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F. Shepherd
Moderator of
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OA06 - Prognostic & Predictive Biomarkers (ID 452)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 8
- Moderators:F. Shepherd, Y. Yatabe
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 1
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OA06.01 - Clinical Utility of Circulating Tumor DNA (ctDNA) Analysis by Digital next Generation Sequencing of over 5,000 Advanced NSCLC Patients (ID 6096)
14:20 - 15:50 | Author(s): P. Mack, K.C. Banks, J.W. Riess, O.A. Zill, S.A. Mortimer, D.I. Chudova, J. Odegaard, C.E. Lee, R.J. Nagy, H. Eltoukhy, A. Talasaz, R.B. Lanman, D.R. Gandara
- Abstract
- Presentation
Background:
Detection of actionable genomic alterations is now required for NCCN guideline-compliant work-up of NSCLC adenocarcinoma. Next-generation sequencing (NGS) of ctDNA, if sufficiently sensitive and specific, could provide a non-invasive, comprehensive genotyping platform relevant to clinical decision-making when tissue is insufficient or at time of progression on targeted therapies.
Methods:
A highly accurate, deep-coverage (15,000x) ctDNA plasma NGS test targeting 54-70 genes (Guardant360) was used to genotype 5,206 advanced-stage NSCLC patients accrued between 6/2014 – 4/2016. The frequency and distribution of somatic alterations in key genes were compared to those described in TCGA (Pearson and Spearman correlations). The clinical impact of ctDNA testing was evaluated by identification of resistance mechanisms emergent at progression on targeted therapies, and through analysis of additional driver mutations detected by ctDNA at baseline in 362 consecutive NSCLC patients with tissue mutation data available. The positive predictive value (PPV) of ctDNA sequencing was assessed in 229 patients with known tumor driver alterations.
Results:
ctDNA alterations were detected in 86% of cases; EGFR mutations in 25%, KRAS mutations in 17%, MET amplification in 4%, BRAF mutations in 3% and other rare but potentially actionable alterations in 9%. Mutation patterns among driver oncogenes were highly consistent with those from TCGA (Pearson r=0.92, 0.99, 0.99 for EGFR, KRAS, and fusion breakpoint location). PPV of ctDNA-detected variants was 100% for EGFR[L858R], 98% for EGFR[E19del], 96% for ALK, RET, or ROS1 fusions, and 100% for KRAS[G12/G13/Q61] mutations. In 362 cases with tissue information available, 63% (229/362) were tissue quantity-insufficient or undergenotyped (QNS/UG). ctDNA analysis identified driver mutations in 51 of the 229 QNS/UG cases, a 38% increase in detection rate over tissue alone. Among 1,111 EGFR-mutant cases, resistance mutations were identified at progression at frequencies consistent with published literature: EGFR[T790M] 47%, MET amp 5%, ERBB2 amp 5%, FGFR3 fusions 0.4%, ALK/other fusions 1%, BRAF mutations 1.8%, PTEN inactivation 2.5%, NF1 inactivation 3%, RB1 inactivation 3%, KRAS mutations 1.9%. In 143 consecutive NSCLC patients with detailed follow-up and serial analysis seen at the UC Davis Cancer Center, informative driver mutations were observed in 48 (34%).
Conclusion:
This series represents the largest NSCLC ctDNA study to date. Genotypic patterns of truncal mutations were highly consistent with TCGA in terms of frequency and distribution. At baseline, ctDNA augmented tissue analysis by identifying additional, actionable mutations when tissue was QNS/UG. ctDNA NGS conducted at progression identified emergent resistance mutations that could inform subsequent courses of therapy.
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OA06.02 - Mutational Load Predicts Survival in LDCT Screening-Detected Lung Cancers (ID 5577)
14:20 - 15:50 | Author(s): G. Sozzi, C. Verri, C. Borzi, T. Holscher, M. Dugo, A. Devecchi, K. Drake, S. Sestini, P. Suatoni, E. Romeo, M. Boeri, U. Pastorino
- Abstract
- Presentation
Background:
The issue of overdiagnosis in low-dose computed tomography (LDCT) screening trials for lung cancer has to be addressed by the development of complementary biomarkers able to improve detection of aggressive disease. We previously identified a 24 plasma miRNA signature endowed with good performance in terms of sensitivity and specificity in subjects enrolled in independent LDCT screening trials. However, the relationship between circulating miRNAs in plasma and the molecular heterogeneity of the patients’ tumors needs to be considered. Linking tumor genomics to circulating miRNA profiles represent an attractive approach. In fact a plasma miRNA assay able to classify molecular subclasses of tumors could constitute a sort of “liquid biopsy” endowed with not only diagnostic but also prognostic and, potentially, therapeutic value.
Methods:
We evaluated the mutation profile by targeted Next-Generation Sequencing (NGS) analysis (Cancer Hotspot Panel v.2) in 94 Low Dose Computed Tomography (LDCT) screening-detected lung tumors resected from subjects participating in 3 screening trials for lung cancer. Mutation profile was associated with clinicopathologic, survival features and with a plasma MSC risk level of patients. The mutational profile obtained was compared with the mutations of a selected dataset of clinically detected lung tumors through The Cancer Genome Atlas (TCGA).
Results:
We showed alterations in the main genetic drivers in 79% of screening lung tumors whereas 21% of tumor samples had no alteration within these amplicons. Significant associations between TP53, squamous histology and smoking intensity as well as KRAS mutations with worse OS were detected. EGFR alterations were present in 4 tumors from heavy smokers. The 5-year overall survival (OS) of screening patients with and without mutations in the tumors was 64% and 100%, respectively (p=0.019). By combining the mutational status with the MSC risk profile, patients were stratified into 3 groups with 5-year OS ranging from 41% to 96% (p<0.0001) and the prognostic value was significant even when controlling for stage (p=0.017). A similar mutational profile and mutation frequency was observed in screening- and in clinical (TCGA) tumors, whereas difference in 5-year OS between subjects with and without mutations was exclusively detected in screening patients.
Conclusion:
The mutation profile of screening-detected tumors, while similar to that of clinically-detected tumors, was a strong predictor of OS. The combination of tumor mutational status with a circulating miRNA-based risk classifier predicts tumor aggressiveness and clinical outcome and may find rapid application in LDCT screening programs by reducing the number of unnecessary interventions and helping plan targeted treatment
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OA06.03 - Transcriptome Analysis of ATM-Deficient NSCLC (ID 6196)
14:20 - 15:50 | Author(s): L.F. Petersen, E. Enwere, M. Konno, O. Kovalchuk, D..G. Bebb
- Abstract
- Presentation
Background:
Current targeted therapy options in lung cancer, such as EGFR and ALK inhibitors, are effective, though limited in use by the low percentage of patients that carry targetable mutations for these biomarkers. Targeting a broader biological process like DNA damage response (DDR), as with recent synthetic lethality exploits in BRCA-deficient tumours, may offer a form of precision therapy for a larger number of patients. We have shown that NSCLC cells deficient in the DDR protein ATM, exhibit similar synthetic lethality when treated with a PARP1 inhibitor, and that NSCLC patients lacking detectable ATM have poorer overall survival. In vitro, ATM deficient, or “ATMic” cells show increased sensitivity to chemotherapeutics at much lower levels when given in combination with PARP inhibitor. This data suggests that ATM status may be an important determinant for treatment modalities including low dose radiation or platin therapy, or novel synthetic lethality therapies. Here, we seek to determine the cause of ATM loss in NSCLC patients through targeted sequencing, and thorough transcriptomic and epigenetic analysis.
Methods:
We perform whole-transcriptome analysis on NSCLC patient samples previously characterized as normal or ATMic, to detect differences in intracellular pathway activation in these tumours. Additional analysis using OncoFinder software identifies possible effective therapies based on which signalling pathways are most active in the normal or ATMic patients. We also perform targeted NGS on these samples. To our knowledge, no sequencing of ATM has been performed on samples that have also been characterized through other methods (i.e. quantitative IHC) to be ATM deficient.
Results:
We have generated a substantial body of evidence showing that ATM loss has significant impact on the cell sensitivity to several therapeutic modalites. As such ATMic tumours may be treated more effectively using specific treatment strategies than their ATM competent counterparts. Initial analysis of NSCLC cell lines using the outlined methodologies distinguishes ATM status and identifies different therapeutic agents based on inherent molecular differences. A complete analysis of the transcriptome profiles of ATMic NSCLC patients will be presented and discussed.
Conclusion:
This research helps complete the overall picture of what the therapeutic implications of ATM loss in NSCLC actually are and how ATMic tumours can best be identified in the clinic. Together, these analyses will give us a stronger understanding of the mechanism for ATM loss in NSCLC, as well as allow us to develop an ATMic “signature” for reliably determining ATM status in patients for directing their treatment options.
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OA06.04 - Discussant for OA06.01, OA06.02, OA06.03 (ID 6962)
14:20 - 15:50 | Author(s): R. Soo
- Abstract
- Presentation
Abstract not provided
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OA06.05 - Proteomic Analysis of ERCC1 Predicts Benefit of Platinum Therapy in NSCLC: A Reevaluation of Samples from the TASTE Trial (ID 5361)
14:20 - 15:50 | Author(s): J. Soria, K. Olaussen, F. Cecchi, E. An, C. Yau, M. Wislez, G. Zalcman, D. Moro-Sibilot, D. Perol, B. Besse, F. Morin, T. Hembrough
- Abstract
- Presentation
Background:
It is hypothesized that low or absent expression of the excision repair cross-complementation group 1 (ERCC1) protein predicts improved survival in NSCLC patients treated with platinum-based therapy. However, the International Adjuvant Lung Cancer Trial Collaborative Group concluded that current ERCC1 assessment methods are inadequate for clinical decision-making. Due to the unreliability of ERCC1 immunohistochemistry (IHC), the IFCT-0801 TASTE (Tailored Postsurgical Therapy in Early-Stage NSCLC) trial of adjuvant therapy for NSCLC was discontinued. We reevaluated a subset of samples from the TASTE trial using mass spectrometry-based proteomics to quantitate ERCC1 protein. We correlated ERCC1 proteomic status with survival after chemotherapy with cisplatin/pemetrexed and compared it to ERCC1 IHC ranking.
Methods:
Formalin-fixed, paraffin-embedded NSCLC tumor tissues were laser microdissected, solubilized, digested, and proteomically analyzed. A multiplexed, selected reaction monitoring mass spectrometric assay was used to quantitate levels of multiple proteins including ERCC1. The Kaplan-Meier method and univariate Cox analysis assessed overall survival (OS) and relapse-free survival (RFS). A chi-squared test compared binary proteomic levels of ERCC1 (detectable vs. undetectable) with the IHC status assessed using an anti-ERCC1 antibody (8F1) during the TASTE trial.
Results:
Of 146 evaluable patients, 33 (22.6%) had undetectable ERCC1 by quantitative proteomics. Proteomics found no detectable ERCC1 protein in 8/36 (22.2%) IHC-positive patients nor in 8/22 (19.3%) IHC-indeterminate patients. ERCC1 was detected in 71/88 (80.7%) IHC-negative patients (range: 36-137 amol/µg total tumor protein). Undetectable ERCC1 by proteomics was prognostic of OS (hazard ratio [HR]: 5.45; p=0.031). In survival analyses of cisplatin-treated patients (n=122), only one of the 15 deaths occurred among the patients with undetectable ERCC1 protein. These patients had better OS than cisplatin-treated patients with detectable ERCC1, although the difference statistically nonsignificant (HR: 3.98; p=0.102). RFS was similar between patients with and without detectable ERCC1. GARFT protein (predictive of response to pemetrexed) was quantified in 100% of patients (range: 492-4006 amol/µg). The 10 cisplatin/pemetrexed-treated patients with GARFT levels >900 amol/µg had nonsignificantly worse OS than their counterparts with lower GARFT levels (p=0.08).
Conclusion:
Although underpowered to detect statistically significant survival differences, this study clearly demonstrates that quantitative proteomics can increase accuracy in identifying NSCLC patients who will respond to platinum-based therapy because they do not express ERCC1. Approximately 28% of such patients were misclassified by ERCC1 IHC in the TASTE trial. Clinicians should be aware that multiplexed quantitative proteomics can quantitate ERCC1 simultaneously with multiple clinically relevant proteins in lung tumors and small biopsies.
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OA06.06 - Druggable Alterations Involving Crucial Carcinogenesis Pathways Drive the Prognosis of Squamous Cell Lung Carcinoma (SqCLC) (ID 5342)
14:20 - 15:50 | Author(s): S. Pilotto, M. Simbolo, I. Sperduti, S. Novello, C. Vicentini, U. Peretti, S. Pedron, R. Ferrara, M. Caccese, M. Milella, A. Mafficini, P. Visca, M. Volante, F. Facciolo, A. Santo, L. Carbognin, M. Brunelli, M. Chilosi, A. Scarpa, G. Tortora, E. Bria
- Abstract
- Presentation
Background:
We previously built and validated a risk classification model for resected SqCLC by combining clinicopathological predictors to discriminate patients’ (pts) prognosis (Pilotto JTO 2015). Here we (AIRCMFAG project no. 14282) investigate the molecular portrait of prognostic outliers to identify differentially expressed, potentially druggable alterations.
Methods:
Based on the published 3-class model, 176 and 46 pts with good and bad prognosis, respectively, were identified. Somatic Mutations (SM) and Copy Number Alterations (CNA) were evaluated with Next Generation Sequencing (NGS) for 59 genes (Ion Proton system, Ion Ampliseq custom panel). Moreover, RNA expression assays, immunohistochemistry (IHC) and immunofluorescence (FISH) were performed. Descriptive statistic was adopted and continuous variables were dichotomized according to AUC or medians.
Results:
Herein, the analysis of 60 pts (good/poor 27/33) is reported. In the overall population, the median rate of SM (3.3%) is lower compared to the median rate of CNA (28.3%), without significant differences between the two prognostic groups. The most frequent SM resulted to be missense (66.7%) and nonsense (20.3%) mutations, whereas the copy number gain is the most common CNA (76.7%), The distribution of relevant alterations in the main carcinogenesis pathways in term of SM, CNA and expression (by RNA, IHC and FISH), according to the prognostic subgroups, are reported in the table.Pathway Gene [method] Good [%] Poor [%] p-value Squamous differentiation SOX [CNA] 74.1 51.5 0.11 TP63 [CNA] 37.0 21.2 0.25 Epithelial to mesenchymal transition SNAI1 [RNA] 59.2 90.9 0.006 Vimentin [RNA] 44.4 69.7 0.07 mTOR PI3KCA [SM] 0 9.0 0.24 RICTOR [CNA] 3.7 27.3 0.017 p-mTOR [IHC] 11.1 18.1 0.5 Tyrosine kinase receptors DDR2 [SM] 11.1 0 0.085 FSR2 [CNA] 3.7 18.1 0.12 MET [FISH] 11.1 24.2 0.32 FGFR3 [FISH] 25.9 42.4 0.28 Cell cycle regulators CDKN2A [CNA] 22.2 3.0 0.38 SMAD4 [CNA] 33.3 57.6 0.074 Immune checkpoints PD-L1 [IHC] 18.5 6.1 0.23 PD-1 [RNA] 51.8 93.9 <0.0001
Conclusion:
Although performed on a limited number of pts, such comprehensive analysis of DNA, RNA and proteins, using different methodologies, is feasible and allow identifying potentially druggable prognostic modulators, such as RICTOR/PI3K/mTOR signaling pathway. The possibility to inhibit this pathway with selective agents is currently under investigation in in vitro preclinical models.
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- Abstract
- Presentation
Background:
Veliparib is a potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor that has synthetic lethality interaction with cancers harboring homologous recombination deficiency. In preclinical models, it has also been shown to delay the repair of DNA damage induced by chemotherapeutics (platinum, alkylators, topoisomerase inhibitors). Clinically meaningful improvements in progression-free survival and overall survival were observed in a phase 2 trial of veliparib with carboplatin/paclitaxel in previously untreated metastatic or advanced NSCLC (M10-898 study). Intriguingly, smoking history had a major impact on veliparib effect—smokers benefited most from veliparib addition. The underlying mechanism for this observation remains unclear. The efficacy benefit of veliparib in smokers is not dependent on tobacco exposure during study treatment, but correlates with the duration of smoking history, suggesting a genetic basis.
Methods:
Genomic signatures in NSCLC associated with smoking status have been identified by The Cancer Genome Atlas (TCGA) Lung Cancer Project. Relevant observations were leveraged in the reported analysis. To comprehensively identify genes or genomic features that are associated with smoking status and veliparib response, patient tumor samples from the M10-898 trial were subjected to whole-exome (N = 38) and RNA sequencing (N = 75) analysis. Alexandrov somatic mutational signature was calculated from exome sequencing data.
Results:
Data from TCGA show that cancer genomes in smokers harbor significantly more genetic alterations than those in non-smokers. These alterations include high mutational burden, high C>A transversion, high mutation frequency of key cancer genes (particularly TP53), and high homologous recombination defect signature. Similar observations were confirmed in the M10-898 study. Of the 38 patients with exome data, 26 were determined to be positive for a smoking-related signature—signature 4. Elevated mutational burden was observed among current and former smokers, with a mean of 199 somatic mutations in current or former smokers vs 60 in never-smokers (p = 0.004). The small sample size of our genomic cohort nevertheless precludes conclusive association of genomic signatures and veliparib benefits.
Conclusion:
Cancer genomes in smokers are enriched with genetic alterations associated with poor outcome using standard chemotherapy, as well as with vulnerability factors that can prime tumors to respond to veliparib. For further validation, a targeted sequencing assay to detect key DNA damage and repair genes as well as key genomic signatures has been established and will be used in all phase 3 veliparib trials.
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OA06.08 - Discussant for OA06.05, OA06.06, OA06.07 (ID 7006)
14:20 - 15:50 | Author(s): M. Gottfried
- Abstract
- Presentation
Abstract not provided
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Author of
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.11 - CNS Response to Osimertinib in Patients with T790M-Positive Advanced NSCLC: Pooled Data from Two Phase II Trials (ID 4920)
14:20 - 15:50 | Author(s): F. Shepherd
- Abstract
- Presentation
Background:
Brain metastases develop in 25–40% of patients with NSCLC. Osimertinib is an oral, potent, irreversible EGFR-TKI, selective for both sensitising (EGFRm) and T790M resistance mutations. Preclinical and early clinical evidence support central nervous system (CNS) penetration and activity of osimertinib. Two Phase II studies (AURA extension [NCT01802632] and AURA2 [NCT02094261]) evaluating the efficacy and safety of osimertinib are ongoing. We present a pre planned subgroup analysis assessing pooled CNS response from these two studies; data cut-off (DCO) was 1 November 2015. An earlier pooled analysis from these two studies (1 May 2015 DCO) showed the objective response rate (ORR) in patients with CNS metastases was consistent with ORR in the overall patient population.
Methods:
Patients with advanced NSCLC who progressed following prior EGFR-TKI therapy with centrally-confirmed T790M positive status (cobas® EGFR Mutation Test) received osimertinib 80 mg once daily (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment. CNS efficacy was assessed in an evaluable for CNS response analysis set, which included patients with at least one measurable CNS lesion on baseline brain scan (RECIST v1.1) by blinded independent central neuroradiology review (BICR). Effect of prior radiotherapy on CNS response was assessed.
Results:
As of 1 November 2015, 50/192 patients with baseline brain scans had at least one measurable CNS lesion identified by BICR. Baseline demographics were broadly consistent with the overall patient population. Confirmed CNS ORR was 54% (27/50; 95% CI: 39%, 68%), with 12% complete CNS response (6/50 patients). The median CNS duration of response (22% maturity) was not reached (95% CI: not calculable [NC], NC). The estimated percentage of patients remaining in response at 9 months was 75% (95% CI: 53, 88). CNS disease control rate (DCR) was 92% (46/50; 95% CI: 81%, 98%). Median time to first response was 5.7 weeks (range: 5.6–6.6). Median best percentage change from baseline in CNS target lesion size was 53% (range: -100% – +80%). Median follow up for CNS progression-free survival (PFS) was 11 months; the median CNS PFS was not reached (95% CI: 7, NC). At 12 months, 56% (95% CI: 40%, 70%) of patients were estimated to remain on study, alive and CNS progression-free. CNS response was observed regardless of prior radiotherapy to the brain.
Conclusion:
Osimertinib demonstrates durable efficacy in patients with T790M NSCLC and measurable CNS metastases, with a CNS response rate of 54% and a DCR of 92%.
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MA17 - Genetic Drivers (ID 409)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Satouchi, G.R. Simon
- Coordinates: 12/07/2016, 14:20 - 15:50, Lehar 1-2
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MA17.06 - Landscape of Somatic Mutations Involving Lung Cancer Associated Genes in Non-Small Cell Lung Cancer (NSCLC) Patient-Derived Xenografts (ID 6084)
14:20 - 15:50 | Author(s): F. Shepherd
- Abstract
- Presentation
Background:
Patient-derived tumor xenografts (PDXs) have high fidelity to their histological origins, and maintain the molecular heterogeneity and genetic aberrations of the donor patient tumors more faithfully than established in non-small cell lung cancer (NSCLC) cell lines. This study evaluated whether our panel of PDX models recapitulate known cancer-related gene mutations.
Methods:
Whole-exome sequencing was completed on 103 NSCLC PDX models, 47 adenocarcinoma (AdC) and 56 squamous (SqCC), with a mean coverage of 84x. After filtering for contaminating mouse reads, the exome data were aligned using the Burrows-Wheeler Aligner, processed using the standard GATK pipeline, and mutations were identified using MuTect. Additional filtering using dbSNP, ExAC and ESP was performed for cases without corresponding normal adjacent lung exome data (n = 80). The identified mutations were compared to 1260 frequently mutated cancer-related genes, which were compiled from a panel of cancer-related mutated genes (555) and a panel of lung cancer-specific mutated genes (1082).
Results:
High rates of somatic mutations were observed in both AdC (mean of 12.4 mutations/megabase) and SqCC (mean of 11.7 mutations/megabase) PDX models. Compared to the rates observed in primary lung cancers in The Cancer Genome Atlas studies (mean of 8.9 mutations/megabase in AdC; 8.1 mutations/megabase in SqCC), these values appear higher, but may be inflated due to the lack of data from corresponding normal tissues. AdC models had a total of 953 mutated genes (median: 57 genes/model; range: 5-307), while SqCC models were characterized by 1007 mutated genes (median: 55 genes/model; range: 21-354). Specific mutation frequencies were compared to those determined in a recent study involving genomic alterations in human primary lung AdC and SqCC (Nature Genetics 2016; 48; 607–616). This comparison, based on mutated genes common in both studies, demonstrated significant correlation of the frequencies in 791 genes in AdC (ρ=0.78; p<2.2×10[-16]), as well as in 799 genes in SqCC (ρ=0.73; p<2.2×10[-16]). Three genes that were reported as significantly mutated in both AdC and SqCC primaries, and had higher mutation frequencies in SqCC, were also observed to be higher in our SqCC PDX models (TP53: 48.9% in AdC vs. 55.4% in SqCC; CDKN2A: 4.3% vs. 7.1% and PIK3CA: 2.1% vs. 23.2%); however, the statistical significance of these differences needs to be tested.
Conclusion:
Mutation landscapes in cancer genes are recapitulated in AdC and SqCC PDX models. The fidelity of these landscapes in matched patient primary tumour samples is being investigated.
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OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)
- Event: WCLC 2016
- Type: Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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OA03.01 - First-Line Nivolumab Monotherapy and Nivolumab plus Ipilimumab in Patients with Advanced NSCLC: Long-Term Outcomes from CheckMate 012 (Abstract under Embargo until December 5, 7:00 CET) (ID 5364)
11:00 - 12:30 | Author(s): F. Shepherd
- Abstract
- Presentation
Background:
Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved efficacy and tolerability vs docetaxel in patients with advanced NSCLC that progressed on or after platinum-based chemotherapy and is approved in >50 countries in this patient population. We report efficacy and safety data from a phase 1 study (CheckMate 012; NCT01454102) evaluating first-line nivolumab in patients with advanced NSCLC.
Methods:
Patients (N=52) with advanced, chemotherapy-naive NSCLC (any histology) were treated with nivolumab monotherapy at 3 mg/kg IV Q2W until disease progression or unacceptable toxicity. Safety and tolerability was the primary study objective. Efficacy, as measured by objective response rate (ORR) and 24-week progression-free survival (PFS) rate per RECIST v1.1, was the secondary objective. Overall survival (OS) was an exploratory endpoint.
Results:
Treatment-related adverse events (TRAEs) were reported in 71% (any grade) and 19% (grade 3‒4) of patients. The most frequent select TRAEs (those with potential immunologic causes) by category were skin, endocrine, and gastrointestinal (Table). With a median follow-up of 14.3 months (range, 0.2 to 30.1), the confirmed ORR was 23% (12/52) and 8% (4/52) of patients had complete responses. Of the 12 responses, 8 (67%) were ongoing at the time of database lock; median duration of response was not reached. Median OS was 19.4 months (range, 0.2‒35.8+). The 24-week PFS rate was 41% (95% CI: 27‒54); 18-month OS rate was 57% (95% CI: 42‒70). Updated long-term data will be presented, including 2-year OS and will represent the longest follow-up to date for a PD-1/PD-L1 inhibitor for first-line advanced NSCLC. Updated data from patients treated with nivolumab plus ipilimumab (N = 77) will also be presented.Nivolumab monotherapy (N=52) Safety Any grade / grade 3‒4 TRAEs,[a] n (%) 37 (71) / 10 (19) Any grade / grade 3‒4 select TRAEs,[a,b] by category (≥10% of patients), n (%) Skin 13 (25) / 2 (4) Endocrine 7 (14) / 0 (0) Gastrointestinal 6 (12) / 1 (2) Any grade / grade 3‒4 TRAEs leading to discontinuation, n (%) 6 (12) / 6 (12) Efficacy Confirmed ORR,[c] n (%) [95% CI] 12 (23) [13‒37] CR 4 (8) PR 8 (15) SD 14 (27) PD 20 (38) Unable to determine[d] 6 (12) Median DOR, mo (range) NR (4.2‒25.8+) Ongoing responders, n/N (%) 8/12 (67) Median PFS, mo (range) 3.6 (<0.1+‒28.0+) 24-week PFS, % (95% CI) 41 (27‒54) Median OS, mo (range) 19.4 (0.2‒35.8+) 1-year OS, % (95% CI) 73 (59‒83) 18-month OS, % (95% CI) 57 (42‒70) Efficacy and safety analyses, except for OS, were based on a March 2015 database lock; OS analyses were based on an August 2015 database lock.[a]No grade 5 events were reported.[b]AEs with a potential immunologic cause.[c]Includes patients with initial observations of CR and PR that were subsequently confirmed by repeat scans performed no earlier than 4 weeks after the original observation.[d]Includes patients who discontinued therapy because of disease progression before first assessment or patients only with assessments suggestive of, but that did not satisfy, the required minimum duration for SD. CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; DOR = duration of response; NR = not reached.
Conclusion:
First-line nivolumab monotherapy in patients with advanced NSCLC had a similar safety profile as previously reported in second-line NSCLC and other tumors, was well tolerated, and demonstrated durable efficacy.
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OA21 - Palliative and Supportive Care for Lung Cancer Patients (ID 405)
- Event: WCLC 2016
- Type: Oral Session
- Track: Palliative Care/Ethics
- Presentations: 1
- Moderators:C.A. Silva, H. Watzke
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 5
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OA21.02 - ALK-Rearranged Non-Small Cell Lung Cancer is Associated with a High Rate of Venous Thromboembolism (ID 4290)
11:00 - 12:30 | Author(s): F. Shepherd
- Abstract
- Presentation
Background:
Patients with lung cancer are at increased risk for venous thromboembolism (VTE), particularly those receiving chemotherapy. It is estimated that 8-15% of patients with advanced non-small cell lung cancer (NSCLC) experience a VTE in the course of their disease. The incidence in patients with specific molecular subtypes of NSCLC is unknown. We undertook this review to determine the incidence of VTE in patients with ALK-rearranged NSCLC.
Methods:
We identified all patients with ALK-rearranged NSCLC, diagnosed and/or treated at the Princess Margaret Cancer Centre (PM CC) in Canada between July 2012 and January 2015. Retrospective data were extracted from electronic medical records. We then included a validation cohort comprising all consecutive patients with ALK-rearranged NSCLC treated in two tertiary centers in Israel.
Results:
Within the PM CC cohort, of 55 patients with ALK-rearranged NSCLC, at a median follow-up of 22 months, 23 (42%) experienced VTE. Patients with VTE were more likely to be Caucasian (p=0.006). The occurrence of VTE was associated with a trend towards worse prognosis (overall survival HR=2.88, p=0.059). Within the validation cohort (N=43), VTE rate was 28% at a median follow-up of 13 months. Combining the cohorts (N=98) the VTE rate was 36%. Patients with VTE were younger (age 52 vs 58, p=0.04) and had a worse ECOG performance status (p=0.04). VTE was associated with shorter OS (HR=5.71, p=0.01)Figure 1.
Conclusion:
We found the rate of VTE in our ALK-rearranged cohort is 3-5-fold higher than previously reported for the general NSCLC population. This warrants confirmation in larger cohorts.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-036 - An EGFR Tyrosine Kinase Inhibitor Sensitive Patient-Derived Lung Cancer Xenograft Model without Classical Sensitizing Mutations (ID 5398)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
Mutations in the tyrosine kinase (TK) domain of EGFR are oncogenic driver in 10-20% of lung adenocarcinoma (AdC) patients in Western countries. Approximately 90% of EGFR-TK inhibitor (TKI) sensitizing mutations occur as small in-frame deletions in exon 19 or L858R point mutations in exon 21. Recently, novel driver mutations in EGFR with oncogenic and TKI sensitizing activity have been reported. We present here an AdC patient-derived xenograft (PDX) model (PDX12) that is highly sensitive to EGFR-TKI, yet failed to demonstrate classical TKI sensitizing mechanisms.
Methods:
Comprehensive genomics profiling was used to characterize the genotype of PDX12, which was established from a resected stage IIIA AdC patient grafted in NGS mouse. The primary human lung cancer cell line (PHLC12) was extracted from its PDX model (PDX12). Aberrant EGFR cell lines used were H3255 (L858R), H2935 (exon 19 deletion), H1975 (L858R and T790M), and H1944 (wild type). Cell viability was assessed after erlotinib treatment at 1nM - 2μM for 72 hours using MTS assay. Levels of EGFR activation in both pre- and post-treatment by Western blot analysis.
Results:
PDX12 model had no known oncogenic mutations (EGFR wild type) on exons 18-21 by next-generation sequencing, RT-qPCR, and SISH, but was highly sensitive to EGFR-TKI. The IC50 to erlotinib treatment at 72 hr was 67.13 ± 7.63 nM for PHLC12, compared to 9.70 ± 2.64 nM for H3255, 64.88 ± 8.49 nM for HCC2935, > 2 μM for H1975, and > 2 μM for H1944 EGFR mutant or wild type cells, respectively. Western blot analysis demonstrated a relatively higher molecular weight band for EGFR protein with high expression level in PHLC12 when compared to other lung cancer cell lines. Using RT-qPCR, relative expression level of each EGFR domain (extracellular, tyrosine kinase, and c-terminal domain) in PHLC12 showed no difference compared to EGFR wild type. Phosphorylation status of EGFR in PHLC12 was similar in activity as compared to erlotinib sensitive cell lines.
Conclusion:
PHLC12 represents an enigmatic EGFR TKI sensitive lung PDX model without classical TKI sensitizing aberrations. Additional potential mechanisms of EGFR dependency including exon duplication, or post-translational modification of EGFR protein are being investigated.
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P1.03 - Poster Session with Presenters Present (ID 455)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.03-041 - Do Several Rounds of Negative Screening Low Dose CT Scans Influence the Risk to Develop Lung Cancer? (ID 5373)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
The purpose of this study was to assess whether several years of negative screening low-dose computed tomography (LDCT) scans predict a subsequent lower risk of developing lung cancer. This would have implications for recommended intervals and duration of LDCT lung cancer screening.
Methods:
The cohort was an at-risk population who had previous negative screening LDCTs and had not been screened for at least 5 years. Between 2003 and 2009, 4782 individuals had been enrolled in a lung cancer screening study based on age and smoking alone. At this time, their risk was re-calculated using a multifactorial assessment model, and they were contacted in decreasing order of their re-calculated risk. An initial phone interview assessed interim history, general health, interim diagnosis of lung cancer or interim chest CT. Those participants without lung cancer or recent CT were invited for a single LDCT (40mA, 135kV, 1mm axial reconstructions). Subsequent investigation was recommended depending on the LDCT findings: negative, no new or growing nodules (no further recommendation), positive, low suspicion for malignancy (follow up CT in 3-6 months) or positive, high suspicion for malignancy (referral to the local lung cancer rapid diagnostic assessment program).
Results:
To date, 361 individuals or family members have been contacted. Fifty-five individuals had passed away (20 from lung cancer), 24 were alive with lung cancer. 129 did not qualify for a LDCT scan (declined participation, or recent CT). A total of 153 have attended for LDCT, on average 7 years after their last LDCT. Ninety-one (59%) studies were reported as negative. Fourty-five (29%) LDCTs were positive with low suspicion and a follow up scan was recommended; in 13 cases nodules had resolved on follow up imaging, the remaining 32 are awaiting surveillance LDCTs. Seventeen (11%) LDCTs were reported as positive with high suspicion; 11 of those have a subsequently biopsy proven lung cancer and 6 are currently undergoing further investigations or LDCT surveillance. All lung cancers diagnosed were either stage I or II. Of the 11 individuals with biopsy proven cancers, 7 had normal previous CTs, 4 had a pre-existing groundglass nodules in the tumor location on the most recent exam. The overall prevalence of lung cancer in this cohort is 15.2% (55/361) and it may increase. The detection rate of LDCT to date is 7.2% (11/153).
Conclusion:
Lung cancer risk remains high despite several negative annual screening LDCT scans. Continued screening beyond three years is recommended in high risk individuals.
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-006 - Identification of miRNAs and mRNAs Associated with Metastasis in Early-Stage Non-Small Cell Lung Cancer (NSCLC) (ID 5829)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
Early-stage NSCLC patients whose tumours can form primary xenografts (XG) in immune deficient mice have significantly shorter disease-free survival and are at a greater risk of early metastasis compared with patients whose tumours do not form xenografts (non-XG). Genomic and proteomic characterization of XG and non-XG-forming primary patient tumours may reveal clinically relevant genetic aberrations that are associated with early metastasis.
Methods:
miRNA-seq and RNA-seq data of 100 early-stage NSCLC patients with known engraftment status were acquired. The cohort includes 62% adenocarcinoma (ADC) and 38% squamous cell carcinoma (SQCC). Least absolute shrinkage and selection operator (LASSO) was applied to identify features associated with XG status using integrated miRNA and mRNA abundance profiles. Gene Ontology (GO) annotation was subsequently performed to elucidate biological processes that may be altered between the two patient groups.
Results:
Using miRNA and mRNA data alone, ADC patients were classified as XG and non-XG with 88.7% and 95.2% accuracy. The integration of these two data types classified the patients with 100% accuracy using 20 features (7 miRNAs and 13 mRNAs). While less is known regarding the roles of the identified miRNAs in lung ADC, several of the genes have been suggested to affect the metastatic ability of lung cancer cells; these include PITX1, GPNMB and KRT14. In SQCC, both the miRNA and mRNA data alone and the integrated profiles were able to classify patients into XG and non-XG-forming groups with 100% accuracy. However, the roles of the selected features (1 miRNA and 11 mRNAs) in the metastasis of SQCC are not well defined. GO annotation of the identified mRNAs in ADC revealed enrichment of biological processes related to B cell differentiation, wound healing and regulation of the immune response and signalling pathway, while catabolic and metabolic processes were enriched in SQ.
Conclusion:
The use of single-dimensional data to classify patients into different prognostic groups may not be sufficient in the presence of heterogeneous patient populations. Integrative analysis of multi-omic data can provide greater insights into clinically relevant genetic aberrations, which can be used to improve the molecular classification of NSCLC.
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P1.06 - Poster Session with Presenters Present (ID 458)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.06-039 - Retrospective Study of the Incidence and Outcomes from Lung Cancer That Developed Following a Solid Organ Transplant (ID 5136)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
Organ transplant recipients (OTR) have an increased risk of developing post-transplant malignancies with lung cancer being one of the most common. We investigated incidence and outcomes of lung cancer in OTR managed at the University Health Network.
Methods:
The study population, patient characteristics, treatments and outcomes were summarized from solid OTR databases, our cancer registry and patient charts from January 1, 1980 to December 31, 2015. Univariate Kaplan-Meyer curves estimated overall survival (OS) by histology, stage and chemotherapy.
Results:
Amongst 7994 OTR (heart [N=765], lung [n=1668], liver [n=238], kidney [n=3273]), 123 developed lung cancer (1.54%) of which (55) 44.7% occurred in lung OTR; 108 (1.35%) patients had sufficient data for subsequent analyses. Median age: 62 years (29 - 85); male: 66%; smoking status at time of transplant - former/current/never/unknown: 62%/10%/15%/8%. Histologies included non-small cell lung cancer (NSCLC): 81%; small cell lung cancer (SCLC): 10%; neuro-endocrine tumours: 9%. NSCLC: Adjuvant chemotherapy, after it became standard of care (SOC), was given to 16% of eligible NSCLC patients. At recurrence, 28% received chemotherapy while 28% received a TKI. In patients initially presenting with stage IV NSCLC, 18% received chemotherapy and 3% received a TKI. SCLC: For limited and extensive stage SCLC patients, 83% and 60% received SOC chemotherapy, respectively. All: Where chemotherapy dosing was known (n=23), 42% of patients received initial dose reductions. For early stage patients, 22% required dose reduction and 11% had chemotherapy discontinuation due to toxicity. For stage IV patients, 42% required dose reductions and 50% required discontinuations.Median OS by Subgroup
Patients by Histology, Stage at Diagnosis & Systemic Treatment n median OS (months) 95% C.I. NSCLC: Stage I/II Systemic Treatment No treatment 48 11 37 24.9 25.7 24.9 (17.3-36.6) (14-51.6) (16.2-72.9) NSCLC: Stage III Systemic Treatment No treatment 7 1 6 24.6 84.0 24.6 (4.5-NA) NA (4.5-NA) NSCLC: Stage IV Systemic Treatment No treatment 33 7 26 3.2 8.7 2.3 (2-4) (4.7-52.4) (1.5-3.5) SCLC: Limited Stage Systemic Treatment No treatment 6 5 1 9.6 14.3 2.0 (2-NA) (8.4-NA) NA SCLC: Extensive Stage Systemic Treatment No treatment 5 3 2 1.7 5.5 0.2 (0.2-NA) (1.7-NA) (0.2-NA)
Conclusion:
Survival was poor in our OTR population compared to historical norms in non-transplant patients. A minority of NSCLC patients received adjuvant or palliative chemotherapy, while most SCLC patients were treated. Both often had sub-standard dosing. Chemotherapy appeared better tolerated in early stage disease.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-015 - Differentially Expressed microRNAs in Lung Adenocarcinoma Invert Effects of Copy Number Aberrations of Prognostic Genes (ID 4771)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
Across multiple cancer histologies, many significantly down-regulated genes reside within chromosomal regions with increased number of copies, and vice versa. These “paradoxical genes” have been usually ignored as a noise, but could be a consequence of epigenetic regulatory mechanisms, including microRNA-mediated control of mRNA transcription.
Methods:
To identify paradoxical genes in lung adenocarcinoma (LUAD) we curated and analyzed gene expression and copy number aberrations across 1,064 LUAD samples, including newly-generated aCGH data from 65 samples. We then analyzed 9 LUAD microRNA expression studies to compile a list of consistently deregulated microRNAs. Finally, using microRNA:gene networks from mirDIP we examined possible association between microRNAs and paradoxical genes.
Results:
We identified 85 genes whose differential expression consistently contrasts the aberrations of their copy numbers. 70 genes were validated using TCGA-LUAD data. We showed that paradoxical expression of these genes is associated with 19 microRNAs, whose significant deregulation in LUAD has been consistently reported. Importantly, these genes form a clinically significant prognostic signature.Figure 1Figure 2
Conclusion:
Paradoxical gene expression, caused by microRNA deregulation, is preserved across patient cohorts, and forms a prognostic LUAD signature.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 4
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-008 - The Impact of Brain Metastases and Their Treatment on Health Utility Scores in Molecular Subsets of Lung Cancer Patients (ID 4348)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
New therapies, particularly in advanced patients with EGFR-mutated and ALK-rearranged tumors, result in prolonged survival. Brain metastases and/or their treatment, may have a negative impact on health-related quality of life. Technological assessment of the cost-effectiveness of various treatments for brain metastases will benefit from measurements of health-related qualify of life and health utility scores (HUS). This study evaluated the impact of brain metastases on HUS across multiple health states defined on the basis on disease stability, brain-specific therapies, and molecularly-defined subsets of NSCLC.
Methods:
A longitudinal cohort study at Princess Margaret Cancer Centre evaluated 1571 EQ5D-3L-derived HUS in 476 Stage IV lung cancer outpatients, from Dec, 2014 through May, 2016: EGFR+ (n=183), ALK+ (n=38), wild-type (WT) non-squamous (n=171), squamous (n=29), and small cell lung cancer (SCLC) (n=30). Patients were stratified according to presence or absence of brain metastases at the time of assessment; mean HUS (± standard error of the mean, SEM) by presence of brain metastases and various health states and disease subtypes were reported. For patients with repeated measures, only the earliest time point was analyzed.
Results:
172 patients had brain metastases, median age 62, (range 32-86) years and 304 patients did not have brain metastases, median age 66 (29-96) years. Overall HUS was related to disease subtype but not presence of brain metastases: EGFR/ALK+ patients with (0.78±0.02) or without brain metastases (0.79±0.01) versus WT/SCC/SCLC with (0.74±0.02) and without brain metastases (0.73±0.01) (p=0.01 by subtype; p>0.10 by presence of brain metastases). However, symptomatic CNS disease (0.69±0.04) had lower HUS (versus asymptomatic disease (0.77±0.02)) (p=0.03). Patients achieving intracranial stability or response to treatment had significantly higher HUS (0.81±0.05) than patients with progressive CNS metastases (0.72±0.02) (p=0.03). Extra-cranial control also correlated with higher HUS (0.81±0.02 versus 0.69±0.03, p<0.0001). When local treatment for brain metastases was delivered within 6 months, HUS was lower (0.71±0.02 versus 0.82±0.02, p=0.0005). CNS disease treated only with systemic therapy or on no active therapy had mean HUS of 0.81±0.03, while patients treated only with stereotactic radiosurgery (SRS) had values of 0.80±0.04; there was a trend for lower HUS with whole brain radiation (WBRT) only (0.72±0.03) or WBRT+SRS (0.74±0.03) (p=0.11).
Conclusion:
Brain metastasis stability has significant impact on HUS in lung cancer patients. Treatment modalities of brain metastases may also impact HUS. Data collection is ongoing; updated HUS data including longitudinal assessments and multivariable analyses will be presented.
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P2.03b-071 - Therapeutic Targeting of the Phosphatidylinositol-3 Kinase Pathway in Lung Squamous Cell Carcinoma (ID 5369)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
The phosphatidylinositol-3 kinase (PI3K) belongs to a family of lipid kinases involved in the regulation of cell proliferation and survival and is often dysregulated in cancer. Comprehensive molecular profiling by The Cancer Genome Atlas (TCGA) has identified PIK3CA mutations, amplifications, and the tumor suppressor PTEN loss in 30-40% of lung squamous cell carcinoma (LUSC) patients. Inhibitors of PI3K such as BKM120 have been initiated in BASALT-1 trial (NCT01820325) of PI3K activated LUSC, however with modest response rate (40% of patients with stable disease and 3.3% with partial response). We aim to assess the efficacy of PI3K inhibition in LUSC patient-derived xenografts (PDX) harboring different PI3K pathway alterations to identify potential mechanisms of innate resistance.
Methods:
PDX models were established from early stage LUSC patients and molecularly characterized via exome sequencing, SNP array for copy number variation (CNV) and gene expression analysis. PIK3CA mutations were validated by direct sequencing, amplifications by fluorescence in situ hybridization (FISH), and PTEN loss by immunohistochemistry (IHC). For in vivo drug screening, each PDX model was implanted in two mice; one treated with BKM120 (50mg/kg) and the other with vehicle control by daily oral gavage. Tumors were monitored twice weekly with caliper measurement. A responder is a tumor that regresses completely, shrinks more than 30%, or remains a stable size according to the RECIST criteria.
Results:
Of the 75 LUSC PDX models that our laboratory has established, 11 (14%) harbored PIK3CA E545K and E542K mutations, 36 (47%) harbored PIK3CA amplifications, and 23 (30%) showed loss of PTEN protein expression. Using the RECIST criteria, BKM120 screening in selected PDX models revealed stable disease and progressive disease in 4/9 (46%) and 5/9 (54%) of the PDX models, respectively, after 21 days of treatment. Of the 9 PDX models tested, 3/5 PIK3CA mutant models were responsive to BKM120, whereas none of the other 4 PIK3CA amplified and/or PTEN deleted models were responsive to BKM120. Additionally, downregulation of pErk1/2 and pS6 in a responder model and no change in phosphorylated proteins in non-responding models were observed. Pharmacodynamics studies, validation of responders with more mouse replicates, and testing on the remaining models are ongoing and the results will be reported.
Conclusion:
60% of LUSC PDXs with PIK3CA mutation demonstrate high sensitivity to pan-PI3K inhibitor. Understanding innate resistance mechanisms of PI3K inhibition may provide important insights on tractable targets and therapeutic strategy for LUSC patients with aberrant PI3K pathway.
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P2.03b-077 - EGFR/ALK+ Patient-Derived Xenografts from Advanced NSCLC for TKI Drug Selection & Resistance Development: The REAL-PDX Study (ID 6081)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
Lung cancer patient-derived xenografts (PDX) have shown to be representative models for individual patient tumors. Theoretically, such models could inform the choice of subsequent lines of therapy, since PDX development, TKI resistance induction, and subsequent drug-screening can be completed before TKI resistance develops in the patient. The goal of Resistance modeling in EGFR and ALK Lung cancer (REAL)-PDX is to develop PDX models for real-time treatment selection of subsequent lines of therapy in advanced-stage NSCLC patients.
Methods:
Since August 2015, Princess Margaret Cancer Centre patients with EGFR/ALK+, as well as lifetime never-smoking lung cancer patients with unknown mutation status, were consented to have additional tumor sampling for PDX development during routine- or trial-related biopsies. Tumor sufficiency was confirmed prior to implantation into non-obese severe combined immunodeficient (NOD-SCID) mice, with successful engraftment defined as propagation beyond first passage; unsuccessful implantations had no palpable tumor after 6 months.
Results:
72/82 (88%) approached patients consented; 49/72 (68%) had adequate tumor tissue for implantation (71% stage III/IV): 46 adenocarcinomas, 2 squamous cell carcinoma, 1 LCNEC. 36/49 (73%) were lifetime never smokers. Patients received adjuvant chemotherapy (3), TKI therapy (15), both (5), or no treatment (26) prior to sampling. Tumor samples were taken from surgically resected lung (18), metastatic adrenal (1) and brain (2), CT-guided lung biopsies (5), endoscopic ultrasound-guided (EBUS) biopsies (6), and thoracentesis pleural fluid (17) specimens. Twenty-eight implanted tumors were EGFR+ (12 exon19 deletions, 2 exon19 deletion/T790M, 1 exon19 del/exon18 mutation, 12 L858R, and 1 L858R/T790M); 7 had ALK-rearrangements, and 1 had ROS1-rearrangement. Engraftment rates of 31 assessable implanted tumors were as follows: lung resections 12/12 (100%), metastatic resections 2/3 (67%), CT- or EBUS-guided biopsies 1/5 (20%), and pleural fluid 2/11 (18%); Engraftment rate was associated with no prior treatment (14/17 no treatment vs 3/14 any treatment, p=0.001). Of 17 assessable tumors with EGFR activating mutations, 9 engrafted (53%). Of 3 assessable tumors with ALK-rearrangement, 1 was successful (33%).
Conclusion:
PDX development of EGFR/ALK+ models for testing with novel therapeutics from various tumor biopsy sites is feasible and will provide valuable real-time information for subsequent treatment decisions in advanced NSCLC patients. Updated engraftment and drug screening data will be presented.
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P2.03b-089 - CD1C in Lung Adenocarcinoma: Prognosis and Cellular Origin (ID 4809)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
Adaptive immune response is critical for cancer surveillance and elimination. Dendritic cells (DC) arise from a hematopoietic lineage distinct from other leukocytes which play a central role in adaptive immunity. CD1C is expressed in DC, presenting exogenous lipid antigens to T cell receptor to activate “unconventional” T cells. This study aims to evaluate the cellular expression and prognostic value of CD1C.
Methods:
The study used 5 gene expression datasets: UHN181 [lung adenocarcinoma (ADC, n=128), squamous cell carcinoma (SqCC, n=43)], GSE30219 (ADC n=81, non-ADC n=138)], and 3 integrated cohorts [non-SqCC NSCLC (n=1106), PRECOG (39 types of cancer, n=~18,000), and TCGA (33 types of cancer, n=11,000)]. Cancer Cell Line Encyclopedia (CCLE) data were used to determine if CD1C was expressed by cancer cell lines. CIBERSORT algorithm was used to estimate immune cell fraction and Cox proportional model was used to evaluate the association of CD1C expression with survival. Immunohistochemistry (IHC) was used to measure protein expression of CD1C.
Results:
Except for hematopoietic and lymphoid cancer cell lines, all CCLE cell lines lack CD1C expression. CIBERSORT analysis together with Pearson correlation analyses on the ADC cases in UHN181, the integrated cohort, and GSE30219 showed that CD1C was expressed by DC. IHC showed staining with a dendritic cell shape pattern. However, the staining of CD1C did not overlapped with CD11c staining, suggesting a specific DC subtype. Cox proportional regression revealed that CD1C was significantly prognostic in the UHN181 ADC cohort (HR=0.75, p=0.05) as the training set. When CD1C expression was categorized into 3 equal groups, the risk of death was reduced in high compared to low CD1C expression group (HR=0.55, 95%CI 0.28-1.07, p=0.07). CD1C is protective only in PD-L1 low expression group (n=108, HR=0.37, 95%CI 0.15-0.89, p=0.026). The favorable prognosis associated with CD1C expression was validated in the integrated cohort of non-SqCC NSCLC (HR=0.55, 95% CI 0.43-0.72, p<0.0001), and in GSE30219 ADC cohort (HR=0.30, 95% CI 0.11-0.84, p=0.02). In PRECOG and TCGA datasets, high CD1C expression is significantly good prognostic in all cancer types (p<1×10[-7] and p<0.001, respectively), suggesting a universal protective role of CD1C expression in cancers. CD1C IHC score was highly correlated with CD1C mRNA expression in ADC patients of UHN181 and was prognostic (HR=0.46, 95%CI 0.22-0.96, p=0.039).
Conclusion:
CD1C preferentially is expressed on a subset of DCs and higher expression of CD1C is significant protective factor in all cancer types, especially in lung adenocarcinoma
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-011 - Phase 2 Study of MM-121 plus Chemotherapy vs. Chemotherapy Alone in Heregulin-Positive, Locally Advanced or Metastatic NSCLC (ID 4158)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
The role of the HER3 receptor and its ligand heregulin (HRG) in the progression of multiple cancers has been well established. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. The correlation between the level of HRG mRNA in tumor tissue and progression free survival (PFS) were retrospectively analyzed in three completed randomized Phase 2 studies of seribantumab plus standard of care (SOC) versus SOC alone (NSCLC, breast cancer and ovarian cancer). In each of these studies, high levels of HRG mRNA predicted shortened PFS for patients who received SOC treatment, while the addition of seribantumab to SOC improved PFS for patients with HRG-positive (HRG+) tumors. This is consistent with the hypothesis that HRG expression defines a drug tolerant cancer cell phenotype shielded from the effects of cytotoxic or targeted therapies and that blockade of HRG-induced HER3 signaling by seribantumab counters the effects of HRG on cancer cells, with the potential to improve outcomes for HRG+ patients. It is estimated that up to approximately 50% of cases of all solid tumor indications are HRG+. This HRG expression may contribute to rapid clinical progression in a subset of patients with poor prognosis.
Methods:
In the ongoing randomized, open-label, international, Phase 2 study, NSCLC patients with HRG+ tumors are being prospectively selected using a HRG RNA in situ hybridization assay performed on a recent tumor tissue sample collected via fine needle aspiration, core needle biopsy or excision. Approximately 560 patients will be screened to support enrollment of 280 HRG+ patients, who will be randomized in a 2:1 ratio to receive seribantumab plus investigator’s choice of docetaxel or pemetrexed, or docetaxel or pemetrexed alone. Patients will be wild-type for EGFR and ALK and will have progressed following one to three systemic therapies, one of which must be an anti-PD-1 or anti-PD-L1 therapy, for locally advanced and/or metastatic disease. Overall survival (OS) is the primary endpoint of the study and secondary endpoints include PFS, objective response rate and time to progression. Safety and health-related quality of life will also be assessed. An interim analysis is planned when 50% of final OS events have been reported. Enrollment has been initiated with approximately 80 sites expected to participate worldwide. Clinical Trials Registry number: NCT02387216
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-028 - Characterizing Residual Erlotinib-Tolerant Population Using EGFR-Mutated NSCLC Primary Derived Xenografts: The Last Holdouts (ID 5455)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
Three generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have led to multi-fold improvements in progression free survival of advanced stage non-small cell lung cancer (NSCLC) patients carrying EGFR kinase domain mutations. However, cure is not yet achievable with any EGFR TKI monotherapy, as patients will eventually progress due to acquired resistance. In vitro evidence suggests that minor populations of epigenetically modified drug tolerant cells (DTCs) may be one important mechanism for tumor cells surviving the TKI. We hypothesize that characterizing the genomic and epigenomic alterations observed in DTCs in vivo and comparing them to the bulk tumour will delineate a number of mechanisms of tolerance exhibited by DTCs.
Methods:
DTCs were induced via chronic erlotinib treatment of a lung adenocarcinoma primary derived xenograft (PDX) harbouring an erlotinib sensitive exon 19 deletion. Molecular profiles of DTCs are compared to untreated controls via immunohistochemistry (IHC) and gene expression array. We are now undertaking exome-sequencing, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), methylated DNA immunoprecipitation and sequencing (MeDIP-seq).
Results:
When compared to untreated tumours, DTCs exhibit decreased apoptosis (CC3 IHC) and proliferation (Ki67 IHC). DTCs maintained strong signaling via the EGFR pathway (pERK, pAKT, pS6). DTCs exhibited 2437 significantly differentially expressed genes (DEGs; >1.5-fold change and adjusted p-value <0.05) including multiple cancer stem cell markers (ALDH1A1, ALDH1A3, CD44). DEGs also were involved in vesicle-mediated transport (including lysosomes, exosomes and endosomes), autophagy, stress/unfolded protein response, cytoskeleton organization, chromatin organization, ion pumps and transporters, cell adhesion, WNT, NOTCH, PI3K and MAPK pathways. DTCs remained resistant to three cycles of cisplatin/vinorelbine either alone or when combined with erlotinib. Genomic and epigenomic profiling are on-going and results will be presented.
Conclusion:
DTCs may be a major impediment to cure by single-agent EGFR targeted therapies. Understanding the mechanisms and developing strategies to overcome DTCs may give insights on therapeutic strategy to further improve the survival of EGFR-mutated NSCLC patients.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-076 - Correlation of Neutrophil to Lymphocyte Ratio (NLR) with Clinical Benefit from Checkpoint Inhibitors in Advanced Lung Cancer (ID 5965)
14:30 - 15:45 | Author(s): F. Shepherd
- Abstract
Background:
Immune checkpoint inhibitors (ICI) have become standard therapy after platinum failure in advanced non-small cell lung cancer. ICI response patterns differ from chemotherapy with the potential for delayed regression and pseudo-progression in patients benefiting from treatment. Additional markers beyond PDL-1 expression are needed to assist in patient selection, response evaluation and treatment decision-making.
Methods:
The relationship between clinical outcome (response, treatment duration, survival) and hematologic parameters (absolute neutrophil count [ANC], neutrophil to lymphocyte ratio [NLR]) was explored in a cohort of patients treated with ICIs at a major cancer centre from 05/2013 to 05/2016. Clinical benefit was defined as achievement of complete or partial response (CR, PR) or stable disease (SD) at 8 weeks. Hematologic parameters at baseline (T0) and on treatment (T1=2 or 3 weeks, T2=8 weeks) were included.
Results:
Of 101 Non-SCLC patients treated with ICIs, 84 (83%) had documented response assessment. All received PD-1 axis inhibitors, (71 anti-PD-1, 12 anti-PDL-1, 1 anti-PDL-1 plus -CTLA-4); tumour PDL-1 expression was +/-/unknown in 32/12/40; median follow-up was 5.1 months (range 0.4 – 36.8) from treatment start. Clinical benefit was seen in 62% (20 PR, 32 SD). Baseline NLR≤4 was associated with greater clinical benefit (75% vs 51%, p=0.025) and median survival (21.7 vs 6.9 months) compared with NLR>4; (HR=0.45, 95% CI: 0.22-0.90, p=0.03). This appears independent of tumour PDL-1 expression. Lower on-treatment (T1, T2) ANC values (trend analysis p=0.0037) and NLR≤4 (T2) were also associated with PR/SD (Table 1). Longer treatment duration was associated with on-treatment NLR≤4 (T1 6.2 vs 3.4 months, p=0.037; T2 6.2 vs 2.7 months, p=0.0075) and lower ANC (T1 p=0.014, T2 p=0.012). Figure 1
Conclusion:
Pretreatment NLR≤4 may be a potential predictor of clinical response in patients receiving ICIs, as well as lower on-treatment ANC and NLR.
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.03 - Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) (Abstract under Embargo until December 6, 7:00 CET) (ID 4452)
08:35 - 10:25 | Author(s): F. Shepherd
- Abstract
- Presentation
Background:
Osimertinib is a potent, irreversible, CNS active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for sensitising (EGFRm) and T790M resistance mutations. Osimertinib is indicated for the treatment of patients with locally advanced or metastatic EGFR T790M-positive NSCLC. AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib versus platinum-based chemotherapy plus pemetrexed in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on first-line EGFR-TKI therapy.
Methods:
Eligible patients were ≥18 years with documented EGFRm, radiological disease progression following first-line EGFR-TKI and centrally confirmed T790M-positive (by cobas® EGFR Mutation Test) from a tissue biopsy after disease progression. Asymptomatic, stable CNS metastases were allowed. Patients were randomised 2:1 to osimertinib 80 mg orally, once daily or platinum-pemetrexed (pemetrexed 500 mg/m[2] plus either cisplatin 75 mg/m[2] or carboplatin AUC5) every three weeks for up to six cycles; pemetrexed could be continued as maintenance treatment. Primary endpoint was progression-free survival (PFS) by investigator assessment according to RECIST v1.1; sensitivity analysis was by blinded independent central review (BICR).
Results:
A total of 419 patients were randomised to treatment (osimertinib, n=279; platinum-pemetrexed, n=140). Baseline characteristics were generally balanced across treatment groups: female 64%, Asian 65%, never smoker 68%, CNS metastases 34%, EGFR exon 19 deletion 66%. Osimertinib significantly improved PFS compared with platinum-pemetrexed: hazard ratio [HR] 0.30; 95% CI: 0.23, 0.41; p<0.001 (median 10.1 months vs 4.4 months). The result was consistent with PFS analysis by BICR: HR 0.28; 95% CI: 0.20, 0.38; p<0.001 (11.0 months vs 4.2 months). Objective response rate was significantly improved with osimertinib (71%) vs platinum-pemetrexed (31%); odds ratio 5.39 (95% CI: 3.47, 8.48; p<0.001). Median duration of response was 9.7 months (95% CI 8.3, 11.6) with osimertinib and 4.1 months (95% CI 3.0, 5.6) with platinum-pemetrexed. Grade ≥3 causally-related adverse events (AEs) as assessed by the investigator were reported in 6% of patients (n=16) treated with osimertinib and 34% (n=46) treated with platinum-pemetrexed. Most common causally-related AEs in the osimertinib group: diarrhoea (29% [grade ≥3, 1%]), rash (28% [<1%]); in the platinum-pemetrexed group: nausea (47% [3%]), decreased appetite (32% [3%]).
Conclusion:
In patients with EGFR T790M-positive advanced NSCLC following progression on EGFR-TKI treatment, osimertinib demonstrated a superior clinically-meaningful efficacy over platinum-pemetrexed, with a 70% reduction in the risk of disease progression, and well-characterised safety profile, establishing the new standard of care for these patients.
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PL05 - Closing Plenary Session: A Life in Thoracic Oncology - Reflections from Giants on Milestones in the Treatment Advances in Lung Cancer (ID 433)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:P.A. Bunn, Jr., T. Mok
- Coordinates: 12/07/2016, 16:00 - 18:00, Hall C1
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PL05.06 - Targeted Therapy (ID 6922)
16:00 - 18:00 | Author(s): F. Shepherd
- Abstract
- Presentation
Abstract not provided
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