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G. De Lima Lopes
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ED 02 - Molecular Testing Around the World (Genomics in Clinic (Timelines/Bioinformatics), Testing Platforms & Algorithms (NGS, Targeted Panels, FISH, IHC), Cost Considerations, Strategies for Identifying Rare Genomic Subsets in Clinical Trials) (ID 2)
- Event: WCLC 2015
- Type: Education Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 4
- Moderators:M. Ladanyi, G. De Lima Lopes
- Coordinates: 9/07/2015, 14:15 - 15:45, Four Seasons Ballroom F1+F2
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ED02.01 - North America (ID 1774)
14:20 - 14:40 | Author(s): V. Miller
- Abstract
- Presentation
Abstract not provided
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ED02.02 - Asia (ID 1775)
14:40 - 15:00 | Author(s): J. Chung
- Abstract
- Presentation
Abstract:
Substantial progress has been made toward understanding the tumor biology of non-small cell lung cancer (NSCLC) during the last few years, and major discoveries in the molecular pathogenesis of lung cancer have led to successful applications of targeted therapeutic strategies. One representative of these successes is the subset of lung cancer patients with epidermal growth factor receptor (EGFR) mutations who have shown improved clinical response to tyrosine kinase inhibitors (TKIs).1 The prevalence of EGFR mutation is higher in the East Asian population than in Western populations. Asian NSCLC patients were reported to show a higher response rate and a longer survival to EGFR tyrosine kinase inhibitors (EGFR TKIs) as well as traditional chemotherapy. Therefore, genetic testing prior to treatment is becoming increasingly important and considered essential to select appropriate treatment strategies for NSCLC patients, especially in Asia. The exact mechanisms underlying these differences are not clear. However, approximately 45% of patients with NSCLC in the US are women whereas only 25% to 30% of patients with lung cancer are women in Eastern Asia. In addition, In the US, approximately 10% of patients with lung cancer are neversmokers (<100 lifetime cigarettes). In Asia, more than 30% of patients with lung cancer are neversmokers.2 Some international studies and global surveys have been conducted during the past few years to establish the current status of EGFR mutation testing and to establish the standard testing protocols.3-5EGFR mutation test is not yet available in many South East Asian medical institutions. In the medical facilities which do perform EGFR mutation test, the overall testing rate of newly diagnosed NSCLC is 31.8%, varying from 18.3% - 64.8%, the highest EGFR mutation testing rate was observed in Japan and the lowest in South East Asian Countries. Sex, smoking status and histological subtype are the main determining factors for EGFR mutation tests.5 However, the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and Association for Molecular Pathology (AMP) guidelines recommended that patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics that include ethnicity, smoking history, and sex. Factors associated with EGFR mutation status were country, sex, ethnicity, smoking status, smoking pack-years, disease stage and histology type. 4 In most countries, EGFR mutation rate and clinical pathologic factors are in line with previous reports in Asia, and the variations of EGFR mutation prevalence between countries are due to the selection of the tested populations. The majority of Asian institutions use PCR-based DNA direct sequencing methods to detect EGFR mutation. Other predictive biomarkers for EGFR TKI therapy are also available, including EGFR gene copy number, single-nucleotide polymorphisms of the EGFR gene, EGFR protein expression. 3 Next Generation Sequencing (NGS) and multiplex assays have made feasible the widespread adoption of molecular diagnostics for clinical use. According to our survey, the NGS is not available in clinics in most Asian medical institutions, and can be used for diagnosis of rare diseases and/or research. In China, sequencing based methods are the most commonly used, followed by the amplification mutation refractory system (ARMS).6 In Korea, the PNA clamp method is the most commonly used testing method, followed by direct sequencing methods.7 PCR-INVADER is the most commonly used test in Japan, followed by PNA-LNA PCR clamp.5 The materials for EGFR mutation analysis are usually from diagnostic samples, thus in most countries, small biopsy and cytology specimens are the most commonly used, followed by surgically resected tissues. Cytological specimens including smear slides and/or cell blocks have been shown to be suitable for EGFR mutation test.3, 5At present, the potential barriers to EGFR mutation testing in Asia include the cost, the number of laboratories capable of performing the test, communications between the clinicians and pathologists, and the predefined criteria for the type of patients who should be tested.3 The cost for EGFR mutation tests vary from U.S.$170 to 500. In most countries the costs are funded by the patients, but in a few countries are funded by pharmaceutical companies, while the insurance does not cover the cost of molecular testing in most Asian countries. Currently, National Comprehensive Cancer Network (NCCN)'s guidelines recommend EGFR-TKI as the first line treatment for patients with NSCLC harboring EGFR sensitizing mutations. Randomized first-line trials have demonstrated consistent improvement in tumor response rate and progression-free survival, but failed to prove overall survival benefit. These finding make TKI the second-line or third-line treatment options for NSCLC. Current data on treatment outcomes of second- and/or third-line EGFR therapy are still inconsistent.8 Patients treated with EGFR-TKI inevitably experience ac¬quired resistance by various molecular mechanisms. Many clinical trials are ongoing to explore the novel agents and strategies for better response and overcoming TKI resistance. In our questionnaire-based survey, four of seven Asia countries have ongoing clinical trials. The clinical trials include the first line and second line and maintance therapy using first generation and new generation EGFR TKIs. In 2013, more than 1000 studies with Chinese trials were registered on ClinicalTrials.gov and some trials used a local pharmaceutical company TKI, icotinib. Phase II studies of crizotinib in East Asian patients with ROS1-positive NSCLC are onging in China, Japan, South Korea and Taiwan. Anaplastic lymphoma kinase (ALK) rearrangement accounts for about 2–13% of unselected Asian patients with NSCLC, and occurs predominantly in younger individuals with adenocarcinoma who never smoked or light smokers (< 40 pack years). There is no strong evidence to suggest an ethnic difference of translocations among patients with NSCLC. The CAP/IASLC/AMP guideline recommended ALK FISH assay using FDA-approved specific companion test (Vysis ALK Break-Apart FISH Probe Kit, Abbott Molecular, Des Plaines, IL) for selecting patients for ALK tyrosine kinase inhibitor therapy. ALK immunohistochemistry (IHC) may be considered as a screening methodology to select specimens for ALK FISH testing. The ALK rearrangements have been shown to be 4.3% in men and 7.5% in women in Asian NSCLC by meta-analysis. Most Asia countries use FISH to detect ALK rearrangement, in Japan, reverse transcription–PCR (RT–PCR) is commonly used. In China, the Chinese Food and Drug Administration (CFDA) had approved VENTANA ALK IHC assay to aid the identification of patients for crizotinib treatment. The price of FISH detection range from US$415-800, and IHC range from US$14-220, most of which is funded by the patients.9 Recently, two additional oncogenes, RET and ROS1, were added to the list of driver oncogenes that are targetable with existing TKIs, and several clinical trials investigating the efficacy of such TKIs in Asia have been conducted. FISH and IHC are suitable for the diagnosis of ROS1 fusion, but some studies showed IHC is not suitable for the diagnosis of RET fusion.10 Over the past decades, we have witnessed rapid advances in molecular and cellular biology of lung cancer biology, and new data are upcoming which should facilitate personalized biomarker-based therapy in lung cancer, including characterization of driver mutations, genomic abnormalities and epigenetic changes. Individual centers should develop a multidisciplinary approach to integrate a molecular testing algorithm. Next generation sequencing should be able to resolve much of the complexity of molecular testing, especially in situations where there is only a small amount of tissue available. REFERENCES 1. Janku F, Stewart DJ, Kurzrock R. Targeted therapy in non-small-cell lung cancer--is it becoming a reality? Nat Rev Clin Oncol 2010;7:401-414. 2. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-957. 3. Salto-Tellez M, Tsao MS, Shih JY, et al. Clinical and testing protocols for the analysis of epidermal growth factor receptor mutations in East Asian patients with non-small cell lung cancer: a combined clinical-molecular pathological approach. J Thorac Oncol 2011;6:1663-1669. 4. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154-162. 5. Yatabe Y, Kerr KM, Utomo A, et al. EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey. J Thorac Oncol 2015;10:438-445. 6. Wang S, Wang Z. EGFR mutations in patients with non-small cell lung cancer from mainland China and their relationships with clinicopathological features: a meta-analysis. Int J Clin Exp Med 2014;7:1967-1978. 7. Shim HS, Chung JH, Kim L, et al. Guideline Recommendations for EGFR Mutation Testing in Lung Cancer: Proposal of the Korean Cardiopulmonary Pathology Study Group. Korean J Pathol 2013;47:100-106. 8. Sculier JP, Berghmans T, Meert AP. Advances in target therapy in lung cancer. Eur Respir Rev 2015;24:23-29. 9. Fan L, Feng Y, Wan H, et al. Clinicopathological and demographical characteristics of non-small cell lung cancer patients with ALK rearrangements: a systematic review and meta-analysis. PLoS One 2014;9:e100866. 10. Kohno T, Nakaoku T, Tsuta K, et al. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl Lung Cancer Res 2015;4:156-164.
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ED02.03 - Europe (ID 1776)
15:00 - 15:20 | Author(s): C. Mascaux
- Abstract
- Presentation
Abstract:
Introduction Identification of molecular targets is now essential for the diagnosis, classification, selection and treatment monitoring of an increasing number of cancers. The analysis of these biomarkers must therefore be accessible to all patients, regardless of the healthcare facility where they are treated. Despite a decrease, lung cancer remains the leading cause of cancer-related deaths worldwide, often detected at an advanced stage with association with a poor prognosis. Recently, genetic alterations involved in adenocarcinomas have been discovered; some of these tumors harbor a driver mutation involving EGFR, KRAS, HER2, BRAF or PI3KCA gene or a rearrangement (ALK, ROS1, RET genes). Nearly 40% of NSCLC harbor one of those genetic abnormalities and several targeted therapies have been approved in USA and in Europe, such as erlotinib and gefitinib and crizotinib for NSCLC with EGFR mutation or ALK translocation, respectively. As many other targeted therapies are ongoing in lung cancer, molecular testing becomes a huge challenge worldwide, raising both financial and organizational issues.The French INCa molecular testing network: In 2006, the French National Cancer Institute (INCa) and the French Health Ministry have created a national network of 28 regional genetics platforms throughout the French territory, in order to offer molecular tests to all patients regardless of the institution where they are treated, i.e. university hospitals, cancer centers, hospital centers or private institutions, to enable that each innovative test could be rapidly implemented after new targeted therapies become available, and to guarantee the quality of the tests. The 28 regional platforms include a pathology laboratory in charge with the samples monitoring, and several laboratories with complementary expertise in molecular testing of hematological malignancies and solid tumors; as the tests are free of charge for the patients and the institutions, initial funds were given to all INCa genetics platforms to buy equipment (€4.7 million) and to hire non-medical personnel. The majority of these were technicians (58.32 FTE) and engineers (20.5 FTE); in addition, genetics platforms are financed on a basis of quarterly and annual activity reports to adjust budget and allocation. This initial funding was followed by the allocation of €4 million in annual funding for the centres and staff from the French Ministry of Health. The data sent in those reports are the number of tests performed each year, the number of patients undergoing tests, the percentage of patients found to have a molecular abnormality, the percentage of non-contributive results and the origin of requests. The INCa also set up a quality-assurance program with mandatory external quality evaluations, and publishes guidelines available on the Inca website. The markers studied are predictive markers that determine access to targeted therapy, markers guiding the diagnostic process, markers that contribute to establishing a diagnosis, prognostic markers guiding patient treatment strategy, and markers allowing the monitoring of residual diseases. Molecular genetics platforms do not have to perform all molecular tests: they must ensure that patients in their region have access to these tests via a referral platform. Tests concerning a large number of patients are carried out by all or almost all platforms (BCR-ABL quantification, KRAS and EGFR mutations, JAK2 mutations, MSI tests). For tests concerning a small number of patients, some platforms perform regional or national referral activity (ABL mutation screening in CML, cKIT and PDGFRA mutations in GIST, NMYC amplification in neuroblastomas, chromosomal abnormalities in sarcomas). Whereas the initial program included only EGFR and KRAS mutations’ detection in lung cancers and KRAS and BRAF mutations in colorectal cancers, a new program for detection of emerging biomarkers was set up in 2011; for lung non-squamous cell carcinoma patients at advanced stages those biomarkers were EGFR, K-RAS, HER2, BRAF and PI3KCA mutations and ALK translocations, and BRAF and KIT mutations in metastatic melanomas. In 2008, 1,269 EGFR activating mutation tests were performed, versus 2,667 in 2009, and 21,995 and 8,696 regarding EGFR mutation and ALK rearrangement, respectively in 2012. In 2013, 23,336 lung cancer samples were tested for EGFR mutations (10% were mutated), 18,861 for ALK rearrangement (3.5% rearranged), 22,9858 for KRAS mutations (27% mutated), 20,100 for BRAF mutation (2% mutated), 17,843 for HER2 mutation (0.7% mutated) and 17,375 for PI3KCA mutations (2.4% mutated).The German Network Genomic Medicine (NGM) Lung Cancer: The NGM is a health care provider network offering centralized high-quality next generation sequencing -based multiplex genotyping for lung cancer patients. Since NGS based genotyping is not reimbursed in Germany, the AOK Rheinland/Hamburg, one of the largest German public health insurances has contracted with the NGM for reimbursement of NGS-based multiplex genotyping of lung cancer in April 2014. In 2014, 4,500 lung cancer patients were gentotyped, representing nearly 10% of stage IV NSCLC patients in Germany.The Cancer Research UK (CRUK) Stratified medicine programme 1 and 2: There is no to date any national policy in UK for molecular testing for lung cancer patients, and a great variation exists regarding providers, funding and access; most of the time, the decision of referring for molecular testing depends on the clinician in reference to NICE clinical guidance. Nearly 7,300 UK patients were tested for EGFR mutations in 2010-2011 and depending on the units, ALK testing is performed either by IHC and /or FISH. In 2011, the Cancer Research UK (CRUK) Stratified Medicine Programme 1 and 2 has set-up a collaborative network of 26 hospitals and 8 CRUK Experimental Cancer Medicine Centres to provide genetic testing in lung, bowel, breast cancers and melanoma. The next plan for the NHS of England is to increase testing activity, to equitable access, to improve the quality assurance procedures and the cost values.References: 1. Collection Reports and summaries, collective volume edited by INCa, Boulogne-Billancourt, sept 2010 http://www.e-cancer.fr/Expertises-et-publications/Catalogue-des-publications/Molecular-genetic-testing-for-equal-access-to-targeted-therapies-in-France-in-2011 http://www.e-cancer.fr/Expertises-et-publications/Catalogue-des-publications/The-French-national-network-of-28-hospital-molecular-genetics-platforms-summary-of-the-activity-in-2009 http://www.e-cancer.fr/Expertises-et-publications/Catalogue-des-publications/Molecular-genetic-tests-for-access-to-targeted-therapies-in-France-in-2012 2. Nowak, F. et al. Tumour molecular profiling for deciding therapy—the French initiative. Nat. Rev. Clin. Oncol. 9, 479–486 (2012) 3. Nowak, F. et al. Europe Does It Better: Molecular Testing across a National Health Care System—The French Example; 2013 ASCO EDUCATIONAL BOOK | asco.org/edbook 4. Kostenko, A. et al. The network genomic medicine cost reimbursement model for implementation of comprehensive lung cancer genotyping in clinical routine. J Clin Oncol 33, 2015. ASCO Abstract e12556 5. CR UK Stratified Medicine Programme 1 and 2. http://www.cancerresearchuk.org/funding-for-researchers/how-we-deliver-research/our-research-partnerships/stratified-medicine-programme
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ED02.04 - Central/South America (ID 1777)
15:20 - 15:40 | Author(s): M.L. Dalurzo
- Abstract
- Presentation
Abstract:
This presentation comprises data from Central and South America, as well as Mexico since all of us, as Latin American countries share similar characteristics. The countries included in this group are considered “developing countries” and are characterized by their racial, geographic, cultural, political and economic heterogeneity. In order to obtain data about the current situation in the region, I have sent a survey to the institutions that perform molecular tests in these countries for which I could get contact information. The survey has been sent to 34 laboratories in 12 countries. I tried to be as inclusive as possible, although in some cases it was rather difficult to get adequate contact information. My apologies to those who did not received the survey and would have liked to participate. Nineteen laboratories answered the survey ¹. Although not updated, I also added information from 5 other laboratories presented at LALCA 2014². Despite these results do not represent every country nor all molecular laboratories in the region, many common factors can be identified which allow for a relatively accurate analysis. The results show: Molecular tests are run by a small group of laboratories concentrated in the main cities of these countries. Most frequently, molecular testing is financed by pharmaceutical companies or private health care programs; however, in some cases the government, through the public healthcare system, supports the cost of the tests, and occasionally the patient pays for it. The pharmaceutical companies centralize molecular testing in a few laboratories in each country. Although frequency is generally low, some specimens are analyzed abroad, mainly in the USA. Some regional laboratories perform the tests for those countries that do not have adequate technology for molecular testing. The general opinion was that sending specimens to molecular center did not pose major complications, except in big countries where the geographic distance tends to delay the transport. Pharmaceutical companies provide the logistic structure to aid in the transfer of specimens, thus, accelerating the process. Specimen rejection rate can be divided into two groups: insufficient tissue or inadequate specimen quality by poor tissue preservation. The average rejection rate was 5 to 22%, more frequently around 15%. As for quantity, some institutions improved the amount of tissue obtained and specimen handling over time. When consulted on the possibility to perform molecular tests for treatment and/or research, the answer were: 2 laboratories only make test for research, 10 only run them for treatment purposes and 9 perform tests both for treatment and research. In most of the countries research is more frequently economically supported by the government than by other sources. When oncologists participate in clinical trials the tests are usually run abroad, mainly in the USA. Table 1 shows the available test platforms in the laboratories that participated in the survey and their access to quality control (QC) programs. For sequencing, all the laboratories began with Sanger sequencing, but many of them have changed to PCR-allele specific real-time platform. Some countries are introducing NGS. Most countries do not have local regulations for quality control of molecular tests. A half of the laboratories included in the survey have a kind of international QC, represented by participation in CAP or European QC programs or sending material to reference laboratories for interobserver concordance of results. Table1
* LALCA surveys information not updated Information on the total tests performed in the region is still incomplete and the number varies from country to country. In spite of this, the main reference laboratories are included in the survey and the data obtained reveals an insufficient number of tests related to the frequency of advanced lung cancer cases in the region. I did not include in this survey the test results but published Latin American data³¯⁴¯⁵ shown regional/country variability in the frequency of EGFR mutation and sometimes in ALK fusion test, probably related to genetic variability in the Latin American population. What are the challenges of molecular testing in Latin America? One of them is the quality and quantity of tissue available for molecular tests. In the region we still struggle against badly-fixed or inadequately processed specimens. In this field, probably, there is much education and interdisciplinary work to do yet. Reimbursement is another challenge. In most of the countries, pharmaceutical companies have financed so far the cost of molecular tests, but if this were not the case in the future when the need for many other tests arises, health care systems will have to bear testing and treatment costs. A careful evaluation will be required in each country to organize the most balanced use of the available resources. A particularly important challenge for the region is molecular testing quality certification. The access to international quality control programs is very expensive for the majority of the regional laboratories but quality control must be ensured. A group of us is trying to organize a stratified system that allows for a more affordable program to all laboratories. It is still a project in development. 1-Survey participants: Argentina: Esteban Mocetti: Hospital Italiano. Buenos Aires. Marina Gutierrez: Laboratorio Stamboulian. Buenos Aires. Erica Rojas Bilbao:Hospital Roffo. Buenos Aires. Guillermo Bramuglia: Argenomics. Fundacion Investigar. Buenos Aires. Valeria Denninghoff: Instituto CEMIC. Buenos Aires. Jorge Palazzi: IICT Labs. Rosario. Brasil: Fernando Soarez. Isabela Werneck da Cunha: AC Camargo Cancer Center. Sao Pablo. Fabio Tabora:Argos Lab / Messejana Hospital. Fortaleza. Chile: Cristina Fernández Ferradás:. Instituto Nacional del Tórax. Santiago de Chile. Antonio Piottante Becker: Clínica Las Condes. Santiago de Chile. Colombia: Andres Felipe Cardona. July Rodriguez: Foundation for Clinical and Applied Cancer Research Bogotá. Ruby E. Ríos Quintana-Roberto Jaramillo: Unidad de Diagnostico Hemto-Oncologico. Cali.Costa Rica: Luis Corrales Rodriguez: Centro de Investigación y Manejo del Cancer.(CIMCA y CCSS). San José. Mexico: Graciela Cruz Rico: Instituto Nacional de Cancerología. Distrito Federal. Erica Sagrario Peña Mirabal: Instituto de Enfermedades Respiratorias. Distrito Federal. Perú: Juan Carlos Gomez de La Torre Petrell: Laboratorios ROE. Lima. Uruguay: Alejandra Torres: Laboratorio Genia. Montevideo.Gonzalo Manrique, María Noel Zubillaga. Asociación Española. Montevideo. 2. LALCA 2014 surveys, not updated: Cintya Sternberg. INCA. Rio de Janeiro.Brasil, Vinicius Duval Da Silva Pontificia Universidade Catolica do Rio Grande do Sul. Brasil. Yumay Pires. Clinica Alemana. Santiago de Chile. Ana Margarita Baldión Elorza. Hospital Universitario Fundación Santafé de Bogota. Colombia. Nicolas Vivar Diaz. Hospital Carlos Andrade Marin. Quito Ecuador 3: Arrieta O, Cardona A, Martin C et al. Updated Frequency of EGFR and KRAS mutations in NSCLC in Latin America. The Latin-America Consortium for the Investigation of Lung Cancer (CLICaP) JTO 2015;10: 838-843 4: Bacchi C. et al. EGFR and KRAS mutations in Brazilian lung cancer patients. CLINICS 2012;67 (5):419-424 5: De Melo A et al. Mutational Profile and new IASLC/ATS/ERS classification provide additional prognostic information about lung ADC. A study of 125 patients from Brazil. Oncology 2015; Apr 1.(Epub ahead of print)Country Argentina Brazil Chile Colombia Costa Rica Ecuador Mexico Peru Uruguay Laboratories 6 2/2* 2/1* 2/1* 1 1* 2 1 2 EGFR 6 3 3 3 1 1 2 1 2 ALK 6 4 3 3 1 1 2 1 Other tests 5 3 2 3 1 2 1 2 Sanger Seq. 5 2 1 2 2 PCR allele specific-real time 4 2 2 2 1 1 2 1 1 NGS 3 1 1 FISH 4 3 3 2 1 1 2 1 IHQ 5 2 1 2 1 1 1 External QC 3 1 1 1 1 1 1
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ORAL 06 - Next Generation Sequencing and Testing Implications (ID 90)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 8
- Moderators:G. De Lima Lopes, V. Miller
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 1a-1f
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ORAL06.01 - Genomic Characterization of Large-Cell Neuroendocrine Lung Tumors (ID 1667)
11:05 - 11:16 | Author(s): L. Fernandez-Cuesta, M. Peifer, J. George, A. De Reyniès, R. Sun, J. Altmueller, P. Nuernberg, M. Olivier, M. Ardin, Y. Blum, J. Laffaire, N. Elarouci, F. Petel, J. McKay, G. Byrnes, H. Nagy-Mignotte, D. Moro-Sibilot, C. Brambilla, S. Lantuejoul, A. McLeer, A. Soltermann, O.T. Brustugun, Å. Helland, S. Solberg, M. Lund-Iversen, S. Ansén, G. Wright, P.A. Russell, B.J. Solomon, L. Roz, U. Pastorino, I. Petersen, J.H. Clement, J. Saenger, T. Zander, R. Buettner, S. Haas, E. Brambilla, R.K. Thomas
- Abstract
Background:
Neuroendocrine lung tumours account for 25% of all lung cancer cases, and they range from low-aggressive pulmonary carcinoids (PCA) to highly malignant small-cell lung cancer (SCLC) and large-cell neuroendocrine lung carcinoma (LCNEC). The last two are strongly associated with heavy smoking and are typically detected at a clinically advanced stage, having a poor survival. Comprehensive genomic analyses in lung neuroendocrine tumours are difficult because of limited availability of tissue. While more effort has been done in the context of SCLC, the detailed molecular features of LCNEC remain largely unknown.
Methods:
We conducted 6.0 SNP array analyses of 60 LCNEC tumours, exome sequencing of 55 tumor-normal pairs, genome sequencing of 11 tumour-normal pairs, transcriptome sequencing of 69 tumours, and expression arrays on 60 tumors. Data analyses were performed using in house developed and published pipelines.
Results:
Analyses of chromosomal gene copy number revealed amplifications of MYCL1, FGFR1, MYC, IRS2 and TTF1. We also observed deletions of CDKN2A and PTPRD. TTF1 amplifications are characteristic of lung adenocarcinoma (AD); CDKN2A deletions are frequent alterations in both AD and squamous-cell lung carcinoma (SQ); FGFR1 amplifications are found in SQ and, less frequently, in SCLC; and MYCL1 and IRS2 amplifications are frequent events in SCLC. Similar to the copy number data, we found patterns of mutations characteristic of other lung cancer subtypes: TP53 was the most frequently mutated gene (75%) followed by RB1 (27%), and inactivation of both TP53 and RB1, which is the hallmark of SCLC, occurred in 20% of the cases. Mutations in STK11 and KEAP1-NFE2L2 (frequently seen in AD and SQ) were found in 23% and 22% of the specimens, respectively. Interestingly, mutations in RB1 and STK11/KEAP1 occurred in a mutually exclusive fashion (p-value=0.016). Despite the heterogeneity observed at the mutation level, analysis of the pattern of expression of LCNEC in comparison with the other lung cancer subtypes (AD, SQ, SCLC, and PCA) points to LCNEC as being an independent entity. An average mutation rate of 10.7 mutations per megabase was detected in LCNEC, which is in line with the rate observed in other lung tumours associated with smoking. We found that, similar to SCLC, the mutation signatures associated with APOBEC family of cytidine deaminases, smoking, and age (based on Alexandrov et al 2013) were the predominant ones in LCNEC. However, the contribution of the individual SCLC and LCNEC samples to these three signatures was quite different, and we are currently exploring it.
Conclusion:
Taking into account somatic copy number and mutation data, we distinguished two well-defined groups of LCNEC: an SCLC-like group, carrying alterations in MYCL1, ISR2, and in both RB1 and TP53; and a group resembling AD and SQ, with alterations in CDKN2A, TTF1, KEAP1-NFE2L2, and STK11. Although these results suggest that LCNEC might be a mix of different lung cancer subtypes, mutation clonality and expression analyses show that they are likely to be a separate entity, sharing molecular characteristics with the other lung cancer subtypes. Their heterogeneity suggests that LCNEC might represent an evolutionary trunk that can branch to SCLC or AD/SQ.
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- Abstract
- Presentation
Background:
Identification of clinically relevant molecular drivers in patient tumors is essential in selecting appropriate targeted therapy. Using next-generation sequencing (NGS) -based clinical cancer gene test, we performed genomic profiling of lung adenocarcinoma tumors.
Methods:
We collected formalin-fixed paraffin-embedded tumors from 41 lung adenocarcinoma patients whose tumors previously tested negative for EGFR/KRAS/ALK by conventional methods in an ongoing trial (NCT01964157). We performed hybridization capture of 4,557 exons from 287 cancer-related genes and 47 introns from 19 genes frequently rearranged in cancer (FoundationOne). Illumina HiSeq2000 platform was used to sequence to high uniform depth.
Results:
Figure 1Tumors were sequenced to a median coverage of 529x. Overall, we identified a total of 170 known and 492 unknown individual genomic alterations. The number of known alterations per sample was average of 3.8 alterations (range 0-10). Cancer genomes are characterized by 45% (77/170) non-synonymous base substitutions, 17% (29/170) insertions or deletions, 2% (4/170) splice site mutations, 20% (34/170) gene amplifications, 5% (8/170) homozygous loss and 5% (8/170) gene fusions. TP53 was the most commonly mutated gene (13%, n=10/77) among non-synonymous base substitutions, followed by KRAS (10%, n=8/77) and PIK3CA (8%, 6/77). Insertions or deletions commonly occurred TP53 (17%, 5/29) and ERBB2 (14%, 4/29), and splice site mutations occurred in TP53, INPP4B, ATR, and MAP2K4 (n=1 each). Among gene amplification, MDM2 amplification was the most frequent (12%, 4/34), followed by ERBB2 (8%, 3/34) and CDK4 (8%, 3/34) amplification. All 8 cases of homozygous loss were observed with CDKN2A and CDKN2B. Fusion genes were most commonly observed with RET (50%, n=4/8). Based on NCCN guidelines, actionable genomic alterations with a targeted agent were identified in 16 patients (39%) (BRAF mutation [n=1], EGFR mutation [n=7], ERBB2 mutation [n=4], MET amplification [n=1], KIF5B-RET rearrangement [n=2], CCDC6-RET rearrangement [n=1], and CD74-ROS1 rearrangement [n=1]). Nine out of all patients (22%) showed discordance in targetable alterations when compared between NGS and conventional non-NGS methods.
Conclusion:
Thirty-nine percent of lung adenocarcinoma wild type for EGFR/KRAS/ALK may harbor a genomic alteration revealed by NGS approach. These results highlight the importance of profiling lung adenocarcinomas using NGS in the clinic.
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ORAL06.03 - Genome-Wide Gene Copy Number Analysis by OncoScan<sup>TM</sup> FFPE Assay in 976 Resected NSCLC From LACE-Bio2 (ID 1561)
11:27 - 11:38 | Author(s): M.S. Tsao, F. Rotolo, E. Brambilla, S.L. Graziano, K. Olaussen, T. Le-Chevalier, J. Pignon, R. Kratzke, J. Soria, F. Shepherd, L. Seymour, S. Michiels
- Abstract
- Presentation
Background:
Genome wide SNP array studies have identified systematic gene copy number aberrations (CNA) in non-small cell lung cancer (NSCLC), but their prognostic implication is unknown. This study aimed to investigate associations between CNAs and survival using the LACE-Bio bio-bank. The LACE-Bio consortium includes large clinical trials comparing adjuvant platinum-based chemotherapy to observation after complete resection of stage I-III NSCLC.
Methods:
DNA was extracted from FFPE tumor samples from 3 pivotal adjuvant chemotherapy trials (CALGB 9633, IALT, JBR.10); 1013 samples were profiled using Affymetrix OncoScan[TM] arrays with over 300,000 probes and normalized relative to a pool of normal tissues. Segmentation was performed using the CBS algorithm and minimally recurrent regions (MCR) across the series identified by CGHregions. All analyses were performed on the level of MCRs. CNAs were correlated with clinicopathological factors and adjusted for the False Discovery Rate (FDR). The primary endpoint, disease-free survival (DFS), was assessed via univariate Cox models stratified by trial and adjusted for treatment, age, sex, PS, histology, T, and N stage.
Results:
Among 976 successfully profiled samples, 414 (42%) were adenocarcinoma (ADC), 430 (44%) squamous cell carcinoma (SCC) and 132 (14%) other NSCLC; 710 (73%) were male. Across the 431 MCRs identified, patients had on average 94 (SD 69) CNAs: 51 gains and 43 losses. A gain or loss was observed in at least 10% of patients for 177 and 166 regions respectively. The most common gains (up to 48%) were on chromosomes 1p, 3q, 5p, 6p, and 22q. The most common losses (up to 40%) were on chromosomes 3p, 8p and 9p. The size of 253 of the 431 MCRs (59%) was smaller or equal to 3Mb (and 79% ≤10 Mb). Sensitivity analyses on the subset of samples with optimal quality (n=777, defined by MAPD<0.3) gave consistent results. The CNA frequency of 195 regions was significantly different with FDR≤0.05 between ADC and SCC (of which 49% regions of size ≤3Mb and 71% ≤10Mb); the most significant were more gains in 3q, 22q and 12 in SCC and more losses in 3p, 4, 5q in SCC. With a median follow-up of 5.3 years, 510 DFS events and 451 deaths were recorded. In univariate analyses for DFS, 13 regions in loci 19p11–13, 7p12, 9p21, 15q14 had a raw p-value <0.005 (FDR<0.13, the top 8 corresponded to FDR≤0.05); 9 of those 13 regions were of size ≤3Mb (12 regions ≤10Mb). In adjusted analyses, 10 of the 13 regions retained raw adjusted p-values ≤0.005 (FDR≤0.15). Losses of focal regions including CDKN2A/B and STK11 (≤3Mb) were associated with poorer DFS: the hazard ratio (HR) for a 2-fold copy number decrease in region 9p21.3 (including CDKN2A/B) was 1.50 (95% CI: 1.2–1.9, P<0.001, FDR=0.02), and the HR for a 2-fold copy number decrease in 19p13 (including STK11) was 2.4 (1.3–4.3, P=0.005, FDR=0.15). Similar results were obtained for overall survival and lung-cancer specific survival. Results of histology-specific analyses will be presented.
Conclusion:
These large-scale genome-wide analyses of gene CNA provide new candidate prognostic markers for stage I-III NSCLC.
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ORAL06.04 - Discussant for ORAL06.01, ORAL06.02, ORAL06.03 (ID 3302)
11:38 - 11:48 | Author(s): R. Govindan
- Abstract
- Presentation
Abstract not provided
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ORAL06.05 - Molecular Tumor Board (MTB) in Non-Small Cell Lung Cancers (NSCLC) to Optimize Targeted Therapies: 4 Years' Experience at Gustave Roussy (ID 2563)
11:48 - 11:59 | Author(s): D. Planchard, L. Faivre, I. Sullivan, V. Kahn-Charpy, L. Lacroix, N. Auger, J. Adam, V. De Montpreville, P. Dorfmuller, C. Le Pechoux, T. Le-Chevalier, A. Gazzah, J. Remon, G. Bescher, J. Soria, J. Pignon, B. Besse
- Abstract
- Presentation
Background:
Molecular biology has changed the treatment of advanced NSCLC, leading to many small subgroups of patients (pts) eligible for targeted therapies, many of them being not approved. Since 2010 we created a monthly MTB dedicated to NSCLC pts with potential driving molecular abnormalitie(s). MTB includes expert physicians from the lung tumor board and phase I unit, radiation therapists, researchers, geneticists, pathologists and biologists. A medical report summarizes the findings and treatment recommendations for each pts. We report 4 years of activity of MTB at Gustave-Roussy.
Methods:
All consecutive files discussed in MTB for a NSCLC were reviewed. MTB included pts with at least one molecular alteration based on a 75 gene panel (NGS analysis and FISH for ALK, HER2, MET, FGFR1, ROS1 and RET). Tumor and pts characteristics were collected as well as treatments. Pts outcome was calculated from the MTB date. Kaplan-Meier methods, and Cox proportional hazards models were used for survival analysis, adjusting for sex, histology, smoking status, metastasis at diagnosis, number of line(s) before MTB.
Results:
502 files were discussed between 02/2010 and 09/2014. Median age was 60 yrs (25–88 yrs), 53% were male, 86% Caucasian, 26% never-smokers, and 93% had PS ≤1. Initial clinical stage was III-IV in 417 pts (84%) and 79%/10%/11% were adenocarcinomas/squamous cell carcinomas/others NSCLC. Median number of treatment-lines before MTB was 1 (0-10), 86% were previously treated by a platinum-based chemotherapy regimen, 17% in a therapeutic trial, and median time from diagnosis to MTB was 5 months. Biopsy for Molecular Analysis (MoA) mostly came from CT guided biopsies (62%), surgery (21%) or endoscopy (16%). Biopsy was repeated in 19% of pts to get enough material for MoA. The MoA results were ALK rearrangement in 11%, exon 18/19/20/21 EGFR mutation (mut) in 2/14/4/7% respectively, KRAS mut in 32%, PI3KCA mut in 3%, BRAF mut in 5%, HER2 mut (Exon 20) in 2%, HER2 amplification in 2%, FGFR1 amplification in 3%, MET amplification in 3% and other rare mutations in 27%. MTB recommended a targeted therapy in 344 pts (68%) either within clinical trials (57%), EMA approved therapy (23%), an off label drug (9%), or an expanded access program (11%). 162pts (47%) actually received the recommended therapy, 141 (41%) did not and 41 (12%) might receive it at the time of progression. Median follow-up was 24 months (1-24; follow-up censored after 24 months). Median OS was 13.1 months [95%CI: 8.8; 18.2] for non-oriented pts, and 14.3 months [11.5; 16.7] for oriented pts (p=0.39). We observed a significant difference between EGFR/ALK/ROS1 mutated/rearranged pts (median 23.8 months) vs. pts with KRAS (8.6 months) or others mutations (11.1 months) or non-oriented pts (13.1 m; p=0.0008, HR=0.56, 1.15 and 0.97 respectively compared to non-oriented).
Conclusion:
MTB is feasible in daily practice with treatment recommendations in a majority of NSCLC pts (68%), enrichment in clinical trials or expanded access programs, and limitation of off-label drugs use. Benefit on survival for all oriented pts has to be clarified based on the type of molecular abnormality. Update results will be presented at the meeting.
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ORAL06.06 - Impact of Reflex EGFR/ALK Testing on Time-To-Treatment and Integration of Personalized Medicine in Advanced Non-Small Cell Lung Cancer Patients (ID 2290)
11:59 - 12:10 | Author(s): P.K. Cheema, I.B. Menjak, S. Raphael, S.Y. Cheng, A. Muinuddin, S. Verma, S.Y. Chang, R. Freedman, N. Toor, Z. Winterton-Perks, M. Anaka, J. Perera
- Abstract
- Presentation
Background:
Testing for biomarkers including EGFR mutations and ALK rearrangements is standard of care in the management of advanced non-small cell lung cancer (NSCLC), as it determines optimal systemic therapy (ST). Our centre began EGFR testing March 2010 and ALK April 2012. Initially, EGFR/ALK were requested by medical oncologists (MO) when patients were deemed eligible for EGFR or ALK targeted therapy. To expedite biomarker information to MO for rapid initiation of ST in patients with advanced stage or earlier stage disease that developed recurrence, June 2013 we implemented a multidisciplinary approach termed “reflex testing”. This was defined as our pathologists requesting EGFR/ALK at time of diagnosis of non-squamous NSCLC irrespective of a patient’s clinical stage. If tissue was at an outside centre, clerical staff requested EGFR/ALK at time of referral to MO. The objective of this study was to determine if reflex testing improved time-to-treatment (TTT) and the integration of personalized medicine in patients with advanced NSCLC.
Methods:
This was a retrospective chart review of patients with non-squamous NSCLC seen by MO at the Sunnybrook Odette Cancer Centre from March 18, 2010 to April 30, 2014. Patient and EGFR/ALK test characteristics were compared before and after reflex testing was implemented using Chi-square tests of association. Time outcomes were compared using Mann-Whitney U non-parametric tests. TTT was defined as the interval between first MO visit with advanced NSCLC to initiation of ST.
Results:
Of the 301 patients included, median age was 68, 43% female, 65% Caucasian, 75% smokers, 93% adenocarcinoma, 22% EGFR positive and 1% ALK positive. The majority presented with stage IV (65%) and 82% either presented with or developed advanced NSCLC. In advanced NSCLC patients (n=247), reflex testing significantly reduced median TTT compared to routine testing [(24 days (IQR: 7 to 42) vs. 36 days (IQR: 16 to 72), p=0.04)], reduced the rate of EGFR unknown (4% vs. 26%, p=0.002) and ALK unknown (10% vs. 50%, p<0.001). There was minimal impact on advanced NSCLC patients receiving any first-line ST (58% vs. 63%, p=0.48). However, among these patients, with reflex testing, fewer were initiated on first-line ST without biomarker results known by MO (EGFR 23% vs. 39%, p=0.12, ALK 17% vs. 42%, p=0.02), and at last follow up significantly fewer had EGFR unknown (0% vs. 13%, p=0.004) and ALK unknown (7% vs. 38%, p=0.003). Across all stages, rates of EGFR results available to MO at first consultation increased (34% vs. 4%, p<0.001). Reflex testing also impacted the quality of biomarker testing with a decrease in unsuccessful EGFR tests due to inconclusive results, insufficient or inappropriate tissue, or tissue not sent from holding lab to testing lab (4% vs. 15%, p=0.03).
Conclusion:
A multidisciplinary approach to earlier biomarker testing in NSCLC is feasible. Reflex testing for EGFR/ALK improved TTT and the integration of personalized medicine for patients with advanced NSCLC by improving biomarker testing rates, the quality of testing and fewer patients given ST without biomarkers known. These outcomes provide support for reflex EGFR/ALK testing by pathologists at time of diagnosis of non-squamous NSCLC.
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ORAL06.07 - An Integrated Cost-Effectiveness and Outcome Analysis Based on Multiplex Lung Cancer Genotyping in the Network Genomic Medicine (ID 2800)
12:10 - 12:21 | Author(s): A. Kostenko, F. Kron, M. Scheffler, S. Michels, J. Sueptitz, R.N. Fischer, S. Merkelbach-Bruse, P. De-Mary, J.P. Glossmann, R. Buettner, J. Wolf
- Abstract
Background:
The Network Genomic Medicine (NGM) Lung Cancer is an interdisciplinary and intersectoral network offering comprehensive and centralized next generation sequencing (NGS)-based multiplex genotyping for all inoperable lung cancer patients in Germany. In 2014 NGM and the AOK Rheinland/Hamburg, one of the largest German public health insurances, have successfully contracted and established the first "flat rate" cost reimbursement model for NGS-based comprehensive lung cancer genotyping in Europe. After a year the first joint health-economic evaluation of NGM patients was initiated.
Methods:
The AOK Rheinland/Hamburg cooperates with NGM within the integrated care contract (ICC) according to § 140 German Social Insurance Code. Besides the cost reimbursement model for the NGS-based diagnostics the ICC comprises optional second opinion consultation hours and a joint evaluation program. The NGS panel used for all patients currently consists of 14 genes and 102 amplicons to cover potentially targetable aberrations. Other German public and private health insurances are currently negotiating to join the ICC. In April 2015 we elaborated a model to analyze molecularly guided therapy cost and outcome of inoperable lung cancer patients integrating health insurance cost data (diagnostic, therapy and drug-related costs). This model includes NGS-based molecular diagnostic results, treatment strategies and cost-effectiveness. Additionally, time-points of molecular genotyping and their influence on patient-related outcome and quality of life will be examined.
Results:
In 2014 about 4500 lung cancer NGM patients were centrally genotyped on the central NGS platform in Cologne. Since April 2014 167 patients, insured by the AOK Rheinland/Hamburg, consented for ICC. 149 patients received NGS-based molecular diagnostic of their tumors. 18 samples were not suitable for testing. ICC patients were stratified according to their molecular diagnostic results and molecular guided therapy options (targeted drugs including off-label use, participating in clinical trials or standard chemotherapy). Clinical outcome data were collected within NGM (by over 200 clinical partners) and reimbursement data are provided by the AOK Rheinland/Hamburg. This model will be extended to all NGM patients independent of their insurance status. Final cost-effectiveness and outcome data will be presented.
Conclusion:
NGM stands for the implementation of personalized cancer therapy into clinical routine in Germany. Now we systematically evaluate NGS-based molecular results, clinical outcome and cost-effectiveness data besides of clinical trials. First-time in Europe data evaluation is provided in a close cooperation between health care providers and health insurance companies and even matching the patient’s data. Furthermore, in 2015 a joint database (NGM Cancer Information System) for retrospective evaluation of personalized cancer treatment in Germany will be launched. Our model of implementing personalized cancer care in broad clinical routine is currently transferred to other tumor entities.
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ORAL06.08 - Discussant for ORAL06.05, ORAL06.06, ORAL06.07 (ID 3303)
12:21 - 12:31 | Author(s): P. Yang
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 15 - Chemotherapy Developments for Lung Cancer (ID 128)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Crinò, C.P. Belani
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI15.09 - Bayesian Network Meta-Comparison of Maintenance Treatments for Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients (ID 636)
17:30 - 17:35 | Author(s): G. De Lima Lopes
- Abstract
- Presentation
Background:
Recent trials suggested that maintenance treatments improve outcomes for patients not progressing after first-line therapy for advanced NSCLC. However, physicians have little guidance on selecting which patients benefit the most and what drug or regimen is optimal. Here, we report a systematic review and network meta-analysis (NMA) of current evidence assessing relative efficacies of maintenance options in unselected populations, as well as in subgroups determined by EGFR mutation, histology, and response to induction.
Methods:
PubMed and conference proceedings were reviewed and individual study relative efficacy measures were meta-analyzed in a Bayesian hierarchical model. The primary and secondary outcomes, Overall Survival (OS) and Progression Free Survival (PFS), respectviely, were evaluated in terms of (i) posterior surface under cumulative ranking curve (SUCRA), (ii) probability of being best treatment, (iii) probability of outperforming no maintenance, and (iv) posterior median hazard ratios with 95% credible intervals, in an unselected population, as well as by EGFR mutation status, histology, and response to induction. Secondary outcomes were overall survival (OS) and adverse events.
Results:
Twelve trials evaluating eight maintenance treatments in 3,850 patients were included in NMA. Selected maintenance treatments showed substantial PFS and OS benefits with probabilities ≥99% and ≥92% respectively of outperforming no maintenance. Results suggest the following strategy for optimal OS and PFS: (i) switch to or continue pemetrexed or switch to anti-EGFR TKI for nonsquamous patients, (ii) continue gemcitabine for squamous patients, (iii) switch to docetaxel or continue gemcitabine for responders to previous induction, and (iv) switch to or continue pemetrexed or switch to anti-EGFR TKI for patients with stable disease post-induction.
Conclusion:
Maintenance treatments improve PFS and OS in good performance status patients with stage IIIb/IV NSCLC not progressing after first-line chemotherapy. Benefits are optimized by targeting specific maintenance treatments to selected patient groups guided by histology and response to previous induction.
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P1.10 - Poster Session/ Advocacy (ID 228)
- Event: WCLC 2015
- Type: Poster
- Track: Advocacy
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.10-001 - EGFR Mutation Testing Patterns and Results in Brazil and the Need for Greater Public Health Awareness of Molecular Testing (ID 1540)
09:30 - 09:30 | Author(s): G. De Lima Lopes
- Abstract
Background:
Epidermal growth factor receptor (EGFR) mutation testing allows for optimal selection of therapy with tyrosine kinase inhibitors in patients with non-small-cell lung cancer (NSCLC). Previous studies have shown a variation in EGRF genotype according to ethnic background, with scarce data about EGFR mutation status and testing patterns among Brazilian patients with NSCLC.
Methods:
Between 2011 and 2013, as part of a program sponsored by a pharmaceutical company in Brazil, tumor samples of patients with stage IIIb/IV NSCLC were submitted, at the discretion of the attending physicians, for EGFR mutation testing. All analyses were performed at 02 reference laboratories, as follows: after microdissection, DNA was isolated from serial sections of formalin-fixed, paraffin-embedded tumor tissue to obtain at least 70% tumor cells. Exons 18, 19, 20 and 21 of the EGFR gene were analysed using Sanger sequencing. EGFR mutation rate was calculated and its frequency compared between clinical subgroups using chi-square test. Data about smoking status was incomplete and thus not included in this analysis. Furthermore, a commercial database with 3,296 patients treated in Brazil in 2014 was evaluated for mutation testing patterns.
Results:
3,364 tests out of 3,771 samples analyzed (1,799 male; 1,942 female) yielded informative results. EGFR mutation was present in 25.5% (857/3364) of informative samples. Deletions in exon 19 were the most frequent alteration detected (54%), followed by point mutations in exon 21 (28%) and exon 20 (9.7%). The most important predictors for the presence of EGFR mutations were adenocarcinoma histology (p<0.001), 89% of positive tests occurred in this histology; and female gender (p<0.001), for which 30.2% of the patients tested were positive. No differences in EGFR mutation frequency were found between age groups or regions within the country. In the commercial database of patients with NSCLC treated in the country in 2014, 1,792 patients had adenocarcinomas, 930 had squamous cancer, 71 had large cell cancer and 99 had other histologies. Overall, 34% of patients were tested for mutations (47% in the private sector and 20% in public centers); the corresponding number was 50% for patients with adenocarcinoma (62% of cases in the private and 33% in the public settings, respectively) and 10% for patients with squamous cancer. Of note fewer than 5% of patients overall were tested for ALK alterations.
Conclusion:
To the best of our knowledge, this is the largest study to assess EGFR mutation status in Latin America and in Brazil. Our findings suggest that the frequency of EGFR mutation in this cohort was lower than that found in Asia, but higher than in Caucasian populations, confirming findings seen in other Latin American countries. Despite this high prevalence, a significant number of patients, especially in the public sector, are not currently tested for mutations in the country, and further advocacy efforts are necessary to improve this situation.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-097 - Phase 3 Study of Pembrolizumab vs Platinum-Based Chemotherapy for PD-L1<sup>+</sup> NSCLC (ID 2182)
09:30 - 09:30 | Author(s): G. De Lima Lopes
- Abstract
Background:
Platinum-based chemotherapy with or without maintenance therapy is the standard of care for treatment-naive non-small cell lung carcinoma (NSCLC) that lacks EGFR sensitizing mutations and ALK translocations. The PD-1 pathway is frequently used by tumors to evade an immune response. Pembrolizumab (MK-3475), an anti–PD-1 monoclonal antibody, has demonstrated manageable toxicity and promising antitumor activity in patients with treatment-naive NSCLC enrolled in the phase 1b KEYNOTE-001 study. In this study, a relationship between increased tumor PD-L1 expression and improved pembrolizumab antitumor activity was observed. KEYNOTE-042 (ClinicalTrials.gov identifier NCT02220894) is a randomized, open-label, international, phase 3 study designed to compare the efficacy and safety of pembrolizumab with those of platinum-doublet chemotherapy as first-line therapy for PD-L1–positive advanced NSCLC.
Methods:
Eligibility criteria include age ≥18 years, advanced NSCLC without EGFR sensitizing mutations or ALK translocation, no prior systemic chemotherapy, PD-L1 expression in ≥1% of tumor cells, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1. Patients are randomly assigned in a 1:1 ratio to a 200-mg fixed dose of pembrolizumab every 3 weeks (Q3W) or investigator’s choice of carboplatin AUC 5 or 6 plus paclitaxel 200 mg/m[2] Q3W or carboplatin AUC 5 or 6 plus pemetrexed 500 mg/m[2] Q3W. Randomization is stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), region (East Asia vs non-East Asia), and PD-L1 expression (strong [staining in ≥50% of tumor cells] vs weak [staining in 1%-49% of tumor cells], as assessed by immunohistochemistry at a central laboratory). Pembrolizumab will be continued for 35 cycles or until disease progression, intolerable toxicity, or investigator decision; treatment may be continued beyond initial radiographic disease progression in eligible patients. Discontinuation of pembrolizumab is permitted for patients who experience a complete response confirmed on a follow-up scan performed ≥4 weeks after initial observation. Chemotherapy will be given for a maximum of 6 cycles and may be followed by optional pemetrexed 500 mg/m[2] Q3W maintenance therapy in patients with nonsquamous histology. Adverse events will be collected throughout the study and for 30 days (90 days for serious adverse events) thereafter and graded per NCI CTCAE v4.0. Response will be assessed every 9 weeks per RECIST v1.1 by independent central review. Patients will be followed for survival every 2 months. Primary end point is overall survival in the PD-L1–strong-positive stratum; secondary end points are progression-free survival in the strong-positive stratum and progression-free and overall survival in all patients. Enrollment is ongoing and will continue until approximately 1240 patients have been allocated to study treatment.
Results:
Not applicable.
Conclusion:
Not applicable.
