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I. Wistuba
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.07 - Impact of Major Co-Mutations on the Immune Contexture and Response of KRAS-Mutant Lung Adenocarcinoma to Immunotherapy (ID 6343)
16:42 - 16:48 | Author(s): I. Wistuba
- Abstract
- Presentation
Background:
Activating mutations in the KRAS proto-oncogene define a prevalent and clinically heterogeneous molecular subset of lung adenocarcinoma (LUAC). We previously identified three major subgroups of KRAS-mutant LUAC on the basis of co-occurring genetic events in TP53 (KP), STK11/LKB1 (KL) and CDKN2A/B (KC) and reported that LKB1-deficient tumors exhibit a “cold” tumor immune microenvironment, with reduced expression of several immune checkpoint effector/mediator molecules, including PD-L1 (CD274). Here, we extend these findings and examine the clinical outcome of co-mutation defined KRAS subgroups to therapy with immune checkpoint inhibitors.
Methods:
We conducted a single-institution analysis of clinical and molecular data (PCR-based next generation sequencing of panels of 50, 134 or 409 genes) prospectively collected from patients enrolled into the MD Anderson Lung Cancer Moon Shot GEMINI database. KRAS-mutant LUAC were separated into KP, KL and K (wild-type for TP53 and STK11) groups. The log- rank test and Fisher’s exact test were used for comparison of progression-free survival (PFS) and objective response rate (ORR) respectively between the groups. In addition, automated IF-based enumeration of lymphocyte subsets was performed in 40 surgically resected LUAC (PROSPECT cohort) with available whole exome sequencing data.
Results:
Among 229 patients with KRAS-mutant LUAC who consented to the protocol we identified 35 patients with metastatic disease (17 KP, 6 KL, 12 K) that received immunotherapy with nivolumab (N=29), pembrolizumab (N=3), nivolumab/urelumab (N=1) and durvalumab/tremelimumab (N=2) and had robust clinical outcome data. There was no impact of different KRAS alleles (G12C/G12V/G12D) on PFS (P=0.6149, log-rank test) or ORR to immune checkpoint inhibitors (P=0.88, Fisher’s exact test, 2x3 contingency table). In contrast, co-mutation defined KRAS subgroups exhibited significantly different median PFS to immunotherapy (KP: 18 weeks, KL: 6 weeks, K: 16 weeks, P=0.0014, log-rank test). Objective responses were observed in 9/17 (52.9%) KP and 3/12 (25%) K tumors compared to 0/6 (0%) KL tumors (P=0.049, Fisher’s exact test, 2x3 contingency table). In the PROSPECT cohort of surgically resected LUACs with available whole exome sequencing data, somatic mutation in STK11 was associated with reduced intra-tumoral densities of CD3+ (P=0.0016), CD8+ (P=0.0125) and CD4+ (P=0.0036) lymphocytes.
Conclusion:
Mutations in STK11/LKB1 are associated with an inert tumor immune microenvironment and poor clinical response of KRAS-mutant LUAC to immune checkpoint blockade. The mechanism that underlies this phenotype and strategies to overcome it are under investigation. The impact of additional co-mutations on the immune profile and response of KRAS-mutant LUAC to immunotherapy is also being explored.
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.07 - Improved Small Cell Lung Cancer (SCLC) Response Rates with Veliparib and Temozolomide: Results from a Phase II Trial (ID 5517)
15:02 - 15:08 | Author(s): I. Wistuba
- Abstract
- Presentation
Background:
PARP1 is overexpressed in small cell lung cancer (SCLC) and represents a novel therapeutic target for this disease. Preclinical data indicates that combining veliparib (an oral PARP-1/2 inhibitor) and temozolomide (TMZ) results in synergistic tumor growth delay or regression. In this study, we investigated whether adding veliparib to TMZ would improve outcomes in patients with relapsed sensitive and refractory SCLCs. Candidate predictive biomarkers, including SLFN11, were then explored.
Methods:
SCLC patients previously treated with 1 or 2 prior regimens were enrolled in the trial and randomized 1:1 to receive oral TMZ 150-200mg/m[2]/day (D1-5) with either veliparib or placebo 40mg twice daily, orally (D1-7) (NCT01638546). Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in patients with platinum sensitive (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Archived tissue was available for 53 patients for biomarker analysis.
Results:
104 patients were enrolled and 100 patients were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. Progression free survival at 4-months was similar between the two arms, 36% vs. 27% (p=0.39). However, in 93 evaluable pts, response rate was significantly higher in pts treated with veliparib/TMZ compared to TMZ alone (39% vs 14%, p =0.016). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Levels of SLFN11, a marker of SCLC response to PARP inhibition in preclinical models, were assessed by immunohistochemistry. High SLFN11 in patient tumors (obtained at original diagnosis) was associated with a trend towards better overall survival in the veliparib/TMZ arm, but no difference in outcome in the TMZ alone arm. Additional correlative studies are ongoing, including assessment of MGMT promoter methylation, and will be available at the time of presentation.
Conclusion:
The combination of veliparib/TMZ increased response rates significantly, compared to TMZ alone. Hematologic toxicities of the combination may have impacted PFS (which was not significantly different between the arms) by limiting dosing. Biomarkers such as SLFN11, ATM, or MGMT promoter methylation could potentially help guide patient selection in the SCLC population.
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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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MA17.10 - YES1 Kinase is a New Therapeutic Target in Non-small Cell Lung Cancer (ID 7159)
15:26 - 15:32 | Author(s): I. Wistuba
- Abstract
- Presentation
Background:
Next-generation sequencing techniques have allowed the discovery of driver mutations in non-small cell lung cancer (NSCLC) that can be translated into advances in cancer diagnosis and treatment. However, specific oncogenic alterations are still unknown in a high proportion of NSCLC patients, that therefore cannot benefit from targeted therapies. The challenge is to identify new genetic alterations that allow the use of molecular-targeted therapies. In previous studies from our group (Aramburu et al. BMC Genomics 2015), the analysis of tumor molecular profiles from patients with NSCLC allowed us to identify the DNA copy number amplification of YES1 kinase (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) as a prognostic marker in lung cancer. YES1 kinase is member of the Src family of non-receptor protein tyrosine kinases that are involved in the regulation of cell growth, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. The aim of this project is to evaluate if YES1 is a driver gene in NSCLC, and if targeting its activation may be a potential new therapeutic strategy.
Methods:
We first evaluated the prognostic role of YES1 protein expression in two independent series of 76 and 234 NSCLC patients, respectively. In both series, the multivariate analysis revealed that high YES1 expression is an independent poor prognostic factor for overall survival (CUN series HR: 3.416 [0.933-12.508]; MD Anderson series HR: 1.570 [1.032-2.391]). We next evaluated the effect of YES1 knockdown in 5 NSCLC cell lines with YES1 amplification and overexpression, and in 3 cell lines without YES1 amplification and with low protein expression. YES1 downregulation by two specific siRNAs decreased proliferation and cell survival only in those cells overexpressing YES1. Congruently, YES1 inhibition led to apoptosis only in those cells.
Results:
Consistent with these results, constitutive overexpression of YES1 in cells with low YES1 expression significantly enhanced cell proliferation. We next evaluated the effect of the multitarget Src kinase inhibitor dasatinib on the proliferation of NSCLC cell lines with high (8 cell lines) or low (4 cell lines) YES1 expression. Dasatinib dramatically inhibited proliferation in high YES1-expressing cell lines, whereas low YES1 cell lines were more resistant to dasatinib treatment (GI50s were four orders of magnitude higher in resistant cells).
Conclusion:
In conclusion, our results indicate that YES1 is a promising therapeutic target in NSCLC. Furthermore, amplification and high expression of YES1 may define a subset of patients who may potentially benefit from dasatinib treatment.
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MTE21 - Next Generation Sequencing (Ticketed Session) (ID 314)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 07:30 - 08:30, Schubert 1
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MTE21.01 - Next Generation Sequencing (ID 6576)
07:30 - 08:00 | Author(s): I. Wistuba
- Abstract
- Presentation
Abstract:
Non small cell lung cancer(NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations invariably develop resistance to EGFR tyrosine kinase inhibitors (TKIs). 20%-30% of NSCLC patients haboring sensitive mutations have no good initial clinical response to EGFR-TKIs, which is defined as having intrinsic resistance to EGFR-TKIs; while the rest of patients with activating mutations who are initially responsive to EGFR-TKIs eventually develop acquired resistance after 10–12 months of consistent clinical beneft, followed by disease progression. The drug resistance is a really tough and urgent clinical problem. Part of resistant mechanisms have been reported, including BIM deletion polymorphism, combined with other bypass signal pathway activation, epithelial-mesenchymal transition (EMT) for primary resistance; T790M, cMET amplification, SCLC transformation for acquired resistance. However, partial resistant mechanisms still unknown. In contrast to acquired resistance to EGFR-TKIs, intrinsic resistance is more complicated. Next-generation sequencing (NGS) is a promising tool for analysis of tumor mutations. We aimed to investigate the intrinsic resistant mechanisms to EGFR-TKIs by NGS, further to optimize treatment strategies and improve clinical outcome in EGFR activating mutant patients having intrinsic resistance to EGFR-TKIs. At present, the study is underway, and the results will be presented at the 2016 WCLC.
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OA19 - Translational Research in Early Stage NSCLC (ID 402)
- Event: WCLC 2016
- Type: Oral Session
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:G. Heller, G. Goss
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 3
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OA19.02 - Sex Differences Are Detected in the Profile of Tumor Associated Inflammatory Cells (TAICs) Are Lung Adenocarcinoma (ID 5451)
11:10 - 11:20 | Author(s): I. Wistuba
- Abstract
- Presentation
Background:
A number of studies have characterized TAICs in lung cancer and associated their levels of infiltration with patients’ outcome. There is limited information about the correlation of TAICs infiltration with clinical and pathological features of lung cancer. We investigated the association between patterns of tumor infiltrating lymphocytes and macrophages with detailed clinical and pathological features in lung adenocarcinoma.
Methods:
We studied archival tumor tissue from 93 surgically resected lung adenocarcinomas, stages I to III. Density of TAICs expressing CD3, CD4, CD8, and CD68 was evaluated using immunohistochemistry (IHC) and image analysis. TAICs density was correlated with tumor’s histological characteristics and patients’ characteristics.
Results:
We found significant differences in the TAICs infiltrate density of lung adenocarcinomas based on patients’ characteristics. Overall: a) females showed higher levels of CD8+ (P=0.01) and CD3+ (P=0.03) cell density than males; b) smaller tumors (<3cms) showed more CD4+ (P=0.01) and CD3+ (P=0.03) cells than larger tumors; and, c) tumors with solid histology pattern showed higher levels of CD8+ (P=0.03) cells than non-solid pattern. No overall significant differences on TAICs infiltrates were detected by age, tobacco exposure by pack-years and TTF-1 IHC expression score. However when TAICs density of tumors was examined by sex we found the following: a) in larger tumor (>3cms), females demonstrated higher levels of CD8+ cells (P=0.0007) than males; b) tumors from females older than the median age (63 years) showed more CD4+ (P=0.04), CD8+ (P=0.009) and CD3+ (P=0.042) cells than males; c) tumors from females with <40 pack-years of tobacco history showed significantly higher levels of CD3+ (P=0.004) and CD68+ (P=0.004) cells than males; d) tumors from females with high levels of TTF1 expression (score >150) showed higher levels of CD8+ cells(P=0.03) than males; e) females with tumors having non-solid histology pattern showed higher CD8+ (P=0.02) and CD3+ (P=0.02) cells than males. Finally, tumors expressing low levels of TTF-1 and lower CD4+ cells correlated significantly with worse overall recurrence free survival and overall survival in both males (P<0.0001) and females (P=0.0072).
Conclusion:
In lung adenocarcinoma, TAICs infiltration correlates with clinical characteristics of patients and pathological features of tumors, particularly, sex, age, size and TTF-1 expression. Compared with men, lung adenocarcinomas from females showed higher levels of TAICs, particularly at older age, larger tumor size, less exposure to tobacco, and more differentiated histological patterns. (UT Lung SPORE and MD Anderson Moon Shot Program).
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OA20 - Immunotherapy and Markers (ID 401)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 2
- Moderators:M. Früh, C.S. Baldotto
- Coordinates: 12/07/2016, 11:00 - 12:30, Stolz 2
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OA20.05 - The Influence of Neoadjuvant Chemotherapy, on Immune Response Profile in Non-Small Cell Lung Carcinomas (ID 5738)
11:35 - 11:45 | Author(s): I. Wistuba
- Abstract
- Presentation
Background:
The clinical efficacy observed with PD-1/PD-L1 inhibitors in non-small cell lung carcinoma (NSCLC) has prompted to characterize the immune response in lung tumors treated with chemotherapy. Our goal was to determine the characteristics of immune microenvironment of localized, surgically resected, NSCLCs from patients who received and did not receive neo-adjuvant chemotherapy. Using multiplex immunofluorescence (mIF) and image analysis, we investigated PD-1/PD-L1 expression, and quantified tumor infiltrating lymphocytes (TILs) and tumor associated macrophages (TAMs).
Methods:
We studied formalin-fixed and paraffin embedded (FFPE) tumor tissues from 111 stage II and III resected NSCLC, including 61 chemonaïve (adenocarcinoma, ADC=33; squamous cell carcinoma, SCC=28) and 50 chemotherapy-treated (ADC=30; SCC=20) tumors. mIF was performed using the Opal 7-color fIHC Kit™ and analyzed using the Vectra™ multispectral microscope and inForm™ Cell Analysis software (Perkin Elmer, Waltham, MA). The markers studied were grouped in two 6-antibody panels: Panel 1, AE1/AE3 pancytokeratins, PD-L1 (clone E1L3N), CD3, CD4, CD8 and CD68; and Panel 2, AE1/AE3, PD1, Granzyme B, FOXP3, CD45RO and CD57.
Results:
Positive PD-L1 expression (>5%) in malignant cells (MCs) was detected in 48% (n=53/111) of NSCLCs. Overall, chemotherapy-treated tumors showed significantly higher percentages of MCs expressing PD-L1 (median, 18.2%) than chemo-naïve cases (median, 1.8%; P=0.033). Higher densities of inflammatory cells expressing granzyme B (P=0.036), CD57 (P=0.001) and PD-1 (P=0.016) were detected in chemotherapy-treated NSCLCs compared with chemo-naïve tumors. In contrast, lower densities of FOXP3-positive regulatory T cells were detected in chemotherapy-treated tumors when compared with chemo-naïve cases (P=0.032). Following chemotherapy ADCs exhibited significantly higher levels of CD57-positive cells (P<0.0001) and lower density of FOXP3-positive cells (P=0.002) than chemo-naïve tumors. Chemotherapy-treated SCCs demonstrated higher density of PD-1-positive cells than chemo-naïve tumors (P=0.004). In chemotherapy-treated cancers, lower levels of CD4 helper T positive cells and tumor associated macrophages (TAMs) CD68-positive cells were associated with worse overall survival (OS; P=0.04 and P=0.005, respectively) in univariate analysis. In chemotherapy-treated ADC patients, lower levels of CD68-positive (P=0.010) and higher levels of FOXP3-positive cells correlated with worse OS (P=0.044).
Conclusion:
We developed a robust mIF panel of 10 markers to study inflammatory cells infiltrates in FFPE NSCLC tumor tissues. Chemotherapy-treated NSCLCs exhibited higher levels of PD-L1 expression and T cell subsets compared to chemo-naïve tumors, suggesting that chemotherapy activates specific immune response mechanisms in lung cancer. (Supported by CPRIT MIRA and UT Lung SPORE grants, and MD Anderson Moon Shot Program).
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OA20.06 - Prospective ImmunogenomiC PrOfiling of Non-Small Cell Lung Cancer - The ICON Project (ID 5560)
11:45 - 11:55 | Author(s): I. Wistuba
- Abstract
- Presentation
Background:
Previous attempts to define tumor and stromal immunologic environment in non-small cell lung cancer (NSCLC) utilized archival tissue. We established prospective comprehensive immonogenomic profiling protocol in NSCLC (ICON Project). The goal is to integrate immunomic, genomic, transcriptomic, proteomic, demographic, clinical, pathologic, and outcome data from 100 surgically resected early stage NSCLC.
Methods:
Tumor and normal lung tissue are collected at the time of surgery, blood samples before and after surgery. Tumor samples are processed for tumor infiltrating lymphocyte (TILs) isolation and expansion; development of patient derived xenografts (PDX), immunohistochemical immune markers, and immunopeptidome profiling. Blood samples are analyzed with flow cytometry.
Results:
57 patients with median age of 65 years (27 males) have been enrolled within 5 months, of which 33 (66%) contributed samples to the study. Four were never smokers, with others being former or current smokers. Majority (N=27) had adenocarcinoma, 4 squamous cell carcinoma, and 2 pleomorphic carcinoma. 15 patients had stage I, 11 stage II, and 7 stage III disease; 5 patients received induction chemotherapy. Median tumor size was 3.5 cm and 29 underwent R0 and 4 R1 resection. Pre-REP TIL expansion was successful in the majority of samples (68.2%, n=22). Twelve PDX models with a take rate of 40% have been generated. Interim analysis of tumor samples by IHC demonstrated higher median distribution of all cell types: CD3+ T cells, cytotoxic T cells CD8+, PD1+ cells, tumor associated macrophages (TAM) CD68+, TAM CD68+PD-L1+, CD20+B cells, memory T cells CD45R0, natural killer cells CD57+, regulatory FOXP3+ T cells, and cytotoxic granzyme B cells (cells/mm[2]) in the stroma as compared to the tumor compartment. Intra-tumoral regulatory FOXP3+T cells were more abundant in squamous cell carcinomas compared to adenocarcinomas (median 312 vs 51 cells/mm[2], p = 0.05). Higher concentration of intra-tumoral CD68+PD-L1+ expressing cells was observed following neoadjuvant chemotherapy (median 97 vs 60 cells/mm[2] no chemo; p= 0.077), as was the concentration of memory T cells CD45R0 (median 129 vs 30 cells/mm[2], no chemo; p = 0.077). Mass spectrometry-based immunopeptidome analysis identified several thousand peptides, of which 4 promising antigens have been chosen for further development as immunotherapeutic T-cell targets.
Conclusion:
The ICON is an ongoing, ambitious prospective project that aims to define the baseline immunologic characteristics of surgically resectable NSCLC. The rapid enrollment illustrates the enthusiasm for tumor immunoprofiling amongst patients and physicians alike. Data from this patient cohort will serve as a baseline comparison for upcoming neoadjuvant immunotherapy trials.
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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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P1.05-028 - Phenotypic and Functional Profiling of Tumor-Infiltrating Lymphocytes (TIL) in Early Stage Non-Small Cell Lung Cancer (NSCLC) (ID 6044)
14:30 - 14:30 | Author(s): I. Wistuba
- Abstract
Background:
The ICON study aims to perform a comprehensive immunogenomic characterization of early stage localized non-small cell lung cancer (NSCLC) and lay the foundation for the identification of barriers to tumor immunity that may be targeted in future trials. Earlier work has demonstrated the prognostic significance of TIL in localized NSCLC. This work evaluates the functional status of T cells infiltrating the NSCLC tumors and their capacity to expand ex-vivo and perform effector function in the first 22 patients enrolled.
Methods:
Patients enrolled on the ICON study underwent surgery. Fresh tumor samples were mechanically disaggregated and immediately stained for flow cytometry. Panels consisted of markers of T cell subsets, differentiation status, T cell function, activation and exhaustion. PD-L1 expression was assessed on malignant cells as well as CD68+ tumor-associated macrophages (TAMs) by IHC. Fragments from the tumor tissue were also placed in culture in media containing IL-2 for ex-vivo TIL expansion. TIL cultures were maintained for 3-5 weeks and subsequently underwent phenotypical and functional characterization.
Results:
Analysis of freshly disaggregated tumor tissue (n=22) from NSCLC tumor or adjacent normal tissue by flow cytometry demonstrated that effector CD8[+] T cells found in the tumor were less functional than T cells infiltrating normal tissue, revealed by a decrease in the co-expression of the cytotoxic effector molecules perforin and granzyme B (p=0.0004) together with an enhanced expression of the inhibitory receptor PD-1 (p<0.0001). Immunohistochemistry analysis showed PD-L1 expression on malignant cells and/or CD68+ TAMs on all tumor samples except one, strongly suggesting that the PD-1/PD-L1 inhibitory axis was engaged contributing to decreased T cell functionality. TIL could be expanded from the majority of samples (68.2%, n=22). The degree of infiltration predicted the ability to grow TIL ex-vivo (median CD3+ infiltrate of 15.25% of live cells in disaggregated tumor tissue for samples from which TIL could be grown versus 2.9% when TIL could not grow p = 0.015). Immunophenotyping following expansion showed an enrichment in CD8+ aβTCR+ T-cells expressing both perforin and granzyme B indicating that TILs propagated with IL-2 regained functionality (p=0.016). Lastly, NSCLC TIL were rapidly expanded using anti-CD3 antibody, feeder cells and IL-2 over two weeks (n=6) and reached clinically relevant numbers for TIL ACT (range 381-1282 fold expansion).
Conclusion:
Overall, while TILs present in NSCLC are functionally inhibited, they can be expanded ex-vivo from most tumor samples and regain a functional phenotype for potential use in adoptive T-cell therapy.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-024 - EGFR Mutations in Small Cell Lung Cancer (SCLC): Genetic Heterogeneity and Prognostic Impact (ID 4154)
14:30 - 14:30 | Author(s): I. Wistuba
- Abstract
Background:
EGFR mutations in SCLC were first reported in cases of lung adenocarcinoma which transformed to SCLC after TKI treatment and such mutation was speculated to be a TKI resistance mechanism. Recently case reports and high throughput sequencing in a small number of samples suggested that EGFR mutations do exist in de novo SCLC. But the genetic and clinical characteristics have not been studied in large number of samples. This study aims to conduct a large scale survey of the EGFR mutations among Chinese SCLC patients, and to analyze the genetic and clinical characteristics of such mutations.
Methods:
Mutation status in exon 18-21 of EGFR was assessed by dideoxy-sequencing in 565 SCLC tumors treated in Zhejiang Cancer Hospital, Hangzhou, China from 2009 to 2014 and correlated with clinical parameters. Chi-square test were used to show the correlation of clinic variables with EGFR mutation. Survival analysis was performed using the Kaplan-Meier method.
Results:
40 instances of EGFR mutation are detected in 565 clinical samples. The mutation rate is 7.1%. Besides classic mutations E19 deletion（n=3）and E21 L858R(n=3), the rest of the mutations detected are atypical including E18 (G719D/S, G696R, S695N/D, N700D, I715F, L688F, P694L), E19(K757N, A755V, V742I, E736K, N756Y, E749K, P753L, A755T), E20 (T790M, H773R, S768R/N, R776H/C, G796D, D807N, R803W/Q, Y813C, G810S, A763T, G779D, Q791R, C781Y, N771S), E21(L858V, G874R, K867E). Among the EGFR mutation positive patients, 27.5% (11/40) are non-smokers, higher than the EGFR negative group (16.4%, 86/525). But it is not statistically significant (p=0.129). And EGFR mutation is not correlated with sex (female vs male), age (≥65y vs <65y) or clinical stages (limited stage vs extensive stage). After matching the treatment history of the EGFR mutation positive and negative patients (excluding patients who were not treated ,only treated by traditional Chinese medicine or one cycle chemotherapy or biological therapy , treatment unkown ), univariate analysis shows that the EGFR mutation positive patients have better overall survival than the EGFR negative group, with medium OS of 24.433m±4.864m vs 14.00m±0.838m respectively (p=0.018). COX regression analysis suggests that limited stage (HR=2.610), <65 years (HR=1.476) and EGFR mutation (HR=0.587, p=0. 0.039) were independently predictive of better OS.
Conclusion:
Among the de novo SCLC patients diagnosed, there exists a group harboring EGFR mutations, most of which are non-classic mutations. After matching the treatment history of patients, analysis reveals that EGFR mutations are predictive of better OS.
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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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P2.01-061 - Image Analysis-Based Expression of Nine Immune Checkpoints Identifies Distinct Immunoprofiling Patterns in Non-Small Cell Lung Carcinomas (ID 5548)
14:30 - 14:30 | Author(s): I. Wistuba
- Abstract
Background:
The understanding of the co-expression of immune checkpoints in non-small cell lung carcinoma (NSCLC) is important to potentially design combinatorial immunotherapy approaches in this disease. We examined the expression of a panel of immune checkpoints markers by immunohistochemistry (IHC) and quantitative image analysis in a large cohort of surgically resected NSCLCs, and correlated those findings with patients’ clinicopathological features and tumors’ inflammatory cells infiltrate and molecular characteristics.
Methods:
We studied 225 formalin fixed and paraffin embedded (FFPE) tumor tissues from stage I-III NSCLCs, including 123 adenocarcinomas (ADC) and 83 squamous cell carcinomas (SCC), placed in tissue microarrays (TMAs). Nine immune checkpoints markers, 4 (PD-L1, B7-H3, B7-H4, IDO1) expressed predominantly in malignant cells (MCs), and 5 (ICOS, VISTA, TIM3, LAG3 and OX40) expressed mostly in stromal tumor associated inflammatory cells (TAICs). All IHC markers were examined using quantitative image analysis system (Aperio).
Results:
Using > median value of the immune checkpoint expressions as positive expression we observed that MCs H-score expressing PD-L1, B7-H3, B7-H4 and IDO1was higher in SCC than ADC, with 3 out of 4 markers showing statistically significant (P<0.05) differences. In contrast, density of TAICs expressing ICOS, VISTA, OX40, LAG3 and TIM3 was higher in ADC than SCC, with 3 out of 5 markers demonstrating significant (P<0.05) differences. Furthermore, we identified frequent co-expression of markers: a) 11% ADC (13/123) and 10% SCC (8/83) co-expressed 8 to 9 markers; b) 45% ADC (55/123) and 32% SCC (27/83) co-expressed 6 to 7 markers, c) 28% ADC (35/123) and 40% SCC (33/83) co-expressed 4 to 5 markers, and d) 16% ADC (20/123) and 18% SCC (15/83) co-expressed 2 to 3 markers. In ADC, higher number of TAICs expressing OX40 and lower levels of MCs expressing B7-H4 were detected in tumors with EGFR (median, 7.49 vs. 1.16, P=0.021) and KRAS (median, 6.88 vs. 0.67, P=0.033) mutation compared with wild-type tumors, respectively. Univariate analysis demonstrated that high B7-H4 and low OX40 expression in MCs and in TAICs respectively correlated with worse overall survival (OS; P=0.016 and P=0.037, respectively) in ADC patients.
Conclusion:
We detected different patterns of immune checkpoints expression in NSCLC with higher level of markers found in malignant cells of SCC and in stromal inflammatory cells of ADC. Immune checkpoints expression correlated with the outcome of NSCLC patients. Importantly, co-expression of several immune checkpoints is a frequent event in NSCLC (Supported by CPRIT MIRA and UT Lung SPORE grants).
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P2.02 - Poster Session with Presenters Present (ID 462)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.02-037 - Final Results of Prospective Phase II Study of Adding Erlotinib to Chemoradiation for patients with Stage III Non-Small-Cell Lung Cancer (ID 5748)
14:30 - 14:30 | Author(s): I. Wistuba
- Abstract
Background:
Concurrent chemoradiotherapy is the standard of care for inoperable stage III non-small cell lung cancer (NSCLC) patients. We explored if adding erlotinib would increase the effectiveness of chemoradiotherapy, since we have demonstrated radiation sensitization by erlotinib in a preclinical setting using a mouse model.
Methods:
48 patients with stage III NSCLC, PS 0-1, received radiotherapy (63 Gy/35 fractions) on Monday‒Friday, with chemotherapy (paclitaxel 45 mg/m², carboplatin AUC=2) on Mondays, for 7 weeks. All patients also received EGFR-TKI erlotinib (150 mg orally 1/day) on Tuesday–Sunday for 7 weeks followed by consolidation paclitaxel–carboplatin. The primary endpoint was time to progression; secondary endpoints were overall survival (OS), toxicity, response, and disease control and whether any endpoint differed by EGFR mutation status.
Results:
46 out of 48 patients were evaluable for response; 40 were former or never smokers and 41 were evaluated for EGFR mutation status: 37 were wild-type and 4 were found to have mutation (3 exon 19 deletion, 1 exon 21 mutation). Median time to progression was 14 months and did not differ based on EGFR mutation status. Toxicity was acceptable: no grade 5 toxicity, I grade 4, and 11 grade 3). Twelve (26%) had complete responses (10 with wild type (wt) and 2 with mutation (mt) and 1 unknown). At 73.5 months median follow-up (range 46.2 - 93.7 months), 2 and 5 year OS rates were 67.4 % and 36.25%; there were no significant differences by mutation status. Twelve patients had no progression and 34 had local and/or distant metastasis. All 4 patients with EGFR mutation had local control. Eleven of 27 patients failed in the brain (7 wt, 3 mt and 1 unknown).
Conclusion:
Toxicity was acceptable and OS was promising, but time to progression did not meet expectations. The prevalence of distant failures underscores the need for effective systemic therapy. Those patients with EGFR mutation might need induction erlotinib followed by local treatment when they fail locally in the lung or brain which is fairly frequent among EGFR mutated patients.
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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-023 - Circulating Tumor DNA (ctDNA)-Based Genomic Profiling of Known Cancer Genes in Lung Squamous Cell Carcinoma (LUSC) (ID 5393)
14:30 - 14:30 | Author(s): I. Wistuba
- Abstract
Background:
Next-generation sequencing (NGS) of ctDNA is increasingly used for non-invasive genomic profiling of human cancers. However, studies to date have not detailed the ctDNA genomic landscape in LUSC.
Methods:
From June 2014 to June 2016, ctDNA from 467 patients with stage 3 or 4 (AJCC 7[th] edition) LUSC (60% male, 40% female; median age of 69 [range 27-96]) were tested with Guardant 360[TM], a ctDNA NGS assay that detects single nucleotide variants (SNVs) of 54-70 cancer genes and certain copy number amplifications (CNAs), indels, and fusions. The median time between diagnosis and ctDNA testing was 238 days. Somatic alterations were compared with those in the 2016 LUSC TCGA dataset.
Results:
426 patients (92.2%) had at least one somatic alteration detected. The most commonly observed SNVs (> 5% frequency) were TP53 (64.8%), PIK3CA (7.8%), CDKN2A (6.1%), and KRAS (5.9%). Frequencies of SNVs known to be significant in LUSC correlated well between our cohort and the TCGA (Spearman r = 0.93) but were generally lower in our cohort (Table 1). Several of our most frequently observed CNAs are strongly associated with LUSC (EGFR, CDK6, MYC, ERBB2, PDGFRA, KIT, CCND1). In addition, MET exon 14 skipping (1.3%), EGFR exon 19 deletion (1.9%), EGFR exon 20 insertion (0.5%), ERBB2 exon 20 insertion (0.3%) and EML4-ALK fusion (0.7%) were detected. These alterations have rarely been reported in LUSC.
Conclusion:
Patterns of SNVs and CNAs in LUSC obtained by ctDNA profiling are largely consistent with those from TCGA tissue profiling, although the frequency of key SNVs is lower. The presence of actionable alterations atypical for LUSC in 4.7% of this clinical cohort may represent underappreciated treatment options. Further investigation is warranted to evaluate whether these findings reflect a distinct mutational landscape in heavily treated advanced disease (which is under-represented in the TCGA) and/or challenges in histopathological classification. Figure 1
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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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P2.06-019 - A Phase II Study of Atezolizumab as Neoadjuvant and Adjuvant Therapy in Patients (pts) with Resectable Non-Small Cell Lung Cancer (NSCLC) (ID 4642)
14:30 - 14:30 | Author(s): I. Wistuba
- Abstract
Background:
There is no curative treatment for patients with NSCLC who develop metastatic disease after resection. Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with stages IB, II, and IIIA disease. Clearly, developing new treatment strategies to improve survival following resection is critical to improving outcomes for this patient population. Immunotherapy with checkpoint inhibitors such as antibodies to PD-1 and PD-L1 has demonstrated superior survival compared to chemotherapy in randomized clinical trials. PD-L1 expression is being investigated as a predictive biomarker for these therapies, but its ability to predict response has varied in published trials. Atezolizumab is a humanized IgG1 monoclonal PD-L1 antibody that was recently evaluated in the POPLAR trial (NCT01903993), a phase II randomized trial of patients with NSCLC who progressed on platinum based chemotherapy. Atezolizumab therapy improved overall survival compared with docetaxel (12.6 months vs. 9.7 months, HR 0.73 [95% CI 0.53 – 0.99]) with a manageable safety profile. Improvement in survival correlated with PD-L1 immunohistochemistry expression of tumor and tumor-infiltrating immune cells.
Methods:
Trial design: This phase II, open-label, single-arm study is designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. There are two parts to this study: the first/primary part will evaluate the ability of neoadjuvant atezolizumab to produce objective pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit (evidence of pathologic response or absence of radiographic progression) in Part 1. After surgical resection, patients may receive SOC adjuvant chemotherapy (with or without radiation) before starting atezolizumab adjuvant therapy in Part 2. The primary objectives are safety and major pathologic response based on surgical resection. Secondary objectives include overall response rate based on PD-L1 status, mutational load, antigen burden, and RNA-sequencing. This trial presents a unique opportunity to evaluate exploratory biomarkers, including pre- and post-treatment biopsy assessment of evolution of immune related markers associated with response.
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-021 - Reproducibility of Comprehensive Histologic Assessment and Refining Histologic Criteria in P Staging of Multiple Tumour Nodules (ID 5365)
14:30 - 14:30 | Author(s): I. Wistuba
- Abstract
Background:
Multiple tumor nodules (MTNs) are being encountered, with increasing frequency with the 8[th] TNM staging system recommending classification as separate primary lung cancers (SPLC) or intrapulmonary metastases (IM). Pathological staging requires assessment of morphological features, with criteria of Martini and Melamed supplanted by comprehensive histologic assessment of tumour type, predominant pattern, other histologic patterns and cytologic features. With publication of the 2015 WHO classification of lung tumours, we assessed the reproducibility of comprehensive histologic assessment and also sought to identify the most useful histological features.
Methods:
We conducted an online survey in which pathologists reviewed a sequential cohort of resected multifocal tumours to determine whether they were SPLC, IM, or a combination. Specific histological features for each nodule were entered into the database by the observing pathologist (tumour type, predominant adenocarcinoma pattern, and histological features including presence of lepidic growth, intra-alveolar cell clusters, cell size, mitotic rate, nuclear pleomorphism, nucleolar size and pleomorphism, nuclear inclusions, necrosis pattern, vascular invasion, mucin content, keratinization, clear cell change, cytoplasmic granules¸ lymphocytosis, macrophage response, acute inflammation and emperipolesis). Results were statistically analyzed for concordance with submitting diagnosis (gold standard) and among pathologists. Consistency of each feature was correlated with final determination of SPLC vs. IM status (p staging) by chi square analysis and Fisher exact test.
Results:
Seventeen pathologists evaluated 126 tumors from 48 patients. Kappa score on overall assessment of primary v. metastatic status was 0.60. There was good agreement as measured by Cohen’s Kappa (0.64, p<0.0001) between WHO histological patterns in individual cases with SPLC or IM status but proportions for histology and SPT or IM status were not identical (McNemar's test, p<0.0001) and additional histological features were assessed. There was marked variation in p values among the specific histological features. The strongest correlations (<0.05) between p staging status and histological features were with nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intra-alveolar clusters and necrosis pattern. Correlation between lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization and emperipolesis did not reach a p value of 0.05.
Conclusion:
Comprehensive histologic assessment shows good reproducibility between practicing lung pathologists. In addition to main tumour type and predominant patterns, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate appear to be useful in distinguishing between SPLC and IM.
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SC18 - Precision Screening for Lung Cancer (ID 342)
- Event: WCLC 2016
- Type: Science Session
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:A. Nicholson, G. Ostoros
- Coordinates: 12/06/2016, 16:00 - 17:30, Lehar 1-2
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SC18.01 - Field Cancerization in the Airways and its Application to Lung Cancer Early Detection (ID 6671)
16:00 - 16:20 | Author(s): I. Wistuba
- Abstract
- Presentation
Abstract:
Molecular alterations that are characteristic of lung tumors have been shown to be present in normal-appearing airway epithelium adjacent to lung tumors suggestive of an airway field cancerization phenomenon (1, 2). These field effects include altered gene expression, loss of heterozygosity (LOH), gene mutation and methylation and microsatellite instability (3-7). Microarray studies have pointed to expression profiles that are dissimilar between airways in smokers with and without lung cancer (8, 9). It has been recently demonstrated gene expression profiles that are shared between normal-appearing airway cells and nearby NSCLCs and that can distinguish airways of smokers with lung cancer from those without the malignancy (8). Studies from several groups suggest that the field cancerization provides biological insights into non-small cell lung carcinoma (NSCLC) ad small cell lung carcinoma (SCLC) pathogenesis and clinical opportunities for lung cancer detection (6, 8). It is important to note that smoking perpetuates inflammation throughout the exposed airway epithelium (10). This effect is pronounced in patients with Chronic Obstructive Pulmonary Disease (COPD) (10). Notably, among smokers, even after smoking cessation, airway inflammation persists while the risk of lung cancer continues to increase (10). It is not known which tumor promoting profiles in the airway field cancerization may drive lung cancer development in COPD patients. Using microarray profiling, studies have pointed to expression profiles that are dissimilar between airways in smokers with lung cancer and airways in smokers without cancer (11-13). Importantly, these gene-expression changes within the “field of injury” have been leveraged for development and validation of a clinically-relevant biomarker that can improve the diagnostic performance of bronchoscopy for detection of lung cancer (predominantly NSCLC) among smokers with suspect disease (8, 12). In addition, gene expression array analysis pointed to airway field expression profiles that are spatially and temporally modulated in early stage patients following surgery and that may be associated with disease relapse (13). Further, we have recently demonstrated that there is significant enrichment in gene expression profiles measured in both small (adjacent to tumor) and large (mainstem bronchus) airway compartments of the airway field of injury, suggesting that gene-expression changes in the large airway can serve as a surrogate for the molecular changes occurring in the airway epithelium adjacent to the tumor (9). Taken together, studies from our group and others suggest that, by sampling “normal” and relatively accessible tissue (e.g., bronchial airway), the airway field of injury provides biological insights into the earliest phases in the development of lung malignancy and potential valuable clinical opportunities such as early detection (1, 2). Identifying molecular aberrations that precede cellular morphological changes will provide biological insights into why some smokers develop lung cancer and, thus, clinical opportunities for improved lung cancer detection. References: 1. Kadara H, Wistuba, II. Field cancerization in non-small cell lung cancer: implications in disease pathogenesis. Proceedings of the American Thoracic Society. 2012;9(2):38-42. 2. Steiling K, Ryan J, Brody JS, Spira A. The field of tissue injury in the lung and airway. Cancer Prev Res. 2008;1(6):396-403. 3. Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E, Baylin SB, Herman JG. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci U S A. 1998;95(20):11891-6. 4. Mao L, Lee JS, Kurie JM, Fan YH, Lippman SM, Lee JJ, Ro JY, Broxson A, Yu R, Morice RC, Kemp BL, Khuri FR, Walsh GL, Hittelman WN, Hong WK. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst. 1997;89(12):857-62. 5. Tang X, Shigematsu H, Bekele BN, Roth JA, Minna JD, Hong WK, Gazdar AF, Wistuba, II. EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients. Cancer research. 2005;65(17):7568-72. 6. Wistuba, II, Behrens C, Milchgrub S, Bryant D, Hung J, Minna JD, Gazdar AF. Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma. Oncogene. 1999;18(3):643-50. 7. Wistuba, II, Lam S, Behrens C, Virmani AK, Fong KM, LeRiche J, Samet JM, Srivastava S, Minna JD, Gazdar AF. Molecular damage in the bronchial epithelium of current and former smokers. J Natl Cancer Inst. 1997;89(18):1366-73. 8. Spira A, Beane JE, Shah V, Steiling K, Liu G, Schembri F, Gilman S, Dumas YM, Calner P, Sebastiani P, Sridhar S, Beamis J, Lamb C, Anderson T, Gerry N, Keane J, Lenburg ME, Brody JS. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med. 2007;13(3):361-6. 9. Kadara H, Fujimoto J, Yoo SY, Maki Y, Gower AC, Kabbout M, Garcia MM, Chow CW, Chu Z, Mendoza G, Shen L, Kalhor N, Hong WK, Moran C, Wang J, Spira A, Coombes KR, Wistuba, II. Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer. J Natl Cancer Inst. 2014;106(3):dju004. 10. Punturieri A, Szabo E, Croxton TL, Shapiro SD, Dubinett SM. Lung cancer and chronic obstructive pulmonary disease: needs and opportunities for integrated research. J Natl Cancer Inst. 2009;101(8):554-9. 11. Gustafson AM, Soldi R, Anderlind C, Scholand MB, Qian J, Zhang X, Cooper K, Walker D, McWilliams A, Liu G, Szabo E, Brody J, Massion PP, Lenburg ME, Lam S, Bild AH, Spira A. Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci Transl Med.2(26):26ra5. 12. Silvestri GA, Vachani A, Whitney D, Elashoff M, Porta Smith K, Ferguson JS, Parsons E, Mitra N, Brody J, Lenburg ME, Spira A, Team AS. A Bronchial Genomic Classifier for the Diagnostic Evaluation of Lung Cancer. N Engl J Med. 2015;373(3):243-51. 13. Kadara H, Shen L, Fujimoto J, Saintigny P, Chow CW, Lang W, Chu Z, Garcia M, Kabbout M, Fan YH, Behrens C, Liu DA, Mao L, Lee JJ, Gold KA, Wang J, Coombes KR, Kim ES, Hong WK, Wistuba, II. Characterizing the molecular spatial and temporal field of injury in early-stage smoker non-small cell lung cancer patients after definitive surgery by expression profiling. Cancer prevention research. 2013;6(1):8-17.
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