Virtual Library

Abstract:
Introduction The new tumor, node and metastasis (TNM) classification of lung cancer –the 8[th] edition– has already been discussed in the two previous World Conferences of Lung Cancer. (J Thorac Oncol 2015; 10 (Supp 2): s69; J Thorac Oncol 2017; 12 (Supp 1): s2-s3.) The purpose of this educational session is to revise the innovations of the 8[th] edition, to point out its lights and shadows, and to highlight how they can affect our clinical practice. The innovations introduced in the 8[th] edition were based on sound statistical analyses of 70,189 patients with non-small cell lung cancer and 6,189 with small cell lung cancer diagnosed from 1999 to 2010. (1) Although a large number of patients was registered in the International Association for the Study of Lung Cancer database, data originated mainly from Asia and Europe and the other geographic regions of the world were scarcely represented. The innovations are applicable to both types of carcinomas (2) and also to bronchopulmonary carcinoids. (3) Rules to classify lung cancers with multiple lesions were provided based on data where data were available or on multidisciplinary consensus. (4) Primary tumor (T component) New T categories were introduced based on tumor size: T1a 1-2cm, T1c >2-3cm, T2a >3-4cm, T2b >4-5cm, T3 >5-7cm and T4 >7cm. In addition, endobronchial location less than 2 cm from the carina and total atelectasis /pneumonitis were reclassified as T2, while invasion of the diaphragm was reclassified as T4 and invasion of the mediastinal pleural was deleted as a T descriptor. The definition of visceral pleural invasion proposed for the 7[th] edition, i.e., the invasion of its elastic layer, was confirmed for the 8[th] edition and the recommendation to use elastic stains was reinforced. (5, 6) Codes for adenocarcinoma in situ –Tis(AIS) – and minimally invasive adenocarcinoma –T1mi– were defined, too. (7) Because tumor size has more prognostic relevance, its measurement must be as accurate as possible. The recommendation is to measure it on computed tomography with the lung window, because the mediastinal window may underestimate it. The registered size should be the greatest dimension in any of the available projections: axial, coronal or saggital. For part-solid non-mucinous adenocarcinomas, only does the size of the solid part on computed tomography at clinical staging or the size of the invasive part at pathologic examination count to assign a T category based on tumor size. (7) Nodal involvement (N component) The present N categories (NX, N0, N1, N2 and N3) and their descriptors remain unchanged. An important confirmation in the analyses of survival was that quantification of nodal disease at pathologic staging impacts prognosis: the more involved nodal stations, the worse the prognosis. (8) Therefore, identifying the number of involved nodal stations is important both at clinical and pathologic staging, although it is difficult to determine them accurately at clinical staging unless a lymphadenectomy is performed at the time of mediastinoscopy. The proposed subclassification of the N categories for prospective testing are: N1a – involvement of a single N1 station; N1b – involvement of multiple N1 stations; N2a1 – involvement of a single N2 station without N1; N2a2 – involvement of a single N2 station with N1; and N2b – involvement of multiple N2 stations. N1b and N2a1 have similar prognosis. Metastatic disease (M component) Intrathoracic metastases (M1a: malignant pleural and pericardial effusions and/or nodules, and contralateral separate tumor nodules) remain the same. Extrathoracic metastases were divided into single extrathoracic metastasis (the redefined M1b category) and multiple extrathoracic metastases in one or in several organs (the new M1c category). (9) These innovations imply that counting the number of metastases is important, at least from the prognostic point of view, but also from the therapeutic, because single extrathoracic metastasis can be the base to define oligometastatic disease, the treatment of which is aimed to be radical, with whatever therapeutic means are available, instead of palliative, as it usually is the case with polymetastatic disease. Stage grouping More stages have been created to accommodate the new T1 (T1a N0 M0 is stage IA1, T1b N0 M0 is stage IA2 and T1c N0 M0 is stage IA3) categories; to isolate locally advanced tumors (T3-T4 N3 M0 are now stage IIIC); or to separate metastatic disease (M1a and M1b are stage IVA and M1c is stage IVB). (10) Some tumors have shifted their positions. Tumors that are stage shifters should be treated according to evidence and not according to the treatment for those stages in which they now are based on prognosis, because a mere change in taxonomy does not imply a change in treatment. Clinical judgment in the multidisciplinary team discussions should led to the best therapeutic option for these patients whose tumors have moved from one stage to another. Conclusion The 8[th] edition facilitates the indication of prognosis and the stratification of tumors in future clinical trial, but requires more discipline from us when measuring tumor size, quantifying nodal disease and determining the number of extrathoracic metastasis. References 1. Rami-Porta R, Bolejack V, Giroux DJ et al. J Thorac Oncol 2014; 9: 1618-1624. 2. Nicholson AG, Chansky K, Crowley J et al. J Thorac Oncol 2016; 11: 300-311. 3. Travis WD, Giroux DJ, Chansky K, et al. J Thorac Oncol 2008; 3: 1213-1223. 4. Detterbeck FC, Nicholson AG, Franklin WA et al. J Thorac Oncol 2016; 11: 539-650. 5.Travis WD, Brombilla E, Rami-Porta R et al. J Thorac Oncol 2008; 3: 1384-1390. 6. Rami-Porta R, Bolejack V, Crowley J et al. J Thorac Oncol 2015; 10: 990-1003. 7. Travis WD, Asamura H, Bankier A et al. J Thorac Oncol 2016; 11: 1204-1223. 8. Asamura H, Chansky K, Crowley J et al. J Thorac Oncol 2015; 10: 1675-1684. 9. Eberhardt WEE, Mitchell A, Crowley J et al. J Thorac Oncol 2015; 10: 1515-1522. 10. Goldstraw P, Chansky K, Crowley J et al. J Thorac Oncol 2016; 11: 39-51.

Abstract:
The 2015 WHO Classification had a major impact on the new 8[th] Edition TNM Classification. Compared to the 2004 Classification, major changes include: 1) use of immunohistochemistry throughout; 2) New emphasis on genetic studies and personalized therapeutic strategies; 3) A new classification of lung cancer in small biopsy and cytology samples; 4) adoption of the 2011 IASLC/ATS/ERS lung adenocarcinoma classification; 5) reclassification of large cell carcinoma based upon immunohistochemistry and genetics. Since publication of the 2015 WHO Classification new advances include recognition of ciliated muconodular papillary tumors, SMARCA4 and SMARCB1 deficient neoplasms and digital image analysis as a novel way to assess lung cancer morphology. This presentation will primarily focus on the impact of the new WHO Classification on the 8[th] Edition TNM classification. First the new TNM classification incorporates the introduction of the concepts of adenocarcinoma in situ (AIS) which should be staged as Tis (AIS) and minimally invasive adenocarcinoma (MIA) which should be staged as T1mi. AIS is defined as a lung adenocarcinoma with pure lepidic growth measuring ≤3 cm. MIA is defined as a ≤3 cm lepidic predominant adenocarcinoma with an invasive component measuring 0.5 cm or less. Both AIS and MIA should lack stromal, vascular, or pleural invasion and spread through alveolar space invasion (STAS). Lepidic predominant adenocarcinomas are lung adenocarcinomas with a predominant lepidic component that measure > 3 cm in total size or that have an invasive component measuring >0.5 cm. It is recommended to use invasive size for T-descriptor size in nonmucinous adenocarcinomas with a lepidic component. This is in keeping with a recommendation made in three editions of the UICC TNM Supplement since 2003. It is also supported by a growing amount of evidence showing that invasive size is a better predictor of survival than total size in nonmucinous adenocarcinomas with a lepidic component. Both radiologists and pathologists should report the greatest dimension for tumor size for both clinical and pathologic staging. In addition for nonmucinous lung adenocarcinomas, both the total size and invasive size should be reported with invasive size used for T-factor size determination. By computed tomography (CT) in nonmucinous lung adenocarcinomas, the presence of ground glass versus solid opacities generally correspond to lepidic versus invasive patterns respectively seen pathologically. Since, this is not an absolute correlation, when CT features suggest nonmucinous AIS, MIA and LPA, reporting of the suspected diagnosis and clinical staging, should be made as a preliminary assessment that may need to be revised after evaluation of resected specimens pathologically. Since the mucinous variants of AIS, MIA and invasive mucinous adenocarcinomas usually present by CT as a solid or consolidated nodule, and due to the lack of proven correlation between ground glass/solid CT appearance with lepidic/invasive growth pathologically it is not recommended to apply the total vs solid size assessment by CT in suspected invasive mucinous adenocarcinomas. Furthermore there is insufficient data in invasive mucinous adenocarcinomas that invasive size is a better predictor of survival than total size. Pathologic assessment of total vs invasive tumor size in resected nonmucinous lung adenocarcinomas with a lepidic component can be improved by reviewing CT scans because the lepidic component is often poorly appreciated pathologically on gross exam and size is underestimated. In addition, tumor size can be more accurately assessed after radiologic pathologic correlation in the following settings: 1) Lepidic nonmucinous adenocarcinomas that do not fit onto a single slide, 2) Sausage or bilobed shaped tumors where the maximum single diameter may be better assessed using all three CT views (axial, coronal and sagittal) rather than just axial alone, 3) Tumors removed in multiple parts, 4) Intraoperative defects in tumors, 5) Marked non-neoplastic reactions, 6) Mistaken pathologic assessment. In neoadjuvant tumors, it can be difficult to measure tumor size because tumors that show considerable treatment effect often do not have a uniform response allowing a single focus of viable tumor to be measured. It has been shown that 90% or more treatment effect is the most important prognostic finding instead of tumor size in surgically resected nonsmall cell lung cancer patients following induction therapy. One way to estimate viable tumor size is to multiply the percent of viable tumor cells times the size of the total tumor bed. This can be utilized in the setting of a single focus or multiple foci of viable tumor. Recording the percentage of treatment effect is important in addition to estimating tumor size for T-factor determination. REFERENCES 1. Travis WD, et al The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. JThoracic Oncol 2011;6:244-85. 2. Travis WD, et al WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer; 2015. 3. 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. J Thorac Oncol 2016;11:1204-23. 4. Tsutani Y, et al Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma. JThoracCardiovascSurg 2012;143:607-12. 5. Maeyashiki T, et al The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer. Eur J Cardiothorac Surg 2013;43:915-8. 6. Yoshida A, et al Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Modern pathology : 2017;30:797-809. 7. Luo X, et al Comprehensive Computational Pathological Image Analysis Predicts Lung Cancer Prognosis. J Thorac Oncol 2016;12:501-9. 8. Kamata T, et al . Ciliated Muconodular Papillary Tumors of the Lung: A Clinicopathologic Analysis of 10 Cases. The American journal of surgical pathology 2015;39:753-60. 9. MacMahon H, et al Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology 2017;284:228-43. 10. Kamata T, et al. Frequent BRAF or EGFR Mutations in Ciliated Muconodular Papillary Tumors of the Lung. J Thorac Oncol 2016;11:261-5.

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Abstract:
Multiple tumor nodules arising in the lungs can be due either to separate primary lung cancers (SPLCs) or intrapulmonary metastases (IPM) (separate tumor nodules). The recently revised Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) staging manuals (8th editions), based on proposals from work undertaken by the IASLC Staging and Prognostic Factors Committee (SPFC), include updates in T, N and M components, that reflect increased interest in staging of patients with multiple tumor nodules (1-4) due to increased frequency of presentation (1) and advances in classification of tumor subtypes (5). T categories for multiple tumor nodules are unchanged when compared to the 7[th] edition, with SPLCs continuing to be staged individually, with the recommendation that multiple lesions be grouped with the number of lesions in brackets (e.g. (2)), or (m) for multiple. Patients with IPM are staged as T3 (same lobe), T4 (different lobe in ipsilateral lung) and M1a (contralateral lung). However, although unchanged, these categories have been impacted by changes in the histologic classification of lung cancer (6), in particular adenocarcinomas (7). For the current edition, those tumors that present with multiple areas of pneumonic consolidation, these frequently corresponding to invasive mucinous adenocarcinomas, are viewed as a potential subgroup of IPM. There is also increased interest in those patients who present with multiple ground glass lesions, these typically corresponding to patients with non-mucinous adenocarcinomas with a lepidic component. These types of multiple tumor nodules are currently viewed as a potential subgroup of SPLCs. It is hoped that the next decade will see further research from within the lung cancer community that informs the 9[th] edition in relation to the staging of these types of tumor (3). In relation to pathologic staging, from 1975 until recently, distinction between SPLC and IPM was undertaken using criteria proposed by Martini and Melamed: tumors occurring in different lobes, having different major histologic types or being separated by a time interval of more than two years were to be classified as SPLCs (8). Recently, these criteria have been supplanted by the process of comprehensive histologic assessment (CHA) (9). CHA involves determination of major histologic type, assessment of predominant and minor histologic patterns according to histologic subtyping and evaluation of cytological features. CHA has been shown to significantly improve the pathologic distinction between SPLC and IPM to a level comparable to molecular analysis (9). Recent work undertaken by the IASLC Pathology Committee has also shown that usage of this methodology has good reproducibility amongst diagnostic pathologists. Furthermore, p staging status strongly correlated with nuclear pleomorphism, cell size, acinar formation, nucleolar size, and mitotic rate. In addition to the above, immunohistochemistry already has a role in refining the distinction between SPLC and IPM, and molecular techniques are also likely to be used increasingly in the situation. Studies have been published showing that comprehensive genotypic and morphological assessment is feasible, though they are not yet sufficient to establish clonal relationships between multiple tumour nodules (10). Ultimately, a multidisciplinary approach is likely to be the best methodology for distinction between SPLC and IPM, in particular the assessment of imaging data alongside histologic, immunohistochemical and molecular profiles, both in the context of biopsies and resections. 1. Detterbeck FC, Franklin WA, Nicholson AG, Girard N, Arenberg DA, Travis WD, 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. J Thorac Oncol. 2016. 2. Detterbeck FC, Bolejack V, Arenberg DA, Crowley J, Donington JS, Franklin WA, 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. J Thorac Oncol. 2016. 3. Detterbeck FC, Nicholson AG, Franklin WA, Marom EM, Travis WD, Girard N, 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. J Thorac Oncol. 2016. 4. Detterbeck FC, Marom EM, Arenberg DA, Franklin WA, Nicholson AG, Travis WD, 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. J Thorac Oncol. 2016. 5. Travis WD, Asamura H, Bankier AA, Beasley MB, Detterbeck F, Flieder DB, 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. J Thorac Oncol. 2016;11(8):1204-23. 6. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson, AG WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, 2015. 7. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6(2):244-85. 8. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;60:606-12. 9. Girard N, Deshpande C, Lau C, Finley D, Rusch V, Pao W, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol. 2009;33(12):1752-64. 10. Schneider F, Derrick V, Davison JM, Strollo D, Incharoen P, Dacic S. Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging. Mod Pathol. 2016;29(7):735-42.

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Abstract:
Lung cancer has shown a decrease in incidence and mortality in recent decades; however, it remains one of the cancers with the highest incidence and ranks first in cancer-related deaths in the United States. Despite advances in early detection and standard treatment, most patients are diagnosed at an advanced stage and have a poor prognosis, with an overall 5-year survival rate of 10% to 15%. Lung cancer is a heterogeneous disease comprising several subtypes with pathologic and clinical relevance. The recognition of histologic subtypes of non-small cell lung carcinoma (NSCLC), namely adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma as the most frequent subtypes, has become important as a determinant of therapy in this disease. In addition, in recent years, the identification of molecular abnormalities in a large proportion of patients with lung cancer has allowed the emergence of personalized targeted therapies and has opened new horizons and created new expectations for these patients. The use of predictive biomarkers to identify tumors that could respond to targeted therapies has meant a change in the paradigm of lung cancer diagnosis. This paradigm change affects all stakeholders in the fight against lung cancer including pathologists. Currently, several multiplex genotyping platforms for the detection of oncogene mutations, gene amplifications and deletions, and rearrangement are moving to the clinical setting. Genome-wide molecular investigations using next-generation sequencing (NGS) technologies have been evaluated in the research setting, with promising results. Further investigations in NSCLC are required for a better understanding of the implications of intratumor heterogeneity and the roles of tumor suppressor genes and epigenetic events with no known driver mutations. NGS in the clinical setting will provide comprehensive information cheaper and faster by using small amounts of tissue. Recently, NGS genotyping platforms utilization has extended to liquid biopsy (cell free DNA). Pathologists should be able to precisely handle tissue adequacy in terms of quantity and quality and maintaining tumor cells for detection of molecular alterations. The clinical successes of targeted therapy and immunotherapy approaches to lung cancer have posed additional challenges to the scientific community and pathologists to develop predictive biomarkers of response to these therapies and have highlighted the need for proper procurement and processing of tissue specimens from patients with lung cancer.

Abstract:
Tumour biopsies are the ‘gold standard’ with which to interrogate a patient’s tumour biology and assess biomarkers useful for treatment decision making. However, for longitudinal monitoring of disease in certain cancer types (e.g. lung) and particularly in patients with multiple metastatic lesions), serial biopsies may not be readily acquired and easily repeatable and a less invasive tumour sample is required. Liquid biopsies are beginning to gain acceptance as a surrogate for tumour profiling and in NSCLC, regulatory approval has been given for EGFR mutation testing in circulating tumour DNA (ctDNA) where biopsies are not available. My presentation will cover the development and utility of liquid biopsies in lung cancer, focusing on both ctDNA and circulating tumour cells (CTC). An avalanche of new technology platforms for circulating tumour cell (CTC) analysis is arriving in translational research laboratories, employing different approaches to CTC enrichment, purification and molecular characterisation. The semi-automated, robust and validated CellSearch platform (Menarini) remains the only technology that is FDA approved to determine patient prognosis (in breast, prostate, and colorectal cancers) by enumeration of EpCam expressing CTCs. CellSearch CTC count is also prognostic in both SCLC and NSCLC. The the ability to preserve CTCs for analysis 96h after blood draw is a major advantage for multicentre clinical trial scenarios. However, since CTCs are heterogenous and may downregulate epithelial markers during epithelial to mesenchyme transition (EMT) it is critical that marker independent CTC technologies are adopted to better explore CTC biology and heterogeneity, and the potential for a wider range of CTC based biomarkers is becoming apparent. I will review a range of CTC enrichment and isolation approaches and discuss our data on single CTC molecular profiling. I will compare and contrast the challenges for CTC profiling in small cell lung cancer (where EpCam positive CTCs are prevalent) and NSCLC (where EpCam positive CTCs are rare). I will also discuss the development of CTC patient-derived explant models (CDX) from SCLC and NSCLC patients and the advantages these may provide over conventional PDX models generated from a tissue biopsy. I will describe the utility of CDX models in drug development and in exploring the biology of progressing lung cancers, including vasculogeneic mimicry whereby SCLC cells adopt endothelial characteristics that may facilitate tumour growth and metastasis. I will present our ctDNA profiling approaches for selection of patients to early clinical trials and finally I will scan the horizon to the potential use of CTC and ctDNA as potential early detection biomarkers that complement CT scans. Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Carter L, Rothwell DG, Mesquita B, Smowton C, Leong HS, Fernandez-Gutierrez F, Li Y, Burt DJ, Antonello J, Morrow CJ, Hodgkinson CL, Morris K, Priest L, Carter M, Miller C, Hughes A, Blackhall F, Dive C, Brady G. Nat Med. 2017 Jan;23(1):114-119. Vasculogenic mimicry in small cell lung cancer. Williamson SC, Metcalf RL, Trapani F, Mohan S, Antonello J, Abbott B, Leong HS, Chester CP, Simms N, Polanski R, Nonaka D, Priest L, Fusi A, Carlsson F, Carlsson A, Hendrix MJ, Seftor RE, Seftor EA, Rothwell DG, Hughes A, Hicks J, Miller C, Kuhn P, Brady G, Simpson KL, Blackhall FH, Dive C. Nat Commun. 2016 Nov 9;7:13322. Circulating Tumor Cells Detected in the Tumor-Draining Pulmonary Vein Are Associated with Disease Recurrence after Surgical Resection of NSCLC. Crosbie PA, Shah R, Krysiak P, Zhou C, Morris K, Tugwood J, Booton R, Blackhall F, Dive C.J Thorac Oncol. 2016 Oct;11(10):1793-7. Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study. Morrow CJ, Trapani F, Metcalf RL, Bertolini G, Hodgkinson CL, Khandelwal G, Kelly P, Galvin M, Carter L, Simpson KL, Williamson S, Wirth C, Simms N, Frankliln L, Frese KK, Rothwell DG, Nonaka D, Miller CJ, Brady G, Blackhall FH, Dive C. Ann Oncol. 2016 Jun;27(6):1155-60. Genetic profiling of tumours using both circulating free DNA and circulating tumour cells isolated from the same preserved whole blood sample. Rothwell DG, Smith N, Morris D, Leong HS, Li Y, Hollebecque A, Ayub M, Carter L, Antonello J, Franklin L, Miller C, Blackhall F, Dive C, Brady G. Mol Oncol. 2016 Apr;10(4):566-74. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Hodgkinson CL, Morrow CJ, Li Y, Metcalf RL, Rothwell DG, Trapani F, Polanski R, Burt DJ, Simpson KL, Morris K, Pepper SD, Nonaka D, Greystoke A, Kelly P, Bola B, Krebs MG, Antonello J, Ayub M, Faulkner S, Priest L, Carter L, Tate C, Miller CJ, Blackhall F, Brady G, Dive C. Nat Med. 2014 Aug;20(8):897-903. Molecular analysis of circulating tumour cells-biology and biomarkers. Krebs MG, Metcalf RL, Carter L, Brady G, Blackhall FH, Dive C.Nat Rev Clin Oncol. 2014 Mar;11(3):129-44 Clinical utility of circulating tumour cell detection in non-small-cell lung cancer. Fusi A, Metcalf R, Krebs M, Dive C, Blackhall F. Curr Treat Options Oncol. 2013 Dec;14(4):610-22.

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Abstract:
Along with the prevalence of screening with computed tomography (CT), small pulmonary ground-glass density nodules (GGN) have been detected more frequently. A GGN is a round area of increased pulmonary opacity with intact bronchial and vascular structures. GGNs showing no or slow growth during follow-up period are most likely to be “early” adenocarcinomas showing lepidic pattern pathologically. There are three problems in diagnostics and therapeutics of GGNs. First, should they be treated or not? They might not change for years. We might take a risk of postoperative comorbidity for a harmless disease. Some large prospective observational studies on these pulmonary small GGNs have been performed: From clinical practice performed in these clinical trials, We found that 5-30% of GGN were resected during the observation period, because of the increased size or appearance of solid part in the GGN. Almost all of the pathologies of the resected GGN were adenocarcinomas. Part-solid GGNs were more likely to be diagnosed as invasive adenocarcinomas than pure GGNs. That is, we can correctly diagnose small pulmonary GGNs as adenocarcinomas when their CT images are changed. However, it is still unclear whether surgical intervention will contribute to increased survival from lung cancer. Second, how to detect pulmonary GGOs at surgery, if they are located deep in lung parenchyma? GGNs are difficult to identify even by bimanual palpation through open thoracotomy, because they are as soft as lung parenchyma if they show pure GGN appearance. Preoperative marking of these GGN is mandatory to ensure a definite resection. Many methods for detecting small pulmonary nodules have been developed: Preoperative hookwire placement under CT observation has been most widely performed. The punctured hook wire with thread can easily be identified that excisional biopsy may be done through thoracoscopy. However, arterial air embolism is reported to be occasionally associated with the placement of hookwire which can cause lethal results. Instead, dye marking, or fiducial placement through bronchoscopy has been revived to replace the hookwire method. We have recently developed Virtual-assisted lung mapping (VAL-MAP), a relatively brand-new lung marking technique using dye multiple dye markings through bronchoscope. Before bronchoscopy, we create a virtual 3-D bronchoscope map with CT and plan where to mark. Multiple dye markings enable us to determine the extent of resection with safe margin from the tumor. Actually safer margin from the tumor was shown to be secured by this method. Third, how to determine the extent of pulmonary resection for these small GGNs? Still there is no evidence other than lobectomy and lymph node dissection for early non-small cell lung cancer (NSCLC), clinical trials have been performed to prove feasibility and no-inferiority of sublobar resections (wedge resection and segmentectomy) for small NSCLC, especially those ≤2cm in diameter. In Japan and USA, prospective randomized studies are on the way to obtain more reliable evidence. In conclusion, management of small pulmonary nodules suspected of an early carcinoma includes the determination of operative indication, detection technique of the tumor, aiming to safer and effective treatment of these tumors.

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Background:
The ARCHER 1050 study (NCT01774721) demonstrated benefits of dacomitinib compared with gefitinib as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) and EGFR-activating mutation. Here, we present the results of a prospective subgroup analysis by EGFR mutation subtype.

Method:
In this ongoing phase 3, open-label study, eligible patients with newly diagnosed stage IIIb/IV or recurrent NSCLC and EGFR-activating mutation (exon 19 deletion or L858R mutation ± T790M mutation) with an Eastern Cooperative Oncology Group performance status of 0–1 were randomized (1:1) to receive dacomitinib or gefitinib, stratified by race and EGFR mutation subtype. The primary endpoint was progression-free survival (PFS) by blinded independent radiologic central (IRC) review. Secondary endpoints included overall survival and objective response rate (ORR), as determined by IRC and investigators’ assessments.

Result:
A total of 452 patients were randomized (dacomitinib, n=227; gefitinib, n=225). Among the dacomitinib and gefitinib arms, respectively, 134 (59%) and 133 (59%) had exon 19 deletions and 93 (41%) and 92 (41%) had L858R mutations. The Table shows PFS, ORR, and duration of response by EGFR mutation per IRC. Results based on investigators’ assessments were consistent with those based on IRC review. Overall survival data are immature.

	Exon 19 Deletion		L858R Mutation
	Dacomitinib (n=134)	Gefitinib (n=133)	Dacomitinib (n=93)	Gefitinib(n=92)
PFS per IRC
Median, months (95% CI)	16.5 (11.3–18.4)	9.2 (9.1–11.0)	12.3 (9.2–16.0)	9.8 (7.6–11.1)
Hazard ratio (95% CI) 1-sided P value	0.551 (0.408–0.745) <0.0001		0.626 (0.444–0.883) 0.0034
ORR per IRC
CR, n (%)	7 (5.2)	3 (2.3)	5 (5.4)	1 (1.1)
PR, n (%)	95 (70.9)	90 (67.7)	63 (67.7)	67 (72.8)
ORR (CR + PR), n (%) (95% CI)	102 (76.1) (68.0–83.1)	93 (69.9) (61.4–77.6)	68 (73.1) (62.9–81.8)	68 (73.9) (63.7–82.5)
1-sided P value	0.1143		0.5395
DoR in responders per IRC
Median, months (95% CI)	15.6 (13.1–19.6)	8.3 (7.9–10.1)	13.7 (9.2–17.4)	7.5 (6.5–10.2)
Hazard ratio (95% CI) 1-sided P value	0.454 (0.319–0.645) <0.0001		0.403 (0.267–0.607) <0.0001
CI, confidence interval; CR, complete response; DoR, duration of response; PR, partial response.

Conclusion:
By IRC and investigators’ assessments, PFS with dacomitinib was superior to that with gefitinib in patients with either EGFR mutation. Despite a similar ORR among the treatment and EGFR mutation subgroups, duration of response was longer with dacomitinib for both mutations.

Background:
FLAURA (NCT02296125) is a Phase III, double-blind, randomized study assessing efficacy and safety of osimertinib vs standard of care (SoC) EGFR-TKI as first-line treatment for patients with EGFRm advanced NSCLC. Concordance between tissue and plasma testing for EGFRm (Ex19del/L858R), and progression-free survival (PFS) by baseline plasma EGFRm status were evaluated.

Method:
Eligible patients: ≥18 years (Japan ≥20 years); Ex19del/L858R mutation-positive lung adenocarcinoma; no prior systemic anti-cancer/EGFR-TKI therapy for advanced NSCLC. Randomization: 1:1 to osimertinib 80 mg once daily (qd) orally (po) or SoC (gefitinib 250 mg or erlotinib 150 mg, qd po). At baseline, patients provided tumor tissue samples for central analysis of EGFRm status (cobas EGFR Mutation Test) and blood samples for retrospective analysis of EGFRm status by plasma ctDNA (cobas EGFR Mutation Test v2). PFS by baseline plasma EGFRm status was assessed. Comparison of EGFRm status between baseline tumor tissue and evaluable ctDNA samples was an exploratory endpoint.

Result:
Globally, 556 patients were randomized: osimertinib, n=279; SoC, n=277. Good concordance was observed between central laboratory tissue and plasma testing for EGFRm in the screened population (see table). In plasma EGFRm-positive patients (n=359), osimertinib (n=183) reduced the risk of progression or death by 56% vs SoC (n=176), hazard ratio (HR) 0.44 (95% CI 0.34, 0.57). This was consistent with the overall PFS result observed with osimertinib vs SoC in the full analysis set (FAS; tumor tissue EGFRm-positive by local/central testing), HR 0.46 (95% CI 0.37, 0.57); p<0.0001 and in plasma EGFRm-negative patients (n=124: osimertinib, n=60; SoC, n=64), HR 0.48 (95% CI 0.28, 0.80).Figure 1



Conclusion:
In the subgroup of plasma EGFRm-positive patients, clinical benefit of osimertinib was superior to SoC, consistent with the overall FLAURA FAS. These results, and good concordance between tissue and plasma testing for EGFRm, support the utility of plasma EGFRm testing for selecting patients eligible for first-line osimertinib treatment.

Background:
Epidermal growth factor receptor (EGFR) activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small cell lung cancer (NSCLC) and occur in ~50% of East Asian patients with NSCLC. While initial TKI treatment can be effective, acquired resistance inevitably develops with a secondary mutation (T790M). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI which inhibits both activating (eg, exon 19 deletions, L858R) and resistance (eg T790M) mutations.

Method:
This dose-escalation/dose-expansion study (NCT02192697) was conducted in two phases. In Phase 1, adult Japanese patients (≥20 yr) with NSCLC previously treated with ≥1 EGFR TKI were enrolled and received escalating ASP8273 doses (25–600mg) to assess safety/tolerability as well as to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). In phase 2, adult T790M-positive NSCLC patients in Japan, Korea, and Taiwan were enrolled to further define the ASP8273 safety/tolerability profile at RP2D and determine antitumor activity (assessed using RECIST v1.1). Antitumor activity in phase 2 was evaluated according to Simon’s 2-stage design (uninteresting response=0.3, desired response=0.5, α=0.05, β=0.1). If ≥9 of 24 ASP8273-treated patients achieved a desired response in the first stage, then 39 additional patients would be enrolled. If ≥ 25 of the 63 total patients achieved response, ASP8273 would be considered to have antitumor effects.

Result:
A total of 123 patients (n=47 phase 1; n=76 phase 2) were enrolled. In both phases, more women were enrolled. The median age was 65 years in phase 1 and 63 years in phase 2. Based on phase 1 findings, MTD and RP2D were 400mg and 300mg, respectively. As 27 of the 63 patients treated with ASP8273 300mg in the first and second stages combined achieved a clinical response (based on independent central review), ASP8273 was determined to have antitumor activity (ORR=42.9%; 95% CI: 30.5–56.0). The ORR at week 24 in all patients in the full analysis set was 42.1% (n=32/76; 95% CI: 30.9, 54.0). The median duration of PFS (central review) was 8.1 months (95%CI: 5.6,--). The most commonly reported treatment-emergent AEs (TEAE) in phase 2 were diarrhea (n=50/76), nausea (n=31/76), increased alanine aminotransferase (n=27/76), decreased appetite and vomiting (n=26/76 each), and hyponatremia (n=25/76). Drug-related TEAEs were reported in 93.4% (n=71/76) of patients, the most common of which was diarrhea (n=43/76).

Conclusion:
ASP8273 was generally well tolerated and demonstrated antitumor activity in Asian patients with both EGFR activating and T790M mutations.

Abstract not provided

Background:
Brigatinib, a next-generation ALK inhibitor, recently received accelerated approval in the United States for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. We report updated data from the randomized phase 2 trial (ALTA; NCT02094573), which was designed to investigate the efficacy and safety of 2 brigatinib regimens in patients with crizotinib-refractory, advanced ALK+ NSCLC.

Method:
Patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib and randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint.

Result:
Among 222 patients (n=112/n=110, arm A/B), median age was 51/57 years; 71%/67% had brain metastases. As of February 21, 2017, 17 full months since the last patient enrolled, median follow-up was 16.8/18.6 months and 32%/41% of patients continued to receive brigatinib in A/B. The table shows brigatinib efficacy. Per independent review committee, confirmed ORR was 51%/55% and median PFS was 9.2/16.7 months in A/B. Among patients with measurable baseline brain metastases (n=26/n=18, A/B), confirmed intracranial ORR was 50%/67% as of January 24, 2017; median intracranial DoR was not reached/16.6 months. The most common treatment-emergent adverse events (TEAEs) were: nausea (38%/47%, A/B), diarrhea (28%/44%), cough (28%/40%), headache (30%/35%), and vomiting (36%/30%); the most common grade ≥3 TEAEs were: increased creatine phosphokinase (5%/13%), hypertension (6%/8%), pneumonia (4%/5%), and increased lipase (5%/4%). Dose reduction (9%/30%, A/B) or discontinuation (4%/11%) due to TEAEs was reported.

Conclusion:
In ALTA, brigatinib continues to show substantial efficacy and acceptable safety at both dose levels, with numerically longer PFS and higher intracranial ORR at the recommended dosing regimen of 180 mg qd (with lead-in) vs 90 mg qd.

	Investigator Assessment		Independent Review[a]
	Arm A (n=112)	Arm B (n=110)	Arm A (n=112)	Arm B (n=110)
Confirmed ORR, %	46 (35–57[b])	55 (44–66[b])	51 (41–61[c])	55 (45–64[c])
Median DoR in responders,[d] months	12.0 (9.2–17.7[c])	13.8 (10.2–17.5[c])	13.8 (7.4–NR[c])	14.8 (12.6–NR[c])
Median PFS,[d] months [% of events]	9.2 (7.4–11.1[c]) [65]	15.6 (11.1–19.4[c]) [50]	9.2 (7.4–12.8[c]) [54]	16.7 (11.6–NR[c]) [41]
Median OS,[d] months [% of events]	NR (20.2–NR[c]) [38]	27.6 (27.6–NR[c]) [29]	—	—
1-year OS probability,[d ]%	70 (61–78[c])	80 (71–87[c])	—	—
DoR, duration of response NR, not reached OS, overall survival PFS, progression-free survival [a]Last scan date: February 28, 2017 [b]97.5% CI for primary endpoint [c]95% CI [d]Kaplan-Meier estimate

Background:
Lorlatinib, a selective, potent, brain-penetrant ALK/ROS1 TKI, is active against most known ALK kinase domain mutations. In phase 1 of this ongoing study (NCT01970865), lorlatinib displayed robust clinical activity among patients with ALK[+]/ROS1[+] non-small-cell lung cancer (NSCLC), most of whom were heavily pretreated and had CNS metastases. Phase 2 evaluated efficacy (overall and intracranial), according to prior treatment, and safety at the recommended phase 2 dose (100 mg QD).

Method:
Patients with NSCLC ± asymptomatic CNS metastases enrolled in 6 cohorts (EXP1–5, ALK[+]; EXP6, ROS1[+]). The primary endpoint was objective response rate (ORR) and intracranial ORR by independent central review. Safety, patient-reported outcomes and molecular profiling were also assessed.

Result:
As of 15-March-2017, 227 ALK[+] patients were evaluated for ORR (Table), including 140 with CNS involvement who were evaluated for intracranial ORR.

	Confirmed ORR		Confirmed IC-ORR
	N	n (%)	N	n (%)
ALK[+] cohorts
EXP1 (treatment-naïve, no prior ALK-TKIs or CT)	30	27 (90)	8	6 (75)
EXP2 (prior crizotinib only)	27	20 (74)	17	10 (59)
EXP3 (1 prior ALK TKI ± CT)	59	30 (51)	32	20 (63)
EXP3A (prior crizotinib + CT)	32	21 (66)	20	15 (75)
EXP3B (any 1 other ALK TKI ± CT)	27	9 (33)	12	5 (42)
EXP4 (2 prior ALK TKIs ± CT)	65	27 (42)	45	25 (56)
EXP5 (3 prior ALK TKIs ± CT)	46	16 (35)	38	(15 (39)
CT, chemotherapy; IC, intracranial.

Of 219 ALK+ patients analyzed for ALK kinase domain mutations at baseline, 46/219 (21%) had ≥1 mutation detected in circulating free DNA; most derived treatment benefit with an ORR of (27/46) 59%. Across all cohorts (N=275), the most common treatment-related adverse events (AEs) and grade 3/4 treatment-related AEs were hypercholesterolemia (81%/16%) and hypertriglyceridemia (60%/16%); 30% and 22% of patients had treatment-related AEs associated with dose interruptions and reductions, respectively. No treatment-related deaths occurred; 7 patients (3%) had treatment-related AEs leading to treatment discontinuation. 157/275 (57%) patients remained on treatment at data cutoff. Most patients reported stable/improved global quality of life (40%/43%).

Conclusion:
Lorlatinib showed clinically meaningful activity, including substantial intracranial efficacy, among ALK[+]/ROS1[+] patients who were either treatment-naïve or failed ≥1 prior ALK TKI. Overall lorlatinib was well tolerated and when needed, AEs were managed by dose delay/reduction or standard medical therapy.

Background:
Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with ALK+ non-small cell lung cancer (NSCLC) who are treatment-naive or have progressed on crizotinib at the recommended dose of 750 mg/day under fasted state. Gastrointestinal (GI) adverse events (AEs), eg, diarrhea, nausea, vomiting, are common with ceritinib 750 mg/day under fasting conditions. ASCEND‑8 study, (NCT02299505) evaluated alternative methods of ceritinib administration, utilizing potential benefit of dosing ceritinib with food to reduce GI toxicity, while maintaining the pharmacokinetic exposure at lower doses. Based on the primary pharmacokinetics analysis previously presented (n=137; WCLC 2016), ceritinib 450 mg with food had similar exposure and a more favorable GI safety profile vs ceritinib 750 mg fasted in patients with ALK+ NSCLC.

Method:
This is a multicenter, randomized, 3-arm (450 mg or 600 mg ceritinib taken with low-fat meal vs 750 mg ceritinib taken in fasted state), open-label, phase 1 study (ASCEND-8). Patients were eligible if they had stage IIIB or IV ALK+ advanced NSCLC, were aged 18 years or older, who were either previously treated with chemotherapy and/or crizotinib or treatment naive. We plan to report the updated safety (n=228) and preliminary efficacy for treatment-naïve patients (ALK+ by immunohistochemistry [IHC]) who were randomized at least 18 weeks before the cutoff date (March 28, 2017; n=79). Updated analysis is planned to be made available by August 2017 and the following data will be included at the time of final abstract submission: patient disposition; patient demographics; disease characteristics and prior therapies; overall response rate and duration of response by blinded independent review committee (BIRC; key secondary endpoints) in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; progression-free survival per BIRC in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; updated safety results with detailed information on GI (diarrhea, nausea, vomiting) and liver (alanine transaminase/aspartate transaminase) toxicities.

Result:
LBA shell - not applicable

Conclusion:
LBA shell - not applicable

Background:
Alectinib (ALC) is a selective, CNS-active ALK tyrosine kinase inhibitor. In two Phase 3 studies (J-ALEX and ALEX), ALC proved superior efficacy and tolerability compared to crizotinib (CRZ). Here we report the final efficacy and safety results of the 46 pts enrolled in the phase II part of study AF-001JP with a longer follow-up period than that observed in J-ALEX and ALEX studies.

Method:
ALC 300 mg b.i.d was given to ALK+ NSCLC pts who were ALK inhibitor-naive and had disease progression after at least one line of chemotherapy to investigate the efficacy and safety until the investigator confirmed no further clinical benefits.

Result:
This study was completed in December 2016. The median treatment duration was 46.1 months (range: 1-62). 20 of 46 pts were on treatment with alectinib at the study termination. Progressive disease (PD) was confirmed in 20 pts (43%). Median PFS was not reached and 4-year PFS rate was 52% (95% CI: 36-66). 14 of 46 pts had CNS metastasis at baseline. Median PFS was 38 months (95% CI: 9-NE) in pts with CNS metastases and was not reached in pts without CNS metastases. Four pts had CNS progression and the 4-year cumulative incidence rate of CNS progression was 9.5%. Median OS was not reached and the 4-year OS rate was 70% (95% CI: 54-81). Safety profile was similar to that reported previously and there were no treatment-related Grade 4 or 5 adverse events for this long administration period.

Conclusion:
Regardless of CNS metastases at baseline, ALC have demonstrated excellent efficacy in ALK+ NSCLC pts without prior ALK inhibitor treatment. ALC was well tolerated over a prolonged administration period.

Abstract not provided

Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in T790M-positive lung cancer. Acquired resistance to osimertinib is driven by EGFR C797S in ~20-30% of cases. Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) can be used to identify resistance mechanisms. The allelic configuration (cis vs. trans) of C797S with respect to T790M has therapeutic implications, but the relative frequency of each and other co-occurring genomic alterations are not well defined in clinical samples.

Method:
We queried the Guardant Health database for lung adenocarcinoma patients and an EGFR C797S mutation. All patients had comprehensive ctDNA testing using the Guardant360 NGS assay between June 2015 and June 2017. Cis/trans configuration for T790M and C797S was determined using Integrated Genomics Viewer software.

Result:
We identified 50 unique patients with a total of 66 samples which were C797S positive. All had a co-existent EGFR activating mutation (del19 74%, L858R 24%, other 2%). 60/66 (91%) C797S+ samples were also T790M+. In the 6 samples with C797S but without T790M in ctDNA, 4 were from patients who were T790M+ on a prior Guardant360 assay, 1 never had T790M in blood or tissue and developed C797S while on 1[st]-line afatinib, and 1 had no further clinical details available. T790M and C797S were on the same allele (cis configuration) in 44/46 evaluable patients (98%); 1 (2%) was in trans. One sample had two different C797S mutations, one cis and one trans to T790M. 13 C797S+/T790M+ samples (22%) had multiple C797X mutations detected and 12 samples carried other mutations in or adjacent to the EGFR ATP-binding pocket (e.g. L792, F795, G796, etc). The most common non-EGFR mutations co-occurring with C797S were BRAF amplification/mutation (20%), MET amplification (17%), PIK3CA mutation/amplification (15%), CCNE1 amplification 14% and MYC amplification (14%).

Conclusion:
Understanding EGFR TKI resistance mechanisms is critical to developing more effective therapies. ctDNA offers a non-invasive method to characterize the resistance landscape. Our data suggests C797S most commonly occurs with T790M in cis (98%), a state associated with resistance to all currently available EGFR TKIs. The trans configuration, which may respond to combined 1[st]/3[rd]-gen EGFR TKIs, is rare (2%). Moreover, C797S is frequently detected along with other resistance mechanisms in ctDNA, underscoring the heterogeneity of resistant cancers. New treatments targeting C797S/T790M are needed, as is a deeper understanding of therapeutic targeting of heterogeneity in resistant cancers.

Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in EGFR-mutant NSCLC with resistance to prior TKI. Improved understanding of the clinical and molecular characteristics of acquired resistance to osimertinib is needed.

Method:
We initially studied resistance biopsies and plasma specimens from an institutional cohort of 119 patients treated with osimertinib for T790M-positive NSCLC with resistance to prior TKI. For validation, we studied plasma from 157 patients treated with osimertinib on the AURA trial (NCT01802632).

Result:
45 of 119 patients underwent a resistance biopsy and 33 had resistance tumor genotyping available. 11 patients maintained T790M at resistance: 7 acquired EGFR C797S, 1 had a PIK3CA mutation. 22 patients had loss of T790M at resistance: 14 harbored a competing resistance mechanism, including histologic transformation to SCLC, MET amplification, mutations in BRAF, PIK3CA, or KRAS, or fusions in RET or FGFR. Median time to treatment failure (TTF) on osimertinib was 3 months in patients with loss of T790M and 15 months in patients with maintained T790M. In the validation cohort, 110 of 157 patients had detectable tumor DNA in plasma and were eligible for analysis. 58 patients (53%) maintained T790M at resistance; 24 (22%) also acquired a C797S mutation. 52 patients (47%) had loss of T790M at resistance and no C797S. Median TTF was shorter in patients with loss of T790M than in those with maintained T790M at resistance (5.7 vs 12.5 months). 50 patients had both pre- and post-osimertinib plasma genotyping. Studying the relative allelic fraction (AF) of T790M compared to driver EGFR mutation, patients with T790M loss had only slightly lower relative T790M AF pretreatment (29% vs. 38% median, p = 0.06). The ability of plasma response to predict subsequent resistance was studied in 19 patients from the initial cohort with baseline and follow-up plasma genotyping after 1-3 weeks on osimertinib. Studying the difference between the relative change in plasma levels of T790M and the EGFR driver, patients with T790M loss at time of resistance consistently had a greater T790M response than driver response (median difference 16%), suggesting incomplete suppression of the driver due to competing resistance mechanisms.

Conclusion:
In patients with acquired resistance to osimertinib, repeat testing for T790M could offer key insights into disease biology. Patients with early resistance on osimertinib are at risk of T790M loss with emergence of a complex variety of competing resistance mechanisms, and represent intuitive candidates for combination approaches such as combined EGFR & MET inhibition.

Background:
MET amplification is a well described mechanism of acquired resistance to EGFR inhibition in EGFR-mutant NSCLC, making combined MET/EGFR inhibition a compelling therapeutic approach. We previously reported tolerability of the oral, CNS active, third-generation EGFR-TKI osimertinib, which is selective for both EGFR-TKI sensitizing and EGFR T790M resistance mutations, combined with the highly selective MET-TKI savolitinib (volitinib, HMPL-504, AZD6094). Here we assess safety and preliminary activity of this combination in a cohort of patients (pts) with EGFR-mutant NSCLC and MET-positive acquired resistance in the multi-arm, Phase Ib TATTON study (NCT02143466).

Method:
Eligible pts were aged ≥18 years (WHO performance status 0/1) with locally advanced or metastatic EGFR-mutant NSCLC who progressed on at least one prior EGFR-TKI with centrally confirmed MET-amplification (fluorescence in-situ hybridisation, MET gene copy ≥5 or MET/CEP7 ratio ≥2). Pts received osimertinib 80 mg QD plus savolitinib 600 mg QD. Primary objective was safety and tolerability; secondary objectives included preliminary assessment of anti-tumour activity and pharmacokinetics.

Result:
As of data-cut off (15 April 2017), 45 pts with centrally confirmed MET-amplification (FISH) were enrolled and received treatment, including 25 pts previously treated with a third-generation EGFR-TKI and 20 without prior third-generation EGFR-TKI treatment (T790M negative n=13; T790M positive n=7). At baseline, median age was 58 years (range 38–76), 24 (53%) were female, 36 (80%) were Asian. The most frequent adverse events (AEs) were nausea (n=21, 47%), decreased appetite (n=15, 33%), fatigue (n=13, 29%) vomiting (n=13, 29%), rash (n=11, 24%), myalgia (n=8, 18%), pyrexia (n=7, 16%), ALT/AST increased (n=6, 13%), and WBC decreased (n=6, 13%), consistent with the known safety profiles. Serious AEs were reported in 15 (33%) pts; events reported in >1 patient were pneumonia, dyspnoea, acute kidney injury and pyrexia (all n=2). Four pts died due to AEs, none were considered related to study drugs. At data cut-off, confirmed partial responses were reported in 5/25 (20%) pts previously treated with a third-generation EGFR-TKI; 5/12 (42%) T790M negative pts without prior third-generation EGFR-TKI and 3/7 (43%) T790M positive pts without prior third-generation EGFR‑TKI. Twenty-eight (62%) pts are ongoing treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and osimertinib were consistent with historical data.

Conclusion:
These findings demonstrate promising safety, tolerability, and preliminary activity of osimertinib plus savolitinib and support further investigation of this combination for the treatment of pts with locally advanced or metastatic EGFR-mutant NSCLC and MET-amplification. Updated data will be presented.

Abstract not provided

Background:
While previous reports have established MET and HER2 amplification as two mechanisms of non-T790M driven EGFR TKI resistance in EGFR mutant NSCLC, resistance occurs in the absence of these modifications in a significant number of patients. Therefore, there exists an unmet need to define additional mechanisms of resistance to EGFR TKIs. We hypothesized that targeted next-generation sequencing could detect additional targetable activating mutations in paired tumor samples from patients with acquired resistance to first or second generation EGFR TKIs.

Method:
We conducted an analysis of clinical and molecular data prospectively collected from 285 EGFR-mutant NSCLC patients enrolled into the MD Anderson Lung Cancer GEMINI database. Of 157 patients treated with first-line therapy (erlotinib, gefitinib, or afatinib), we identified 75 patients with TKI-acquired resistance with matched pre/post-TKI tumor samples. Matched tumor samples were analyzed with targeted gene sequencing. Recurrent alterations were defined as an alteration occurring more than 2 times. Recurrent acquired mutations were expressed in Ba/F3 and EGFR mutant (T790M+/-) NSCLC cells. Mutation expressing Ba/F3 cell lines were assayed for IL-3 independence, and mutation expressing NSCLC cell were screened against combination targeted TKIs.

Result:
EGFR mutant NSCLC patients treated with first-line therapy had a median PFS of 14 months; and, of the patients with pre/post-TKI tumor molecular data, 47% of patients were T790M negative. There were 30 recurrent acquired alterations identified in 13 different genes. Genes included ARAF, BRAF, EGFR, FGFR, GNAS, JAK2, MCL1, PDGFRα, PIK3CA, RAF1, RB1, SMAD4, and TP53. Of the alterations identified, most occurred in 1 of 4 targetable genes: BRAF (N=3), FGFR (N=5), PDGFRα (N=3), or PIK3CA (N=2). Both previously reported and novel mutations were identified, and preliminary screening of mutant expressing Ba/F3 cell lines found that of the mutations tested (BRAF WT & G469H, FGFR2 A371G, PDGFRα WT & L682F, and PIK3Ca E545K) all grew independent of IL-3. HCC827 and H1975 cell lines expressing acquired mutations in BRAF, FGFR, PDGFRα, or PIK3CA were more sensitive to combination targeted therapy compared to EGFR TKIs or mutation specific TKIs alone unlike control cell lines, supporting the possibility that targeting these mutations would be of therapeutic benefit.

Conclusion:
Analysis of patient data identified 30 recurrent genomic alterations in 13 different genes including novel alterations in BRAF, EGFR, FGFR, PDGFRα, RB1, and SMAD4, many of which were found to be activating mutations. Our analysis identified potentially targetable mutations of BRAF, FGFR, PDGFRα, and PIK3CA which merits further pre-clinical and clinical investigation.

Background:
EGFR-tyrosine kinase inhibitor (TKI) treatment failure has been attributed to innate and/or acquired MET-amplification in patients with advanced EGFR-mutant NSCLC. Savolitinib (volitinib, HMPL-504, AZD6094), a highly selective small molecule MET-TKI, demonstrated greater efficacy combined with gefitinib than either compound alone in preclinical EGFR-mutant NSCLC models (D’Cruz et al. AACR, 2015).

Method:
This open-label, multi-centre, Phase Ib study (NCT02374645) assessed savolitinib plus gefitinib in patients enrolled in China with EGFR-mutant advanced NSCLC who progressed on prior EGFR-TKI. Primary objective was safety, tolerability, and identification of recommended Phase II dose (RP2D). Secondary objectives included preliminary anti-tumour activity (RECIST 1.1), pharmacokinetics, and ctDNA analysis for EGFR T790M mutation status. Eligible patients (≥18 years) had measurable disease, radiological disease progression on treatment, ECOG performance status 0/1, and adequate organ function. Patients had central evaluation of EGFR mutation (plasma based BEAMing digital PCR) and central screening for MET-amplification (MET/CEP7 ratio ≥2 or MET gene number ≥5, defined by tumour tissue FISH). Patients received gefitinib 250 mg once daily (QD) plus savolitinib 600 mg QD.

Result:
As of data-cut off (March 2017), 44 patients received study treatment. Median age was 61 years, 64% of patients were female; 6 patients were EGFR T790M positive and 5 were T790M negative (interim readout). The most common (≥20% patients) all causality adverse events (AEs), were vomiting (n=18, 41%), nausea (n=17, 39%), rash (n=16, 36%), increased ALT (n=14, 32%), increased AST (n=13, 30%), hypoalbuminaemia and gamma‑glutamyl transpeptidase increase (both n=11, 25%), and increased blood alkaline phosphatase (n=9, 21%). Grade ≥3 all causality AEs were reported in 14 (32%) patients; increased AST and increased ALT (both n=3, 7%) were most frequent. Three (7%) patients died due to an AE (respiratory failure [n=1], lung neoplasm [n=2]); none were considered treatment related. Anti-tumour activity was observed; confirmed partial responses were reported in 11/44 (25%) patients and a further 4 patients are awaiting confirmation of response (confirmed and unconfirmed response rate 15/44 [34%]). At the time of the scheduled 12 week study assessment, 20 (46%) patients remained on study treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and gefitinib were consistent with historical data.

Conclusion:
These encouraging findings warrant further assessment of savolitinib plus gefitinib for patients with EGFR-mutant, MET-amplified NSCLC who progressed on prior EGFR-TKI. The RP2D was confirmed as savolitinib 600 mg QD plus gefitinib 250 mg QD. This study is ongoing; updated safety and efficacy including anti-tumour activity by T790M status will be presented.

Background:
cMET activation is a valid mechanism of secondary TKI resistance in EGFR mutation-positive (EGFR-M+) NSCLC. However, its role in the treatment-naïve setting remains unclear. We sought to ascertain the prevalence and clinical impact of co-existing cMET copy number gain(CNG) in TKI-naïve early-stage and metastatic EGFR-M+ NSCLC.

Method:
Multi-region SNP array analysis (n=59 sectors) was performed on 13 early-stage resected EGFR-M+ NSCLC. cMET FISH was performed in a separate cohort of 206 metastatic treatment-naïve EGFR-M+ patients, all of whom were treated with first-line EGFR TKIs. We defined cMET-high as CNG≥5 copies, with an additional criteria of MET:CEP7 ratio >2.0 for amplification. Time-to-treatment failure(TTF) in patients cMET-high/low was estimated by Kaplan-Meier method and compared using log-rank test. A cell line from a cMET-high patient exhibiting primary TKI resistance was established.

Result:
Relative to median ploidy across sectors, 7/13(53.8%) early-stage EGFR-M+ tumors showed cMET CNG in at least one sector, with majority displaying(n=6/7) copy number intra-tumor heterogeneity. In the metastatic cohort, 55/206 patients (26.7%) were found to be cMET-high at diagnosis: 6(10.9%) had MET amplification, 49(89.1%) MET polysomy, with the following distribution: 5-6 copies(n=11), 6-8 copies(n=32), and >8 copies(n=12). We next evaluated clinical outcomes stratified by MET-high v low: median TTF was 14.7m(12.2–NE) vs 14.6m(12.7–16.5), p=0.985 respectively, with no significant difference in response rates(RR) to EGFR TKI (66.7%v73.7%; p=0.940). Further stratification by level of CNG did not reveal any differences in RR (5-6 copies:75.0%, 6-8 copies:63.0%, >8 copies:71.4%; p=0.868). In MET-high amplified group, only 2/6 (33.3%) had a partial response to EGFR TKI. In the cohort with suboptimal TKI response (PFS<6m, n=22), we did not observe significant enrichment for MET-high, relative to rest of the cohort (36.4%v25.5%, p=0.278). Finally, in 6 patients with progressive disease within 4 weeks of initiating EGFR TKI, 2/6(33.3%) were MET-high. In a cell line model derived from a MET-high patient (L858R, cMET:7.3 copies) genomic profiling of cell colonies revealed clonal cMET CNG and subclonal EGFR, with the patient demonstrating clinical response to crizotinib.

Conclusion:
Although up to 26% of TKI-naïve EGFR-M+ NSCLC harbor high cMET CNG by FISH, this occurs on the background of a highly variegated copy number landscape. cMET CNG alone does not significantly impact clinical outcomes to EGFR TKI, with the exception of one patient with a clonal cMET-driven tumor. Our data challenges the utility of arbitrary copy number thresholds to define clinically relevant MET pathway dysregulation and underscores the importance of targeting dominant truncal drivers.

Abstract not provided

Background:
Although immune checkpoint inhibitors of the PD-1/PD-L1 axis provide significant clinical benefit for patients with lung cancer, effective use of these agents is encumbered by a high rate of primary or acquired resistance. Strategies for optimal therapeutic application of immunotherapy require a thorough understanding of resistance mechanisms. To date, there have been only a few studies reporting potential mechanisms of resistance to PD-1/PD-L1 blockade.

Method:
In multiple immunocompetent syngeneic and spontaneous animal models of K-ras/p53 mutant lung cancer, we explored the resistance mechanisms to PD-1/PD-L1 blockade using both pharmacologic and genetic approaches (therapeutic antibody treatment and CRISPR/Cas9-mediated editing). The molecular and immune profiles of the tumor microenvironment were evaluated. Additionally, to determine the applicability to patients with lung cancer, we analyzed 259 tumor specimens with IHC staining and mRNA expression, and further confirmed the analyses in publically-available TCGA datasets.

Result:
In multiple models of antibody blockade and genetic knockout of PD-L1, we identified the up-regulation of CD38 on tumor cells as a marker of treatment resistance. Furthermore, by manipulating CD38 on a panel of lung cancer cell lines we demonstrated in vitro and in vivo that CD38 expression inhibits CD8[+] T cell proliferation, anti-tumor cytokine secretion, and tumor cell killing capability. The T cell suppressive effect is dependent upon the ectoenzyme activity of CD38 that regulates the extracellular levels of adenosine. To test whether CD38 blockade might be therapeutically efficacious to prevent anti-PD-L1/PD-1 resistance, we applied combination therapy with anti-CD38 and anti-PD-L1 and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Additionally, in a set of 259 resected lung cancer specimens, ~15% exhibited positive staining for CD38 on tumor cells, and the expression correlated with cytolytic T cell score and an immune/inflammatory signature across multiple large datasets.

Conclusion:
CD38 was found to be a novel mechanism for tumor escape from immune checkpoint PD-1/PD-L1 inhibitor therapy. Targeting this resistance pathway may broaden the benefit of PD-L1/PD-1 axis blockade for lung cancer treatment.

Background:
Pembrolizumab was initially approved as a single agent by the US FDA on October 2, 2015, for treating patients with mNSCLC who have disease progression on or after platinum-containing chemotherapy and PD-L1 tumor expression ≥50%, as determined by the FDA-approved test (Dako 22C3). Subsequent approvals for first-line therapy and expanded second-line therapy followed in October 2016. Our aim was to study PD-L1 testing patterns in US oncology practices from October 2015 through March 2017 and the potential impact of the PD-L1 IHC assay type on measurement of PD-L1 tumor expression.

Method:
This retrospective, observational study drew on de-identified, longitudinal data from a large electronic medical record database (Flatiron Health) representing 17% of incident oncology cases in the US. Eligible patients were adults (≥18 years) with histologically/cytologically confirmed initial diagnosis of mNSCLC (stage IV) or metastatic recurrence from October 2015 through March 2017. We determined the rate of PD-L1 testing (test date defined as the result date) and distribution of PD-L1 tumor expression (percentage of tumor cells staining for PD-L1) by IHC assay type.

Result:
The 7879 eligible patients included 4111/3768 (52%/48%) men/women; 5123 (65%) were >65 years old, and 6706 (85%) had a history of smoking. The rate of PD-L1 testing increased consistently over time from 15% in Q4/2015 to 70% in Q1/2017. Of 1728 patients with mNSCLC tested for PD-L1, 77%, 5%, 4%, and 19% were tested using Dako 22C3, Dako 28-8, Ventana SP142, and laboratory-developed tests (LDTs), respectively. Measured PD-L1 expression varied significantly (χ[2] p<0.0001) across the four assay types, although there was no significant difference (p=0.053) among the remaining three assays when the SP142 assay was excluded (Table).Figure 1



Conclusion:
We found no significant differences in measuring PD-L1 tumor expression using Dako 22C3, Dako 28-8, and LDTs; however, results of the SP142 assay appeared discordant.

Background:
Immunotherapy targeting the PD-1/PD-L1 pathway has dramatically changed the treatment landscape of non-small-cell lung carcinoma (NSCLC). We previously demonstrated that HHLA2, a recently identified B7 family immune inhibitory molecule, was widely expressed in NSCLC. To better understand the immune evasion mechanisms within the tumor microenvironment, we compared the expression profiles and functional roles of PD-L1 with potential alternative immune checkpoints, B7x and HHLA2.

Method:
Expression was assessed by immunohistochemistry using tissue microarrays consisting of 392 NSCLC tumor tissues (mostly resected stage I to III), including 195 tumors in the discovery (D) set and 197 cases in the validation (V) set. Positive PD-L1 cases were defined as samples with percentage of tumor cells revealing membranous staining of PD-L1 ≥ 1% with SP142 antibody. Human T cells were purified from eleven donors. Control human IgG, human PD-L1-Ig, human B7x-Ig and human HHLA2-Ig were used to determine the effects of PD-L1, B7x and HHLA2 on T cell proliferation and cytokine production [Human Th Cytokine Panel: IL-5, IL-13, IL-2, IL-6, IL-9, IL-10, IFN-γ, TNF-α, IL-17F, IL-17A, IL-4, IL-21 and IL-22].

Result:
PD-L1 expression was detected in 25% and 31% of tumors in the D and V sets respectively, and was associated with higher stage and lymph node involvement in both cohorts. Multivariate analysis further showed that stage, TIL status and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69% and 68% of cases, while HHLA2 was positive in 61% and 64% of tumors in the two sets. Triple positive expression was detected in 13% whereas triple negative in 15% of cases. The double-expression of PD-L1 with B7x or HHLA2 was rare, 6% and 3% respectively. Interestingly, the majority (78%) of PD-L1 negative cases expressed B7x, HHLA2 or both. Moreover, the triple positive group correlated with more TIL infiltration as compared to the triple negative group (P = 0.0175). At the same concentration, B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of both CD4 and CD8 T cells significantly more robustly than PD-L1-Ig. All three significantly suppressed a variety of cytokine production by T cells.

Conclusion:
The majority of PD-L1 negative lung cancer cases express alternative immune checkpoint molecules (B7x, HHLA2 or both). The potential role of the B7x/HHLA2 pathway in mediating immune evasion in PDL1 negative tumors deserves to be explored to provide the rationale for an effective immunotherapy strategy in these tumors.

Abstract not provided

Background:
Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types responding to immune checkpoint blockade, likely through harnessing of the anti-tumor T cell response. However, the lung is continuously exposed to the outside environment, which may result in a continuous state of inflammation against outside pathogens unrelated to the tumor microenvironment. Therefore, further investigation into the T cell repertoire and T cell phenotypes across normal lung and tumor is warranted.

Method:
We performed T cell receptor (TCR) sequencing on peripheral blood mononuclear cells (PBMC), normal lung, and tumor from 225 NSCLC patients, among which, 96 patients were also subjected to whole exome sequencing (WES) of PBMC, tumor and normal lung tissues. We further performed Cytometry by Time-of-Flight (CyTOF) on 10 NSCLC tumors and paired normal lung tissues to phenotype immune and T cell subsets.

Result:
Comparison of the T cell repertoire showed 9% (from 4% to 15%) of T cell clones were shared between normal lung and paired tumor. Furthermore, among the top 100 clones identified in the tumor, on average 57 (from 0 to 95) were shared with paired normal lung tissue. Interestingly, T cell clonality was higher in the normal lung in 89% of patients suggesting potential differences in the immune response and immunogenicity. A substantial number of somatic mutations were also identified not only in NSCLC tumors (average 566; from 147 to 2819), but also in morphologically normal lung tissues (average 156; from 50 to 2481). CyTOF demonstrated striking differences in the immune infiltrate between normal lung and tumor, namely a lower frequency of PD-1+CD28+ T cells (both CD4+ and CD8+) in the normal lung (2.7% versus 3.0% in tumor). In addition, a unique GITR+ T cell subset (0.96%) was entirely restricted to the normal lung. Conversely, increases in regulatory T cell frequency (CD4+FoxP3+) were observed in the tumor (10.4% vs 1.7% in normal lung), further highlighting the differences in T cell phenotype and response across normal lung and tumor.

Conclusion:
These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be residential T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes including increases in immunosuppressive T cells within the tumor which may further highlight the differences in the anti-tumor immune response.

Background:
Indoleamine 2, 3-dioxygenase 1 (IDO1) serves as an immunosuppressive effector and it is closely related to the prognosis in several types of cancer. We herein aim to elucidate the clinicopathological features and prognoses in patients with IDO1-expressing lung adenocarcinoma, and especially, show its correlation with the expression of programmed cell death-ligand 1 (PD-L1).

Method:
The expressions of IDO1 and PD-L1 proteins in 427 patients with surgically resected primary lung adenocarcinoma were evaluated by immunohistochemical analyses and any associations identified between IDO1 and the clinicopathological features, the prognosis and co-expression of IDO1 with PD-L1 were investigated. The expressions of IDO1 and PD-L1 at the protein and mRNA levels in lung adenocarcinoma cell lines were examined by an Enzyme-Linked Immuno Sorbent Assay, flow cytometry, and reverse transcription and real-time PCR analysis, respectively.

Result:
IDO1 was expressed in 260 patients (60.9%) at a 1% cut-off and in 63 patients (14.8%) at a 50% cut-off, respectively. PD-L1 was positive for 145 patients (34.0%). A ultivariate analysis showed IDO1 positivity (1% cut-off) to be significantly associated with a higher tumor grade, the presence of vascular invasion, and the expression of PD-L1. IDO1 and PD-L1 proteins were co-expressed in 123 patients (28.8%), and the patients whose tumor expressed both proteins exhibited significantly higher malignant traits than those whose tumor expressed only one protein or none. According to a multivariate analysis, the co-expression of both proteins was significantly associated with a shorter disease-free survival and overall survival. The expressions of IDO1 and PD-L1 in lung adenocarcinoma cell lines were elevated by treating them with interferon-γ and transforming growth factor-β.Figure 1



Conclusion:
The findings of this study suggest that the co-expression of IDO1 and PD-L1 may indicate more aggressive features of lung adenocarcinoma. Combination therapy targeting both of these proteins may therefore improve the clinical outcomes in patients with lung adenocarcinoma.

Background:
Clonal evolution and the heterogeneity of non-small cell lung cancer (NSCLC) may affect patient outcomes through variations in treatment planning, response to therapy, and drug resistance. Even less is known about the diversity of the adaptive immune response to primary and metastatic lesions in this disease. We sought to characterize the richness, abundance and overlap of T cell clones between paired primary NSCLC lesions and brain metastases.

Method:
We identified 20 patients with NSCLC with paired, fully resected primary lesions and brain metastases with sufficient tissue available in our clinical archives. DNA was purified from formalin-fixed paraffin-embedded specimens. The complementarity determining region 3 of T-cell receptor β was profiled by next generation sequencing to identify unique T cell clones. Sample richness (including iChao1 and Efron-Thisted Estimator), and clonal abundance (Simpson’s diversity index) were compared between paired lesions with the paired t test. Overlap in clonality was measured with the Morisita index.

Result:
There was a significant contraction of T cell clonality in paired metastases compared to primary lesions (mean of differences -2803, 95% CI -4202 to -1405; p=0.0005). The decreased richness in clonality in brain metastases was also supported by significant differences in iChao1 (mean of differences -20355, 95% CI -29561 to -11149; p=0.0002) and the Efron-Thisted Estimator (95% CI -21331 to -7216; p=0.0004). Simpson’s diversity index was higher in brain metastases than primary lesions (mean of differences 0.002, 95% CI 0.001 to 0.004; p=0.05), but low overall. Only a fraction of T cell clones in primary lesions were also found in brain metastases (mean Morisita Index 0.23).

Conclusion:
There is greater richness but less abundance of T cell clones in primary NSCLC lesions compared to paired brain metastases. Although the blood brain barrier may restrict T cell trafficking to tumors, the minimal overlap in T cell clones may reflect the genetic divergence of metastatic tumor clones.

Abstract not provided

Background:
Cohort G of the multicenter, open-label, phase 1/2 KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated efficacy and safety of pembrolizumab + pemetrexed and carboplatin (PC) compared with PC alone as first-line therapy for patients with advanced nonsquamous NSCLC. At the primary analysis of cohort G (minimum follow up, 6 months; median, 10.6 months), pembrolizumab significantly improved ORR (estimated treatment difference, 26%; P=0.0016) and PFS (hazard ratio [HR], 0.53; P=0.010). The HR for OS was 0.90 (95% CI, 0.42‒1.91). In a subsequent analysis (median follow-up, 14.5 months), the HR for OS was 0.69 (95% CI, 0.36‒1.31). We present results from the May 31, 2017 data cutoff.

Method:
Patients with stage IIIB/IV nonsquamous NSCLC, no prior systemic therapy, and no EGFR mutation or ALK translocation were randomized 1:1 (stratified by PD-L1 TPS ≥1% versus <1%) to receive 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m[2] Q3W with or without pembrolizumab 200 mg Q3W. Pembrolizumab treatment continued for up to 2 years; maintenance pemetrexed was permitted in both arms. Eligible patients in the PC arm with radiologic progression could cross over to pembrolizumab monotherapy. Response was assessed by blinded, independent central review per RECIST v1.1. All P values are nominal (one-sided P<0.025).

Result:
123 patients were randomized. Median follow-up was 18.7 months (range, 0.8‒29.0 months). 40 of 53 (75%) patients in the PC arm who discontinued received subsequent anti-PD-1/anti-PD-L1 therapy (including 25 who received pembrolizumab in the on-study cross over). ORR was 57% with pembrolizumab + PC versus 32% with PC (estimated difference, 25%; 95% CI, 7%‒41%; P=0.0029). PFS was significantly improved with pembrolizumab + PC versus PC (HR, 0.54; 95% CI, 0.33‒0.88; P=0.0067) with median (95% CI) PFS of 19.0 (8.5‒NR) months versus 8.9 (6.2‒11.8) months. The HR for OS was 0.59 (95% CI, 0.34‒1.05; P=0.0344). Median (95% CI) OS was not reached (22.8‒NR) months for pembrolizumab + PC and 20.9 (14.9‒NR) months for PC alone; 18-month OS rates were 70% and 56%, respectively. Grade 3–5 treatment-related AEs occurred in 41% of patients in the pembrolizumab + PC arm versus 29% in the PC arm.

Conclusion:
Over the course of the 3 analyses, the HR for OS continues to improve for pembrolizumab + PC versus PC (HR: 0.90 to 0.69 to 0.59). The significant improvements in PFS and ORR with pembrolizumab + PC versus PC first observed in the primary analysis have been maintained with longer follow-up (median, 18.7 months).

Background:
The anti–PD-L1 mAb atezolizumab blocks the interactions between PD-L1 and its receptors, PD-1 and B7.1, thus restoring anti-tumor immunity. A Phase II study of atezolizumab monotherapy was conducted across multiple lines of therapy in PD-L1–selected patients with advanced NSCLC (BIRCH; NCT02031458). The primary analyses showed meaningful and durable clinical benefit with atezolizumab monotherapy in 1L and 2L+ NSCLC. Here we present updated survival data (median follow-up, 29.7 months) in patients receiving 1L atezolizumab.

Method:
Eligible patients had chemotherapy-naive, locally advanced or metastatic NSCLC without CNS metastases. Prior TKI therapy was required in patients with EGFR mutation or ALK rearrangement. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was centrally evaluated (VENTANA SP142 IHC assay). Patients who were TC2/3 or IC2/3 (PD-L1 expression on ≥ 5% of TC or IC) were enrolled. Atezolizumab 1200 mg was administered IV q3w until disease progression or unacceptable toxicity. The primary endpoint was independent review facility (IRF)–assessed ORR. Secondary endpoints included investigator (INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.

Result:
With a median follow-up of 29.7 months, median OS was 26.9 months (TC3 or IC3 subgroup) and 24.0 months (all treated patients); INV-assessed ORR was 35% (TC3 or IC3 subgroup) and 26% (all treated patients; Table). Among evaluable patients, the ORR was 31% for mutant EGFR (4/13) vs 23% for wild-type EGFR patients (24/103), and 31% for mutant KRAS (10/32) vs 24% for wild-type KRAS patients (16/66). No new safety signals were observed.

Conclusion:
With more than 2 years of follow-up, atezolizumab continued to demonstrate durable clinical activity in 1L NSCLC, regardless of EGFR and KRAS mutational status. These data suggest that atezolizumab monotherapy has promising activity as a frontline therapy. Ongoing Phase III trials are evaluating atezolizumab-based regimens vs chemotherapy in 1L NSCLC.

Endpoint (95% CI)	TC3 or IC3[a ](n = 65)	TC2 or IC2[b] (n = 73)	All Treated Patients (N = 138)
INV-assessed ORR, %	35% (23.9, 48.2)	18% (9.8, 28.5)	26% (19.0, 34.2)
EGFR mutant/wild-type, %	25%/33%	33%/15%	31%/23%
KRAS mutant/wild-type, %	38%/33%	25%/15%	31%/24%
mDOR, mo	16.5 (8.5, NE)	12.5 (8.3, 17.9)	13.1 (9.9, NE)
mOS, mo	26.9 (12.0. NE)	23.5 (18.1, NE)	24.0 (18.1, 31.9)
12-mo OS rate, %	61% (49.0, 74.0)	71% (59.8, 81.5)	66% (58.1, 74.6)
24-mo OS rate, %	52% (39.3, 65.2)	49% (37.0, 61.1)	50% (41.5, 59.2)
30-mo OS rate, %	48% (35.3, 61.5)	39% (27.2, 51.2)	43% (34.3, 52.1)
mPFS, mo	7.3 (4.9, 12.0)	7.6 (4.0, 9.7)	7.6 (5.7, 9.7)
12-mo PFS rate, %	38% (25.1, 49.9)	30% (19.2, 41.2)	34% (25.3, 41.9)
24-mo PFS rate, %	28% (16.5, 40.0)	13% (4.5, 21.5)	20% (12.9, 27.5)
30-mo PFS rate, %	19% (5.4, 33.5)	9% (1.4, 16.4)	14% (6.5, 21.9)
NE, not estimable. [a ]TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells.[b ]TC2/3 or IC2/3 excluding TC3 or IC3.

Background:
Platinum-based doublet chemotherapy is the standard-of-care first-line treatment for most patients with advanced NSCLC, but responses are not durable (~4.5–6 mo). Chemotherapy may sensitize NSCLC tumors to immune checkpoint inhibitors. Nivolumab, a fully human programmed death (PD)-1 antibody, demonstrated long-term survival benefit in patients with previously treated advanced NSCLC. Here we report the 3-year update of safety and efficacy of first-line nivolumab combined with chemotherapy in the phase 1 CheckMate 012 study (NCT01454102).

Method:
Chemotherapy-naïve patients with stage IIIB/IV NSCLC were randomly assigned based on histology in 3 cohorts combining nivolumab Q3W with 3 platinum-based doublet chemotherapy regimens: nivolumab 10 mg/kg + gemcitabine-cisplatin (all squamous histology), nivolumab 10 mg/kg + pemetrexed-cisplatin (all non-squamous), and nivolumab 10 mg/kg or 5 mg/kg + paclitaxel-carboplatin (any histology). After 4 cycles of nivolumab plus chemotherapy, patients received nivolumab monotherapy until progression or unacceptable toxicity. The primary objective was safety. ORR, PFS, and OS were secondary/exploratory endpoints.

Result:
56 patients were treated. Median age was 63.5 years, 46% were male, and 14% were never-smokers; 29% of tumors had squamous histology. At database lock (September 19, 2016) the minimum follow-up was 45.5 mo. Median duration of chemotherapy treatment was ~12 weeks (4 cycles; range: 3–18 weeks) and median duration of nivolumab treatment was 17–22 weeks across cohorts (range: 3–204). No new safety signals were observed in patients receiving nivolumab maintenance compared with the September 2014 database lock. ORR was 46%. Median duration of response was 10.4 mo (95% CI: 5.1, 26.3). Median PFS was 6.0 mo (95% CI: 4.8, 8.3). Median OS was 19.2 mo (95% CI: 14.1, 23.8), and the 3-year OS rate was 25%. ORR and OS were similar in patients with tumor PD-L1 expression <1% (n=23) vs ≥1% (n=23): ORR 48% vs 52%; median OS 19.2 mo (95% CI: 12.2, 23.8) vs 20.2 mo (95% CI: 10.9, 27.2). The 3-year OS rate was 22% in both PD-L1 expression subgroups.

Conclusion:
Nivolumab plus chemotherapy resulted in prolonged survival in a subset of patients, with a 3-year OS rate of 25%. In all patients, ORR and OS were similar irrespective of tumor PD-L1 expression. These results support further evaluation of nivolumab-chemotherapy combinations as first-line treatment for advanced NSCLC, which are being explored in CheckMate 227 (NCT02477826).

Abstract not provided

Background:
Nivolumab is a standard option for second‐line treatment in pts with advanced NSCLC. Real‐life data are lacking regarding the efficacy of nivolumab and post‐nivolumab treatment.

Method:
This analysis included the first 600 consecutive pts with stage IIIB/IV NSCLC who received ≥1 dose of nivolumab 3mg/kg q2w through the French EAP from 01/2015 for Squamous ﴾Sq﴿ and 06/2015 for Non‐Sq NSCLC, until 08/2015.

Result:
Median age was 64 yo, there were 409 ﴾68%﴿ men, 521 ﴾87%﴿ smokers, 478 ﴾80%﴿ PS0/1 pts, 230 ﴾38%﴿ Sq and 370 ﴾62%﴿ Non‐Sq NSCLC, 130 ﴾22%﴿ pts with brain metastases. Nivolumab was administered as 2nd/3rd/≥4th‐line for 26%/33%/41% pts, respectively. Best response was PR/SD/PD for 17%/30%/37% of patients, respectively, with 16% not assessable. Toxicities occurred in 187 ﴾31%﴿ pts, including 10% grade ≥3 events. After a median follow‐up of 22.1 ﴾95% CI 21.6‐22.6﴿ months, median PFS and OS from the initiation of nivolumab were 2.1 ﴾95%CI 1.9‐2.3﴿ and 9.5 ﴾95%CI 8.4‐10.8﴿ months, respectively. In the 92 pts with PS2 at initiation of nivolumab, PR/SD rates were 7%/28%; median OS was 3.6 (95%CI 2.7-5.2) months. A total of 130 pts had brain metastases at initiation of nivolumab: PR/SD rates were 12%/25%; median OS was 6.6 (95%CI 3.8-8.3) months. Post‐nivolumab treatment was administered to 262 ﴾44%﴿ pts, and mostly consisted of gemcitabine ﴾19%﴿, docetaxel ﴾18%﴿, paclitaxel ﴾14%﴿, erlotinib ﴾12%﴿, vinorelbine ﴾9%﴿, platin‐based doublet ﴾8%﴿, or pemetrexed ﴾8%﴿. Access to post‐nivolumab treatment was higher in PS0/1 vs. PS2 pts ﴾48% vs. 23%, p<0.001﴿, but was not different according to histology or treatment line or disease control with nivolumab. Best response to post‐nivolumab treatment was PR/SD/PD for 15%/42%/42% of pts, respectively. In the whole cohort, median post‐nivolumab OS was 4.0 ﴾95%CI 2.8‐4.6﴿ months, and was significantly higher in case of PR to nivolumab ﴾HR=0.38; 95%CI 0.23‐0.64; p<0.001﴿, and if subsequent treatment was delivered ﴾HR=0.30; 95%CI 0.24‐0.38; p<0.001﴿; median post‐nivolumab OS in pts receiving post‐nivolumab treatment was 7.5 ﴾95%CI 6.8‐8.7﴿ months, and did not differ based on histology or treatment line.

Conclusion:
Efficacy and safety of nivolumab was in line with available data. Post‐nivolumab treatment may be delivered in many pts, including pts with PS2 and brain metastases, with favorable impact on response and OS. Data on the whole cohort of 900 pts enrolled in the EAP will be presented.

Background:
KEYNOTE-024 (ClinicalTrials.gov, NCT02142738) is a multicenter, international, phase 3, randomized, open-label, controlled trial of treatment with the anti‒PD-1 antibody pembrolizumab vs platinum-based chemotherapy as first-line therapy for patients with advanced NSCLC of any histology with PD-L1 tumor proportion score (TPS) ≥50% and without EGFR mutations or ALK translocations. Results from the primary analysis of KEYNOTE-024 demonstrated that after a median follow-up of 11.2 months, pembrolizumab significantly improved PFS (HR=0.50; P<0.001) and OS (HR=0.60; P=0.005) and was associated with a lower rate of treatment-related AEs compared with chemotherapy.

Method:
Patients were randomly assigned to receive either 35 cycles of pembrolizumab 200 mg every 3 weeks or 4–6 cycles of investigator's choice of carboplatin/cisplatin + gemcitabine, carboplatin + paclitaxel, or carboplatin/cisplatin + pemetrexed with optional pemetrexed maintenance (for those with non-squamous histology). Randomization was stratified by ECOG performance status (0 vs 1), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Treatment continued until disease progression per RECIST version 1.1, intolerable toxicity, or withdrawal of consent. Patients in the chemotherapy arm who experienced disease progression could cross over to receive pembrolizumab monotherapy. Response was assessed every 9 weeks by blinded independent central review per RECIST version 1.1. The primary endpoint was PFS; secondary endpoints were OS, ORR, and safety.

Result:
305 patients were enrolled (pembrolizumab, n=154; chemotherapy, n=151). At the time of data cutoff (July 10, 2017) after a median follow-up of 25.2 months, 73 patients (47.4%) in the pembrolizumab arm and 96 patients (63.6%) in the chemotherapy arm had died. The hazard ratio for OS was 0.63 (95% CI, 0.47–0.86; nominal P=0.002). Median (95% CI) OS was 30.0 (18.3–not reached) months in the pembrolizumab arm and 14.2 (9.8–19.0) months in the chemotherapy arm. The Kaplan-Meier estimate of OS at 12 months was 70.3% (95% CI, 62.3%–76.9%) for the pembrolizumab group and 54.8% (95% CI, 46.4%–62.4%) for the chemotherapy group. 82 patients allocated to the chemotherapy arm crossed over to receive pembrolizumab upon meeting eligibility criteria. Treatment-related adverse events were less frequent in the pembrolizumab arm than in the chemotherapy arm (76.6% versus 90.0%, respectively) as were treatment-related grade 3-5 adverse events (31.2% versus 53.3%).

Conclusion:
With more than half of patients having OS events and prolonged follow‒up, first-line pembrolizumab monotherapy remains superior to platinum-based chemotherapy despite the crossover from the control arm to an anti-PD1 inhibitor as subsequent therapy.

Background:
Atezolizumab (anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1, restoring anti-cancer immunity. OAK, a Phase III study of atezolizumab vs docetaxel demonstrated superior OS of atezolizumab. The characteristics of the long-term survivors (LTS) in the OAK primary population (n = 850) are evaluated and describe the largest cohort of cancer immunotherapy-treated NSCLC LTS yet reported.

Method:
Patients received IV q3w atezolizumab (1200 mg) until PD / loss of clinical benefit or docetaxel (75 mg/m[2]) until PD / unacceptable toxicity. No crossover was allowed. LTS were defined as patients with OS ≥ 24 months and non-LTS as those who died within 24 months of randomization. Patients with OS censored prior to 24 months were not included. Data cutoff, January 23, 2017.

Result:
A higher 2-year survival rate was observed for the atezolizumab-arm (31%) vs docetaxel-arm (21%). After a minimum follow-up of 26 months, there were 119 LTS vs 279 non-LTS in the atezolizumab-arm and 77 LTS vs 299 non-LTS in the docetaxel-arm. Characteristics of atezolizumab-arm LTS and non-LTS are shown (Table). Atezolizumab-arm LTS were enriched for non-squamous histology and high PD-L1–expressing tumors, but also included low/no PD-L1–expressing tumors (40.3%). Atezolizumab-arm LTS had higher ORR (39.5%) than non-LTS (5.0%) but included LTS subjects with PD. 52.9% atezolizumab-arm vs 71.4% docetaxel-arm LTS received anti-cancer non-protocol therapy (NPT) after discontinuation of protocol-defined therapy. 51.9% of docetaxel-arm LTS vs 12.7% non-LTS received non-protocol immunotherapy. Median treatment exposure in atezolizumab-arm LTS was 18.0 months. Atezolizumab-arm LTS had a comparable safety profile to all atezolizumab-treated population.

Conclusion:
Atezolizumab provides superior 2-year OS benefit vs docetaxel and is well tolerated. The majority of docetaxel-arm LTS received a checkpoint inhibitor as NPT. Atezolizumab LTS appeared to have favorable prognostic factors, including non-squamous histology, but notably were not limited to patients with RECIST v1.1 response or with PD-L1 expression.

Table. Characteristics of Atezolizumab-Arm Long-Term Survivors (LTS) vs Non-Long Term Survivors (Non-LTS)
	Atezolizumab LTS (n = 119) n (%)	Atezolizumab Non-LTS (n = 279) n (%)
Sex
Male	61 (51.3)	183 (65.6)
Female	58 (48.7)	96 (34.4)
Tobacco use history
Never smoker	29 (24.4)	47 (16.8)
Current/previous smoker	90 (75.6)	232 (83.2)
Histology
Non-squamous	101 (84.9)	195 (69.9)
Squamous	18 (15.1)	84 (30.1)
No. of prior therapies, 1	89 (74.8)	209 (74.9)
ECOG performance status at baseline
0	60 (50.4)	89 (31.9)
1	59 (49.6)	190 (68.1)
EGFR mutation status, positive	11 (9.2)	26 (9.3)
PD-L1 IHC subgroup
TC3 or IC3	28 (23.5)	39 (14.0)
TC1/2/3 or IC1/2/3	71 (59.7)	156 (55.9)
TC0 and IC0	48 (40.3)	119 (42.7)
Best overall response
Complete response	5 (4.2)	0 (0)
Partial response	42 (35.3)	14 (5.0)
Stable disease	47 (39.5)	97 (34.8)
Progressive disease	25 (21.0)	142 (50.9)
IC, tumor-infiltrating immune cell; TC, tumor cell. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC1/2/3 or IC1/2/3 = PD-L1 ≥ 1% on TC or IC; TC0 and IC0 = PD-L1 < 1% on TC and IC. NCT02008227.

Background:
Patients (pts) with oligometastatic NSCLC may benefit from LAT (e.g., surgery, stereotactic radiation (SRT)). It is unclear if systemic therapy can provide additional benefit after LAT. We are running a Phase II study to evaluate the efficacy of pembrolizumab after LAT, hypothesizing that immunotherapy will be effective in the setting of a minimal disease burden.

Method:
Eligibility stipulates oligometastatic NSCLC (up to 4 sites) with completion of LAT to all known sites of disease. Within 4-12 weeks of completing LAT, pts begin pembrolizumab 200 mg every 21 days for 6 mos, with a provision to continue for a full year in the absence of progression or toxicity. Progression free survival (PFS) and overall survival (OS) are measured from the start of LAT. A sample size of 42 pts provides 80% power for a test at 5% 1-sided type I error to increase PFS to >=10 mos compared to a historical control PFS of 6.6 mo.

Result:
Since January 2015, 39 pts have been enrolled. The median age is 64 years; 54% are male; 90% Caucasian. Current and former smokers comprise 90% of the cohort, with a median of 32 pack yrs. Most common metastatic sites are lung (15 pts), brain (13), and bone (8). LAT has included surgery (24 pts), SRT (23), and concurrent chemoradiotherapy (17). Attributable adverse events (AEs) have been mostly mild and self-limited. There has been one episode of Grade 3 pneumonitis and one episode of Grade 3 adrenal insufficiency. Median follow-up from start of LAT is 16 mos. To date, 11 pts have had progression or death. The median PFS has not yet been reached. The PFS rates (+ SE) at 6, 12 and 18 mos are 92%+5%, 64%+9% and 64%+9%, with 16 and 5 pts at risk beyond 12 and 24 mos, respectively. To date, 8 pts (21%) have died. The median OS has not yet been reached. The OS rates (+ SE) at 6, 12 and 18 mos are 100%, 90%+6% and 75%+9%, with 22 and 5 pts at risk beyond 12 and 24 mos, respectively.

Conclusion:
Use of pembrolizumab after LAT for oligometastatic NSCLC is feasible and well tolerated. In a preliminary analysis, PFS appears favorable. Continued follow-up is necessary to confirm these findings. It is expected that accrual will be complete as of September 2017. Updated survival estimates will be presented.

Abstract not provided