in the Princess Margaret Cancer Centre Personalized Treatment Outcomes in Never Smokers with Advanced Lung Cancer in the Princess Margaret Cancer Centre Grzegorz J. Korpanty1, Suzanne Kamel-Reid2, Ming-Sound Tsao3, David Hwang3, Alona Zer1, Geoffrey Liu1, Natasha Leighl1, Ronald Feld1, Bethany Gill1, Melania Pintilie1, Frances A. Shepherd1 1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; 2 Laboratory Genetics, University Health Network, Toronto, ON, Canada; 3Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada Background Results Lung cancer remains one of the most commonly diagnosed malignancy worldwide and the leading cause of cancer-related death [1]. Until the last decade, non-small cell lung cancer (NSCLC) was considered a single disease, and systemic treatment of metastatic NSCLC was limited to platinum-based chemotherapy doublet resulting in approximately 20% response rates and median survival of 8 months [2]. Only recently we have realized that recognition of histological subtypes of NSCLC is clinically relevant when choosing systemic, platinum-based chemotherapy [3]. In recent years, the oncology community has seen a paradigm shift in the molecular diagnosis and treatment of lung cancer thanks to identification of sensitizing mutations within the epidermal growth factor receptor gene (EGFR) to EGFR tyrosine kinase inhibitors (EGFR-TKIs) (erlotinib, gefitinib, afatinib) and anaplastic lymphoma kinase gene (ALK) rearrangements (i.e. EML4-ALK) to ALK inhibitors (crizotinib, ceritinib) [4]. These breakthrough discoveries provide the unique opportunity for molecularly selected lung cancer patients to receive targeted, personalized treatment options that translate into clinically meaningful benefit [4]. Molecular testing of NSCLC is now widely recommended by oncology societies because it provides personalized treatment options for patients with metastatic disease [5, 6]. Lung cancer in never smokers (LCINS) (less than 100 cigarettes in the lifetime) is becoming a growing health problem and is now recognized as the seventh cause of cancer-related mortality worldwide [7]. Significant sex, histo-pathological, molecular, clinical and geographical differences are recognized in patients who never smoked when compared with the smoking population with lung cancer [8]. LCINS occurs more frequently in younger patients, women and adenocarcinoma histology predominates among those patients. Its incidence is higher is certain geographical regions like Asia when compared with Europe or North America. Certain genomic changes such as epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER-2), BRAF mutations or anaplastic lymphoma kinase (ALK), ROS1 or RET gene fusions and re-arrangements, occur more frequently in the tumours of never smoking patients with lung cancer [9-13]. In our study we analyzed personalized treatment outcomes in never smokers with advanced lung cancer. Patients characteristics Treatment characteristics OS in T-pts by mutation type ALK N=24 Median OS=66 months EGFR * N=176 Median OS=41 months EGFR exon 19 N=110 Median OS=47 months EGFR exon 21 N=65 Median OS=36 months jgg Characteristic T-pts N=203 N (%) NT-pts N=300 Age – years Median Range 59.7 28-90 61.6 18-94 Sex Male Female 56 (28) 147 (72) 85 (28) 215 (72) Race Caucasian Asian Black South Asian Other (Arab, Latin American, Native Canadian, Mixed) 73 (36) 100 (49) 15 (7.5) 6 (3) 9 (4.5) 153 (51) 112 (37) 18 (6) 12 (4) 5 (2) ECOG 1 2 3 86 (41.5) 108 (54) - 116 (39) 145 (48) 25 (8) 14 (5) TNM stage at initial diagnosis 4 16 (8.5) 163 (79.5) 23 (8) 16 (5) 37 (12) 224 (75) Histopathology Adenocarcinoma Large Cell Adenosquamous Small Cell Squamous Cell Other (NSCLC, Mixed tumour, Carcinoid, Lymphoepithelioma) 192 (95) 5 (2.5) 4 (2) 1 (0.5) 241 (80) 11 (4) 7 (2) 3 (1) 19 (6.5) Known TTF-1 results for adenocarcinoma Positive Negative 144 (99) 2 (1) 126 (81) 22 (9) Mutation frequency * 20 tested ONLY for EGFR 45 tested ONLY for EGFR and ALK 21 tested with Next Generation Sequencing platform (MassARRAY technology Sequenom – 12; Illumina MiSeq – 9) SINGLE MUTATIONS 193 (95) 38 (12) Targeted (N=193) Non-Targeted (N=38)   EGFR (N=167) ALK (N=23) HER-2 (N=3) EGFR (N=15) ALK (N=6) KRAS (N=6) TP53 (N=4) BRAF (N=2) PIK3CA (N=2) CTNNB1 (N=1) HER-2 (N=1) SMAD4 (N=1) MULTIPLE MUTATIONS 10 (5) Targeted (N=10) Non-Targeted (N=11) EGFR and other (N=9) ALK and other (N=1) EGFR and other (N=5) KRAS and other (N=2) PIK3CA and other (N=2) MET and other (N=1) No mutations* 86 (29) Unknown mutation status 165 (55) Characteristic T-pts N=203 N (%) NT-pts N=300 Initial treatment for metastatic disease Targeted treatment 143 (70) - Systemic chemotherapy (platinum doublet) 42 (21) 128 (43) Other: 18 (9) 172 (57)  clinical trial 9 (4.5) 25 (8.3)  radiotherapy -  40 (13.3)  chemo-radiotherapy 3 (1.5)  5 (1.6) observation 2 (1)  32 (10.6)  single agent systemic chemotherapy 4 (2)  15 (5) surgery 17 (5.6)  EGFR TKI (EGFR WT or unknown mutation status) 29 (9.6)  Unknown 9 (3) Lines of systemic therapy for metastatic disease 0-1 2-3 ≥4 84 (43.5) 77 (38) 42 (18.5) 145 (48) 115 (38) 31 (11) Targeted treatments characteristics EGFR (N=176)   1. One line of targeted treatment - Gefitinib only (N=102) Erlotinib only (N=30) 132 (75) 2. Two or more lines of targeted treatment Gefitinib followed by Afatinib (N=15) Erlotinib followed by Afatinib (N=11) Gefitinib followed by AZD9291 (N=6) Erlotinib followed by AZD9291 (N=5) Erlotinib followed by Gefitinib (N=3) Erlotinib followed by Afatinib followed by AZD9291 (N=3) Gefitinib followed by Afatinib followed by AZD9291 (N=1) 44 (25) ALK (N=24) Crizotinib (N=16) Ceritinib (N=2) 18 (75) 2. Two lines of targeted treatment Crizotinib followed by Ceritinib (N=6) 6 (25) HER-2 (N=3) Afatinib ONLY (N=1) Erlotinib ONLY (N=1) Dacomitinib followed by Afatinib (N=1) Brain metastases at diagnosis Total 75 (37) 33 (11) EGFR 68 (91) 6 (18) ALK 7 (9) 2 (6) HER-2 1(3) Not “druggable”mutations (KRAS, PI3KCA, TP53) 3 (9) No mutations 18 (55) Unknown mutation status EGFR vs. ALK, HR=1.77, 95% CI: 0.77-4.06; p=0.18 EGFR Exon 21 vs. Exon 19, HR 1.48, 95% CI: 0.95-2.3; p=0.083 Overall survival *1 patient had EGFR exon 18 deletion Time to death (years) OS by ethnicity in T-pts group Caucasian N=73 Median OS = 60 months Asian N=100 Median OS = 38 months Other N=30 Median OS = 40 months Methods The study population consisted of 503 never smokers with stage IV lung cancer treated in Princess Margaret Centre, Toronto from 1988 to 2014. There was 203 patients who received targeted (personalized) treatment (T-pts) and 300 patients who did not (NT-pts). Clinico-pathological and treatment data were extracted from the patients’ medical records. Variables included in the univariate analysis of overall survival (OS) included: age, sex, ethnicity, BMI, ECOG performance status, presence of mutations, targeted treatments and their duration. Caucasian vs. Asian, HR=0.56, 95% CI: 0.35-0.9; p=0.016 Caucasian vs. Other, HR=0.62, 95% CI: 0.34-1.15; p=0.13 Overall survival Tissue analysis for mutations Time to death (years) All patients N=674 Stage IV (N=503) Tissue available for molecular testing N=338 (67%) EGFR ONLY status* N=21 (6%) EGFR and ALK ONLY status* N=129 (38%) Multiple gene testing N=188 (56%) Sequenom N=102 (54%) Mi-Seq** N=86 (46%) No tissue available N=165 (33%) Stage I-III (N=171) * Because of low likelihood of multiple mutations, no further testing was performed when EGFR or ALK mutation was detected OS in EGFR-mutant cohort with brain metastases at diagnosis by mutation type EGFR and no brain mets N=122 Median OS=66 months EGFR and brain mets N=74 Median OS=41 months EGFR exon 19 and brain mets N=44 Median OS=59 months EGFR exon 21 and brain mets N=30 Median OS=21 months Overall survival Results – mutation status Overall Survival OS in EGFR- and ALK-mutant patients with brain metastases at diagnosis EGFR exon 21 vs. exon 19 del, HR= 4.24, 95% CI: 1.86 − 9.67; p=0.002 Time to death (years) T-pts with EGFR or ALK N=200 Median OS = 47 months NT-pts with EGFR or ALK * N=27 Median OS > 47 months NT-pts without mutation N=86 Median OS = 23 months Other pts N=190 Median OS = 19 months Patients N (%) Median OS (months) Three year OS - % p-value ALK* 31 (100) >47 86 % 0.022** ALK (no brain mets) 22 (71) 66 85% 0.651 ALK (brain mets) 9 (29) 88% EGFR* 196 (100) 47 61% EGFR (no brain mets) 122 (62) 63% 0.514 EGFR (brain mets) 74 (38) 56 60% EGFR (brain mets – Exon 19) 44 (60) 57 80% 0.001 EGFR (brain mets Exon 21) 30 (40) 21 32% Mutation rate (252/338) = 75% Conclusions Never smokers with advanced NSCLC can achieve long survival when treated with targeted therapy. Patients with EGFR mutation positive tumours who present with brain metastases at diagnosis have similar survival to those without. However, in patients with CNS metastases at diagnosis EGFR Exon 21 compared to Exon 19 was associated with significantly shorter survival. Our observation of poorer survival in patients with EGFR Exon 21 and brain metastases warrants further study. Log rank p<0.001 Overall survival * 27 pts with resected or asymptomatic stable metastatic disease References: Siegel R, Naishadham D, Jemal A. CA: a cancer journal for clinicians (2013) 63(1):11-30. Azzoli CG, Temin S, Aliff T, Baker S, Jr., Brahmer J, Johnson DH, et al. J Clin Oncol (2010) 29(28):3825-31. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. J Clin Oncol (2008) 26(21):3543-51. Mok TS. Nat Rev Clin Oncol (2011) 8(11):661-8. Keedy VL, Temin S, Somerfield MR, Beasley MB, Johnson DH, McShane LM, et al. J Clin Oncol (2011) 29(15):2121-7. 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