PDL1 Expression on Peripheral Blood Cells Subpopulations in Patients with Non-Small Cell Lung Cancer

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MA14.01 Updated Dataset Assessing Tumor Mutation Burden (TMB) as a Biomarker for Response to PD-1/PD-L1 Targeted Therapies in Lung Cancer (LC) Alexa Schrock,1 Neelesh Sharma,2 Nir Peled,3 Jose Bufill,4 Gordan Srkalovic,5 David Spigel,6 David Fabrizio,1 Garrett Frampton,1 Caitlin Connelly,1 Mary Beth Lipka,2 Anna Belilovski,3 Jun Lo,1 Yali Li,1 James Sun,1 Kyle Gowen,1 Gregory Kalemkerian,7 Luis Raez,8 Sai-Hong Ou,9 Jeffrey Ross,1 Philip Stephens,1 Siraj Ali,1 Vincent Miller1 1Foundation Medicine, Cambridge/ United States of America, 2Hematology and Oncology, University Hospitals, Cleveland/OH/United States of America, 3Davidoff Cancer Center, Petach Tikva/Israel, 4 Michiana Hematology-Oncology, Pc, Mishawaka/IN/ United States of America, 5Sparrow Regional Cancer Center, Lansing/AL/United States of America, 6Sarah Cannon Research Institute, Nashville/United States of America, 7University of Michigan Cancer Center, Ann Arbor/MI/United States of America, 8Memorial Cancer Institute, Miami/FL/United States of America, 9University of California Irvine School of Medicine, Orange County/ CA/United States of America Background: Immune checkpoint inhibitors (ICPIs) nivolumab and pembrolizumab have been FDAapproved in non-small cell LC (NSCLC). Current IHC based diagnostics are challenged by assay and slide scoring issues and modest predictive value, and more robust and comprehensive biomarkers of ICPI efficacy are needed. A discovery set of 64 NSCLCs treated with ICPIs suggested that high TMB (
15 mutations/Mb) significantly correlated with longer time on drug (Spigel et al., ASCO 2016, Abstract:9017). Methods: Comprehensive genomic profiling (CGP) was performed during the course of clinical care. TMB was assessed as the number of somatic, coding, base substitution and indels per Mb of genome. Microsatellite instability-high (MSI-H) or stable (MSS) status was determined using a proprietary algorithm. Results: 15,529 LCs: 66% adenocarcinoma, 1% sarcomatoid, 14% NSCLC NOS, 11% squamous, 5% small cell, and 2% large cell were assessed. TMB was similar across all lung histologies (median: 6.3, 8.1, 9.0, 9.9, 9.9, and 10.8); the median was 7.6 for all LC cases (TMB
15 in 24% of cases), compared to 4.5 for 80,000+ samples of diverse tumor types in the database. Of LCs assessed 0.3% were MSI-H, of which 30/31 were TMB-high; however, 24% of MSS-stable cases were also TMB-high. PD-L1 amplification and DNA repair pathway mutation

Journal of Thoracic Oncology

Vol. 12 No. 1S

(MLH1, MSH2, POLE) were found in 1.0% and 1.1% of LC cases analyzed, respectively. Tumors harboring known drivers (ALK, ROS1, EGFR, BRAF V600E, MET splice) had low TMB (median: 2.5, 3.6, 3.8, 3.8, 4.5), whereas tumors with KRAS mutation, non-V600E BRAF mutation, PD-L1 amplification, or DNA repair alterations were more likely to be TMB-high (median: 9.0, 10.8, 14.4, 21.6). Conclusion: High TMB may be a predictive biomarker of response to ICPIs. Several factors including lack of a known driver, MSI-H status, PD-L1 amplification, and DNA repair mutation correlated with high TMB (P<0.0001 for all cases). However, 95% of TMB-high cases assessed were MSS and lacked both PD-L1 amplification and DNA repair mutation, and thus would likely not be selected for immunotherapy by assessment of individual genomic alterations or MSI status alone. A validation cohort of NSCLC patients treated with anti-PD1/PD-L1 therapies including analysis of clinical outcome, TMB, genomic profile, and available clinicopathologic characteristics will be presented. CGP of LC to simultaneously determine TMB, MSI status, PD-L1 amplification, and the presence of driver alterations may provide clinically useful predictors of response to ICPI and other targeted therapies using a single platform, but prospective clinical trials are needed to confirm these observations. Keywords: NSCLC, tumor mutational burden, comprehensive genomic profiling

MA14.02 Evaluation of PD1/PDL1 Expression on Peripheral Blood Cells Subpopulations in Patients with Non-Small Cell Lung Cancer Oscar Arrieta, Edgar Montes-Servín Unidad Funcional de Oncología Torácica Y Laboratorio de Medicina Personalizada, National Cancer Institute, Mexico City/ Mexico Background: Currently the immune system is considered an important target of study within the therapeutic alternatives for many tumors that have developed resistance in lung cancer. Many molecules called checkpoints regulate antitumor immunity as PD-L1 it is expressed in tumor cells and is a biomarker for anti PDL1/PD-1 therapy. PD-1/PD-L1 is expressed on exhausted activated T cells. This signaling pathway is involved in tumor evasion of the immune system. It has recently been demonstrated that the blockade of PD-1 or its ligand PD-L1 and PD-L2, restore the antitumor immune response leading to a durable tumor regression. However, the expression of PD-1/PD-L1 in T cells from

January 2017

peripheral blood of patients with non-small cell lung cancer has not been widely studied. Methods: We investigated the expression of PD-1 and its ligands PD-L1 and PD-L2 on peripheral blood T cells subpopulations (CD3+ CD4+ / CD8+) of patients with non-small cell lung cancer. We included 50 NSCLC patients (stage IIIB and IV) naive to treatment and 10 healthy subjects. Immunophenotyping was performed using multiparametric flow cytometry. Analyzing its prognostic significance regarding outcome analysis as well as its potential biomarker. Results: Our results showed that the percentage of PD-1, PD-L1 and PD-L2 expression in peripheral blood cells in NSCLC patients was lower compared to healthy subjects [P<0.005] and the Mean Fluorescence Intensity (MFI) was higher in patients compared to the control group [P<0.001]; The expression of PD-1 in T-helper or CD4+ of NSCLC patients was significantly higher than in cells from control subjects [P<0.001]. Similarly, the expression of PD1 in T cytotoxic cells or CD8+ patients was significantly higher than in controls [P<0.001]. In the clinical analysis, we found that a higher percentage of PD-1+ CD3+ cells was statistically associated with tobacco exposure [P¼0.0160], and de MFI was associated with the non-adenocarcinoma histology [P¼0.0001] additionally, the presence of 3 or more metastases was associated to a higher MFI of PD-1 on CD3+ CD8+ [P¼0.0490]. In the overall survival (OS) analysis the percentage of CD3+/CD4+/PD-1+ 20.91 was associated with a higher median OS [P¼ 0.045]. Conclusion: Several studies demonstrate the importance of infiltrating PD-1+ T cells within tumors; however these results showed that the PD-1/PD-L1/PDL-2 expression in peripheral blood cells could be used also as a potential biomarkers in NSCLC patients. Keywords: PD-1, PD-L1, NSCLC, biomarker

MA14.03 The Impact of Genomic Landscape of EGFR Mutant NSCLC on Response to Targeted and Immune Therapy Yasir Elamin,1 Waree Rinsurongkawong,2 Hai Tran,3 Kathryn Gold,4 Jeff Lewis,2 Emily Roarty,5 Andrew Futreal,6 Jianjun Zhang,7 John Heymach8 1 Thoracic/head and Neck Medical Oncology, MD Anderson Cancer Center, Houston/TX/United States of America, 2MD Anderson Cancer Center, Houston/TX/United States of America, 3Thoracic/head and Neck Medical Oncology, MD Anderson Cancer Center, Houston/United States of America, 4Moores Cancer Center, University of California San Diego, La Jolla/United States of America, 5Thoracic, Head & Neck Medical Oncology, The University of Texas

Abstracts

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M. D. Anderson Cancer Center, Houston/TX/United States of America, 6The University of Texas MD Anderson Cancer Center, Houston, Hx/United States of America, 7 Department of Thoracic/head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston/AL/United States of America, 8Thoracic/ head and Neck Medical Oncology, MD Anderson, Houston/ TX/United States of America Background: EGFR mutations define a distinct subset of NSCLC characterized by clinical benefit from tyrosine kinase inhibitors. The impact of genomic alterations that coexist with EGFR mutations is not fully understood. In addition, the responsiveness of EGFR mutant NSCLC to immune checkpoint blockade is not well defined. Methods: We queried our prospectively collected MD Anderson Lung Cancer Moon Shot GEMINI Database to identify EGFR mutant NSCLC patients. We analyzed the genomic landscape of these tumors derived from next generation sequencing, performed as part of routine clinical care, to comprehensively describe the concurrent genomic aberrations in EGFR mutant NSCLC and their impact on clinical outcomes. We used log rank and Fisher’s exact tests to identify associations between coconcurrent mutations and clinical outcomes. Results: 1958 non-squamous NSCLC patients were identified in the GEMINI database. The frequency of EGFR mutations was 14.1% (n¼276). Among EGFR mutant patients, 188 underwent targeted next generation sequencing of a minimum of 46 cancer related genes. The majority of EGFR mutant patients (77.6%, n¼146) had at least one coexisting mutation. The most frequent co-mutations identified were TP53 (47%, n¼88), CTNNB1 (7.5%, n¼ 14) and PIK3CA (6.5%, n¼12). ALK and ROS1 translocations were found to coexist with EGFR mutations in one patient each. Of patients treated with a first or second generation TKI, concurrent TP53 mutations were associated with a shorter progression free survival (HR¼ 1.81, P¼ 0.039). Eight patients with EGFR/CTNNB1 comutations developed acquired TKI resistance with T790M secondary mutation being the resistance mechanism in six (75%) of them suggesting that coexisting mutation can dictate emerging resistance mechanisms. Twenty patients were treated with anti PD1/PD-L1 agents (nivolumab n¼ 18, pembrolizumab n¼2). Only two (10%) patients achieved confirmed radiological response, one lasting for 6 months and the second ongoing at 6 months. Both patients were never smokers, one with EGFR exon 20 insertion and no concurrent mutations, and the other with EGFR exon 19 deletion and TP53 mutation. Sixteen patients developed confirmed progressive disease. Finally, one patient with 17 pack-year smoking history, EGFR G719/S768I double mutation and concurrent PIK3CA mutation achieved stable disease lasting for four months. The median