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M. Filipits
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ED01 - Biology of Lung Cancer (ID 263)
- Event: WCLC 2016
- Type: Education Session
- Track: Biology/Pathology
- Presentations: 3
- Moderators:R. Rosell, M. Filipits
- Coordinates: 12/05/2016, 11:00 - 12:30, Hall C1
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ED01.01 - Understanding Biology: The Road to Cure? (ID 6421)
11:00 - 12:30 | Author(s): D.P. Carbone
- Abstract
- Presentation
Abstract not provided
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ED01.02 - Tobacco Carcinogens and Lung Cancer Susceptibility (ID 6422)
11:00 - 12:30 | Author(s): S.S. Hecht, S..L. Park, S. Carmella, D.O. Stram, C.A. Haiman, L. Le Marchand, S.E. Murphy, J. Yuan
- Abstract
- Presentation
Abstract:
While cigarette smoking is clearly the major cause of lung cancer, only 11% of female and 24% of male lifetime smokers will get lung cancer by age 85 or greater, and this relatively small percentage is not due to competing causes of death from smoking (1) The major goal of the research approach discussed in this presentation is to identify individuals who are highly susceptible to the carcinogenic effects of cigarette smoke. These individuals would be candidates for intensive lung cancer surveillance and screening, increasing the probability of detection of a tumor at an early stage. We are not proposing methods for early detection of tumors such as the identification of metabolites or proteins characteristic of lung tumors, but rather early identification of susceptible individuals. While there are already algorithms relating various parameters to lung cancer susceptibility, they are mostly retrospective in nature, with pack-years of cigarette smoking being a major prognostic factor (2,3). Thus, these algorithms are typically applied to subjects who are older, when the process may be more advanced. Our ultimate goal is to develop a risk model that is prospective in nature. Overall, there would be a greater probability of success if one could identify high risk individuals early in the carcinogenic process. Even if this were effective in only 10% of tobacco users, the outcome could be prevention of more than 15,000 lung cancer deaths per year in the U.S. alone and massive financial savings. Among the more than 7,000 identified chemical compounds in cigarette smoke, there are 72 fully characterized carcinogens among which at least 20 are known to cause lung tumors in laboratory animals (4,5). Important among the lung carcinogens are polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene, tobacco-specific nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and volatiles such as 1,3-butadiene. Other related volatile compounds that may contribute to the carcinogenic process include acrolein, crotonaldehyde, and benzene. Perhaps the most important compound in tobacco smoke is nicotine – while not a carcinogen, it is the addictive constituent of smoke that causes people to continue to inhale this incredibly unhealthy mixture. In pursuit of our goal of identifying smokers susceptible to lung cancer, we have focused on several tobacco smoke toxicant and carcinogen parent substances and metabolites in urine (6). Thus, we and others have developed and applied analytically validated mass spectrometric methods for total nicotine equivalents (the sum of nicotine and six metabolites: nicotine glucuronide, cotinine, cotinine glucuronide, 3′-hydroxycotinine and its glucuronide, and nicotine-N-oxide); total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of NNK; phenanthrene tetraol (PheT) and 3-hydroxyphenanthrene (3-PheOH), metabolites of a representative PAH; S-phenylmercapturic acid (SPMA), a metabolite of the carcinogen benzene; 3-hydroxypropylmercapturic acid (HPMA), a metabolite of acrolein; and 3-hydroxy-1-methylpropylmercapturic acid (HMPMA), a metabolite of crotonaldehyde. We have collaborated with epidemiologists to evaluate the relationship of these urinary metabolites to cancer, as determined in prospective cohort studies. These studies collect and store bio-samples from large numbers of healthy subjects, then follow the subjects until sufficient numbers of cancer cases occur for statistical analysis. Samples from the cases and matched controls without cancer are retrieved from biorepositories and analyzed for specific biomarkers. The results of these studies have been reviewed (7,8). In summary, statistically significant relationships of urinary total cotinine (cotinine plus its glucuronide, the major metabolite of nicotine), total NNAL, and PheT with lung cancer risk were observed among male smokers in Shanghai. Urinary total cotinine and total NNAL were related to lung cancer risk in a study of male and female smokers in Singapore, and total NNAL in serum was related to lung cancer risk in a study of male and female smokers in the U.S. (7,8). Levels of urinary SPMA , HPMA, and HMPMA were not independently related to lung cancer in the Shanghai study. These results indicate that total cotinine, total NNAL, and PheT are possible biomarkers of lung cancer risk. We are also collaborating with scientists from the Multiethnic Cohort study, a prospective cohort study investigating the association of genetic and lifestyle factors with chronic diseases in a population with diverse ethnic backgrounds. They have reported that, for the same number of cigarettes smoked, and particularly at lower levels of smoking, African Americans and Native Hawaiians have a higher risk for lung cancer than Whites while Latinos and Japanese Americans have a lower risk (9). We are investigating the mechanistic basis for these remarkable differences. We analyzed urine samples from 300-700 subjects per group for total nicotine equivalents, total NNAL, PheT, 3-PheOH, SPMA, HPMA, and HMPMA. The results demonstrated that African Americans, although smoking fewer cigarettes per day than any of the other groups except Latinos, had significantly higher levels of total nicotine equivalents, total NNAL, PheT, 3-PheOH, and SPMA compared to Whites while Japanese Americans had significantly lower levels of most of these biomarkers than Whites. The relatively low level of urinary total nicotine equivalents in the Japanese American smokers was related to a high prevalence of CYP2A6 polymorphisms in this group (10). CYP2A6 is the primary catalyst of nicotine metabolism and the CYP2A6 alleles common in Japanese Americans code for low activity and non-functional enzyme. Therefore, Japanese Americans on the average have more unchanged nicotine circulating and will not need to obtain as much nicotine per cigarette. The biomarker profiles of Native Hawaiians and Latinos did not clearly relate to their relative lung cancer risks, but Native Hawaiians had high levels of the acrolein biomarker HPMA compared to other groups while those of Latinos were low. These results provide important new data pertinent to the relatively high risk of African Americans and the lower risk of Japanese Americans for lung cancer. Collectively, our results support the use of urinary nicotine metabolites, total NNAL, and PheT as biomarkers of lung cancer risk in cigarette smokers. Further studies are required to produce a reliably predictive algorithm for lung cancer susceptibility in cigarette smokers. These studies are likely to require the analysis of DNA adduct levels and to incorporate genetic and epigenetic information. Reference List 1. International Agency for Research on Cancer (2004) Tobacco Smoke and Involuntary Smoking. In IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 83 pp 174-176, IARC, Lyon, FR. 2. Tammemagi, C. M., Pinsky, P. F., Caporaso, N. E., Kvale, P. A., Hocking, W. G., Church, T. R., Riley, T. L., Commins, J., Oken, M. M., Berg, C. D., and Prorok, P. C. (2011) Lung cancer risk prediction: prostate, lung, colorectal and ovarian cancer screening trial models and validation. J. Natl. Cancer Inst. 103, 1058-1068. 3. Weissfeld, J. L., Lin, Y., Lin, H. M., Kurland, B. F., Wilson, D. O., Fuhrman, C. R., Pennathur, A., Romkes, M., Nukui, T., Yuan, J. M., Siegfried, J. M., and Diergaarde, B. (2015) Lung cancer risk prediction using common SNPs located in GWAS-identified susceptibility regions. J Thorac. Oncol. 4. Hecht, S. S. (1999) Tobacco smoke carcinogens and lung cancer. J. Natl. Cancer Inst. 91, 1194-1210. 5. Rodgman, A. and Perfetti, T. (2009) The Chemical Components of Tobacco and Tobacco Smoke. CRC Press, Boca Raton, FL. 6. Hecht, S. S., Yuan, J.-M., and Hatsukami, D. K. (2010) Applying tobacco carcinogen and toxicant biomarkers in product regulation and cancer prevention. Chem. Res. Toxicol. 23, 1001-1008. 7. Yuan, J. M., Butler, L. M., Stepanov, I., and Hecht, S. S. (2014) Urinary tobacco smoke-constituent biomarkers for assessing risk of lung cancer. Cancer Res. 74, 401-411. 8. Hecht, S. S., Murphy, S. E., Stepanov, I., Nelson, H. H., and Yuan, J.-M. (2012) Tobacco smoke biomarkers and cancer risk among male smokers in the Shanghai Cohort Study. Cancer Lett. 334, 34-38. 9. Haiman, C. A., Stram, D. O., Wilkens, L. R., Pike, M. C., Kolonel, L. N., Henderson, B. E., and Le Marchand, L. (2006) Ethnic and racial differences in the smoking-related risk of lung cancer. N. Engl. J. Med. 354, 333-342. 10. Park, S.-L., Tiirikainen, M., Patel, Y., Wilkens, L. R., Stram, D. O., Le Marchand, L., and Murphy, S. E. (2016) Genetic determinants of CYP2A6 activity across racial/ethnic groups with different risk of lung cancer and effect on their smoking behavior. Carcinogenesis in press.
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ED01.03 - Insights from TCGA (ID 6423)
11:00 - 12:30 | Author(s): B. Ganesh, S. Devarakonda, R. Govindan
- Abstract
- Presentation
Abstract:
Advances in sequencing technologies have made it possible to characterize and catalogue genomic alterations in several cancers in an unbiased manner. Multiple individual groups and large-scale consortia such as The Cancer Genomic Atlas (TCGA), have sequenced close to a thousand lung cancer samples to date. [1-8]Apart from furthering our understanding of the frequently altered pathways in common histological subtypes of lung cancer, data from these studies have also highlighted the molecular heterogeneity underlying this disease. Investigators from TCGA initially reported genomic, transcriptomic, methylation and copy-number alterations in 230 adenocarcinoma (LUAD) and 178 squamous cell carcinoma (SQCC) samples.[1][,][2]An updated analysis, that included a total of 660 LUAD and 484 SQCC samples, was subsequently published in early 2016.[9] While the majority of lung cancer patients have a history of cigarette smoking, nearly 10% of patients are lifelong never-smokers.[3]Lung cancers that arise in smokers exhibit some of the highest mutational burdens across all human cancers (8-10 mutations/Mb). The vast majority of these mutations are C>A transversions. On the contrary, tumors from never smokers demonstrate a much lower mutational burden (0.8-1 mutations/Mb) and are enriched for C>T transitions. [1][,][2] Single nucleotide variations (SNVs) and copy number alterations (CNAs) While both LUAD and SQCC show frequent inactivation of the tumor suppressors TP53 and CDKN2A, these alterations are considerably more common in SQCCs. CDKN2A harbors the loci for two isoforms, p14ARF and p16INK4A, and is inactivated in SQCC through homozygous deletion (29%), methylation (21%), inactivating mutations (18%), or exon 1b skipping (4%). [1][,][2]These findings indicate a strong selective pressure for the loss of these tumor suppressors in NSCLC. The pattern of oncogenic alterations varies considerably between LUAD and SQCC. While LUADs typically showed activating RTK/RAS/RAF pathway mutations, these mutations are highly infrequent in SQCCs - which predominantly showed alterations in oxidative stress response (NFE2L2, KEAP1 and CUL3) and squamous differentiation pathways (SOX2, TP63, NOTCH1, etc.) in 44% of samples. [1,2]KRAS is the most commonly mutated oncogene in LUAD, followed by EGFR, BRAF, PIK3CA, and MET. The majority of EGFR mutations in LUAD are targetable (L858R or exon 19 deletion) with tyrosine kinase inhibitors (TKIs).[1]In contrast, such alterations are absent in SQCC. Two SQCC samples however demonstrated L861Q mutations in EGFR, which are potentially targetable with TKIs. [1][,][2]Although SQCC and LUAD shared several CNAs at the chromosomal arm level, amplification of 3q was frequent in SQCC. This region harbors important oncogenes such as SOX2, PIK3CA, and TP63. LUADs frequently showed amplifications in genes such as NKX2-1, TERT, MDM2, KRAS, and EGFR.[1][,][2]Oncogenic activation of kinases such as ALK, ROS1, and RET through rearrangement has been well described in LUAD, and these fusions are targetable with TKIs. These fusions were seen in 1-2% (ALK : 3/230, ROS1: 4/230, and RET: 2/230 samples) of LUADs. [1][,][2] Transcriptome analysis Deregulated splicing can be a consequence of mutations that alter splice-sites within a gene or splicing factors. Mutations in the proto-oncogene MET that lead to exon 14 skipping, and abnormal splicing of proto-oncogenes such as CTNNB1 as a result of U2AF1 mutation have been described in LUAD. [1] Transcriptome analyses have also enabled a reclassification of LUADs and SQCCs into three and four distinct subtypes, respectively. LUAD samples can be categorized as terminal respiratory unit (enriched for EGFR mutations and fusions; favorable prognosis), proximal-inflammatory (NF1 and TP53 co-mutation), or proximal-proliferative (KRAS and STK11 alterations) subtypes. Similarly, SQCCs can be classified as classical, basal, secretory, or primitive. Alterations in genes that participate in the oxidative stress response pathway, hypermethylation, and chromosomal instability are characteristic of the classical subtype (associated with heavy smoking and poor prognosis). [1][,][2] Key pathogenic alterations TCGA analysis revealed alterations in well known oncogenic drivers involving RAS signaling pathway in 62% of LUAD.. These samples with readily identifiable oncogenic driver alterations were collectively labeled ‘oncogene-positive’. Additional analyses of the ‘oncogene-negative’ sample cohort showed enrichment for RIT1, and NF1 mutations. Given the role of RIT1 and NF1 in RTK/RAS/RAF signaling, samples with these mutations were reclassified as oncogene positive, increasing the overall percentage of oncogene positive samples in LUAD to 76%. Nearly 69% of SQCC samples showed alterations in genes regulating PI3K/AKT, or RTK/RAS signaling. [1][,][2] The inability to readily identify an oncogenic driver in nearly a third of sequenced lung cancer samples highlights the need for greater powering of subsequent studies to identify novel low frequency genomic alterations. For instance, previously uncharacterized alterations in the RTK/RAS/RAF pathway were observed in RASA1, SOS1 in the updated TCGA analysis which analyzed a much larger cohort of samples.[9] Overall, despite showing a few similarities between LUAD and SQCC, investigators of TCGA reported prominent differences between the genomic landscapes of these subtypes. These subtypes have more of their alterations in common with other cancers than with one another. SQCCs more closely resembled head and neck squamous cell and bladder cancer, while LUAD resembled glioblastoma multiforme and colorectal cancer in this regard. [9] Immunotherapies The vast majority of lung cancers do not harbor alterations that are targetable by TKIs. [1][,][2 ]Immune checkpoint inhibitors are approved for use in patients with metastatic NSCLC. There is a clear need to develop optimal predictive biomarkers to identify those who are likely to respond to immune checkpoint inhibitors. Mutational burden has been correlated with better response to checkpoint inhibitors. Furthermore, using exome and transcriptome sequencing and sophisticated bioinformatics, it is now possible to identify mutated and expressed genes that could potentially serve as a trigger for immune response (so called neoantigens) once immune checkpoints like programmed death-1 or programmed death ligand-1 are inhibited.. Swanton and colleagues performed a neoantigen and clonality analysis on TCGA samples to examine characteristics such as neoantigen burden and intratumor heterogeneity (ITH), and their impact on survival. In LUAD, a higher neoantigen burden was significantly associated with longer survival. Although not statistically significant, there was a trend towards longer survival in molecularly homogeneous tumors (<1% ITH) as opposed to heterogeneous tumors. The updated TCGA analysis showed that 47% of LUAD and 53% of SQCC samples exhibited at least five predicted neoantigens. Efforts are ongoing to develop personalized vaccine therapy using predicted neoantigens in lung cancer and other malignancies. Outcomes for patients with advanced lung cancer are likely to improve in the near future with further advances in genome sequencing, molecularly targeted therapies and immunotherapies . [12] References 1. Network CGAR. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-50. 2. Network CGAR. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25. 3. Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012;150:1121-34. 4. Imielinski M, Berger AH, Hammerman PS, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012;150:1107-20. 5. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47-53. 6. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012;44:1111-6. 7. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104-10. 8. Seo JS, Ju YS, Lee WC, et al. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 2012;22:2109-19. 9. Campbell JD, Alexandrov A, Kim J, et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet 2016;48:607-16. 10. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012;4:120ra17. 11. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 2010;363:1734-9. 12. McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463-9.
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SH01 - WCLC 2016 Scientific Highlights - Prevention, Biology, Pathology (ID 483)
- Event: WCLC 2016
- Type: Scientific Highlights
- Track: Epidemiology/Tobacco Control and Cessation/Prevention
- Presentations: 3
- Moderators:M. Filipits, T. Mitsudomi
- Coordinates: 12/05/2016, 07:30 - 08:30, Hall C1
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SH01.01 - Prevention (ID 7116)
07:30 - 08:30 | Author(s): C. Dresler
- Abstract
- Presentation
Abstract not provided
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SH01.02 - Biology (ID 7118)
07:30 - 08:30 | Author(s): R. Govindan
- Abstract
- Presentation
Abstract not provided
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SH01.03 - Pathology (ID 7119)
07:30 - 08:30 | Author(s): K. Kerr
- Abstract
- Presentation
Abstract not provided
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Author of
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.12 - Discussant for MA08.09, MA08.10, MA08.11 (ID 6954)
11:00 - 12:30 | Author(s): M. Filipits
- Abstract
- Presentation
Abstract not provided
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-075 - PD-1 Protein Expression Predicts Survival in Resected Adenocarcinomas of the Lung (ID 5641)
14:30 - 15:45 | Author(s): M. Filipits
- Abstract
Background:
Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have demonstrated clinical activity in patients with advanced non-small cell lung carcinoma (NSCLC). The ability of PD-1 and PD-L1 immunohistochemistry (IHC) to predict benefit of immune checkpoint inhibitors remains controversial. We assessed the prognostic value of PD-1 and PD-L1 IHC in patients with completely resected adenocarcinoma of the lung.
Methods:
We determined protein expression of PD-1 and PD-L1 in formalin-fixed paraffin-embedded surgical specimens of 161 NSCLC patients with adenocarcinoma histology by IHC. We used the EH33 antibody (Cell Signaling) for PD-1 and the E1L3N antibody (Cell Signaling) for PD-L1 IHC. Cut-points of ≥1% PD-1-positive immune cells at any staining intensity and ≥1% PD-L1-positive tumor cells at any staining intensity were correlated with clinicopathological features and patient survival.
Results:
Positive PD-1 immunostaining in immune cells was observed in 71 of 159 (45%) evaluable tumor samples. PD-1 positive staining was not significantly associated with any of the clinicopathological features. Positive PD-1 immunostaining was associated with longer recurrence-free and overall survival of the patients. Multivariate Cox proportional hazards regression analyses identified PD-1 to be an independent prognostic factor for recurrence (adjusted hazard ratio [HR] for recurrence 0.58; 95% confidence interval [CI] 0.36 to 0.94; P = 0.026) and death (adjusted HR for death 0.46; 95% CI 0.26 to 0.82; P = 0.008). PD-L1 positive staining in tumor cells was seen in 59 of 161 (37%) cases. Positive PD-L1 immunostaining correlated with KRAS mutation (P = 0.019) and type of surgery (P = 0.01) but was not significantly associated with any of the other clinicopathological parameters. Positive PD-L1 immunostaining was not associated with survival of the patients (adjusted HR for recurrence 0.92; 95% CI 0.58 to 1.47; P = 0.733; adjusted HR for death 0.61; 95% CI 0.34 to 1.07; P = 0.084).
Conclusion:
Positive PD-1 but not PD-L1 immunostaining is a favorable independent prognostic factor in patients with completely resected adenocarcinoma of the lung.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-032 - Association between EGFR T790M Mutation Copy Numbers in Cell-Free Plasma DNA and Response to Osimertinib in Advanced NSCLC (ID 5454)
14:30 - 15:45 | Author(s): M. Filipits
- Abstract
Background:
Patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who developed the T790M resistance mutation during treatment with EGFR tyrosine kinase inhibitors (TKIs) benefit from treatment with third-generation EGFR TKIs such as osimertinib. Treatment with osimertinib requires the confirmation of the presence of the T790M mutation by re-biopsy of the tumor or by analysis of cell-free plasma DNA from blood samples (liquid biopsy). The purpose of our study was to compare T790M mutation copy numbers in cell-free plasma DNA with response to osimertinib.
Methods:
From April 2015 to June 2016, we included 44 patients with advanced T790M-positive NSCLC who received osimertinib after previous disease progression with an EFGR TKI and in whom response to osimertinib was evaluable. T790M mutation status was assessed by droplet digital PCR in cell-free plasma DNA. The threshold for T790M positivity was >1 copy/mL.
Results:
The T790M mutation status was assessed in all patients by liquid biopsy and in 18 patients also by re-biopsy of the tumor. All 44 patients were T790M-positive in the liquid biopsy. Two out of 18 (11%) patients had a T790M-negative re-biopsy. Thirty-seven patients (86%) showed a response to treatment with osimertinib: 13 (29.5%) complete responses (CR), 24 (54.5%) partial responses (PR), one (2%) stable disease (SD), and six (14%) progressive disease (PD) (Table 1). We observed no statistically significant association between response to osimertinib and T790M copy numbers (p=0.54; Table 1). The median T790M copy numbers across response categories were: CR 25 copies/mL (range 1.7-38092 copies/mL), PR 14 copies/mL (range 1.6-7282 copies/mL), SD+PD 6 copies/mL (range 1.8-475 copies/mL).Table 1 Response Copies/mL CR PR SD PD <10 5 (39%) 11 (46%) 0 (0%) 4 (67%) ≥10 8 (62%) 13 (54%) 1 (100%) 2 (33%)
Conclusion:
Patients benefited from osimertinib treatment independent of T790M copy numbers in the blood samples. Although limited by low numbers, we observed a trend towards better response to osimertinib in patients with ≥10 T790M copies/mL.
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P3.02b-101 - EGFR T790M Resistance Mutation in NSCLC: Real-Life Data of Austrian Patients Treated with Osimertinib (ID 4225)
14:30 - 15:45 | Author(s): M. Filipits
- Abstract
Background:
Somatic mutations in the epidermal growth factor receptor (EGFR) are detected in approximately 13% of the Austrian non-small cell lung cancer (NSCLC) patients. The EGFR T790M resistance mutation located on Exon 20 is the most common mechanism of drug resistance to EGFR tyrosine kinase inhibitors (TKI) in these patients. The mutation can be detected by re-biopsy as well liquid biopsy. Osimertinib (AZD9291), a 3[rd] generation EGFR-TKI, showed a highly clinical activity in these patients. We report about our experience with Osimertinib in EGFR-mutated NSCLC patients, who became resistant to first or second generation TKI`s due to EGFR T790M mutation.
Methods:
From April 2015 to June 2016 we administered osimertinib 80 mg daily to 82 patients who had disease progression after previous treatment with an EFGR TKI. The T790M mutation status was assessed by re-biopsy and/or liquid biopsy. For liquid biopsies, blood samples were collected in EDTA-containing vacutainer tubes and processed within 2 hours after collection. Cell-free plasma DNA was extracted by using the QIAamp circulating nucleic acid kit (Qiagen) according to the manufacturer’s instructions. Mutation status was assessed with QX-100™ Droplet Digital™ PCR System (Bio-Rad).
Results:
The T790M mutation status was assessed in 48 patients by liquid biopsy only and in 13 patients by re-biopsy of the tumor. In 21 patients the T790M mutation was detected by both methods. 70 (85%) patients showed a clear clinical and radiographic response. Out of these, 70 patients, 14 (17%) patients reached a complete remission, 56 (68%) patients showed partial response and in 5 (6%) patients, a stable disease after treatment with osimertinib was observed. Five patients had symptomatic brain metastasis initaly without any further option of local treatment, and showed a clear a clear clinical benefit and a partial remission radiographically. Osimertinib was well tolerated. No clinically relevant significant side effects were reported.
Conclusion:
Osimertinib was highly active in our patients, while showing good safety profile. Therefore, re-biopsy or liquid biopsy should be performed in clinical routine to detect the T790M mutation. With the above described method, liquid biopsy could replace re-biopsy in clinical practice in the future.
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SC21 - Predictive Biomarkers for Outcome of Systemic Therapy in NSCLC (ID 345)
- Event: WCLC 2016
- Type: Science Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:K. Kerr, T. Mitsudomi
- Coordinates: 12/06/2016, 16:00 - 17:30, Hall C7
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SC21.02 - Predictive Biomarkers for Chemotherapy of NSCLC (ID 6686)
16:00 - 17:30 | Author(s): M. Filipits
- Abstract
- Presentation
Abstract not provided
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