP1 phosphorylation on Tyr357 and Notch activation was detected. Co-targeting STAT3 and Src with gefitinib or osimertinib ablates activation of STAT3 and YAP1-NOTCH3 signaling pathways (Figure). In vitro and in vivo, the combinatory therapy of gefitinib or osimertinib plus TPCA-1 (a dual inhibitor of IKKs and STAT3) plus saracatinib (a SFK inhibitor) leads to significant tumor shrinkage in PC9 and H1975 cells. In tumor samples of 64 EGFR mutant NSCLC patients treated with gefitinib, the median progression free survival (PFS) was significantly shorter in those with high levels of HES1, ALDH1A1, ALDH1A3, Bmi1, AXL, CDCP1, SHP2 and ILK (Figure). However, the mRNA levels of STAT3 and YAP1 stand out in the prediction of shorter PFS with a hazard ratio of 3.02 and 2.57, respectively (P<0.001)

Conclusion:
For the first time ever, we reported gefitinib induced activation of theYAP1-NOTCH signaling pathway, in addition to activation of STAT3, in EGFR mutant cells. Secondly, co-targeting STAT3 and Src, together with EGFR, causes significant tumor growth inhibition, in comparison with gefitinib or osimertinib single therapy.

Abstract not provided

Background:
Tumors are complex structures consisting of cancer cells surrounded by a tumor stroma that is now recognized to be critical for cancer progression. Although epidermal growth factor receptor (EGFR) mutations are frequently observed in non-small cell lung carcinoma, it remains poorly understood whether EGFR mutations in cancer cells affect the tumor stroma. In this study, we studied the status of EGFR mutations in early-stage lung adenocarcinoma and analyzed the relations of EGFR mutations to tumor-infiltrating stromal cell components.

Methods:
A total of 152 consecutive patients with clinical stage IA lung adenocarcinoma who underwent complete tumor resection in Keio University Hospital between 2010 and 2014 were studied. Genomic DNA was isolated from formalin-fixed, paraffin-embedded tumor sections and mutational analyses of EGFR gene exons 19, 20 and 21 were performed by a polymerase chain reaction-based method. Paraffin sections were also subjected to immunohistochemistry for CD3, FOXP3, CD163 or CD204. Numbers of CD3-, FOXP3-, CD163- or CD204-immunostained cells were counted by observing 5 different fields at x200 magnification.

Results:
EGFR mutations were detected in 71 (47%) of the 152 patients with clinical stage IA lung adenocarcinoma and were found more frequently in women and non-smokers. These contained 38 patients with missense mutations in exon 21 (L858R) and 30 patients with deletions in exon 19. By immunohistochemistry, the number of stromal macrophages positive for CD163 or CD204, markers for tumor-associated macrophages (TAMs), was significantly decreased within tumors with EGFR mutations compared to within those with wild-type EGFR, whereas the number of CD3[+] T cells or FOXP3[+] regulatory T cells was comparable between these groups. Both tumors with missense mutations in exon 21 and deletions in exon 19 had a similar trend toward decreased TAMs in the tumor stroma.

Conclusion:
Our data suggest that EGFR mutations in early-stage lung adenocarcinoma are associated with decreased TAMs in the tumor stroma. EGFR mutation status might act on not only cancer cell behavior but tumor microenvironment.

Background:
Carcinogenesis of non-small cell lung cancer (NSCLC) can be driven by oncogenic addiction that can be targeted by specific inhibitors. It is commonly accepted that these molecular alterations are mutually exclusive. Nevertheless, limited series suggest that concomitant molecular alteration can occur in lung cancer and little is known about their sensitivity to treatment. Based on a nationwide screening program conducted during one year, we aimed to analyze the largest molecular database to date for concomitant mutations in order to determine the prevalence of multiple genomic alterations in NSCLC and their impact on both prognosis and response to treatment.

Methods:
The database of Biomarker France IFCT study collecting the molecular profile of 17 664 NSCLC has been used. The prevalence of multiple alterations and of each association was calculated. Impact on prognosis (overall survival, OS), response to targeted or conventional treatments (progression free survival, PFS and objective response rate, ORR) were established and compared with the population of patients harboring single mutations and full wild-type.

Results:
We identified 162 (0.9%) patients with double genetic alterations and 3 with triple alterations. Multiple mutations involved preferentially KRAS (67.3%), PI3K (53.3%) and EGFR (42.4%). Patients with multiple alterations were male (56.4%) with a median age of 66.7 and essentially adenocarcinoma (83.6%). More never-smokers were observed in comparison with patient with singles alterations (34.7 vs. 25.8 %, p<0.001). OS was not significantly different between single and multiple alterations whatever the type of mutations. Patients with EGFR/KRAS and EGFR/PI3K mutated tumors had worse PFS after biomarker analysis than patients with EGFR single mutation (7.1 and 7.1 months vs. 14.9 months, p=0.02 and 0.002, respectively). Concomitant mutations in patients harboring ALK rearrangement had little impact on OS (17.7 months vs. 20.3 months, p=0.57) or PFS (10.3 months vs. 12.1 months, p=0.93). Patients harboring KRAS mutations with another alteration had similar OS (13.4 vs. 11.2 months, p=0.28), PFS (6.4 months vs. 7.2 months, p=0.78) and ORR to first-line chemotherapy (41.7% vs. 37.2%) to those only harboring KRAS mutations.

Conclusion:
With almost 1% of patients harboring multiple genomic alterations, the dogma of mutually exclusive mutations should be reconsidered. Double mutations do not significantly decrease OS but alter PFS under first line treatment for EGFR mutated patients. Therapies targeting the dominant oncogene remain generally active in this setting.

Background:
Liquid biopsy (LBx) has emerged as an alternative tool for the management of advanced lung cancer patients (pts) identifying driver mutations, and hence, improving personalized medicine. There are still controversial issues such as standardization, validation of different technologies, concordance with tissue molecular profile results (TMPR), and others. LBx offers many advantages including non-invasive, bypass tumor heterogeneity, an opportunity for serial measurements to evaluate response or early recurrence, and others.

Methods:
Guardant 360 was analyzed in 100 consecutive stage IV or recurrent lung adenocarcinoma (adeno) pts. Guardant 360 is a panel of 70 genes including single nucleotide variations, amplifications, translocations, and short insertions/duplications/deletions in exons 19 and 20 of the EGFR, and others. Cell-free DNA (cfDNA) is extracted from plasma and genomic alterations are analyzed by massively parallel sequencing of amplified target genes. TMPRs from each subject was obtained or recovered for comparison with their LBx counterparts. TMPRs from this cohort was developed in different CLIA laboratories

Results:
69 pts were females; median age 72 (range, 27-99). 84/100 pts had at least 1 genomic alteration by LBx (range, 1-10). Most common abnormalities found in LBx were: TP53 (37 pts), EGFR (35 pts), NF1 (20 pts), KRAS (12 pts), MET (14 pts). From this 84 pts with + LBx results, 67 pts (80%) had TMPRs for comparison. Main reason for lack of TMPRs: insufficient tumor (19/100; 19%). For comparison between the 2 modalities, we considered all pts with available results in both tests; hence, 81 pts were used to compare tumor biopsy (TBx) vs. LBx. 37 pts out of 81 (46%) had at least 1 similar genomic abnormality found in both TBx and LBx, respectively. Most of the concordance was in EGFR alterations (19/28; 68%). LBx caught 16 additional EGFR genomic aberrations not being identified by TBx. A total of 35 EGFR genomics aberrations were identified in LBx; 16/35 EGFR mutations found in LBx were actionable and 5 of these 16 actionable EGFR mutant cases were only found in LBx not in TBx.

Conclusion:
LBx offers an alternative to identify genomic alterations. Still, insufficient tumor is the major reason for lacking of TMPRs. EGFR mutations are the most common actionable mutations found in LBx; also, it has a high correlation with TBx (68%). LBx identified more gene abnormalities than TBx, and in some cases, the actionable EGFR mutations were found only in LBx sample.

Abstract not provided

Background:
Overall survival (OS) is considered as the gold standard for evaluating efficacy of antineoplastic treatments, including chemotherapy and targeted therapies. In randomized trials, allowing patients to cross-over to the other arm usually prevents demonstration of a survival benefit. However, it may provide important information with clinical relevance.

Methods:
The phase III IFCT-1503 ULTIMATE study compared weekly paclitaxel and bevacizumab (wPB) vs. docetaxel (DOC) as second- or third-line therapy in non-squamous NSCLC. At progression, patients were allowed to cross over to the other arm. Date of progression was collected for patients who crossed over to the other arm and for those who did not cross over but received a post-discontinuation treatment within 60 days following progression. Post-discontinuation progression-free survival (PFS2) and OS2 were calculated from day 1 of post-discontinuation treatment.

Results:
The study met its primary endpoint, PFS, which was significantly improved in the wPB arm (medians 5.4 vs. 3.9 mo, hazard ratio (HR) 0.62, p=0.006). No overall survival was observed (medians 9.9 vs. 11.4 mo, HR 1.18, p=0.4). Out of patients treated with DOC (n=55), those who crossed over to wPB (n=21, 38.2%) had a median PFS2 of 4.9 mo [3.1-6.2] and a median OS2 of 12.5 mo (7.0-NR), whereas those who did not cross over but received a post-discontinuation treatment (n=13, 23.7%) had a median PFS2 of 1.7 mo [1.1-2.2] and a median OS2 of 4.1 mo [2.1-5.9]. Out of patients treated with wPB (n=111), median PFS2 was 1.9 mo [1.2-2.2] for those who crossed over to DOC (n=9, 8.3%) and median PFS2 and OS2 were 1.9 mo [1.7-2.6] and 5.0 m [3.4-9.0] for those who did not cross over but received a post-discontinuation treatment (n=57, 52.3%).

Conclusion:
Allowing patients to cross over to the other arm demonstrated benefit of wPB following progression on docetaxel and explains the absence of OS benefit.

Background:
Targeting the tumor microenvironment, such as tumor angiogenesis, has led to the successful development and approval of a number of targeted therapies thereby changing the standard of care for many types of cancer. However, treatment options are limited in third-line non-small cell lung cancer (NSCLC) patients. Fruquintinib is a potent and highly selective oral kinase inhibitor targeting vascular endothelial growth factor receptors and is currently in late stage development for multiple cancers. This Phase II study was designed to evaluate the efficacy and safety of fruquintinib in third-line NSCLC patients (NCT02590965).

Methods:
A total of 91 patients were randomized to receive best supportive care (BSC) plus fruquintinib or BSC plus placebo in a 2:1 ratio from 12 Chinese clinical centers. Fruquintinib initial dose was 5 mg once daily and treatment was given in every 4-week cycle (3 weeks treatment followed by 1 week off). The primary objective was to compare progression free survival (PFS) between the two treatment groups. Secondary efficacy parameters included objective response rate (ORR), disease control rate (DCR), overall survival (OS). Tumor response was assessed per RECIST 1.1.

Results:
As of August 7, 2015, median PFS was 3.8 months for the fruquintinib group comparing with 1.2 months for the placebo group (hazard ratio=0.27, p<0.001). The ORR was 16.4% for the fruquintinib group comparing with 0% for the placebo group (p=0.02). The DCR of the fruquintinib group was significantly higher than that of the placebo group with a difference of 53.8% (36.3, 71.4; 95% CI, p<0.001). OS was not mature and initial analysis revealed 3- and 6-month OS rates of 90.2% and 68.3% for the fruquintinib group, and 73.3% and 58.2% for the placebo group, respectively. Adverse event was reported in 68.9% and 60.0% patients in fruquintinib and placebo group, respectively. The incidence of serious adverse events was 3.3% in the fruquintinib group and 6.7% in the placebo group.

Conclusion:
Fruquintinib in third-line NSCLC met the primary efficacy endpoint of PFS and demonstrated superiority in the secondary endpoints of ORR and DCR as compared with placebo. OS has yet to mature. Fruquintinib was generally well tolerated and safety profile consistent with previously reported. These results support further development of fruquintinib in third-line NSCLC patients. A randomized, double-blind, multi-center Phase III registration study was initiated in December 2015 (NCT02691299). Clinical trial information: NCT02590965.

Abstract not provided

Background:
RET rearrangements are actionable drivers found in 1-2% of non-small cell lung cancers. We previously reported the efficacy and safety of the multikinase RET inhibitor cabozantinib in 16 patients with RET-rearranged lung cancers in the first stage of our Simon two-stage phase 2 clinical trial (overall response rate 38%; Drilon, ASCO 2015). This study has since completed accrual of both stages, now with 26 patients treated with cabozantinib.

Methods:
This was an open-label, single center, phase 2 trial (NCT01639508). Eligibility criteria: stage IV pathologically-confirmed lung cancers, presence of a RET rearrangement, KPS >70%, and measurable disease. RET rearrangements were detected by FISH or next-generation sequencing. Cabozantinib was administered in tablet form at 60 mg daily until progression of disease or unacceptable toxicity. The primary objective was to determine the overall response rate (ORR, RECIST v1.1). Secondary objectives included determining progression-free survival (PFS), overall survival (OS), and toxicity. 5 responses in 25 response-evaluable patients were required to meet the primary endpoint (Simon two-stage minimax design: H~0~ 10% vs H~A~ 30% ORR). All patients who received at least one dose of cabozantinib were evaluable for toxicity.

Results:
26 patients with RET-rearranged lung adenocarcinomas were treated with cabozantinib. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The median number of prior chemotherapy lines was 1 (0-5). One patient who discontinued therapy in cycle 1 and did not undergo a response assessment was not response-evaluable as per protocol. The study met its primary endpoint with confirmed partial responses observed in 7 (ORR 28% [95% CI 12-49%]) of 25 response-evaluable patients. The median PFS was 5.5 months (95% CI 3.8-8.4). The median OS was 9.9 months (95% CI 8.1-not reached). Response by RET fusion partner: Unknown (FISH+) 2/6 (33%), KIF5B 3/15 (20%), CLIP1 1/1, TRIM33 1/1, CCDC6 0/1, ERC1 0/1. In 26 patients evaluable for toxicity, the most common all-grade treatment-related adverse events were increased alanine aminotransferase in 25 (96%) patients, increased aspartate aminotransferase in 19 (73%) patients, hypothyroidism in 18 (69%) patients, diarrhea in 16 (62%) patients, and palmar plantar erythrodysesthesia in 15 (58%) patients. Nineteen (73%) patients required dose reduction.

Conclusion:
This study met its primary endpoint. Cabozantinib is an active agent in patients with RET-rearranged lung cancers. An improved understanding of tumor biology and novel therapeutic approaches will be required to improve outcomes with RET-directed therapy.

Background:
Increasing studies have shown that anti-angiogenic therapy targeting VEGF/VEGFR2 axis are furnishing demonstrable therapeutic effect on lung cancer，but the treatment benefit is transitory in clinic, generally followed by restoration of tumor growth and disease progression. Blockade of VEGF/VEGFR2 pathway can not only induce anti-vascular effect, but also remodel the immunosuppressive tumor microenvironment probably due to promoting suppressive cells infiltration and enhancing PD-L1 expression, resulting in impairing antitumor immunity. Therefore, the current study aimed to investigate whether combining anti-angiogenic and anti-PD-L1 treatments can induce synergistic antitumor effect by enhancing antitumor immune response in murine lung cancer.

Methods:
We evaluated the antitumor effects of anti-VEGFR2 agent (apatinib) as monotherapy or in combination with anti-PD-L1 monoclonal antibody in a murine lung cancer model using Lewis lung cancer cells (LLCs). The changes of immune components in tumor and spleen were dynamically tested in different treatment groups and time points by flow cytometry and immunohistochemistry.

Results:
The results showed that VEGF/VEGFR2 blockade could retard tumor growth and inhibit tumor neovascularization via eradicating Foxp3[+ ]regulatory T cells (Tregs) and myeloid derived suppressive cells (MDSCs) and reducing the density of microvessels in the first two weeks of treatment. On the third week of apatinib monotherapy, the number of Foxp3[+ ]Tregs and MDSCs had increased again. Although VEGF/VEGFR2 blockade induced more tumor infiltrating lymphocytes (TILs), especially CD8[+] T cells, infiltrating into the tumor mass than control group (P < 0.01), the expression of PD-1 and PD-L1was also significantly upregulated than that control group (P < 0.01). Compared to apatinib monotherapy, combining treatment demonstrated that anti-VEGFR2 plus anti-PD-L1 therapy could significantly inhibit tumor growth (P < 0.01) by persistently eliminating Foxp3[+ ]Tregs and MDSCs. Furthermore, combining anti-VEGFR2 and anti-PD-L1 therapy could not only dramatically increase TILs infiltration, especially CD8[+] T cells, but also significantly reduce the expression of PD-1 and PD-L1.

Conclusion:
Simultaneous blockade of VEGF/VEGFR2 and PD-1/PD-L1 pathways induced a synergistic anti-tumor effect in-vivo, possibly through eliminating immunosuppressive components including Tregs and MDSCs and enhance antitumor immune response.

Abstract not provided

Background:
Ramucirumab, an antiangiogenic IgG1 VEGFR2-targeted monoclonal antibody, and erlotinib, an EGFR tyrosine kinase inhibitor, are both active in advanced NSCLC. This global phase 1b/3 study (NCT02411448) will assess safety, tolerability and efficacy of the combination of ramucirumab with erlotinib in previously untreated patients with EGFR mutation-positive stage IV NSCLC. Here we report phase 1b safety results.

Methods:
Eligible patients with ECOG PS 0-1, an activating EGFR mutation, and previously untreated stage IV NSCLC received ramucirumab 10 mg/kg intravenously on day 1 of repeating 14-day (± 3 days) cycle and erlotinib 150 mg orally daily. Treatment continued until disease progression or unacceptable toxicity. The primary objective of part A was to assess the safety and tolerability, in terms of dose limiting toxicities (DLT), of adding the recommended dose of ramucirumab for phase 3 (part B) to standard dose erlotinib. Data were analyzed separately for Japan (JP) (cohort 1) and US/EU (cohort 2). The DLT assessment occurred during the first 2 cycles (approximately 28 days).

Results:
As of Dec 16th, 2015, 14 patients were treated in the phase 1b part of this trial and 12 were DLT evaluable (6 JP; 6 US/EU). Overall, 6 grade (Gr) 3 treatment-emergent adverse events (TEAE) were noted, with at least one TEAE in 5 patients; no serious adverse events or Gr 4-5 TEAEs occurred. In the JP cohort the median age was 73 (64-79), 57% had ECOG PS 1 and 29% had a history of smoking. Four patients (57%) experienced a Gr 3 TEAE, of which one was a DLT (elevation of alanine aminotransferase) while the others (hypertension [n=2], dermatitis acneiform, and diarrhea) were not DLTs. In the US/EU cohort the median age was 71 (31-83), 86% had ECOG PS 1, and no patients had a history of smoking. One patient experienced Gr 3 TEAE of rash; no DLTs were observed in this cohort.

Conclusion:
Enrollment on the phase 1b portion of this trial is complete and the safety results were consistent with previous combinations of antiangiogenic/erlotinib in this patient population. No unexpected toxicities were identified. Phase 3 enrollment has been initiated maintaining the dose of ramucirumab at 10 mg/kg Q2W.

Background:
There is growing evidence that tumor-associated fibroblasts (TAFs) play a major role in critical steps of tumor progression in solid tumors including NSCLC. However the role of TAFs in regulating the response to targeted therapies is poorly understood. One of such targeted therapies is nintedanib (NTD), a multi-kinase inhibitor of VEGF, FGF and PDGF receptors that has been recently approved to treat advanced lung adenocarcinoma (ADC) patients. Although the therapeutic effects of NTD in lung cancer have been associated with its anti-angiogenic functions, NTD has also been shown to exhibit anti-fibrotic effects in patients with idiopathic pulmonary fibrosis. Since lung fibrosis is largely driven by activated fibroblasts/myofibroblasts, and TAFs are positive for myofibroblasts markers, it is conceivable that NTD anti-tumor effects may be additionally driven through its direct action on lung TAFs. The main goal of this study was to analyze the latter hypothesis.

Methods:
Patient derived lung TAFs from ADC and SCC patients as well as paired control fibroblasts from non-malignant pulmonary tissue were exposed to increasing concentrations of NTD and analyzed for growth and activation upon stimulation with growth factors and TGF- β1, respectively. Activation markers included alpha-smooth muscle actin and collagen-I.

Results:
We found that NTD exhibited a dual inhibitory role in TAFs in terms of growth and TGF-β1-induced activation in a subtype-specific fashion. Specifically, NTD-mediated growth inhibition was larger in SCC-TAFs than in ADC-TAFs, which correlated with the larger Erk signaling previously reported by our group in SCC-TAFs in the absence of mitogenic stimuli. Conversely, inhibition by NTD of TGF-β1-mediated activation was larger in ADC-TAFs than SCC-TAFs. Likewise, NTD inhibited the growth and invasive advantages of ADC cancer cells in vitro elicited by the conditioned medium of ADC-TAFs treated with TGF-β1 compared to those advantages elicited in the absence of NTD. These results reveal for the first time that the pro-tumorigenic effects of ADC-TAFs in vitro are markedly reduced in the presence of NTD.

Conclusion:
TAFs in vivo are largely activated and quiescent, and TGF-β1 is a potent fibroblast activator that is frequently upregulated in lung cancer and associated with poor prognosis. Based on these previous observations, we argue that our new findings strongly suggest that the selective therapeutic advantage observed for NTD in ADC patients may be in part related to its selective inhibition of TGF-β1-dependent activation of ADC-TAFs. These findings provide novel mechanistic insights on the subtype-specific therapeutic effects of NTD in NSCLC.

Background:
This phase II, multi-institutional (Roswell Park Cancer Institute, Cleveland Clinic, and Upstate Medical Center) randomized study was conducted to compare incidence of RTOG grade 3 or higher adverse events (AEs) associated with 2 different, established SBRT regimens for NSCLC

Methods:
Patients with documented baseline medical conditions precluding lobectomy and biopsy-proven peripheral (greater than 2 cm from the central bronchial tree) T1/T2, N0 (clinically node negative by PET), M0 tumors were eligible. Patients were randomized to receive either 30 Gy in one fraction (arm 1) or 60 Gy in 3 fractions (arm 2) over at least 8 days. Heterogeneity corrections were not used. Randomization was stratified by treatment center and Karnofsky performance status (100, 90, 80 and below.) The study was designed to detect whether psAEs rate > 17% at a 5% significance level (1-sided) and 81% power. Secondary endpoints included: local control, greater than 1 year toxicity, overall survival (OS) and progression-free survival (PFS).

Results:
The study opened in September 2008, was suspended between April 2010 to June 2010 as well as October 2010 to April 2011 while RTOG 0915 was open, and closed on April 15, 2015 after accruing a total of 98 patients. All patients received planned SBRT treatment. Median follow-up was 27 months. In follow-up, 10 patients were lost to follow-up; 1 was in arm 1 and 9 in arm 2. Baseline patient and tumor characteristics were balanced between both arms. On arm 1, 13 (27%) patients and 16 (33%) patients on arm 2 experienced RTOG grade 3 AEs, there were no grade 4 AEs. Thoracic grade 3 AEs were experienced by 8 (16%) patients on arm 1 and 6 (12%) patients on arm 2. There were no differences in OS or PFS survival, logrank p= 0.44 and 0.99 respectively. OS at 2 years was 71% (95% CI, 55-82%) for arm 1 and 61% (95% CI, 44-78%) for arm 2. PFS at 1 year was 63% (95% CI, 46-75%) for arm 1 and 51% (95% CI, 34-65%) for arm 2.

Conclusion:
This randomized phase II study demonstrated that 30 Gy in one fraction was equivalent to 60 Gy in three fractions in terms of toxicity, progression free survival and overall survival. Acknowledgment: Supported by Roswell Park Alliance Foundation grant

Background:
Stereotactic body radiotherapy (SBRT) has been sometimes used as a curative treatment for both of medically operable patients with stage I non-small cell lung cancer (NSCLC). However, most of these patients are comparatively high-aged and not similar to the patients cohort generally operated with surgery. So, the purpose of this study was to collect results of SBRT for operable and young (70 years old or younger) patients with stage I NSCLC from multiple Japanese institutions.

Methods:
We organized a multi-institutional SBRT study group in Japanese Radiological Society (JRS-SBRTSG) and conducted a study for SBRT for stage I non-small cell lung cancer (NSCLC). This is a retrospective analysis to review 252 patients (male 168, female 84) who were medically operable and 70 years old or younger (range,40-74; median, 67 years) with stage I (IA 211, IB 41) NSCLC treated with curative intent by SBRT in 20 institutions of JRS-SBRTSG. Histology was proven in 177 patients (adenocarcinoma 121, squamous cell carcinoma 41, others 15), and the others were diagnosed clinically. Median tumor size was 22mm (range, 5-49mm). A total dose of 40 -70 Gy mainly was prescribed in 4-10fractions. Median calculated biological effective dose (BED) was 107 Gy (range, 75-134 Gy) based on alpha/beta = 10Gy).

Results:
The median follow-up period for all patients was 37 months. Overall survival rate (OS) at three and five year was 83.3% and 76.6%, respectively. Radiation pneumonitis of grade 3 or more was noted in 0.8% of the total patients. In the total patients, local control rate (LC) at three year was 89.5%, and LC was significantly better in the subgroup of adenocarcinoma than that of squamous cell carcinoma. According to univariate analysis, female, adenocarcinoma, no emphysema, and no pulmonary interstitial change were better prognostic factors for OS. According to multivariate analysis, pulmonary interstitial change was only a worse survival factor for OS. OS at three and five year in the subgroup of patients without pulmonary interstitial change was 89.7% and 84.0%, respectively.

Conclusion:
The outcomes of SBRT for the medically operable and young (75 years or younger) patients with stage I NSCLC in the Japanese large database of practice level was excellent and the overall survival rate would be comparable to that of surgery. The results will support a rationale of applying SBRT for younger and operable patients with operable stage I NSCLC.

Background:
Interstitial lung disease, such as idiopathic pulmonary fibrosis (IPF), have been widely known to be associated with lung cancer. Lung cancer patients concomitant with IPF sometimes develop a life-threatening acute exacerbation after surgery or radiotherapy. Percutaneous cryoablation is evolving as a potentially less invasive local treatment for lung cancer. The purpose of this study is to retrospectively analyze the outcomes of cryoablation for clinical T1N0M0 non-small cell lung cancer (NSCLC) patients for whom surgery or radiotherapy is contraindicated because of IPF.

Methods:
Between December 2003 to March 2016, 210 patients underwent computer tomography guided percutaneous cryoablation for lung tumors at our institution. Of these, 11 histologically proven clinical T1N0M0 NSCLC patients, for whom surgery or radiotherapy was considered contraindicated because of severe IPF, were retrospectively reviewed. Complications, local progression-free survival and clinicopathological factors were evaluated.

Results:
The cohort was composed of 11 men with a mean age of 74 years (range: 68 to 82). The median follow-up time was 20 months (range: 6 to 55 months). The mean Krebs von den Lungen-6 (KL-6) level was 1608 ±1025 U/mL. The mean tumor size was 24 ± 7mm. The mean percentage of predicted diffusing capacity for carbon monoxide (DLCO) was 37±27%. Thirty and 90-day mortality was 0 and 18%, respectively. Two patients required chest tube drainage because of severe pneumothorax. Acute exacerbation of IPF occurred in two patients (18%). The use of oral steroids and need for chest tube drainage were predictors of higher mortality (p < 0.05) and higher incidence of acute exacerbation of IPF (p < 0.05). However, higher level of KL-6 and low percentage of DLCO were not significant risk factors of mortality or acute exacerbation of IPF. Local progression-free survival at 1, 2 and 3 year was 51, 41 and 31%, respectively.

Conclusion:
Percutaneous cryoablation for lung cancer patients with IPF provoked acute exacerbation of IPF in 18% of patients. The use of oral steroids and need for chest tube drainage were predictors of higher mortality and higher incidence of acute exacerbation of IPF.

Abstract not provided

Background:
CT screening programs frequently detect early stage lung adenocarcinoma. Recent studies show that distinct subtypes of lung adenocarcinoma are associated with different prognosis and suggest that treatment should be tailored to histological subtypes as identified in the new WHO Lung Tumor Classification. To develop this personalized approach, it is important to have reliable tools to diagnose tumors before treatment, preferably non-invasively through image analysis. We have developed a CT-image analysis system (iBiopsy) that uses computerized deep learning and artificial intelligence. To validate the accuracy of a noninvasive CT-based image biopsy system (iBiopsy) in differentiating early stage lung adenocarcinoma subtypes of atypical adenomatous hyperplasia (AAH), adenocaricnoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC).

Methods:
We retrospectively identified 365 eligible patients from Zhongshan Hopsital Fudan University, diagnosed with AAH, AIS, MIA or IAC by surgical pathological diagnosis. The last high definition CT scan prior to the surgery of the lesion was analyzed using the iBiopsy system, blinded to pathological result. Based on a pulmonary nodule image feature set (PNIFS) in combination with classified pattern models, such as R-SVM, all the pulmonary nodules were classified into four groups. For diagnosis efficacy, area under the curve (AUC) of Precision-Recall score (PRS), receiver operating characteristic (ROC) of a classification model were calculated in each group.

Results:
365 patients were included in the analysis. The classification recognition rate of the PNIFS was 80.03%. The average value of PRS is 0.92, the mean of ROC is 0.95, and it is more than 0.80 for the cross validation value.

Conclusion:
iBiopsy system allows the non-invasive imaged based stratification of pulmonary adenocarcinoma nodules into four groups, from AAH to IAC. Our result suggest that iBiopsy system could ultimate facilitate the diagnosis and precision management of pulmonary nodules.

Background:
We have recently demonstrated that the presence of the Spread Through Air Spaces (STAS) and the variety of histologic subtypes increase the risk of recurrence after resection for small lung adenocarcinoma (ADC). Currently, the new World Health Organization classification of lung cancers was revised and newly prescribed to describe the presence of each histologic subtypes and STAS. The purpose of this study is to examine the risk factor for recurrence other than TNM staging analyzing clinical information retrospectively.

Methods:
All available tumor slides from patients with clinical stage I, therapy-naive, surgically resected solitary lung ADC ≤2 cm in size (1998-2015) were reviewed. Each tumor was evaluated by comprehensive histologic subtyping, and the percentage of each histologic component was recorded in 5% increments. STAS was defined as the spread of tumor cells into air spaces in the lung parenchyma adjacent to the main tumor according to the WHO classification. Recurrence-free probability (RFP) was estimated using the Kaplan-Meier method.

Results:
354 patients met inclusion criteria (52.3% men; median age: 67yrs; median tumor size: 1.3cm; 325 stage IA/ 29 stage IB; 91 partial resection/ 22 segmentectomy / 241 lobectomy or pneumonectomy). The prognosis didn’t differ significantly between sublobar resection group and lobectomy or pneumonectomy group (5-year RFP: 88.4% (N=113) vs. 91.9% (N=241), P=.162). Presence of STAS was identified in 74 cases (20.9%) (36 Micropapillary pattern / 55 Solid pattern / 15 Single cells). STAS was significantly associated with recurrence (5-year RFP: 94.3% vs. 76.2%, P < .0001). Histologic subtypes were 62 adenocarcinoma in situ (18%), 110 minimally invasive adenocarcinoma (31%) and 182 invasive adenocarcinoma (51%). The recurrence after sublobar resection was seen in 13 cases (1 partial resection (4.5%) / 12 segmentectomy (13%), 5 STAS (+)/ 8 STAS (-), 6 solid predominant / 5 acinar predominant / 2 lepedic predominant, 5 pulmonary recurrence / 4 lymph node recurrence / 2 local recurrence / 2 others). Patients with solid component had significantly worse prognosis (5-year RFP: 71.7% (N=83) vs. 96.3% (N=271), P<.0001). Among them, patients with sublobar resection had significantly more recurrence than with lobectomy or pneumonectomy (5-year RFP: 51.4% (N=19) vs. 77.7% (N=64), P=.0021).

Conclusion:
The patients of small ADC with STAS or solid component had worse prognosis. The patients after sublobar resection with solid component should be made follow-up closely. We propose that the presence of those features should be considered a factor to upgrade the pathologically defined T stage.

Background:
The newly proposed International Association for the Study of Lung Cancer (IASLC) staging system reclassified T2aN0M0 tumors greater than 4 cm as stage IIA instead of stage IB. This study investigated the role of adjuvant chemotherapy in pathologic stage IB non-small cell lung cancer (NSCLC).

Methods:
The patients with pathologic T2aN0M0 NSCLC who underwent complete resection between 2001 and 2013 were identified from prospectively maintained databases, and classified into three groups based on tumor size: A (≤3.0 cm, n = 205), B (3.1-4.0 cm, n = 264), and C (>4.0 cm, n = 254). After propensity score matching, overall survival (OS) and freedom from recurrence (FFR) were compared between each group of paired patients who received platinum-based adjuvant chemotherapy and those who did not.

Results:
Among the 723 patients, 134 patients (18.5%) received adjuvant chemotherapy: Group A, 38 (18.5%) patients; Group B, 47 (17.8%); and Group C, 49 (19.3%). Matching based on propensity scored produced 38, 47, and 49 paired patients in Group A, B, and C, respectively. In Group A and B, there was no significant difference in OS and FFR between patients who received adjuvant chemotherapy and those who did not. In Group C, patients who received adjuvant chemotherapy experienced less recurrence and higher survival than those who did not. The 5-year FFR was 79.0% in in patients who received adjuvant chemotherapy and 66.1% in patients with surgery alone (p = 0.090). The 5-year OS was 95.8% in patients who received adjuvant chemotherapy and 68.9% in patients with surgery alone (p < 0.001). Figure 1



Conclusion:
Adjuvant chemotherapy was related with reduced recurrence and improved survival in patients with T2a tumors exceeding 4 cm. In considering the next upcoming 8[th ]edition of the TNM classification, adjuvant chemotherapy is a worthwhile and justified treatment for tumors greater than 4 cm with early stage disease.

Abstract not provided