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    MA06 - PDL1, TMB and DNA Repair

    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Moderators:
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      MA06.01 - The Intrinsic PD-L1 Promotes Cellular Invasiveness Via their PD-1 Receptor in Lung Adenocarcinoma Cells

      13:30 - 13:35  |  Presenting Author(s): Wen-Pin Su  |  Author(s): Hung-Chang Wu, Shuen-Ru Yang, Jheng-Cheng Huang, Jing-Jou Yan, Wan-Chen Kao, Li-Chan Chang, Wu-Chou Su

      • Abstract

      Background

      Lung cancer is the most frequent cause of cancer death. Programmed death 1 (PD-1) in T cells and its ligand PD-L1 in tumor cells play a key role in immune checkpoint therapy and had applied to advanced stage lung cancer. Migration and invasion of tumor cells is a prerequisite for tumor cell metastasis. Since intrinsic PD-1 receptor functions promote tumor growth was reported, we will investigate the interaction between PD-1 and PD-L1 in lung adenocarcinoma cell lines, the impact on chemosensitivity, and clinical outcome.

      Method

      In vitro experiments, lung adenocarcinoma CL1-5 cells, derived from CL1-0 cells. We prepared PD-L1-overexpression human lung adenocarcinoma cell line, derived from CL1-0 cells (CL1-0-PD1). Migration and invasion ability were assessed by transwell assay; EMT marker and regulator were evaluated by Western blotting. We also observed the morphology of cells. To explore interaction between PD1 and PD-L1, we added anti-PD-1 antibody into CL1-0, CL1-5, and CL1-0-PDL1 cells, and then test migration, invasion and cellular morphology. We also suppressed PD-1 by siRNA to test whether PD-1/PDL-1 interaction contributed to the EMT change. Further, we evaluated cellular proliferation and chemosensitivity by MTT assay and colony formation assay. We will correlate PD-L1 expression in lung cancer cells with clinical outcome by IHC stain clinically.

      Result

      In CL1-5 cells, derived from CL1-0 cells, with high PD-L1 expression possessed higher cellular migration ability than the parental CL1-0 cells with less PD-L1 expression. CL1-0 cells with PD-L1 overexpression had more expression of EMT (epithelial mesenchymal transition) regulator and mesenchymal marker. We also observed that CL1-5 and CL1-0-PDL1, which had more PD-L1 expression, are shaped like spindles; while CL1-0 cells are more rounded. Therefore, PD-L1 up-regulated cell migration and invasiveness in human lung adenocarcinoma cells and promotes EMT.

      After adding anti-PD1 antibody in CL1-5, CL1-0, and CL1-0-PDL1 cells, migration and invasion ability decreased. These result indicated anti-PD-1 antibody block the link between PD-1 and PD-L1 in cancer cells. The phenomenon was confirmed by PD-1 siRNA. Therefore, PD-1/PD-L1 axis regulated cancer cells migration and invasiveness. PD-L1 expression also decreased cellular proliferation and had little influence on chemsensitivity. Finally, we found that higher PD-L1 expression was correlated with lymph node metastasis in clinical specimen.

      Conclusion

      Lung adenocarcinoma cells with higher PD-L1 expression promote cell migration, invasiveness, EMT, and little chemoresistance. PD-L1 expression lowers proliferation rate. PD-1 and PD-L1 interaction on lung adenocarcinoma cells contribute cellular migration and invasiveness.

      • Abstract

      Background

      Our previous work has demonstrated that higher level of genomic complexity is associated with more heterogeneous neoantigen repertoire, suppressed T cell repertoire and postsurgical relapse in localized non-small cell lung cancers (NSCLC) highlighting the complex interaction of tumor molecular and immune landscape and their impact on cancer biology and patient survival. We launched the ICON Project (Immune Genomic Profiling of NSCLC) to prospectively delineate the molecular and immune landscape of early stage NSCLC and their impact on patient survival through a multidisciplinary approach. Here we report the updated genomic and immune analyses.

      Method

      Surgical specimens from stage I-III NSCLC were subjected to whole-exome and RNA sequencing for mutational analysis, in silico neoantigen prediction and gene expression analysis as well as T cell receptor sequencing, cytometry by time-of-flight and multiplex immunofluorescence staining.

      Result

      From 2016-2018, 127 patients were accrued and 50 surgical samples have undergone WES, RNAseq, TCR sequencing and immune phenotyping. Median age is 66 yrs (range: 39-86), 52% (26/50) were female and 76% (38/50) former smokers. 76% (38/50) are non-squamous carcinomas and 24% (12/50) squamous cell carcinomas. 34% have stage I disease (17/50), 30% stage II (15/50), 34% stage III (17/50) and 2% stage IV (1/50). The majority of patients had upfront surgery (45/50; 90%). With median follow-up of 19 months, 15 patients have relapsed. Median tumor mutational burden is 7.8mut/Mb and predicted neoantigen burden was 10/sample (range: 0-250). Predicted neoantigen burden is significantly correlated with tumor mutational burden (r=0.41, p=0.002). The most commonly mutated genes are TP53, KRAS, CDKN2A, PIK3CA, EGFR, BRAF, GRIN2A and ATM. C->A transversions and C->T transitions were the most common mutational subtypes. PD-1 expression and regulatory T-cell (CD4+/FoxP3+) infiltration are significantly increased in tumor tissue compared to normal tissue (p=0.003 and p=0.02 respectively), while CD3, CD8, granzyme B and CD45RO are decreased in tumor tissue compared to normal lung.

      Conclusion

      NSCLC tumors have an immunosuppressive microenvironment compared to tumor adjacent normal lung tissues. Clinical data will be adequate to conduct genomic and immune profiling comparisons across different clinical subgroups. Mutational and neoantigen profiling are consistent with previously reported studies and correlations between molecular and immune landscapes and its impact on patient survival are ongoing.

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      MA06.03 - PD-1 and Id-1 Combined Blockade Impacts Tumor Growth and Survival Through PD-L1 Expression and Tumor Infiltration by Immune-Related Cells 

      13:40 - 13:45  |  Presenting Author(s): Ignacio Gil-Bazo  |  Author(s): Iosune Baraibar, Marta Roman Moreno, Ines Lopez, Jesus Corral, Juan Jose Lasarte, Alfonso Calvo, Silve Vicent, Daniel Ajona

      • Abstract

      Background

      PD-1/PDL-1 inhibitors are approved in advanced non-small cell lung cancer (NSCLC). Long-term survival rates associated to PD-1/PDL-1 blockade have changed treatment paradigm. However, many patients do not benefit from PD-1/PDL-1 blockade. New therapeutic combinations are under investigation. Id1 is involved in proliferation, angiogenesis and immunosuppression. We described Id1 as an independent prognostic factor in NSCLC (Ponz-Sarvise, Clin Cancer Res 2011) and more recently showed Id1’s role in lung cancer metastasis (Castanon, Cancer Letters 2017). Here we test a combined therapeutic strategy targeting PD-1 and Id1 in a murine lung cancer model.

      Method

      Three in vivo studies evaluated the impact of Id1 inhibition in tumor cells, tumor microenvironment and in both, on tumor volumes and mice survival. A syngeneic tumor model using C57BL/6 and Id1-/- Id3+/- mice was created by subcutaneous injection of Lewis Lung Carcinoma (3LL) cells and Id1 silenced 3LL (Id1Sh) cells. After injection, mice were treated with an anti-PD-1 (RMP-1-14) monoclonal antibody or PBS. Tumor volumes according to mice strain, Id1 status in tumor cells and treatment were quantified. Mice's survival was calculated in those groups. Tumor CD8+ and CD3+ TILs and CD68+ cells were quantified by specific immunostainings.

      Result

      Id1 inhibition in the tumor environment and the injected tumor cells, combined with anti-PD-1 treatment, induced a significant tumor growth impairment (p < 0.0001) and increased survival (p = 0.0051). CD3+ and CD8+ TILs and tumor CD68 + cells were significantly higher in tumors from mice with the combined Id1-PD-1 blockade treated with the anti-PD-1 inhibitor compared to control animals suggesting that tumor increased immune-related cells infiltration exerts the effector phase of the antitumor immune response. Additionally, PD-L1 expression seemed to be higher when Id1 expression was absent in the immune microenvironment (p = 0.04). Additional data based on multiplexed immunohistochemistry results will be presented at the meeting.

      Conclusion

      Id1 and PD-1 combined blockade in our syngeneic murine lung cancer model significantly impaired tumor growth and increased survival. Increased tumor PD-L1 expression and CD3+ and CD8+ TILs and CD68+ cells may explain these findings.

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      MA06.04 - Discussant - MA 06.01, MA 06.02, MA 06.03

      13:45 - 14:00  |  Presenting Author(s): Akihiko Yoshida

      • Abstract

      Abstract not provided

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      MA06.05 - The Micro-Environmental Cross Talk Between Mast Cells and Lung Cancer Cells Through Cell-to-Cell Contact

      14:00 - 14:05  |  Presenting Author(s): Rachel Shemesh  |  Author(s): Yaara Gorzalczany, Smadar Geva, Laila C. Roisman, Ronit Sagi-Eisenberg, Nir Peled

      • Abstract

      Background

      Mast cells (MCs) are key effectors in allergic reactions, but are also involved in tissue remodeling, wound healing and protection against pathogens. MCs infiltrate tumors and their number within the tumor microenvironment in certain cancer types, such as lung cancer, have been correlated with poor prognosis. The nature of crosstalk between lung cancer and MCs remain poorly resolved. In this study, we investigated the activation patterns within the MCs following cell-to-cell contact with lung cancer cells showing CD73 involvement and implying metabolic changes.

      Method

      Human MCs (HMC-1 and LAD-2) were exposed to Human lung cancer cells (H1299), derived membranes to recapitulate cell contact mediated activation. Lysates of MCs were tested for protein expression and posttranslational modifications (i.e. phosphorylation) by targeted western blotting. We unraveled the intracellular signaling molecules that are necessary for this signaling pathway by a pharmacological approach using several inhibitors. Each condition was repeated at least twice.

      Result

      H1299 membrane exposure activated the ERK 1/2 MAP kinases in HMC-1 and in LAD-2 cells. AKT signaling was also activated in LAD-2 cells as a result of this contact. CD73 dephosphorylates AMP to adenosine within the MCs. Interestingly enough, this ERK 1/2 activation was inhibited by CD73 inhibitor and A3 receptor antagonists in HMC-1 cells. ERK 1/2 activation was inhibited by A3 receptor antagonists and PI3K in LAD-2 cells. Furthermore, we discovered that protein kinase C (PKC) inhibitor augments the activation of ERK 1/2 in LAD-2 cells. In contrast, PKC inhibitor inhibits the activation of ERK 1/2 in HMC-1 cells. In addition, we discovered that the AKT activation was inhibited by A3 receptor and PI3K inhibitors but not by CD 73 inhibitors.

      Conclusion

      Our results suggest that H1299 membranes activate ERK 1/2 in HMC-1 cells by a mechanism that involves autocrine formation of adenosine and is mediated by CD 73 and A3 receptor. In addition, we discovered that there is an important difference between the ERK 1/2 MAP kinase signal transduction in HMC-1 and LAD-2 cells, PKC is an inhibitor of the H1299 activation of ERK 1/2 in LAD-2 cells. In contrast, the H1299 membrane activation of ERK 1/2 kinase in HMC-1 cells is mediated by PKC. Furthermore, we can conclude that H1299 membranes activate AKT in an A3 receptor dependent mechanism that is mediated by PI3K.

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      MA06.06 - An Ex-Vivo Patient-Derived, Immunocompetent (PDI) Culture System to Evaluate Immunotherapeutic Agents’ Anti-Tumor Efficacy

      14:05 - 14:10  |  Presenting Author(s): Zachary E. Tano  |  Author(s): Stefan Kiesgen, Navin Chintala, Jordan Dozier, John Messinger, Kay See Tan, Prasad S. Adusumilli

      • Abstract

      Background

      Anti-tumor efficacy of human immunotherapeutic agents, such as antibodies, chimeric antigen receptor (CAR) and T-cell receptor transduced T cells, are currently being investigated in immunodeficient mice prior to clinical translation. We developed and optimized an ex-vivo culture system utilizing malignant pleural effusions (MPEs) to compliment these investigations in a human, immunocompetent, tumor-like environment. We hypothesized that CAR T cells’ cytotoxicity will vary by the different immune compositions in each MPE, which are conditions unavailable in current efficacy assays.

      Method

      Mesothelin-targeted CAR T cells from multiple donors were exposed to MPEs derived from non-small cell lung cancer patients (n=15) and RPMI culture medium. Influence of the MPEs on CAR T-cell efficacy was evaluated by viability and phenotype (flow cytometry), cytotoxicity (chromium release assay), and gene expression (NanoString). Group-based trajectory modeling was used to stratify the inhibitory effect of MPEs. MPE composition (ELISA and Luminex assays) was evaluated to interpret its influence on CAR T cells.

      Result

      With the incorporation of our optimized protocols, T cells retain their viability, phenotype (CD4/CD8), and percentage of CAR expression when cultured in MPEs. MPE soluble factor levels remained stable over multiple freeze/thaw cycles. CAR T cells co-cultured in MPE exhibited variable antigen-specific cytotoxicity (Fig. A). MPE-induced T-cell inhibition was stratified into groups of strong, mild, or no inhibition. (Fig. B). Compared to MPEs with either mild or no inhibition, MPEs with strong inhibition had significantly higher levels of TGFβ-2 (average TGFβ-2 level in strong vs. mild inhibition: 402 vs. 50 pg/mL, p<0.05) (Fig. C), IL-6, RANTES, and IL-5.

      pdi culture system.jpg

      Conclusion

      We present the first human immunocompetent culture system that can be used to evaluate immunotherapeutic agents’ efficacy prior to their clinical translation. Furthermore, analyses of the culture system’s soluble factors sheds light on their relative influence on T-cell efficacy.

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      MA06.07 - Genetic and Epigenetic Alterations are Associated with Tumor Mutation Burden in Non-Small Cell Lung Cancer

      14:10 - 14:15  |  Presenting Author(s): Liang-Liang Cai  |  Author(s): Hua Bai, Zhi-Jie Wang, Shuhang Wang, Jian-Chun Duan, Shu-Geng Gao, Jie He, Jie Wang

      • Abstract

      Background

      Although several studies have indicated that tumor mutation burden (TMB) is associated with non-small cell lung cancer (NSCLC) development and clinical efficacy of immune checkpoint inhibitors (CPIs), identification of factors associated with TMB is still a major biological issue. It is well-known that DNA transcription can be regulated through methylation and demethylation, gene silencing caused by DNA hypermethylation is associated with cancer development. However, the relationship between DNA methylation and TMB in NSCLCs remains unclear.

      Method

      The landscape of DNA sequence in Chinese NSCLCs population were surveyed by using whole-exome sequencing (WES) by profiling 178 lung tissues (89 without any systemic anti-cancer therapy tumors and matched normal lung tissues). According to the 104 median-level of TMB in our cohort, high TMB (n=16, 252-465 range mutations per tumor) and low TMB (n=13, 57-79 range mutations per tumor) groups were divded. The NSCLC methylome between high and low TMB was characterized on a genome-wide scale using Illumina Infinium MethylationEPIC arrays combined with the WES data.

      Result

      The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures in high TMB lung cancer. Combining with clinical data, cigarette smoking associated with high TMB were observed in our cohort. Cancer-specific epigenetic alterations were observed in 294,141 CpG sites, comprising both tumor hyper- (769,38) and hypo- (217,203) methylation in high TMB lung cancer while none in low. These different methylations sites cover 1232 genes including 25 HOX genes.

      Conclusion

      Global DNA hypomethylation and TP53 mutation, associated with increased chromosomal instability, were associated with TMB in NSCLCs.The high TMB NSCLCs are characterized by numerous copy number alterations and aberrantly methylated sites and display distinct mutational signatures. 25 hypermethylated HOX genes can be potentially useful as DNA methylation markers for prediction of TMB level. The results provide insights into the epigenetic impact of TMB, which may contribute to improve precison management of NSCLCs.

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      MA06.08 - Discussant - MA 06.05, MA 06.06, MA 06.07

      14:15 - 14:30  |  Presenting Author(s): Jyoti Patel

      • Abstract

      Abstract not provided

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      MA06.09 - XRCC6BP1: A DNA Repair Gene in Cisplatin Resistant Lung Cancer Stem Cells That May Predict Survival Outcomes in Patients

      14:30 - 14:35  |  Presenting Author(s): Martin P Barr  |  Author(s): Robert Farrell, Saravjeet Singh, Emma Foley, Yuexi He, Lauren Brady, Vincent Young, Ronan Ryan, Siobhan Nicholson, Niamh Leonard, Sinead Cuffe, Stephen Finn

      • Abstract

      Background

      Alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating resistance to chemotherapeutic agents.

      Method

      DNA Repair Pathway RT2 Profiler Arrays were used to elucidate key DNA repair genes implicated in chemoresistant NSCLC cells using cisplatin resistant (CisR) and corresponding parental (PT) H460 cells. DNA repair genes significantly altered in CisR cells were validated at the mRNA and protein level. The translational relevance of differentially expressed genes was examined in a cohort of chemo-naïve matched normal and tumour lung tissues from NSCLC patients. Loss of function studies were carried out using siRNA technology. The effect of XRCC6BP1 gene knockdown on apoptosis was assessed by FACS. Cellular expression and localisation of XRCC6BP1 protein and γH2AX foci in response to cisplatin were examined by immunofluorescence (Cytell™). To investigate a role for XRCC6BP1 in lung cancer stem cells, Side Population (SP) studies were used to characterise stem-like subpopulations within chemoresistant cells. XRCC6BP1 mRNA analysis was also examined in ALDH1+ and ALDH1- subpopulations. Immunohistochemistry analysis was carried out in resected lung tumour tissues and XRCC6BP1 expression was correlated with survival in addition to a number of clinicopathological parameters such as tumour stage & grade, gender, smoking status and chemotherapy.

      Result

      We identified a number of critical DNA repair genes that are differentially regulated between PT and CisR NSCLC cells. XRCC6BP1 mRNA and protein expression was significantly increased H460 CisR cells relative to their PT counterparts. Relative to matched normal lung tissues, XRCC6BP1 mRNA was significantly increased in lung adenocarcinoma patients. Gene silencing of XRCC6BP1 induced significant apoptosis of chemoresistant cells and reduced their DNA repair capacity. Immunofluorescence studies showed an increase in XRCC6BP1 protein expression and gH2AX foci in CisR cells. SP analysis revealed a significantly higher stem cell population in resistant cells, while XRCC6BP1 mRNA expression was considerably increased in SKMES-1, H460 and H1299 CisR cells positive for ALDH1 activity (ALDH1+) compared to ALDH1- cells. IHC scoring of XRCC6BP1 demonstrated poor survival outcomes for NSCLC patients with high expression of this DNA repair gene.

      Conclusion

      Our data highlight the potential of targeting components of the DNA repair pathway, in particular XRCC6BP1, in chemoresistant lung cancer. Furthermore, XRCC6BP1 may play an important role in subsets of lung cancer stem cells which, at least in part, may be responsible for driving and maintaining the cisplatin resistant phenotype in NSCLC.

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      MA06.10 - Germline Mutation in ATM Affect Lung Cancer Risk with High Effect

      14:35 - 14:40  |  Presenting Author(s): Xuemei Ji  |  Author(s): Dakai Zhu, Claudio Pikielny, Olga Gorlova, Maria Teresa Landi, John Kirkpatrick Field, Paul Brennan, Mattias Johansson, Rayjean J. Hung, James D McKay, Christopher Ian Amos

      • Abstract

      Background

      Genome wide association studies have identified several lung cancer susceptibility regions and common variants influencing lung cancer risk. However, few previous studies investigated the association between germline mutations and lung cancer risk.

      Method

      We analyzed data from a case-control study with 19053 lung cancer cases and 15446 healthy controls of European ancestry in a discovery phase and performed a validation analysis using a case-control study comprising 4261 lung cancer cases and 4152 healthy controls of European ancestry for replication. Logistic regression was used to identify germline mutations with high effect within exome regions associated with lung cancer risk.

      Result

      We found rs56009889 in ATM was statistically associated with lung cancer risk in the discovery set (OR = 3.05, P = 3.68 × 10−8) and was nonsignificantly associated with lung cancer risk in the validation set (OR = 1.83, P = 0.16). Stratified analyses by gender with adjustment for age and smoking status showed that females carrying at least one mutated allele of rs56009889 (T/C + T/T) had an increased risk of lung cancer with ORs being 7.77 (95% CI 3.45 - 17.47) in discovery and 6.73 (95% CI 1.46–30.98) in replication, compared to C/C homozygotes among females. Individuals carrying at least one T allele showed a significant 6.9-fold increased risk for lung adenocarcinoma in discovery (adjusted OR = 6.85; 95% CI 4.37 – 10.75) and approximately a 4.9-fold increased risk in replication (adjusted OR = 4.89; 95% CI 2.01 – 11.91). Never smokers with combined genotypes (T/C + T/T) had a greater than 8-fold increased risk of lung cancer in discovery (adjusted OR = 8.03, 95% CI 4.00 – 16.13), while smokers only showed a 2.13-fold increased risk (adjusted OR = 2.13, 95% CI 1.25 – 3.65). In replication, however, the risks from this variant were comparable between smokers and nonsmokers, although the sample size is small for nonsmokers (adjusted OR = 2.16; 95% CI 0.48 – 9.79 for never-smokers and adjusted OR = 2.07; 95% CI 0.66 – 6.52 for smokers). All the T/T homozygotes of rs56009889 developed lung adenocarcinoma in discovery (P = 0.036). The association exhibited a dose-response relationship between the number of T allele of rs56009889 and lung cancer risk in discovery (Ptrend = 1.07 x 10 -9).

      Conclusion

      rs56009889 highly affected the risk of lung cancer, mainly of lung adenocarcinoma, primarily in women and never smokers. These germline mutations provide important insights for the prevention of lung cancer.

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      MA06.11 - Distinct Origins of Lymphatic and Brain Metastasis in Lung Cancer

      14:40 - 14:45  |  Presenting Author(s): Tao Jiang  |  Author(s): Yan Yan, Caicun Zhou

      • Abstract

      Background

      Generally, distant metastases are seeded by lymph node metastases in most solid tumors. This concept provides a mechanistic basis for the TNM staging system and is the rationale for surgical resection of tumor-draining lymph nodes. However, a recent study found that lymphatic and distant metastases could arise from independent subclones in the primary colorectal cancer. The current study aimed to investigate the origins of lymphatic and brain metastasis in lung cancer.

      Method

      39 samples from twelve patients with primary lung cancer and brain metastases were identified. Three of them had the matched lymph node metastases. All tissues and matched peripheral blood samples were collected before any systemic treatment. Whole-exome (>150×) sequencing were conducted on these samples.

      Result

      Compared to the primary lesions, both brain and lymph node metastases had the significantly different patterns of somatic genome alterations. The mutational landscape of brain metastases was also distinctly different from matched lymph node metastases. Primary lesions, matched brain and lymph node metastases showed the similar mutation pattern in terms of transition and transversion, and all of samples displayed a higher percentage of C>T transition. Brain metastases had numerically higher tumor mutational burden (TMB) than primary lesions but it did not reach the statistical significance. Notably, we observed the totally distinct origins of lymphatic and brain metastasis in all three matched cases.

      Conclusion

      The current evidence suggested that brain metastases and matched lymph node metastases had different mutational landscape in patients with lung cancer. Brain metastases had higher TMB than their primary lesions. Lymphatic and brain metastasis had distinct origins in lung cancer. These results had profound clinical implications for application of immunotherapy and improvement of prognosis in patients with lung cancer and brain metastases.

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      MA06.12 - Discussant - MA 06.09, MA 06.10, MA 06.11

      14:45 - 15:00  |  Presenting Author(s): Rebecca Heist

      • Abstract

      Abstract not provided

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    MA07 - Towards Survivorship: The Landscape, Supports and Barriers

    • Type: Mini Oral Abstract Session
    • Track: Advocacy
    • Moderators:
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      MA07.01 - No Longer Outliers: Understanding the Needs of Long-Term Lung Cancer Survivors

      13:30 - 13:35  |  Presenting Author(s): Maureen Rigney  |  Author(s): Jennifer C King, Andrew Ciupek

      • Abstract

      Background

      Lung cancer is the leading cause of cancer death in most developed and developing countries. But people do survive, sometimes for many years. Those diagnosed with lung cancer experience higher levels of distress and have greater unmet physical and emotional needs compared with other types of cancer. But what of long-term survivors?

      Globally, The Cancer Atlas reported an estimated 1,878,000 people were living with lung cancer in 2012. With the introduction of screening and rapid treatment advancements, that number is only expected to increase. Are we prepared to meet the long term and late effects of lung cancer? First, we must better understand the experiences and identified needs of long-term survivors.

      Method

      820 people responded to a 120 question online survey that was distributed via social media and targeted outreach. 471 identified as lung cancer patients/survivors and 349 as loved ones. 21% of survivor-respondents indicated they had been diagnosed 5+ years prior.

      Queried on treatment and smoking histories, long-term survivors identified their most prevalent and problematic symptoms and side effects experienced during treatment, shortly after treatment ended and at 5+ years post-diagnosis. They also answered questions regarding treatment decision-making and palliative care discussions and provision of post-treatment survivorship plans.

      Result

      74% of long-term survivors had surgery, 43% had experienced a recurrence and 5% had participated in a clinical trial. None were current smokers.

      The most common (and problematic) late and long term symptoms and side effects were shortness of breath (39%), fatigue (28%) and anxiety (24%). Memory problems were also rated as common (27%).

      Long-term survivors indicated that during treatment, physical side effects were most problematic but post-treatment and long-term, emotional effects were more difficult. Financial issues were also more problematic 5+ years after treatment compared with other time periods. Both discussions of palliative care and provision of survivorship care plans were rare.

      Conclusion

      Long-term lung cancer survivors were once considered ouliers but today those diagnosed are increasingly living five years and longer. How do the late and long-term physical effects of lung cancer and its treatments differ from survivors of other types of cancer? How do long-term survivors manage stigma and survivor guilt? What physical and emotional support and services do they need? This survey provides initial insights into the physical. emotional and financial effects of living longer with lung cancer but more research is needed to allow us to more fully understand how we can support our long-term survivors.

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      MA07.02 - Line of Therapy and Patient Preferences Treating Lung Cancer: A Discrete-Choice Experiment

      13:35 - 13:40  |  Presenting Author(s): Andrea Ferris  |  Author(s): John F.P. Bridges, Upal Basu Roy, Ellen Janssen

      • Abstract

      Background

      Patient preferences now play an important role in cancer research, regulatory science, and value assessment. While there is a growing literature exploring the preference of patients with lung cancer, few studies have explored how preferences vary with patients’ treatment experience. We sought to quantify patient preferences for the benefits and risks of therapy and explore how they vary across line of treatment.

      Method

      Preferences were estimated using a discrete choice experiment (DCE) developed in partnership with a patient and stakeholder advisory boards. A D-optimal experimental design was used to generate 3 blocks of 9 choice tasks spanning five attributes: progression-free survival (PFS), short-term side effects, long-term side effects, risk of developing late-onset side effects, and mode of administration – each defined across 3 relevant levels. A diverse sample was recruited via email sent to the LUNGevity lung cancer patient database and via social media. A choice mode was estimated use a conditional logistic regression where the dependent variable was the respondents preferred treatment in each profile. The relative attribute importance (conditioned on the chosen attribute levels) was then compared across the respondents’ self-reported line of treatment.

      Result

      In total we had 350 eligible respondents, of which 279 (80%) completed as least on DCE task of which 3% did not receive a pharmacotherapy, 39% received first line therapy, and 58% had two or more lines of theory. As with previous studies, PFS was the most important attribute for patients and was similarly valued (P=0.406) among first- and later (second lines and more) lines of treatment (33.4% v 33.8%). Patients on first-line treatment placed great emphasis (P<0.001) on long-term side (18.9% v 14.1%) and late onset side effects (15.3% v 10.3%), but less emphasis (P<0.001) on short-term side effects (27.8% v 29.8 %) and mode of administration (4.6% v 12.0%) than those on later lines.

      Conclusion

      Population estimate of patient preference remain important, but more effort is needed to understand how patient preference vary across patient with different backgrounds and treatment experiences. We show that line of treatment does not effect how patients value time, but their experience may have an impact on treatment characteristics. Latent class analysis may allow for the identification of groups with similar preferences that could allow for multivariate analyses to explain preference heterogeneity.

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      MA07.03 - Attitudes to Lung Cancer in Europe: Findings from a Global Consumer Survey

      13:40 - 13:45  |  Presenting Author(s): Jesme Fox  |  Author(s): Aoife McNamara, Maureen Rigney, Greg Manuel, Sarah Winstone

      • Abstract

      Background

      If lung cancer is diagnosed early, patients’ chances of successful treatment are increased. Stigma
      around lung cancer, as a tobacco-related cancer, can discourage patients from talking to their doctor
      about potential symptoms. In 2017, the GLCC commissioned Populus to undertake an international
      consumer survey in each of the 25 countries of the GLCC members.

      Method

      1,000 adults, in 16 European countries, participated via an online survey in July 2017. To assess
      attitudes to lung cancer, they were told that lung cancer is mainly caused by smoking and other
      tobacco products. They were then asked the extent to which they agreed or disagreed with the
      statement: “I have less sympathy for people with lung cancer than for people with other cancers.”

      Result

      One in five (20%) people in Europe agreed that they have less sympathy for people with lung cancer
      than other forms of cancer (Chart 1). There was variation between countries with 30% of people in
      Portugal agreeing they have less sympathy in comparison to only 17% agreeing in Denmark, the
      Netherlands, Norway, Russia, Slovenia and Spain. Men in Europe are generally less sympathetic
      than women, and those aged over 55 are most sympathetic. In addition, there was a statistically
      significant correlation between those countries with lower cigarette consumption and people agreeing
      that they have less sympathy for people with lung cancer.

      Chart 1: European attitudes to lung cancer

      glcc - european attitudes - chart 1.png

      Conclusion

      Everyone - no matter what the cause of their cancer - deserves to have high quality treatment and
      care. The persistent and varied levels of stigma associated with lung cancer across Europe needs to
      be addressed, so that people experiencing symptoms are not discouraged from seeking early
      intervention.

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      MA07.04 - Discussant - MA 07.01, MA 07.02, MA 07.03

      13:45 - 14:00  |  Presenting Author(s): Kim Norris

      • Abstract

      Abstract not provided

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      MA07.05 - Psychosocial Needs and Programs of Cancer Patients/Survivors and Their Relatives: Unmet Needs from an International Study

      14:00 - 14:05  |  Presenting Author(s): Csaba László Dégi  |  Author(s): Samantha Serpentini, Savita Goswami

      • Abstract

      Background

      In consideration of the dynamic nature of cancer patients’ needs, systematic understanding of their unmet needs from a socio-ecological perspective may be essential as the patients’ needs and available services are likely to vary by different healthcare systems in different countries. To investigate the role of geographical influence in cancer patients’ unmet needs, this study seeks to compare the unmet needs of and available programs for cancer patients/survivors and their family members by different types of healthcare systems across different countries.

      Method

      The IPOS Survivorship Online Survey is distributed to international and regional Psycho-Oncology organization members, which covers countries in six continents. Survey participants’ countries where they practice/research will be categorized into four groups by the types of healthcare system: Beveridge Model, Bismarck Model, National Health Insurance Model, and Out-of-Pocket Model.

      Result

      With estimated survey to be completed by August 30th, 2018, repeated measures ANOVA will be employed to test differences in patients’ unmet needs by the four healthcare system groups, separately for patients’ unmet needs and their family caregivers’. Differences by individual countries will also be explored.

      Conclusion

      Findings will provide a global overview and a specific knowledge of the geografical differences in the psychosocial unmet needs and psycho-oncological programs for cancer patients/survivors and their family members/caregivers. Findings will also guide how to prioritize areas of cancer care that require improvement in psycho-oncology interventions and practices; and to highlight critical aspects for delivering quality care that vary by healthcare systems.

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      MA07.06 - Telephonic Communication In Palliative Care For Better Management Of Terminal Cancer Patients In Rural India -  An NGO Based Approach. 

      14:05 - 14:10  |  Presenting Author(s): Nabanita Mandal

      • Abstract

      Background

      Due to financial incapability and absence of manpower poor families often fail to carry their advanced cancer patients to the nodal centres. This pilot study will explore whether communication by mobile phone can lessen this burden.

      Method

      Initially a plan was generated regarding management of an advanced cancer patient in a nodal centre at District Head Quarter. Subsequently every two week a trained social worker attached to nodal centre will follow up and give necessary advice and emotional support to the patients and their families through their registered mobile phone number. Patient’s family were also encouraged to communicate with the team by phone in case of fresh complain and urgency in between.

      Result

      Since initiation in January 2017, 210 cancer patients were contacted by mobile phone every two weeks to enquire about their difficulties. In 76% of the situation trained social workers could give necessary advice by phone regarding management of their physical symptoms. Moreover patient’s family were really overwhelmed by the emotional support offered by the team over phone. Only 24% of cancer patients has to attend the nodal centre for expert advice from Palliative Care specialists.

      Conclusion

      This novel approach helped
      * In providing regular physical and emotional support to the patients and their families.

      * In significantly reducing the financial and manpower problems of carrying patients to the nodal units.
      * In improve the quality of life of patients by continuous guidance.


      More and more team members can take help of this new strategy for better communication and uninterrupted care.

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      MA07.07 - Identifying the Severity of Psychosocial Symptoms Among Patients Diagnosed with Lung Cancer. Do We Really Need Emotional Support Groups?

      14:10 - 14:15  |  Presenting Author(s): Arooj Fatima  |  Author(s): Syed Sammar Abbas Zaidi

      • Abstract

      Background

      Lung cancer is the second most common cancer among men and women. Most of the lung cancers are diagnosed at later stages among those patients who are underprivileged. The diagnosis and treatment of lung cancer is a continuous emotional distress for both patient and their family. We aim to identify the severity of depression, emotional distress, stress and mental fatigue among those patients who are diagnosed with lung cancer .

      Method

      A cross sectional study was conducted in Shaukat Khanum Hospital, Lahore from March 2014 to April 2015. Exclusion and Inclusion criteria were made. 150 were enrolled in the study. Socio demographic characteristics were evaluated using Beck Depression Inventory and socio demographic form. Severity of depression was estimated by using Hamilton D (HAM-D). Various variables were analysed including parent’s age, level of education, socioeconomic status, gender and number of children.

      Result

      68% of the participants exhibited severe range of depression. 27% showed moderate depression where as 5% participants were showing the mild range of depression. An inverse co relation was found between educational status, occupational status (paid or unpaid), their marital status, socioeconomic family status and depression. Women 71% were found be more depressed than males.

      Conclusion

      We concluded that majority of patients from psychosocial symptoms particularly depression and it is mainly associated with some factors. There is need to incorporate patients into the diagnosis and treatment process so that we can over come the effects of depression on the health outcomes of patients diagnosed with lung cancer. This can only be possible through appropriate education and emotional support programmes.

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      MA07.08 - Discussant - MA 07.05, MA 07.06, MA 07.07

      14:15 - 14:30  |  Presenting Author(s): Jennifer C King

      • Abstract

      Abstract not provided

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      MA07.09 - Willingness to Perform Multiple Biopsies to Improve Quality of Lung Cancer Care: Understanding the Oncologists’ Perspective

      14:30 - 14:35  |  Presenting Author(s): Upal Basu Roy  |  Author(s): Margery Jacobson, Andrea Ferris

      • Abstract

      Background

      Biomarker testing of advanced-stage non-small cell lung cancer (NSCLC) at the time of diagnosis is required to determine if a patient will benefit from a targeted therapy or immunotherapy. A patient may, however, need additional biopsies (rebiopsy) if the cancer recurs to determine the next line of therapy or to determine eligibility for a new drug or participation in a clinical trial. A LUNGevity study, conducted with 340 patients, revealed that patients were willing to undergo rebiopsies if that meant access to additional treatment options at the time of recurrence. However, only 36% of patients reported that their doctors recommended repeat biopsies at progression.

      Method

      To understand this patient-physician communications gap, we conducted an IRB-approved semi-structured survey-based study of 130 oncologists from academic research centers, community cancer centers, and private practice.

      Result

      Of the 130 oncologists surveyed,

      - Ninety percent of oncologists reported recommending a rebiopsy to their patients. However, when stratified by advanced-stage patient volume, oncologists with higher advanced-stage patient volumes reported higher rebiopsy and testing rates than those with low volumes (95% vs. 78%, p<0.05). Only 29% of the oncologists prescribed a rebiopsy in the past one year.

      - Major barriers to rebiopsy reported by oncologists included cost/reimbursement of a rebiopsy and treatment delay for 2nd- or subsequent lines of therapy

      - Among the types of biomarker testing performed at the time of progression, oncologists were more likely to prescribe testing for biomarkers with approved treatments (driver mutations – 94%, PD-L1 – 85%) unlike biomarkers for treatments in clinical development (43%) (p<0.05).

      - A forward linear regression analysis revealed that positive predictors of rebiopsy included treatment at a NCI Designated Cancer Center, while treatment at a community cancer center or private practice, presence of driver mutations at the time of diagnosis, and performance status of patient were negative predictors of rebiopsy

      - When presented with specific treatment scenarios for biomarkers (EGFR and ALK) that have 2nd-line treatment options, oncologists differed in their approach, suggesting a need for oncologist education about rebiopsying and subsequent biomarker testing

      Conclusion

      Our study demonstrates that rebiopsy practices vary by practice settings and volume of advanced-stage lung cancer patients. Even when rebiopsies are prescribed, a comprehensive biomarker profile of the tumor may not be obtained, due to variations in tests requested. A major implication is the need for appropriate oncologists’ education to ensure practice change for delivery of optimal care to lung cancer patients.

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      MA07.10 - Utilizing a Personalized Navigation Program to Identify Barriers and Increase Clinical Trial Participation Among Lung Cancer Patients

      14:35 - 14:40  |  Presenting Author(s): Andrew Ciupek  |  Author(s): Tara Perloff, Achintya Jaitly, Jennifer C King

      • Abstract

      Background

      Only about 5% of cancer patients participate in clinical trials. We previously conducted a survey of U.S. lung cancer patients and found that only 22% reported discussing clinical trials with their oncologist at the time of making treatment decisions. We hypothesized that a personalized navigation program could both increase rates of trial discussion and identify barriers to participation among lung cancer patients.

      Method

      We asked callers to Lung Cancer Alliance's 1-800 support line if they had considered clinical trial participation and referred willing callers to a navigator for further discussion. Navigators provided basic clinical trial education and a personalized list of trial matches. Patients were encouraged to discuss these trials with their treating oncologist. Navigators then regularly followed up with participants, via email or phone, at two to four-week intervals, to offer further support and collect outcomes information.

      Result

      We referred sixty callers to a navigator. Only 43% of callers reported a prior clinical trials conversation with their provider. Patients who had not started treatment or were on first-line treatment reported lower discussion rates (30%) than those on later treatment lines (60%). Among patients with follow up, 13 of 20 patients who had not discussed trials with their provider reported doing so after navigation. Ten of eleven patients that had a previous trial conversation initiated an additional one. Primary reasons given for not talking discussing after navigation were having stable disease on a current treatment or waiting for a clinical result. Ten patients reported contacting a trial. Primary reasons for not contacting a trial after discussion were disease progression, choosing a standard of care alternative, or waiting for a clinical result. Four patients have enrolled on a trial. Two patients were determined ineligible for a trial they approached for not meeting listed eligibility criteria and two for reasons not appearing in public trial information.

      Conclusion

      We identified barriers throughout the clinical trials consideration and enrollment process. One set of barriers was related to care coordination, as exemplified by low rates of trial discussion during early stages of treatment and patient reports of delayed trial consideration when currently receiving treatment or waiting on a clinical result. Communication of trial information was another area presenting barriers, as exemplified by exclusion of patients from trials for reasons not readily apparent from public trial information. Improving integration of trial discussion during care and ensuring availability of accurate, updated trial information may be essential to increase trial participation.

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      MA07.11 - Drug Price Comparison in Advanced Lung Cancer – High Cost Prices is Accompanied by Patient Benefits?

      14:40 - 14:45  |  Presenting Author(s): Luciene Bonan

      • Abstract

      Background

      In our recent decade we are seen new drugs coming up with high speed development to attend personalized conditions in lung cancer treatment. After the first TKI for EGFR mutation, many other target drugs such as TKI for ALK/ROS1 alteration, third-generation EGFR TKI, anti-PD-1/PD-L1 immunotherapies bring together an improvement in survival with better quality of life than chemotherapies. But this new specialty drugs are also testing the affordability of the market with new launched ceiling prices. Frequently, their prices have been settled down in a context of an unmet condition appeal rather than the truly health benefits. In pricing it is a common practice to use the external reference price between countries to align the prices based on international market. But if the first price is launched (frequently in USA) in countries that don’t use metrics based on evidence or clinical benefits, the price plateau could be replicated even without necessarily deserving this price. The objective of this presentation is to show the price comparison of drugs included in TKI class and immunotherapy class between high and middle-income countries. Then to compare the cost-treatment of therapies commonly used in advanced lung cancer and their magnitude of clinical benefit.

      Method

      All local currencies were converted to US dollars using PPP factor. The magnitude of effect was evaluated based on the ESMO Magnitude of Clinical Benefit Score.

      Result

      USA has the highest drug price followed by Brazil, especially in recent launched drugs. Costs of advanced lung cancer treatment significantly increase 5 times more when compared first-generated TKI and new generation TKI. Immunotherapy for second line costs 6 times more than first line with EGFR TKI and could cost more than 7 to 130 times the chemotherapy with docetaxel. Clinical benefits do not reach the same scale.

      Conclusion

      The market of anticancer drug increasing 10% annually, but clinical benefits don’t advance in the same compass. Specialized drugs come into the market with pricing warrant of unmeet conditions, but if we think in precision medicine all new drug-target biomarker could be priced higher because it will cover a rare or unmet condition. In the context of precision medicine, is it fear a patient pays more because he has a different biomarker for the same clinical condition? If countries do not start to evaluate and pricing drugs based on value, market strategists will continue to test the ceiling price that health systems can(not) afford.

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      MA07.12 - Discussant - MA 07.09, MA 07.10, MA 07.11

      14:45 - 15:00  |  Presenting Author(s): Govind Babu Kanakasetty

      • Abstract

      Abstract not provided

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    MS05 - Diagnostic Dilemma in Lung Cancer

    • Type: Mini Symposium
    • Track: Pathology
    • Moderators:
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      MS05.01 - Staging and Pathology of Multiple Lung Nodules

      13:30 - 13:50  |  Presenting Author(s): Alain C. Borczuk

      • Abstract

      Abstract

      The evaluation of patients with multiple lung nodules, which include situations of synchronous as well as metachronous presentations, has become an area of focused interest. This is in part due to valuable outcome datasets that have evolved in conjunction with staging during the adoption of the AJCC 7th and now 8th edition for lung tumor staging. It has become evident that the evaluation requires an integration of clinical, radiologic, pathologic and molecular data to produce the most precise stage to guide patient management.

      In earlier staging editions, multiple nodules were largely assumed to represent advanced disease; however, the survival data pointed to a more heterogeneous patient group. Differences in histology were cited as reasons for a conclusion of synchronous primary tumors, but these differences needed to be relatively stark – for example adenocarcinoma versus squamous carcinoma. Three major shifts in knowledge impacted this field - 1) in pathology, movement away from the “lumping” of adenocarcinoma into mixed subtype with recognition of categories of early non-mucinous lepidic tumors 2) imaging advances, including the advent of successful lung cancer screening and imaging correlates of early lepidic pattern tumors and 3) the explosion of molecular pathology in lung cancer, particularly in adenocarcinoma.

      The result of these advances is a sophisticated approach that integrates these data into a stage as well as a conceptual conclusion regarding tumor biology and pathogenesis. Once lung malignancy is confirmed pathologically in a patient, the radiologist can use imaging features, especially ground glass nodules and the configuration of part solid nodules, to lead to clinically relevant conclusions about the likelihood of synchronous primaries when multiple nodules are encountered. In fact, other parameters, such as persistence, size, growth, imaging characteristics and evolution of a solid component in a part solid lesion may lead to relevant predictions in the absence of histologic confirmation. For the pathologist, non-mucinous lepidic tumors (adenocarcinoma-in-situ, minimally invasive adenocarcinoma and lepidic predominant adenocarcinoma) and the recognition of unusual patterns of invasive carcinoma, function well in the decision making process, as non-mucinous AIS, MIA and LPA are considered primary tumors and unusual patterns of invasive carcinoma (e.g. micropapillary or invasive mucinous) within the multifocal lesions are an important feature in recognizing intra-pulmonary metastasis. This area still requires refinement, especially among the LPA tumors and tumor in which common patterns such as acinar patterns predominate.

      Several molecular features can also be introduced into the discussion. Certain molecular events, such as particular patterns of copy number alterations, may occur in an individual patient’s tumor but would otherwise be uncommon in that tumor type overall. Such a feature or set of features can assemble to form a molecular fingerprint of that primary tumor that is likely to be preserved in metastatic foci but unlikely to occur by chance in a new primary. In a similar fashion early molecular drivers of adenocarcinoma such as EGFR mutation and KRAS mutation, most often persist in metastatic foci. Discordance in such drivers can be valuable evidence to support synchronous primary carcinoma when used in conjunction with other information. Use of a wider set of mutational alterations may lead to more accurate information with regard to the likelihood of tumor evolution from one primary (i.e. intrapulmonary metastasis).

      After integration of these data, the authors of the AJCC staging 8th edition recognize 4 disease patterns with associated imaging, pathology, TNM classification and conceptual viewpoint. Second primary lung cancer (unrelated tumors), multifocal ground glass or lepidic nodules (separate tumors, despite common non-mucinous lepidic morphology), pneumonic-type adenocarcinoma (often mucinous, single tumor with diffuse pulmonary involvement), and separate tumor nodule (single tumor with intrapulmonary metastasis). While data already exist suggesting the staging, often downstaging, of multiple pulmonary carcinomas, widespread use of the AJCC 8th edition and accrual of cases, with survival information, that fit the above conceptual approach are needed to support its biological significance.

      References:

      Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016 11(5):651-65.

      Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. 2016;11(5):666-80.

      Nicholson AG et al. Interobserver Variation among Pathologists and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung. J Thorac Oncol. 2018;13(2):205-217.

      Girard N et al. Genomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers. Clin Cancer Res. 2009;15(16):5184-90.

      Asmar et al, Use of Oncogenic Driver Mutations in Staging of Multiple Primary Lung Carcinomas: A Single-Center Experience. J Thorac Oncol. 2017;12(10):1524-1535.

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      MS05.02 - Defining Invasion in Minimally Invasive Adenocarcinoma

      13:50 - 14:10  |  Presenting Author(s): Masayuki Noguchi

      • Abstract

      Abstract

      For pathological diagnosis of early invasive forms of adenocarcinoma, such as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and early-stage lepidic adenocarcinoma, morphological criteria for “invasion” were defined by the recent WHO classification in 2015. However, the inter-observer agreement rate has not been examined in detail. The IASLC pathology committee has initiated a trial of the diagnostic reproducibility of morphological criteria for invasive lung adenocarcinoma, especially the minimally invasive form. Although the study is still ongoing, several interesting results have emerged. First, although total tumor size showed a good k-ratio, the extents of tumor invasion calculated by the participants revealed a very low k-ratio. Secondly, although the areas determined by the participants were similar, the criteria upon which their judgements were based varied, and the same morphological features were not always employed. These results suggest that the morphological criteria used for defining tumor invasion are very difficult to generalize.

      On the other hand, driver oncogene mutations such as EGFR, BRAF, and RAS, and activated fusion proteins such as ALK, ROS, and RET have been detected in invasive adenocarcinoma. Except for EGFR mutation, however, other genetic alterations have not been detected in AIS. My group has been investigating the expression and genetic profiles of AIS and early but invasive lung adenocarcinoma using a molecular biological approach, and characterized several genomic and epigenetic abnormalities in these tumors.

      Among them, stratifin (SFN) appears to be a promising biomarker of tumor malignancy at the early stage, its overexpression being very specific to the stage when AIS progresses to early invasive adenocarcinoma (Fig. 1). SFN, a member of the 14-3-3 protein family (14-3-3 sigma), is completely suppressed epigenetically in normal lung tissue. However, during the course of malignant progression, its promoter region becomes di-methylated and expression of SFN increases. SFN binds specifically to SKP1 and inhibits the function of E3 ubiquitin ligase, thus preserving the functions of specific proliferation-associated proteins such as p-cyclin E1 and p-c-Jun. Abnormally high expression of SFN is thought to be a biological marker of lung adenocarcinoma invasion. Interestingly, several inhibitors of SFN-SKP1 binding are very effective for suppressing tumor growth in nude mice.

      Another interesting biomarker of early adenocarcinoma is epithelial cell transforming sequence 2 (ECT2), a guanine nucleotide exchange factor physiologically localized in the nucleus and functioning to regulate cytokinesis. ECT2 is also localized in the cytoplasm of cancer cells. Aberrant cytoplasmic expression of ECT2 is thought to drive tumor growth and invasion. Cytoplasmic expression of ECT2 in 167 lung adenocarcinomas was evaluated by immunohistochemistry and its clinical significance was examined (Fig. 2). Cytoplasmic expression of ECT2 was found to increase during cancer progression. Cytoplasmic positivity for ECT2 was associated with a poor outcome in terms of both disease-free and overall survival (both P<0.001), and was an independent prognostic factor related to overall survival (P= 0.025).

      Reference

      Kosibaty Z, Dai T, Murata Y, Minami Y, Kano J, Nakagawa T, Sakashita S, Noguchi M. Cytoplasmic expression of epithelial cell transforming sequence 2 (ECT2) in lung adenocarcinoma and its implication for malignant progression. Lab Invest, 2018 (in press)

      Kim Y, Shiba-Ishii A, Nakagawa T, Iemura SI, Natsume T, Nakano N, Matsuoka R, Sakashita S, Lee S, Kawaguchi A, Sato Y, Noguchi M. Stratifin regulates stabilization of receptor tyrosine kinases via interaction with ubiquitin-specific protease 8 in lung adenocarcinoma. Oncogene, 2018. [Epub ahead of print]

      Shiba-Ishii A , YunJung Kim, Toshihiro Shiozawa, Shinji Iyama, Kaishi Satomi, Junko Kano, Shingo Sakashita, Yukio Morishita,Masayuki NoguchiStratifin accelerates progression of lung adenocarcinoma at an early stage.Molecular Cancer, 2015,14:142.

      Murata Y, Minami Y, Iwakawa R, Yokota J, Usui S, Tsuta K, Shiraishi K, Sakashita S, Satomi K, Iijima T, Noguchi M.ECT2 amplification and overexpression as a new prognostic biomarker for early-stage lung adenocarcinoma. Cancer Sci, 2014,105(4):490-7.

      Figure 1

      fig 1 mnoguchi.jpg

      Figure 2

      fig 2 mnoguchi.jpg

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      MS05.03 - Tumor Heterogeneity in Lung Cancer

      14:10 - 14:30  |  Presenting Author(s): Elisabeth Brambilla

      • Abstract

      Abstract

      Lung cancer are composed of populations of cells with distinct molecular genetics , epigenetics and phenotypic features : this phenomenon called intra-tumor heterogeneity (ITH) adds complexity to the already well known inter-tumor heterogeneity which is responsible for the huge number of types and subtypes in each main histological category type as defined in the 2015 WHO classification. Intra-tumor heterogeneity impacts on tumor biopsy strategy, characterization of actionable targets , treatment planning and drug resistance.

      Tumor types which display the highest histological heterogeneity are adenocarcinoma (ADC) , adenosquamous carcinoma, pleomorphic carcinoma and the high grade neuroendocrine tumor small cell lung carcinoma (SCLC) and large cell neuroendocrine(LCNEC) when combined . However intra-tumor heterogeneity is not restricted to histology since molecular heterogeneity at the levels of genetics (mutations , copy number alterations), DNA methylation , mRNA expression profiling and immune context /PDL1 expression show high intra-tumor variability in most conventional lung tumor histologies. Capturing the full molecular landscape of each tumor and choosing the right target is indeed a crucial clinical dilemma facing intra-tumor heterogeneity . Although histological main type correlates with characteristic genomics (1) , histological heterogeneity relies more on transcriptomic expressions profiles and functional pathways ( embryonal, stemcellness, EMT ..) than on driver mutations , challenging the mechanisms of tumor plasticity and resistance.(2)

      A -Histological Heterogeneity

      1-Adenocarcinoma (60% of lung cancer) present with up to 5 histological patterns declined as predominant or not , lepidic, papillary, acinar/cribriform, micropapillary and solid (WHO 2015) requiring resection samples to allow an accurate diagnosis of combinations. Advantages derive from this complexity: some patterns have high prognostic value : high grade patterns solid , micropapillary and cribriform (even not predominant >= 5%) are independent determinants of short survival, whereas the pure lepidic pattern (AIS) or minimally invasise MIA predict 100% 5 years survival and predominant lepidic invasive ADC have statistically better prognosis than all other ADC .Spatial heterogeneity is well conserved temporally allowing discrimination of multiple primaries versus lung metastases when different or same combinations are compared . Disadvantage resides in interpretation of small samples showing only a part of the patterns . At molecular levels (genomics, expression profiling, immune context) adenocarcinoma show extended intra-tumor heterogeneity. Unfortunately each pattern does no predict specific driver mutations (EGFR,KRAS, BRAF, gene amplification) .

      2- Adenosquamous carcinoma (2% of lung cancer) is typically composed of both squamous cell carcinoma (SQCC) and adenocarcinoma (ADC) components (at least 10%). Both components might be morphologically obvious (ADC pattern, keratinizing SQCC ) or one is obvious and IHC is necessary to identify the other as SQCC (P40+) or ADC (TTF1) .Diagnostic challenges include size of the sample, one component missing on small sample with its associated mutations ,and variable components in primary and metastases. Molecular features are characteristic of one or both components: 56% tyrosine kinase mutations (32% EGFR; 11% KRAS;1-4% others) in ADC or in both ,FGFR1 amplification in SQCC. Dual histospecific mutations indicate common cell of origin with early clonal trunk mutation maintained at progression (2)

      3-Pleiomorphic carcinoma : ( 0.5% of lung cancer) is the most heterogeneous entity , composed of one or several components of NSCLC ( ADC, SQCC, large cell ) with at least 10% of spindle or giant cell carcinoma a clear feature of EMT (epithelial mesenchymal transition). Diagnosis requires resection sample. In undifferentiated areas IHC (TTF1/P40) will identify the NSCLC component and predict mutations. Mutations regionality is predicted and parallels histological components, if ADC (Kras, EGFR,BRAF Met ,ALK rearrangement ) if SQCC FGFR1 amplification. The most frequent MET exon 14 skipping mutation (20%) is heterogeneously distributed. Tumors with SMARC4 mutations described also in adenocarcinoma with obvious EMT transformation and BRG1 negative IH are now considered as pleomorphic carcinoma.

      4.Combined high grade tumors : Combined SCLC small cell Lung Carcinoma (SCLC) and combined Large cell neuroendocrine carcinoma LCNEC account for 20% of each in resected samples ,less readily detectable on small samples ,10% SCLC or LCNEC are sufficient. The genetic alterations are not therapeutically actionable yet, excepted in trials (DLL3) .Occurrence of mutations in the non- neuroendocrine component deserve recognition since it can induce drug resistance and transdifferentiation. Transformation of SCLC to NSCLC has been reported after cytotoxic SCLC chemotherapy (E. Brambilla JCO 1991 ) suggesting intra-tumor heterogeneity or cell plasticity under therapeutic pressure, and a common initiating stem cell between SCLC and NSCLC . Inter-tumor heterogeneity at molecular level is better documented than is intra-tumor heterogeneity, in absence of multi-region sequencing. NOTCH and DDL3 therapeutic targets shows both inter and intra-tumor heterogeneity(7)

      B-Temporal intra-tumor heterogeneity

      Genetic dynamics characterizes tumor progression , well studied during ADC progression from AAH to invasive ADC. The conservation of driver clonal but not subclonal mutations occur in metastases vs primary. Transdifferentiation is a typical exemple of temporal heterogeneity where a tumor treated ,more rarely spontaneously, transforms in another tumor type , SCLC to NSCLC , EGFR mutant adenocarcinoma to SQC or SCLC or pleiomorphic carcinoma with EMT, showing that tumor plasticity conferred by EMT results in temporal intra-tumor heterogeneity with transdifferentition (2)

      C-Spatial intra tumor heterogeneity across histology

      All studies (2-3) establish the concept of trunk and branches in the phylogenetic tree , the clonal trunk mutations are present in all regions (EGFR MET BRAF TP53 ALK … )in 75% of tumors and additional variant subclonal mutations in some but not all regions.

      Lessons :

      -One biopsy may not capture the extent of landscape ITH but trunk mutation are homogeneously distributed whereas branched mutations are heterogeneouly distributed . Cell free DNA overtime better capture genetic landscape.

      References:

      1-A genomic-based classification of human lung tumors, Sci Transl. Med 2013 5;209,153

      2-Xue et al. Evolution from genetics to phenotypes : reinterpretationof NSCLC plasticity,heterogeneity,and drug resistance Protein Cell 2017;8 :178-190

      3-Zhang J et al. Intra-tumor heterogeneity in localized lung adenocarcinoma delineated by multiregion sequencing, Science 2014; 10 ;346 :256-9 . DeBruin E et al . Spatial and temporal diversity in genomic instability processes defines lung cancer evolution Science 2014 346:251 . Jamal Hanjani M et al. Tracking the evolution of NSCLC, NEJM 2017 ;376:2109

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      MS05.04 - Diagnosis and Classification in Biopsies

      14:30 - 14:50  |  Presenting Author(s): Andre Moreira

      • Abstract

      Abstract

      In the last decade, significant progress has been made in the field of thoracic oncology, mostly in the management of patients with non-small cell carcinoma (NSCLC). The determination of subtypes of NSCLC is now directly linked with options of chemotherapy regimens, and further screening for targetable molecular alterations. In the 2015 W.H.O Classification of Lung cancer, the importance of small biopsies has been highlight as well as the use of immunohistochemical stains as an ancillary test to separate adenocarcinoma from squamous cell carcinomas.

      Despite the use of IHC, the classification of NSCLC remain based on histologic features and IHC is recommended in cases with no clear evidence of differentiation between adenocarcinoma and squamous cell carcinoma. It is important to notice that the diagnosis of Large Cell Carcinoma is not recommended in small biopsy specimens. For the histological diagnosis of adenocarcinoma, the following features need to be presence in the biopsy: acinar, papillary, micropapillary and lepidic patterns, and for the histological diagnosis of squamous cell carcinoma, the presence of keratinization and intracellular bridges must be presence. Therefore, in a biopsy with solid growth pattern and no evidence of keratinization, the use of IHC is recommended. The use of IHC improved diagnostic accuracy in the lung carcinoma classification, but the interpretation can be challenging and the pathologists must be aware of many interpretation pitfalls that can involve antibody clones, interpretation of the staining pattern and when to add more stains to the panels.

      When confronted with a tumor of likely lung origin for which the main question is subtyping of adenocarcinoma versus squamous carcinoma, the recommendation is to use a limited panel that includes TTF1 and p40. The use of this panel can classify most tumors and saves tissue for biomarker testing. Napsin-A can be added to the panel in challenging cases but there is no clear evidence that the latter marker is superior to TTF-1. Differences in sensitivity and specificity for napsin-A depends on whether a monoclonal or polyclonal antibody is used. Keratin 7 is not useful to separate adenocarcinoma from Squamous cell carcinoma.

      According to the classification, a NSCLC with immunohistochemical evidence of adenocarcinoma differentiation (any nuclear TTF-1 positivity) should be diagnosed as NSCLC-favor adenocarcinoma, whereas a tumor with evidence of squamous differentiation (strong and diffuse p40 positivity) should be classified as NSCLC, favor squamous cell carcinoma. In tumors with inconclusive immunoprofile, the best diagnostic term is NSCLC-NOS. For tumors with double positivity (TTF1/p40), it is important to remember that double positivity in the same cells does not define an adenosquamous carcinoma. For the diagnosis of adenosquamous carcinoma each marker should be seen in different components/areas of the tumor. Double staining is seen in adenocarcinomas or in NSCLC-Nos that carries mutations similar to adenocarcinoma.

      For double negative tumors (TTF-1 neg/p40 neg) in patients with no other history of malignancy, the diagnosis of NSCLC-NOS can be accepted because approximately 20-30% of adenocarcinoma of the lung are negative for these markers. If clinical history is not known, however, other stains should be added to the panel to rule out metastatic disease. One important marker is keratin, because metastatic melanomas or other non-epithelial tumors may mimic carcinoma, especially in small biopsy samples. For patients with known history of other malignancies, histological comparison with prior tumors should be pursued, targeted IHC with organ specific markers (PAX-8, GATA-3, NKX3.1, etc.) provides strong support to this interpretation, particularly when previous materials are unavailable for review.

      The current WHO classification recommends that neuroendocrine (NE) markers should be performed only when NE morphologic features are present. IHC positivity for NE markers alone is not diagnostic of a NE tumor because positivity for NE markers may be encountered in approximately 10-30% of adenocarcinomas.

      A panel of chromogranin A, synaptophysin and CD56 is the best combination for the diagnosis of NE tumors. There is no consensus on how many markers should be used for the diagnosis of NE, most cases of NE tumors are positive for ≥2 out of the 3 NE markers. Positivity for at least one NE marker is necessary for the diagnosis of Large Cell Neuroendocrine Carcinoma (LCNEC) in association with histological features (chromatin pattern, palisading etc). The diagnosis of LCNEC in a biopsy or cytology specimen is not recommended but can be suggested if a combination of histological features and NE markers positivity is encountered.

      A proliferative marker such as Ki-67 is very useful for the classification of NE tumors in small biopsy specimens, especially in samples with significant crush artifact. In small biopsies Ki-67 stains can separate a low-grade NE tumor (carcinoid) from a high grade tumor such as small cell carcinoma. Ki-67 is not recommended in the classification of typical from atypical carcinoid in excision specimens. In cytology samples, the marker does not work well in alcohol-fixed specimen and can lead to misclassification of NE tumors.

      Suggested reading:

      Sauter JL, Grogg KL, Vrana JA, et al. Young investigator challenge: Validation and optimization of immunohistochemistry protocols for use on cellient cell block specimens. Cancer Cytopathol 2016;124:89-100

      Rekhtman N, Kazi S. Nonspecific reactivity of polyclonal napsin a antibody in mucinous adenocarcinomas of various sites: a word of caution. Arch Pathol Lab Med 2015;139:434-436.

      Rekhtman N, Ang DC, Sima CS, et al. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol 2011;24:1348-1359

      Thunnissen E et al. The use of Immunohistochemistry improves the diagnosis of Small Cell Lung Cancer and its Differential Diagnosis. An International reproducibility Study in a demanding set of cases. J Thorac Oncol. 2017;12:334-46.

      Moreira AL, Travis WD. Histologic Classification and its need for Treatment of Lung Cancer. In Diagnosing Non-Small Cell Lung Cancer in Small Biopsy and Cytology. Edited By Moreira AL and Saqi A. 2014. Springer Science Business Media, New York. Pages 1-14. Doi 10.1007/978-1-4939-1607-8_1.

      Moreira AL, Mino-Kenudson M. Update on Histologic Classification of Non-Small Cell Lung Cancer. Diagnostic Histopathology, 2014. 20: 385-91.

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      MS05.05 - Q&A

      14:50 - 15:00

      • Abstract

      Abstract not provided

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    MS06 - Practical Issues in the Management of Oligometastatic NSCLC

    • Type: Mini Symposium
    • Track: Oligometastatic NSCLC
    • Moderators:
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      MS06.01 - The Role of Radiation in Treating the Mets

      13:30 - 13:45  |  Presenting Author(s): Hak Choy

      • Abstract

      Abstract not provided

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      MS06.02 - The Role of Interventional Pulmonology and Radiology

      13:45 - 14:00  |  Presenting Author(s): Kwun M Fong

      • Abstract

      Abstract

      The Role of Pulmonology and Interventional Radiology in the Management of Oligometastatic NSCLC

      Oligometastatic disease is a difficult management issue when encountered in NSCLC. Often defined as low metastatic burden and limited organ involvement disease, with clinical impact perceived as between truly localised potentially curable disease and a extensive incurable metastatic tumour, therefore with major implication for the patient in terms of treatment, with the potential to pivot the decision making from palliative to curative intent.

      In addition the site(s) of oligometastatic disease is heterogenous with potential to affect any site in the body, both intra and extra- thoracic, thus requiring a truly multidisciplinary approach to its management.

      It is essential to make an accurate diagnosis, to consider synchronous cancers and to rule out more extensive metastatic disease given the differing management strategies required.

      For the Pulmonologist and Interventional Radiologist, for intrathoracic oligometastatic disease, the issues are the diagnostic challenges and potential therapeutics. The use of image guided trans thoracic needle biopsy has long been used effectively by Interventional Radiology for the pathological diagnosis of suspected lesions. With modern endobronchial ultrasound, Pulmonologists are able to contribute more by accessing central and peripheral lung lesions by navigation and guided bronchoscopy e.g. ultrasound guided, electromagnetic navigation and transparenchymal approaches. With the increasing use of molecular techniques to distinguish cancers even of the same morphological appearance, such diagnostic approaches are of increasing clinical utility.

      For intrathoracic therapeutics, local Interventional Radiology ablative techniques such as radiofrequency ablation has long been used, with microwave ablation increasingly popular. In parallel with diagnostics, emerging Pulmonology techniques are also researching the potential application of these techniques applied endobronchially in addition to new modalities such as steam ablation.

      Interventional Radiologists also have a useful role to play in the management of extra-thoracic oligometastatic disease, as techniques such as radiofrequency and microwave ablation can be used such as for liver lesions.

      This session will review the emerging data for the key role of Pulmonology and Interventional Radiology in the Management of Oligometastatic NSCLC.

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      MS06.03 - The Role of Surgical Resection

      14:00 - 14:15  |  Presenting Author(s): Boris Sepesi

      • Abstract

      Abstract

      Lung cancer is an aggressive malignancy with low (< 10%) 5-year survival rates when metastases appear. Historically, surgical resection in metastatic setting has not been beneficial in term of survival; this was especially true when options for effective systemic therapy were limited. It is now recognized that up 50% of patients who presents with metastatic NSCLC have a limited (up to 5) number of metastases. Common sites of metastases include brain, lungs, adrenal glands, bones, or liver.

      In appropriately selected patients, surgical resection in metastatic lung cancer may be considered for the control of primary tumor, regional nodal disease, and metastases present within the same surgical field (example: metastases in ipsilateral ribs, or another lobe in the same lung as primary tumor). Surgical resection of selected extra-thoracic metastases is also possible; however, radiation is more commonly employed in those circumstances.

      The main goal of surgery in oligometastatic setting is to achieve complete disease control. Careful patient selection must account for the extent and the location of primary tumor and nodal disease, physiologic status and reserve of the patient, tumor histology, biomarkers, synchronous or meta-chronous presence of metastases and number of metastases, previous therapies and planned post-surgical systemic or other local therapies.

      Invasive mediastinal staging with either mediastinoscopy or endobronchial ultrasound is of utmost importance prior to proceeding with surgery. Long-term outcomes with positive ipsilateral mediastinal N2 or contralateral N3 lymph nodes are poor as compared to N0 or N1 nodal status; N2 and N3 disease should be considered contraindication for surgical therapy outside of a clinical trial. Lobectomy with mediastinal node dissection is a preferred procedure for primary tumor in oligometastatic circumstances. Pneumonectomy, especially on the right side should be avoided, and its need should be regarded as a relative contra-indication. If brain metastases are present, they should be treated first; other metastatic sites maybe addressed based on symptoms. Commonly, systemic platinum-based chemotherapy has been administered as the 1st line therapy for 3-4 cycles to sort out the cancer biology and response to chemotherapy. Stable or improved disease following chemotherapy makes proceeding with surgical resection of primary tumor and control of oligometastases reasonable. However, this paradigm continues to evolve in the era of immunotherapy and targeted therapy.

      There are a number of advantages to surgical resection of lung cancer in oligometastatic setting, as compared to other local modalities. Complete resection provides the best chance for prolonged local and regional disease control. It hypothetically removes all or at least the majority of cancer clones, it allows for detailed pathological analysis of the tumor and lymph nodes, and it provides adequate tissue for translational studies or personalized experimental treatment approaches. With current minimally invasive approaches such as video assisted or robotic assisted thoracic surgery recovery from surgical treatment of lung cancer can be expeditious. With the use of enhanced recovery pathways, even recovery after thoracotomy mimics recovery after minimally invasive thoracic surgery. Potential disadvantage of surgical therapy in oligometastatic lung cancer is the risk of post-operative cardiac or pulmonary complications, resolution of which may require time and may delay other necessary therapy. This again highlights the importance of patient selection for surgical therapy.

      Surgical Resection of Oligometastatic Lung Cancer in the Era of Targeted Therapy and Immunotherapy.

      Within the last year, immunotherapy has become the frontline treatment modality for metastatic lung cancer. Response rates, durability of responses, and toxicity profiles with immunotherapy are all better than with chemotherapy. Although imperfect, PD-L1 expression and tumor mutation burden serve as predictive biomarkers for immunotherapy. Many studies of combined chemo-immune regimens, or combination immune regimens are underway. These results are encouraging, however, as we improve systemic disease control, loco-regional lung cancer control will become even more important. The role and timing of local treatments following immunotherapy or targeted therapy in oligometastatic setting are currently under study. While there are reports of radiation therapy potentiating immunotherapy, evidence is not conclusive and biomarkers are still under investigation. Surgical therapy and radiation therapy should be considered complementary modalities in oligometastatic lung cancer. If lobectomy is possible for primary disease control in an acceptable-risk surgical candidate, it should not be discarded as an option over radiation. Considering current operative experience following prolonged immunotherapy, it is hypothesized that salvage surgical resections for local recurrence following immune-radio therapy may be difficult and may convert possible routine early lobectomy to an eventual salvage pneumonectomy.

      As the therapeutic options for oligometastastic lung cancer continue to evolve with much improved systemic options, effective local and regional therapy will become more important. Novel surgical techniques and enhanced recovery pathways have decreased the morbidity and sped up patients’ surgical recovery. Surgical resection should therefore continue to play a role in the multi-modality setting for oligometastatic lung cancer in appropriately selected patients.

      References:

      Gomez DR, Blumenschein GR Jr, Lee JJ, Hernandez M, Ye R, Camidge DR, Doebele RC, Skoulidis F, Gaspar LE, Gibbons DL, Karam JA, Kavanagh BD, Tang C, Komaki R, Louie AV, Palma DA, Tsao AS, Sepesi B, William WN, Zhang J, Shi Q, Wang XS, Swisher SG, Heymach JV. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1672-1682. doi: 10.1016/S1470-2045(16)30532-0. Epub 2016 Oct 24.

      Patrini D, Panagiotopoulos N, Bedetti B, Mitsos S, Crisci R, Solli P, Bertolaccini L, Scarci M. Surgical approach in oligometastatic non-small cell lung cancer. Ann Transl Med. 2018 Mar;6(5):93. doi: 10.21037/atm.2018.02.16. Review.

      Stephens SJ, Moravan MJ, Salama JK. Managing Patients With Oligometastatic Non-Small-Cell Lung Cancer. J Oncol Pract. 2018 Jan;14(1):23-31.

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      MS06.04 - Systemic Therapy for Oligomets: Before, During, or After Local Therapies?

      14:15 - 14:30  |  Presenting Author(s): Ross Camidge

      • Abstract

      Abstract

      Oligometastatic disease reflecting the concept of limited metastatic spread may be discussed in the setting of the sites of disease at diagnosis of stage IV disease. However, an analogous situation may also occur at progression on a therapy controlling all other sites of disease – so called oligoprogressive disease. Both may be considered for local ablative therapies (usually radiation or surgery, but also some other techniques such as radiofrequency ablation). When considering systemic therapy this may be before the local therapy as induction treatment for initial oligometastatic disease; as part of the radical local therapy (for example, combination chemoradiation therapy); or as maintenance therapy after the local therapy. The latter could reflect continuation of a tyrosine kinase inhibitor, pemetrexed or bevacizumab and could also apply to the oligoprogressive scenario.

      The issues to address are the adequacy of assessing oligometastatic disease at the time local therapy is considered; the details that appropriately define oligometastatic or oligoprogressive disease suitable for local therapy; and the potential for a direct interaction with the local therapy.

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      MS06.05 - The Special Case of Brain Metastases: Systemic Therapy, Radiation or Both?

      14:30 - 14:45  |  Presenting Author(s): Laurie Gaspar

      • Abstract

      Abstract not provided

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      MS06.06 - Q&A

      14:45 - 15:00

      • Abstract

      Abstract not provided

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    MS07 - Antibody-Drug Conjugates in Advanced NSCLC

    • Type: Mini Symposium
    • Track: Advanced NSCLC
    • Moderators:
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      MS07.01 - Basic Science

      13:30 - 13:50  |  Presenting Author(s): David E Gerber

      • Abstract

      Abstract

      While in some cases antibodies that specifically bind tumor surface antigens can have therapeutic effects, many unmodified (naked) antibodies lack anti-cancer activity. Conjugation to cytotoxic drugs, radionuclides, or toxins can expand the utility of monoclonal antibodies and improve their potency. In this way, antibodies are employed as a means to target and deliver a toxic payload to the selected tissue. Factors critical to the success of antibody drug conjugates include the target antigen, antibody, linker, and payload. The target antigen should be overexpressed in the tumor relative to healthy tissue. The antibody should have high affinity and avidity for the targeted tumor antigen. The linker should be stable in circulation but must efficiently release the payload after internalization within the cancer cell. The payload should be a highly potent (picomolar range) cytotoxic agent with efficacy against the cancer under treatment, with a reproducible and optimal drug-to-antibody ratio (usually 3-4 drug molecules per antibody molecule), that does not meaningfully compromise the antibody’s biophysical and pharmacokinetic properties. The steps entailed in the mechanism of antibody-drug conjugate action include: (a) antigen binding; (b) antigen-antibody-drug conjugate complex internalization into endosomal vesicles; (c) processing along the endosomal-lysosomal pathway; (d) degradation in this acidic and proteolytic-rich environment; (e) intracellular release of cytotoxic compound. Antibody-drug conjugates may also retain antibody interactions with host immune effector functions, including antibody-dependent cellular cytotoxicity (ADCC). Mechanisms of resistance include (a) reduced target gene expression or presence of increased antigen mutations resulting in reduced target antigen on cell surface; (b) reduced antibody-drug conjugate internalization due to reduced cell surface trafficking or recycling; (c) multidrug resistance ransporter efflux out of the targeted cell.

      In addition to differential expression on tumor cells, antibody-drug conjugate target antigens need to (1) have an extracellular epitope amenable to specific antibody binding, and (2) be able to undergo internalization via receptor-mediated endocytosis into target cells, where the drug payload can be released. High-level expression is advantageous but not necessary. The higher the cell surface density of the target antigen, the more antibody-drug conjugate can be taken up and metabolized by the cell, to release the active cytotoxic agent. Rapid uptake of antibody-drug conjugate not only enhances efficacy, but also reduces opportunity for extracellular payload release. Antigens that are shed should be avoided.

      Antibody-drug conjugate technology has improved considerably in recent years. The employed antibodies are now chimeric, humanized, or fully human, and therefore less immunogenic than early murine antibodies. Efficient linkers (disulfide, dipeptide, hydrazine) have improved stability in circulation as well as better release of active drug within the tumor cell. Finally, highly potent agents with IC50 in the subnanomolar range (maytansine derivatives [DM1, DM4], auristatin [MMAE, MMAF], both of which are microtubule disrupting agents) have replaced conventional chemotherapy drugs such as doxorubicin, vinca alkaloids, and methotrexate.

      Despite the targeted nature of antibody-drug conjugates, toxicities may occur through multiple mechanisms: (1) Non-specific systemic release of the cytotoxic drug payload; (2) Non-selective cytoxicity of target-negative cells in proximity to target-positive cells (bystander effect); (3) internalization of the antibody-drug conjugate by target-negative cells. Prior experience has shown that unrecognized expression of target antigen on healthy tissue can result in profound toxicities: LewisY antigen (gastric mucosaàhemorrhagic gastritis); CD446v6 (deep layers of skinàfatal exfoliation); CA9 (intestinal mucosaàfatal gastrointestinal toxicity). Further complicating the development of antibody-drug conjugates, preclinical models may not adequately predict clinical activity and tolerability. In mouse models, the target antigen is not commonly expressed in host tissues, resulting in misleadingly favorable preclinical activity.

      As evidence of the inherent challenges facing antibody-drug conjugates, only two have been approved by the U.S. Food and Drug Administration: ado-trastuzumab emtansine (anti-HER2; for HER2-positive breast cancer) and brentuximab vedotin (anti-CD30; for Hodgkin’s lymphoma and anaplastic large-cell lymphoma). Target antigens relevant to non-small cell lung cancer under investigation include mesothelin (antetumab ravtansine), folate receptor (mirvetuximab soravtansine), sodium-dependent phosphate transporter (NaPi2b) (lifatuzumab vedotin; DNIB0600A), glycoprotein nonmetastatic B (gpNMB; osteoactivin) (glemtumumab vedotin), and epidermal growth factor receptor (depatuxizumab mafodotin), Perhaps the most developed antibody-drug conjugate in thoracic oncology, rovalpituzumab tersirine (Rova-T) targets delta-like ligand 3 (DLL3), which is highly expressed in approximately two-thirds of small cell lung cancer, but not NSCLC.

      Ultimately, several factors may influence the efficacy of an antibody-drug conjugate, among them target expression, sensitivity to the payload, and aspects of target biology that may impact internalization and intracellular trafficking. Revisiting longstanding principles of cytotoxic therapy may improve the performance of antibody-drug conjugates. These principles include the importance of combination therapies and the recognition that not all tumors are sensitive to microtubule-disrupting agents.

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      MS07.02 - Pharmacology

      13:50 - 14:10  |  Presenting Author(s): Christian Rolfo

      • Abstract

      Abstract not provided

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      MS07.03 - Clinical Data

      14:10 - 14:30  |  Presenting Author(s): Thomas E. Stinchcombe

      • Abstract

      Abstract

      Antibody drug conjugates (ADC’s) are currently being developed for several thoracic malignancies, and preliminary studies have revealed activity in patients with progressive disease after standard therapy for non-small cell lung cancer (NSCLC).

      Sacituzumab govitecan targets the Trop-2 which is overexpressed on many epithelial cancers compared to normal tissues and the antibody is bound to SN-38 which is the active metabolite of irinotecan.1,2 .A single arm phase 2 trial (n=54) investigated in patients with NSCLC with disease progression after at least one line of therapy. The ORR was 17%, median PFS was 5.2 months, and median OS was 9.5 months. The grade ≥ 3 adverse events observed were neutropenia, anemia, diarrhea, nausea, and fatigue. Trop-2 staining was not associated with benefit from therapy and the majority of patients had high Trop-2 staining.

      Telisotuzumab vedotin (ABBV-399) targets the c-Met protein and is conjugated to monomethyl auristatin E, a microtubule inhibitor.3 A phase 1 trial in metastatic solids tumor included an expansion cohort of in patients with NSCLC who were c-Met + (defined as IHC H-score of ≥ 150). An objective response was observed in three of 16 patients (18.8%) with c-Met positive NSCLC, and at week 12 six of 16 (37.5%) experienced disease control The treatment related adverse events observed (at all dose levels) were fatigue, nausea, neuropathy, decreased appetite, vomiting, and hypoalbuminemia. No responses were observed among patients with c-Met negative tumors.

      Ado-trastuzumab emtansine (T-DM1) is an ADC that uses the trastuzumab monoclonal antibody which targets the HER2 protein and delivers the maytansinoid antimicrotubule agent DM1. A single arm phase 2 trial investigated this agent in patients with HER2 positive NSCLC (defined as IHC score of 3+, IHC score or 2+ and FISH positivity, or HER2 mutation).4 Of the 15 patients enrolled 1 patient experienced a partial response (6.7%), the median PFS was 2.0 months, and median OS was 10.9 months. This study was terminated at the interim analysis since it did not meet the predefined efficacy criteria to proceed to the second stage. A phase 2 basket trial investigated T-DM1 in patients with HER2 mutant or amplified NSCLC.5 In the HER2 mutant cohort the ORR was 44% (8 of 18), median PFS was 5 months, and median OS was 11 months. In the HER amplified cohort the ORR was 50% (3 of 6), and the median PFS was 6 months, and the median OS was 12 months. The HER2 mutant cohort met the study’s primary end-point and the HER2 amplified cohort was expanded as per the Simon two-stage design. A phase 2 study investigated T-DM1 in patients with IHC 2+ or 3+ NSCLC, and each cohort was analyzed independently.6 Among the 29 patients enrolled on the IHC 2+ cohort no responses were observed, and the ORR in the IHC 3+ cohort was 20% (4 of 20). In the IHC 2+ cohort the median PFS and OS was 2.6 and 12.2 months respectively, and in the IHC 3+ cohort the median PFS and OS was 2.7 and 12.1 months, respectively. The grade ≥ 3 adverse events observed have been neutropenia, thrombocytopenia, anemia, fatigue, dyspnea, and hepatotoxicity, and have been consistent with the adverse events observed in breast cancer.

      These studies have revealed preliminary activity of ADC’s in patients NSCLC with disease progression after standard therapies. The rate of adverse events to the ADC’s are manageable. Refinement in the biomarker selection of patients for these therapies may improve the efficacy.

      1. Heist RS, Guarino MJ, Masters G, et al. Therapy of Advanced Non-Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate, Sacituzumab Govitecan. J Clin Oncol. 2017;35(24):2790-2797.

      2. Gray JE, Heist RS, Starodub AN, et al. Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I-inhibiting Antibody-Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan. Clin Cancer Res. 2017;23(19):5711-5719.

      3. Angevin E, Kelly K, Heist R, et al. First-in-human phase 1, dose-escalation and -expansion study of ABBV-399, an antibody-drug conjugate (ADC) targeting c-Met, in patients (pts) with advanced solid tumors. Annals of Oncology. 2016;27(suppl_6):371P-371P.

      4. Hotta K, Aoe K, Kozuki T, et al. A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non-Small Cell Lung Cancer. J Thorac Oncol. 2018;13(2):273-279.

      5. Li BT, Shen R, Buonocore D, et al. Phase 2 Basket Trial of Ado-Trastuzumab Emtansine in Patients with HER2 Mutant or Amplified Lung Cancers. WCLC 2017: 18th World Conference on Lung Cancer in Yokohama, Japan. October 15-18. 2017.

      6. Stinchcombe T, Stahel RA, Bubendorf L, et al. Efficacy, safety, and biomarker results of trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-overexpressing locally advanced or metastatic non-small cell lung cancer (mNSCLC). Journal of Clinical Oncology. 2017;35(15_suppl):8509-8509.

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      MS07.04 - Future Directions

      14:30 - 14:50  |  Presenting Author(s): Silvia Novello  |  Author(s): Annapaola Mariniello

      • Abstract

      Abstract

      Despite the success achieved by molecularly targeted agents in oncogene-addicted NSCLC over the past decade, patients inevitably develop acquired resistance with subsequent disease progression.

      Moreover, most lung tumors still do not present actionable targets derived by driver genetic alterations.

      To circumvent these issues, alternative strategies to target tumor cells have been studied.

      Antibody drugs conjugates (ADC) represent a novel class of anti-cancer treatment designed with the aim to combine the cytotoxic activity of chemotherapeutics with the selectivity of target agents, thus increasing the therapeutic interval of available compounds.

      The paradigm of ADCs is to convey cytotoxicity selectively into tumor cells, by way of a monoclonal antibody (MoAb) bound to cytotoxic chemicals via synthetic linkers. This complex is able to recognize tumor antigens which serve as Trojan horse for ADC internalization into cancer cell.

      To date, two ADCs have entered clinical practice, brentuximab vedotin for hematological malignancies and trastuzumab emtansine in advanced breast cancer overexpressing human epidermal growth factor receptor 2 (HER2) [1].

      In the field of thoracic malignancies, ADC research has focused on rarer “orphan” diseases, for which neither target therapies nor valuable second-line treatment options are available. In fact, the two ADCs currently underway in most advanced phases of clinical trials are rovalpituzumab tesirine for SCLC and anetumab emtansine for unresectable mesothelioma; however, with suboptimal early results [2;3].

      In NSCLC, no ADC has been experimented yet in phase III trials. However, several basket trials are currently evaluating anti-cancer activity and safety of ADCs mostly targeting HER2, Trop2 and NaPi2b, among others [4-6].

      In NSCLC treatment, as well as in other malignancies, ADC development has been limited by several factors.

      First, to realize a suitable ADC numerous criteria must be fulfilled [7].

      About the cytotoxin (also known as warhead), this must be a small molecule showing high potency, relative hydrophilicity and a lack of susceptibility to P-glycoprotein, which is a very common resistance mechanism for ADCs. Linkers connecting the MoAb to the warhead must be stable in blood, but they are also required to be able to release the drug inside the target cancer cells.

      Apart from these technical issues, which are underway of further improvement, the major unaddressed concern for ADCs in clinics may be finding the optimal antigen target. Cancer antigen must be transmembrane and able to internalize into the target cell after MoAb binding. Importantly, the ideal antigen should be tumor specific or at least with a minimal expression on healthy tissues, to reduce off-target toxicity. However, the type of non-cancerous cells on which the target antigen is exposed may also play a role in predicting ADCs toxicity. Because of the cell cycle-dependent mechanism of action, non-highly proliferating cells may be less vulnerable to the ADC cytotoxic damage. [8]

      Despite these limitations, the fact that the tumor target antigen is not required to drive tumor growth, constitutes an appealing advantage for ADCs application in malignancies lacking acknowledged driver mutations. In the context of thoracic cancers, squamous lung carcinoma or less differentiated entities would be amenable for greater research efforts in finding an adequate ADC antigen target.

      A further barrier to the design of viable ADCs is the unavailability of a reproducible, standardized and economic technique to identify and validate valuable target antigens. So far, the techniques used are immunohistochemistry or - more recently - functional genomic mRNA profiling, with the latter failing to localize the predicted protein into cancer cells [1].

      In NSCLC setting, concern is raised by the ruthless competition with the numerous systemic treatments already available or on study. A smart approach to find a place for ADCs in the NSCLC treatment algorithm, may be to explore combination strategies with drugs already on market. In the era of immune-oncology we are living, great attention is dedicated to combination strategies with immune checkpoint inhibitors (ICI). ADCs in most advanced phases of clinical experimentation are currently being tested in association with ICIs. Notably, a phase I/II trial of anetumab plus atezolizumab in advanced NSCLC patients has already been planned [9]. The supporting rationale is based on the demonstrated immunogenic cell death properties displayed by ADCs. Moreover, additional ADC immunogenicity is warranted by their antibody-dependent cell-mediated cytotoxicity potential. [10]

      A last and unsolved question regards tumor heterogeneity, which makes it unlikely to eliminate a whole neoplasm by using a single ADC target. As a future perspective, we could envision extensive tumor sequencing that allows for efficient antigen prediction and for the design of tailored ADCs targeting, contemporarily, multiple tumor specific antigens.

      Long and winding is the path for the ADC entry in NSCLC clinical practice. However, the rapidly evolving landscape in tumor sequencing and proteomics along with the clinical research experiences, may pave the way to find the most appropriate setting for ADCs in terms of manageable side effects and NSCLC patients’ selection.

      1. Moek KL, de Groot DJA, de Vries EGE et al. The antibody–drug conjugate target landscape across a broad range of tumour types. Ann Oncol. 2017 Dec 1;28(12):3083-3091.

      2. NCT02610140.

      3. NCT03061812.

      4. Hamilton EP, Barve MA, Bardia A et al. Phase 1 dose escalation of XMT-1522, a novel HER2-targeting antibody-drug conjugate, in patients with HER2-expressing breast, lung and gastric tumors. J Clin Oncol 36, 2018 (suppl; abstr 2546).

      5. Sands JM, Shimizu T, Garon EB et al. First-in-human phase 1 study of DS-1062a in patients with advanced solid tumors. J Clin Oncol 36, 2018 suppl; abstr TPS2605.

      6. NCT03319628.

      7. Beck A, Goetsch L, Dumontet C et al. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017 May;16(5):315-337.

      8. Damelin M, Zhong W, Myers J, Sapra P. Evolving Strategies for Target Selection for Antibody-Drug Conjugates. Pharm Res. 2015 Nov;32(11):3494-507.

      9. NCT03455556.

      10. Gerber, HP, Sapra P, Loganzo F et al. Combining antibody–drug conjugates and immune- mediated cancer therapy: what to expect? Biochem Pharmacol 2016. 102, 1–6.

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      MS07.05 - Q&A

      14:50 - 15:00

      • Abstract

      Abstract not provided

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    MS08 - Lung Cancer in the Real World

    • Type: Mini Symposium
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Moderators:
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      MS08.01 - How Can Real World Data Improve Clinical Evidence Generation and Impact Regulatory Bodies - European Perspective

      13:30 - 13:45  |  Presenting Author(s): Yolande Lievens

      • Abstract

      Abstract

      Health technology assessment (HTA) evaluates the efficacy and effectiveness of new interventions, integrates these data with the costs to define efficiency and addresses future availability and distribution. As such, HTA focuses on accessibility, affordability and equity. Economic evaluations are central in this concept: weighing costs and effects, they support evidence-based decisions on reimbursement, thus endorsing the introduction of innovative healthcare interventions in daily practice.

      After more than 20 years of voluntary cooperation on HTA in Europe, more than 50 HTA bodies are currently operating in the European Union (EU), be it still fragmented with different systems, different procedures and different requirements regarding the type of clinical evidence. Efficacy, the outcome a new intervention provides in the well-defined circumstances of a randomised controlled trial (RCT) and typically the input used to derive cost-effectiveness evidence, may not provide the best insight into the impact of an intervention in daily clinical care. Moreover, in contrast to what is the case for pharmaceuticals, it is much more difficult to perform RCTs on radiotherapy or surgery, especially when it comes to evaluating the incremental evolution typical for new techniques and technologies, or the long-term benefits anticipated to follow more accurate treatment delivery. This has resulted in different regulatory systems for systemic and non-systemic treatment strategies, with attempts to come to a more homogenised HTA approach in the EU having so far failed.

      Real-world data are gradually expanding their role in the evidence generation of lung cancer radiotherapy. A first step moving away from RCTs is to adopt a more pragmatic approach to evidence generation, as is the case in the OligoCare project. This joint ESTRO-EORTC initiative is evaluating the outcome of oligometastatic patients, amongst others from primary lung cancer, treated with radical radiotherapy in a large prospective cohort study. Various patterns of care studies have generated clinical evidence on the uptake of new treatment techniques such as SBRT (Stereotactic Body Radiotherapy), on the value of multimodality treatments for locally-advanced non-small cell lung cancer (NSCLC) beyond the context of RCTs, or have allowed to develop prediction models to support shared decision-making. Furthermore, the wealth of data available in cancer registries and other nation-wide databases can be leveraged to learn more about the quality of care, actual access to different treatment strategies, geographical and institutional variations and their potential impact on lung cancer survival. Real-life data can also be used to generate the cost information necessary to perform cost-effectiveness evaluations. Besides the more frequent approach to derive this evidence from reimbursement data, actual resource costs can also be computed in daily practice. One such initiative was undertaken in Belgium, using Time-Driven Activity-Based Costing to compute real-life costs of radiotherapy, and more specifically of innovative radiotherapy techniques such as SBRT.

      Whereas all these examples provide interesting insight into the clinical and financial consequences of access to standard-of-care and innovative lung cancer radiotherapy, there is a dearth of information on how this evidence defines policy. One interesting approach to change practice is using coverage with evidence generation to provide early access to radiotherapy innovations, while stimulating the further generation of data. Such a programme of provisional financing has been set-up in Belgium to generate evidence from daily practice on SBRT for primary tumours, most typically early-stage NSCLC, and for oligometastatic disease. While this programme allowed radiation oncology centres to develop and provide SBRT without being financially penalised, it also generated the reassuring clinical evidence that will soon lead to the inclusion of SBRT in the formal national radiotherapy reimbursement system.

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      MS08.02 - How Can Real World Data Improve Clinical Evidence Generation and Impact Regulatory Bodies – US Perspective

      13:45 - 14:00  |  Presenting Author(s): Gideon Blumenthal

      • Abstract

      Abstract not provided

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      MS08.03 - Sources of Real World Data: Research Designs, Statistical Modelling and Quality Assurance Requirements

      14:00 - 14:15  |  Presenting Author(s): Mary W. Redman

      • Abstract

      Abstract not provided

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      MS08.04 - The ASCO Perspective

      14:15 - 14:30  |  Presenting Author(s): Bruce E Johnson

      • Abstract

      Abstract not provided

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      MS08.05 - The ESTRO Perspective

      14:30 - 14:45  |  Presenting Author(s): Umberto Ricardi

      • Abstract

      Abstract not provided

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      MS08.06 - Discussion

      14:45 - 15:00

      • Abstract

      Abstract not provided

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    OA05 - Clinical Trials in IO

    • Type: Oral Abstract Session
    • Track: Advanced NSCLC
    • Moderators:
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      OA05.01 - Efficacy/Safety of Entinostat (ENT) and Pembrolizumab (PEMBRO) in NSCLC Patients Previously Treated with Anti-PD-(L)1 Therapy

      13:30 - 13:40  |  Presenting Author(s): Matthew D. Hellmann  |  Author(s): Pasi A Jänne, Mateusz Opyrchal, Navid Hafez, Luis E Raez, Dmitry Gabrilovich, Fang Wang, Peter Ordentlich, Susan Brouwer, Serap Sankoh, Emmett Schmidt, Michael L Meyers, Suresh S. Ramalingam

      • Abstract

      Background

      Treatment options are limited for lung cancer patients whose disease has progressed on anti-PD-(L)1 therapy. HDAC inhibitors may synergize with PD-(L)1 inhibition to overcome resistance. We report the interim results of a Phase 2 trial of entinostat (ENT), a class I selective histone deacetylase (HDAC) inhibitor, plus pembrolizumab (PEMBRO) in patients with NSCLC previously treated with anti-PD-(L)1 therapy.

      Method

      ENCORE-601 is an open-label study evaluating the combination of ENT + PEMBRO in patients with recurrent or metastatic NSCLC and prior progression on anti-PD-1/PD-L1 therapy. Patients were eligible irrespective of histology or baseline PD-L1 expression. Patients were treated with ENT 5 mg PO weekly and PEMBRO 200 mg IV Q3W. The primary endpoint was ORR as assessed by irRECIST. Tumor biopsies and blood samples for immune correlates were taken prior to and during treatment in a subset of patients. A total of 70 patients will be enrolled.

      Result

      Of 57 patients with anti-PD-(L)1 resistant/refractory NSCLC, the confirmed objective response rate with ENT + PEMBRO was 11% (6 of 57, 95% CI: 4-21%). Of 49 patients with post-baseline tumor measurements, 47% had at least some reduction in tumor. Anti-PD-(L)1 therapy was the most recent line of therapy in 38 of 57 patients, and the median time from last dose of prior anti-PD-(L)1 to study entry was 67 days. The median duration of response with ENT + PEMBRO was 5 months, with the longest over 14 months. Of the 6 responders, four were PD-L1 negative at study entry. Response was associated with a higher median baseline level of peripheral classical monocytes (CD14+CD16-HLA-DRhi) with 16.9% of total live PBMCs in responders (n=6) compared to 8.2% in non-responders (n=45). 5 patients (8.8%) experienced Grade 3/4 related irAEs (2 events each of pneumonitis and colitis, 1 event of hyperthyroidism). In addition, 19 patients (33.3%) experienced other Grade 3/4 related AEs with only fatigue, anemia, hypophosphatemia, and hyponatremia occurring in more than 1 patient. Additional correlative analyses to identify biomarkers of response, including whole exome sequencing and RNAseq, are in progress.

      Conclusion

      ENT + PEMBRO demonstrated anti-tumor activity and acceptable safety in patients with NSCLC who have progressed on prior PD-(L)1 blockade. Ongoing analysis of immune correlates may identify strategies for effective patient selection.

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      OA05.02 - Epacadostat Plus Pembrolizumab in Patients with Non-Small Cell Lung Cancer: Phase 1/2 Results from ECHO-202/KEYNOTE-037

      13:40 - 13:50  |  Presenting Author(s): Liza Villaruz  |  Author(s): Bryan J Schneider, Todd M. Bauer, Alexander Spira, Gina D'Amato, Jeffery Wasser, Ani Balmanoukian, Primo Lara, Anthony Olszanski, Thomas Gajewski, Sandip Patel, Ahmad Tarhini, Joshua Michael Bauml, Emmett Schmidt, Jill Bowman, Jeannie Daniel, Sherry Owens, Tara C Mitchell

      • Abstract

      Background

      Epacadostat (E) is a potent, highly selective inhibitor of the indoleamine 2, 3-dioxygenase 1 (IDO1) enzyme. ECHO-202/KEYNOTE-037 is an open-label, phase 1/2 study of E + pembrolizumab (P) in patients (pts) with advanced tumors (NCT02178722). We report updated efficacy and safety data for the phase 1 and 2 non-small cell lung cancer (NSCLC) cohort as of 8 Jan 2018 data cutoff.

      Method

      Adult pts with prior platinum-based therapy (tx), no prior immune checkpoint inhibitors, and those intolerant to EGFR-targeted therapy were eligible. Pts could receive E (25, 50, 100, or 300 mg twice daily [BID]) + P (2 mg/kg or 200 mg every 3 weeks [Q3W]) during phase 1; maximum tolerated dose was not achieved. E (100 mg BID) + P (200 mg Q3W) tx doses were selected for phase 2 evaluation. Efficacy was assessed by RECIST v1.1 criteria. Programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) was evaluated using the 22C3 pharmDx assay. IDO1 status was measured by RNAScope. Safety was assessed in pts receiving ≥1 E + P dose.

      Result

      A total of 70 pts (phase 1, n=12; phase 2, n=58) were evaluated. Median age was 63 years and 57% of pts were female. EGFR mutation status (+/-/not available) was 10%/71%/19%; KRAS status was 19%/26%/56%, respectively. Most pts had adenocarcinoma (70%), a history of smoking (76%), and 0–1 prior lines of tx (64%). PD-L1 TPS results were available in 55/70 pts; IDO1 status (+/-) in 41/70 pts. Overall, the objective response rate (ORR; complete response [CR] + partial response [PR]) and disease control rate (CR + PR + stable disease [SD]) were 29% (20/70; 17 PR) and 50% (35/70; 15 SD), respectively. ORR was 22% (2/9) in pts with TPS ≥50% and 0–1 prior tx; for pts with TPS <50% and 0–1 prior tx, ORR was 22% (5/23). ORR for pts with IDO1+ and IDO1- tumors were 24% (6/25) and 19% (3/16), respectively. At data cutoff, 10/20 responses were ongoing. Median progression-free survival (PFS) was 4.0 mo (90% confidence interval, 2.1–6.2 mo); PFS rates at 6, 12, and 18 mo were 43% (33%–53%), 31% (22%–40%), and 17% (10%–26%), respectively. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 27% of pts; 3 pts discontinued due to TRAEs; and no TRAEs led to death.

      Conclusion

      The E + P combination was generally well tolerated and associated with promising responses in pts with NSCLC.

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      OA05.03 - Safety and Clinical Activity of Adoptive Cell Transfer Using Tumor Infiltrating Lymphocytes (TIL) Combined with Nivolumab in NSCLC

      13:50 - 14:00  |  Presenting Author(s): Ben C. Creelan  |  Author(s): Jamie K Teer, Eric M Toloza, John E Mullinax, Ana M Landin, Jhanelle Elaine Gray, Tawee T Tanvetyanon, Matthew C Taddeo, David R Noyes, Linda L Kelley, Bin Fang, John M Koomen, Amod A Sarnaik, Sungjune Kim, Eric B. Haura, Scott J Antonia

      • Abstract

      Background

      Adoptive transfer of tumor infiltrating lymphocytes (TIL) can cause durable regression by recognition of neoantigens unique to the patient. NSCLC TIL has synergistic preclinical activity with nivolumab, and we hypothesized it may induce remissions in anti-PD1-refractory patients. We initiated a phase I trial with the primary objective to characterize the safety and preliminary activity of the combination.

      Method

      Metastases from patients with Stage 4 NSCLC were resected, morselized, cultured, and tested for autologous reactivity. Reactive TIL fragments were pooled and cryopreserved. Patients received nivolumab over 8 weeks. Patients with progressive disease (PD) proceeded to lymphodepletion cyclophosphamide/fludarabine (Cy/Flu), TIL, and IL-2. Tumor whole exome sequencing, transcriptomics, and LC-MS/MS peptide sequencing was performed. TCR-Vß rearrangements were analyzed from tumor, TIL, and pre-/post-infusion peripheral lymphocytes.

      Result

      Of 14 patients enrolled to date, 13 had successful ex vivo TIL expansion from resected metastases. TIL had high proliferative capacity, expanding to median 81 billion CD3+ cells infused per patient (range 27–138 billion) and median 27% of fragments were autologously reactive (range 0-67%). Demographics: median age 54 (range 44-74), median TMB 4 mutations/MB (range 0.9–25), median PD-L1 proportion-score 0% (range 0–100%), and 4 had LKB1 allelic inactivation. Predicted neoantigens correlated with variants on proteomic sequencing. Outcomes: 9 patients had confirmed PD on nivolumab, and proceeded to receive Cy/Flu/TIL/IL-2. No unexpected serious adverse reactions (SUSARs) were identified. Of these 9 patients, 7 had reduction in sum of target lesions at Day+28 CT scan (Figure 1). Peripheral lymphocytes expanded at Days 2-7 in the majority of patients. In patients tested to date, TIL clonotypes persisted through Day+100, and CCR7+CD95+CD45RA+ stem cell-like memory (TSCM) cells were increased at post-infusion timepoints.

      abstract figure.png

      Conclusion

      Adoptive cell transfer with TIL and nivolumab for NSCLC had acceptable toxicity and preliminary activity in this ongoing trial.

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      OA05.04 - Discussant - OA 05.01, OA 05.02, OA 05.03

      14:00 - 14:15  |  Presenting Author(s): Scott Owen  |  Author(s): Martin J. Edelman

      • Abstract

      Abstract not provided

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      OA05.05 - Avelumab vs Docetaxel for Previously Treated Advanced NSCLC: Primary Analysis of the Phase 3 JAVELIN Lung 200 Trial

      14:15 - 14:25  |  Presenting Author(s): Fabrice Barlesi  |  Author(s): Johan F. Vansteenkiste, David R. Spigel, Hidenobu Ishii, Marina Chiara Garassino, Filippo De Marinis, Mustafa Özgüroğlu, Aleksandra Szczesna, Andreas Polychronis, Ruchan Uslu, Maciej Krzakowski, Jong-Seok Lee, Luana Calabro, Osvaldo Arén Frontera, Barbara Ellers-Lenz, Marcis Bajars, Mary Ruisi, Keunchil Park

      • Abstract

      Background

      Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody that is an approved treatment for metastatic Merkel cell carcinoma (various regions) and platinum-treated advanced urothelial carcinoma (US). We report findings from a global, open-label, phase 3 trial of avelumab vs docetaxel in patients with advanced NSCLC after platinum failure (NCT02395172).

      Method

      Patients with stage IIIB/IV or recurrent NSCLC with disease progression after platinum doublet therapy were randomized 1:1 to avelumab 10 mg/kg Q2W or docetaxel 75 mg/m2 Q3W, stratified by PD-L1 status (PD-L1+/PD-L1−) and histology (squamous/nonsquamous). The primary endpoint was overall survival (OS) in the PD-L1+ population (expression on ≥1% of tumor cells, assessed using the PD-L1 IHC 73-10 assay).

      Result

      Between April 2015 and February 2017, 792 patients were randomized to receive avelumab or docetaxel, including 264 and 265 with PD-L1+ tumors, respectively; 0.8% vs 7.5% did not receive study treatment. Median follow-up in the avelumab and docetaxel arms was 18.9 and 17.8 months; 15.5% vs 1.5% remained on treatment at data cutoff (November 22, 2017). In the avelumab and docetaxel arms, 39.8% vs 47.5% received subsequent anticancer therapy after discontinuation, including checkpoint inhibitors in 5.7% vs 26.4%, respectively. In the PD-L1+ population, median OS in the avelumab and docetaxel arms was 11.4 vs 10.3 months (hazard ratio [HR], 0.90 [96% CI, 0.72-1.12]; P=0.1627, 1-sided). Pre-planned exploratory analyses based on higher PD-L1 cutoffs showed increased OS with avelumab vs docetaxel, including PD-L1-high (≥80% cutoff, 29% of patients; 17.1 vs 9.3 months; HR, 0.59 [95% CI, 0.42-0.83]; P=.0022, 2-sided) and PD-L1-medium/high (≥50% cutoff, 40% of patients; 13.6 vs 9.2 months; HR, 0.67 [95% CI, 0.51-0.89]; P=0.0052, 2-sided) subgroups. In the PD-L1+ population (≥1% cutoff), ORR was 18.9% vs 11.7% (odds ratio, 1.76 [95% CI, 1.08-2.86]; P=0.0105, 1-sided); median duration of response was not reached with avelumab (95% CI, 9.9-not estimable [NE]) vs 6.9 months with docetaxel (95% CI, 3.5-NE). Overall rates of treatment-related adverse events (AEs) were lower with avelumab than docetaxel, including all grades (63.9% vs 85.8%) and grade ≥3 (9.9% vs 49.3%). Immune-related AEs occurred in 16.5% of avelumab-treated patients (grade ≥3 in 2.8%).

      Conclusion

      Avelumab showed increasing clinical activity in patients who had platinum-treated NSCLC with higher tumor PD-L1 expression; however, the trial did not meet its primary objective of improving OS vs docetaxel in PD-L1+ tumors (≥1% cutoff). OS findings may have been confounded by subsequent checkpoint inhibitor therapy in the docetaxel arm.

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      OA05.06 - CheckMate 227: Patient-Reported Outcomes of First-Line Nivolumab + Ipilimumab in High Tumor Mutational Burden Advanced NSCLC

      14:25 - 14:35  |  Presenting Author(s): Julie R. Brahmer  |  Author(s): Michael Schenker, Ki Hyeong Lee, Mariano Provencio, Makoto Nishio, Krzysztof Lesniewski-Kmak, Randeep Sangha, Samreen Ahmed, Judith Raimbourg, Kynan Feeney, Romain Corre, Fabio Andre Franke, Eduardo Richardet, John R. Penrod, Yong Yuan, Faith Nathan, Prabhu Bhagavatheeswaran, Michael De Rosa, Fiona Taylor, Rachael Lawrance, Martin Reck

      • Abstract

      Background

      The randomized, open-label, multipart phase 3 study CheckMate 227 (NCT02477826) demonstrated a significant progression-free survival benefit (co-primary endpoint) with first-line nivolumab+ipilimumab versus histology-based, platinum-doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and high tumor mutational burden (TMB; ≥10 mutations/Mb). Patient-reported outcomes (PROs) for this population within CheckMate 227 are presented.

      Method

      Eligible chemotherapy-naïve patients had stage IV or recurrent NSCLC, ECOG performance status 0−1, and no known sensitizing EGFR/ALK alterations. PROs were assessed as an exploratory endpoint; this analysis included patients with high TMB randomized to nivolumab+ipilimumab or chemotherapy; specific outcomes included proportion of patients with disease-related symptom deterioration by 12 weeks and time to deterioration in symptoms (by Lung Cancer Symptom Scale [LCSS] Average Symptom Burden Index [ASBI]), and assessment of quality of life and overall health status (by EuroQoL-5 Dimension [EQ-5D] utility index [UI] and visual analog scale [VAS]). PROs were evaluated each cycle (Q2W, nivolumab+ipilimumab; Q3W, chemotherapy) for the first 6 months, every 6 weeks thereafter during treatment, and at follow-up visits 1/2. EQ-5D was also assessed during survival follow-up.

      Result

      PRO completion rates were ~90% at baseline and >80% for nearly all on-treatment assessments. Among patients with high TMB, fewer patients in the nivolumab+ipilimumab (n=139) versus chemotherapy (n=160) groups reported symptom deterioration by week 12, irrespective of whether they were still on therapy or had discontinued (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% CI: 2.4–22.5]). Time to first deterioration (TTD) using common assessment time points (on/off treatment) was delayed with nivolumab+ipilimumab versus chemotherapy for the LCSS ASBI (hazard ratio [HR]: 0.40; 95% CI: 0.26–0.63) and 3-Item Global Index (3-IGI; HR: 0.56; 95% CI: 0.38–0.82). The estimated benefit in TTD generally favored nivolumab+ipilimumab for individual symptoms in the ASBI and each item in the 3-IGI (HRs: 0.48–0.74), except for hemoptysis (HR: 1.20), which exhibited very low burden; an advantage for nivolumab+ipilimumab was also seen in the EQ-5D VAS (HR: 0.62; 95% CI: 0.42–0.92) and UI (HR: 0.50; 95% CI: 0.34–0.73). Mean changes from baseline with nivolumab+ipilimumab showed early and clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; for patients treated with chemotherapy, symptoms and quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following completion of chemotherapy (EQ-5D VAS).

      Conclusion

      Nivolumab+ipilimumab demonstrated early and sustained improvements in health-related quality of life versus chemotherapy in patients with advanced NSCLC and high TMB.

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      OA05.07 - IMpower132: PFS and Safety Results with 1L Atezolizumab + Carboplatin/Cisplatin + Pemetrexed in Stage IV Non-Squamous NSCLC

      14:35 - 14:45  |  Presenting Author(s): Vassiliki A Papadimitrakopoulou  |  Author(s): Manuel Cobo, Rodolfo Bordoni, Pascale Dubray-Longeras, Zsuzsanna Szalai, Grigoriy Ursol, Silvia Novello, Francisco Orlandi, Simon Ball, Jerome Goldschmidt Jr., Rachel E Sanborn, Tien Hoang, Diana Mendus, Yu Deng, Marcin Kowanetz, Xiaohui Wen, Wei Lin, Alan Sandler, Makoto Nishio

      • Abstract

      Background

      In addition to the combination of atezolizumab (anti–PD-L1)+platinum+taxane±bevacizumab, non-squamous NSCLC patients may derive benefit from adding atezolizumab to platinum+pemetrexed. The randomized Phase III IMpower132 study (NCT02657434) evaluated first-line pemetrexed+carboplatin or cisplatin±atezolizumab in patients with stage IV non-squamous NSCLC without EGFR or ALK driver mutations.

      Method

      Patients were randomized 1:1 to receive 4 or 6 cycles of carboplatin AUC 6 mg/mL/min or cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 Q3W alone (arm PP) or in combination with atezolizumab 1200 mg Q3W (arm APP), followed by pemetrexed (arm PP) or atezolizumab + pemetrexed (arm APP) maintenance. Atezolizumab could be continued beyond disease progression per protocol guidelines. PFS and OS were co-primary endpoints. Efficacy by PD-L1 expression was an exploratory endpoint. Here, we present investigator-assessed PFS per RECIST v1.1 (final analysis), OS (interim analysis) and safety data.

      Result

      292 pts were enrolled in arm APP and 286 pts in arm PP. 43% and 40% in arms APP and PP, respectively, had ECOG PS 0. At the data cutoff (22 May 2018), median follow-up was 14.8 mo overall. PFS analysis showed a statistically significant improvement between arm APP vs PP (median PFS 7.6 vs 5.2 mo; HR=0.596; 95% CI: 0.494, 0.719; P<0.0001). Interim analysis showed a numerical but non-statistically significant OS improvement (Table). Efficacy results were consistent across all key clinical subgroups. Grade 3-4 TRAEs occurred in 53.6% of patients (APP) vs 39.1% (PP). 7.2% of patients (APP) vs 5.1% (PP) had a Grade 5 AE, 3.8% (APP) vs 2.6% (PP) were treatment related. 48.5% of patients (APP) vs 38.0% (PP) experienced AEs of special interest specific to atezolizumab.

      Conclusion

      IMpower132 met its co-primary endpoint of investigator-assessed PFS in the ITT. Interim OS data (not fully mature) showed numerical improvement. Atezolizumab+pemetrexed+carboplatin or cisplatin was well tolerated, and no new safety signals were identified.

      Table. IMpower132 Efficacy Analyses

      APP Arm
      (atezolizumab+pemetrexed+ carboplatin or cisplatin)
      PP Arm
      (pemetrexed+carboplatin or cisplatin)
      ITT n=292 n=286
      Median PFS (95% CI), mo 7.6 (6.6, 8.5) 5.2 (4.3, 5.6)
      HRa (95% CI; P value) 0.596 (0.494, 0.719; P < 0.0001)
      12-Month PFS (95% CI), % 33.7% (28.2, 39.2) 17.0% (12.6, 21.4)
      Median OS (95% CI), mo 18.1 (13.0, NE) 13.6 (11.4, 15.5)
      HRa (95% CI; P value) 0.813 (0.644, 1.025; P = 0.0797)
      12-Month OS (95% CI), % 59.6% (53.9, 65.3) 55.4% (49.5, 61.2)
      ORR (confirmed, inv-assessed), % 46.9% 32.2%
      DOR (95% CI), mo 10.1 (7.2, 13.3) 7.2 (5.7, 9.0)
      PD-L1–highb n=25 n=20
      Median PFS (95% CI), mo 10.8 (7.9, NE) 6.5 (2.4, 10.6)
      HR (95% CI; P value) 0.464 (0.224, 0.960; P = 0.0339)
      PD-L1–lowb n=63 n=73
      Median PFS (95% CI), mo 6.2 (4.4, 8.4) 5.7 (4.2, 7.9)
      HR (95% CI; P value) 0.804 (0.556, 1.163; P = 0.2462)
      PD-L1–negativeb n=88 n=75
      Median PFS (95% CI), mo 8.5 (6.1, 11.2) 4.9 (4.2, 5.8)
      HR (95% CI; P value) 0.448 (0.313, 0.642; P < 0.0001)

      DOR, duration of response; HR, hazard ratio; inv, investigator; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

      a Stratified. b Baseline tissue available in 60% of patients. PD-L1high (TC3/IC3): patients with PD-L1 expression in ≥50% of tumor cells or ≥10% of tumor-infiltrating immune cells; PD-L1low (TC12/IC12): patients with PD-L1 expression in ≥1% and <50% of tumor cells or ≥1% and <10% of tumor-infiltrating immune cells; and PD-L1negative (TC0/IC0): patients with PD-L1 expression in <1% of tumor cells and <1% of tumor-infiltrating immune cells.

      NCT02657434

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      OA05.08 - Discussant - OA 05.05, OA 05.06, OA 05.07

      14:45 - 15:00  |  Presenting Author(s): Hossein Borghaei

      • Abstract

      Abstract not provided

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    OA06 - Early Stage Lung Cancer: Outcomes and Interventions

    • Type: Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Moderators:
      • Abstract

      Background
      Sex differences in non-small cell lung cancer (NSCLC) susceptibility, tumor biology and survival have been retrospectively reported. We conducted a prospective, case-series intergroup study (SWOG S0424) in 4 cohorts of females (F) and males (M), ever-smokers (ES) and never-smokers (NS) with newly-diagnosed stages I-III NSCLC. This is the first overall survival (OS) report. Method
      Patients were accrued at US sites via SWOG/NCI-CTSU. A questionnaire of demographics and exposures (tobacco, environmental, reproductive, hormonal); stage and histology data; treatment; and OS were obtained. Tumor tissue was submitted for EGFR, RAS and p53 mutations. Nuclear and cytoplasmic estrogen receptor (ER) alpha and beta were measured (Cheng, JNCI 2017). Kaplan-Meier (KM) curves and OS modeled using Cox proportional hazards were examined. The NS cohorts remained open longer to maximize accrual. Patients were followed 5 years for OS or until death. Result
      The accrual goal of 981 was achieved from 10/2005-3/2011. Evaluable cases were FES, n=337; MES, 383; FNS, 188; MNS, 49 (MNS under-accrued despite extension). The 4 cohorts differed significantly in demographics, tumor stage, histology, mutational profile (overall, by histology), ER expression, lifestyle factors and exposures. KM curves showed MNS/MES had overlapping OS and FNS/FES had significantly better OS. Five-year estimates were FNS, 73%; FES, 69%; MNS, 58%; MES, 52%. Markedly improved OS for females persisted after adjusting for other factors. Four multivariate OS models were constructed: all patients (model 1) and women only (model 2), each with mutations and ER expression added (models 3, 4). Model 1: better OS for females (HR 0.56, p <.001); higher BMI (continuous, HR 0.98, p=0.045); and adenocarcinoma, BAC, large cell (all vs squamous, HRs 0.84, 0.48, 0.57); worse OS for stages II and III (HRs 1.87, 3.76: each p<.001) and greater age. Model 2: worse OS if ES (HR 1.48, p=0.05), higher stages; histology and hormonal exposure variables were not significant. Model 3: better OS if EGFR mutation (HR 0.53, p=0.013), female, stage I, higher BMI or greater height; worse OS if p53 mutation, higher ER-alpha cytoplasmic or ER-beta nuclear H-scores. Model 4: worse OS if higher stage, p53 mutation or ER-alpha cytoplasmic H-score; EGFR mutation lost significance. Conclusion
      Sex, histology, mutations and exposures impacted OS, with dramatically better OS for females regardless of the analysis/model. Hormonal influences (persistent association of ER-expression with OS) were independently significant. Despite adjustments, favorable female survival could not be explained away. Randomized studies should stratify by sex and validation analyses should be conducted in targeted therapy and immunotherapy trials.

      SUPPORT: NIH/NCI grants R01CA106815, U10CA180888, U10CA180819 and UG1CA189974.

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      OA06.02 - Video-Assisted Thoracoscopic Surgery vs. Thoracotomy for Non-Small Cell Lung Cancer: Oncologic Outcome of a Randomized Trial

      13:40 - 13:50  |  Presenting Author(s): Dongrong Situ  |  Author(s): Hao Long, Qunyou Tan, Qingquan Luo, Zheng Wang, Gening Jiang, Tie-Hua Rong

      • Abstract

      Background

      Video-assisted thoracoscopic surgery (VATS) has been widely used in the treatment of early-stage non–small cell lung cancer (NSCLC). However, there has not been a robust randomized control trial (RCT) to conclude VATS has similar oncologic efficacy to open surgery. Therefore, a large multicenter RCT in China was designed and initialed in order to verify the role of VATS.

      Method

      A non-inferiority phase 3 RCT was undertaken at five thoracic surgical centers in China. Patients aged 18-75 years who were diagnosed of clinically early-stage NSCLCs were randomized in a 1:1 ratio into VATS and thoracotomy groups. Radical lobectomy plus hilar and mediastinal lymph node dissection was the standard surgical intervention as per protocol. The long-term oncologic outcomes including 3-year locoregional recurrence rate, overall survival (OS) and disease-free survival (DFS) would be analyzed and reported here. This study is registered with the ClinicalTrials.gov, number NCT01102517.

      Result

      A total of 508 patients were recruited in the trial between January 2008 and March 2014. And 433 patients were eligible for final analysis (222 cases in VATS group and 211 cases in thoracotomy group). At 3 years, the locoregional recurrence rates were 4.5% in VATS group and 5.7% in thoracotomy group respectively (P=0.664). Patients who received VATS procedures had a similar DFS rate to those who underwent open surgery (66% versus 69%, P=0.925; Fig 1A). Again, the 3-year OS rates were of no significant difference between VATS and thoracotomy groups (74% versus 73%, P=0.382; Fig 1B).

      fig 1.jpg

      Conclusion

      VATS in the treatment of clinically early-stage NSCLCs was associated with equivalent oncologic efficacy when compared to open surgery.

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      OA06.03 - Sublobar Resection is Equivalent to Lobectomy for Screen Detected Lung Cancer

      13:50 - 14:00  |  Presenting Author(s): Brendon Stiles  |  Author(s): Mohamed K Hussein, Mohamed Rahouma, Benjamin Lee, Sebron Harrison, Jeffrey L. Port, Nasser Altorki

      • Abstract

      Background

      Despite the lack of survival data from modern, ongoing randomized clinical trials (CALGB 140503, JCOG 0802), sublobar resection (SLR) is increasingly offered to patients with small, peripheral lung cancers. In particular, SLR may be an attractive surgical strategy for screen detected lung cancers, some of which may be less biologically aggressive than cancers detected by other means. Utilizing prospective data collected from patients undergoing surgery in the National Lung Screening Trial (NLST), we sought to determine whether the extent of resection affected survival for patients with screen detected lung cancer.

      Method

      The NLST database was queried for patients who underwent surgical resection for confirmed lung cancer. Numerical variables were compared using Mann-Whitney U test. Categorical variables were compared using Chi-squared test. Propensity score matching analysis (lobectomy versus sublobar resection) controlling for age, gender, race, tumor size, and stage was performed (nearest neighbor, 1:1, matching with no replacement, caliper 0.2). Overall survival (OS) and cancer specific survival (CSS) were compared using log rank test in Kaplan Meier curves.

      Result

      Among 1,029 patients who underwent resection for lung cancer, we identified 821 patients (80%) who had lobectomy and 166 patients (16%) who had SLR, among whom the majority (n=114, 69%) had wedge resection. Patients who underwent SLR were older (64 vs. 61, p=0.66), more likely to be female (53% vs. 41%, p=0.004), had smaller tumors (2 cm vs. 4.5 cm, p<0.001), and were more likely to be stage I (80% vs. 75%, p=0.001). At five years, for stage I patients undergoing SLR (n=129) there was no difference in OS (77% vs. 77%, p=0.889) or CSS (83% vs. 83%, p=0.959) compared to patients undergoing lobectomy (n=613). In order to more accurately compare surgical outcomes, we propensity matched 134 patients from each group undergoing SLR and lobectomy. Among these matched groups, there were no differences in age, gender, histology, or stage. Postoperatively, patients undergoing SLR had less total complications (22% vs. 32%, p=0.05) than those undergoing lobectomy (HR 0.59, CI 0.38-0.94). In matched patients at five years, there was no difference in OS (67% vs. 70%, p=0.629) or CSS (74% vs. 74%, p=0.980) for patients undergoing SLR compared to those undergoing lobectomy.

      Conclusion

      For patients with screen detected lung cancer, SLR confers equivalent survival to lobectomy. By decreasing perioperative complications and potentially preserving lung function, SLR may provide distinct advantages in a screen detected lung cancer patient cohort.

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      OA06.04 - Discussant - OA 06.01, OA 06.02, OA 06.03

      14:00 - 14:15  |  Presenting Author(s): Valerie W Rusch

      • Abstract

      Abstract not provided

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      OA06.05 - Do SBRT Planning and Delivery Factors Influence Local Control for Early Stage Non-Small Cell Lung Cancer (e-NSCLC)? 

      14:15 - 14:25  |  Presenting Author(s): Gregory M.M. Videtic  |  Author(s): Chandana A. Reddy, Aditya Juloori, Bindu Manyam, Neil M Woody, Kevin L Stephans

      • Abstract

      Background

      Stereotactic Body Radiation (SBRT) utilizes a variety of techniques to deliver very high-dose radiation to moving targets in the lung. We investigated the impact of dose-delivery factors on local failure (LF) by surveying our 12 year experience with e-NSCLC from our prospective database.

      Method

      Curative SBRT was administered to 1,085 patients (pts) between 2005 and 2016 and planned with either pencil beam (PB) or collapsed cone convolution (CCC) dose calculation algorithms (DCA), using open (dynamic arcs) or modulated beams (IMRT or VMAT), immobilized by abdominal compression or automatic breathing control (ABC), and treated with/without available CBCT (aligned to external fiducials and KV x-rays to bone if no CBCT, PTV margins were not altered based on availability of CBCT). We limited our analysis to standard fractionation regimens, [60 Gy/3, 48 Gy/4, 50 Gy/5, & 30-34 Gy/1) chosen per the treating physician in a risk-adapted approach relative to tumor size and location. The intreaction of technical variables with known patient and tumor factors on LF was analyzed using Fine and Gray univariate regression, with significant predictors selected for a forward step-wise multivariate regression model.

      Result

      At mean follow-up time of 25.6 months the cumulative incidence of LF at 1, 2, & 5 years was 3.0, 8.3, and 9.8% respectively. Overall survival (1, 2, 5 years) was 83, 62, & 28%. Univariate correlates with LF were PB TPS (HR 2.87, p=0.0004), modulated beam (HR 2.3, p=0.005), lack of CBCT (HR 2.69, p=0.0004), SBRT dose relative to 60 Gy/3 (HR 5.2, p=0.0001 for 4-5 fx; HR 2.7, p=0.051 for 1 fx), tumor size (HR 1.2 per cm, p=0.0009), PET SUV (HR 1.04 per SUV, p=0.0039), and squamous histology (HR 1.8, p=0.0051). Immobilization with ABC (n=96) versus abdominal compression (n=989) did not correlate with LF (p=0.99). On multivariate analysis PET SUV, modulated beam, and use of CBCT were no longer significant correlates with LF, while TPS (HR 2.62, p=0.0019), SBRT dose (HR 4.1, p=0.0009 for 4-5 fx relative to 60 Gy/3) & HR 2.9, p=0.039 for 1 fx versus 60 Gy/3), tumor size (HR 1.2 per cm, p=0.042) and squamous histology (HR 1.7, p=0.027) remained statistically significant.

      Conclusion

      While the use of PB versus CCC DCA was associated with higher rates of LF after SBRT, the use of abdominal compression vs ABC (univariate), open vs modulated beam, and CBCT vs bony alignment (multivariate) were not correlated with higher rates of LF after SBRT in e-NSCLC.

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      OA06.06 - MISSILE-NSCLC: A Phase II Trial Measuring the Integration of Stereotactic Radiotherapy Plus Surgery in Early-Stage Non-Small Cell Lung Cancer

      14:25 - 14:35  |  Presenting Author(s): David Palma  |  Author(s): Alexander Louie, Richard Malthaner, Dalilah Fortin, George Rodrigues, Brian Yaremko, Joanna M Laba, Keith Kwan, Stewart Gaede, Ting Lee, Aaron Ward, Andrew Warner, Richard Inculet

      • Abstract

      Background

      Stereotactic Ablative Radiotherapy (SABR) has emerged as a standard treatment option in patients with medically inoperable early-stage non-small cell lung cancer (NSCLC), yet the pathologic complete response (pCR) rate after SABR is unknown. Neoadjuvant SABR in operable patients has been proposed as a mechanism of improving local control and inducing anti-tumor immune activity.

      Method

      This phase II study (NCT02136355) enrolled patients with biopsy-proven clinical T1-2N0M0 NSCLC who were candidates for surgical resection. Patients underwent neoadjuvant SABR using a risk-adapted fractionation of 54 Gy/3 fractions, 55 Gy/5 or 60 Gy/8. Surgical resection took place 10 weeks after SABR. Patients also underwent dynamic FDG-PET and dynamic contrast-enhanced CT prior to SABR and approximately 2 weeks prior to surgery. The primary endpoint was the pCR rate, and secondary endpoints included local, regional, and distant recurrence, quality of life using the FACT Trial Outcome Index (TOI), and toxicity.

      Result

      Accrual began in Sept 2014 and completed in August 2017 with 40 patients enrolled. Median age was 69 years (range 44–83 years), and 58% were female. Thirty-one patients (78%) had T1 tumors and 9 (23%) had T2 tumors; histology was adenocarcinoma (n=26; 65%), squamous cell (n=13; 33%) and NSCLC not otherwise specified (n=1; 3%). Baseline FEV1 was median 73% percent predicted (range 50%–117%). Nine patients (23%) received the 3-fraction regimen, 21 (53%) received 5 fractions and 10 (25%) received 8 fractions. Thirty-five patients underwent surgery and were evaluable for the primary endpoint. The pCR rate was 60% (95% CI 44%–76%). 30-day and 90-day post-surgical mortality rates were both 0%. Eighteen percent of patients had grade 3 or 4 toxicities, most commonly pulmonary in nature (Grade 4: atelectasis and respiratory failure [n=1]; Grade 3: pneumonia/pneumonitis [n=2]; bronchopleural fistula [n=1]). In the patients receiving surgery, 2-year outcomes were: overall survival 77%, local control 100%, regional control 53% and distant control 76%. There were no significant changes in FACT-TOI score within the first year of follow-up.

      Conclusion

      The pCR rate after SABR for T1 and T2 NSCLC was 60%. Toxicity of the combined approach appears favorable, compared to historical series of surgery alone, and there was no perioperative mortality. Larger studies are needed to determine the clinical role of this combined treatment approach.

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      OA06.07 - Predictors and Consequences of Refusing Surgery for Clinical Stage I NSCLC: A National Cancer Database Analysis

      14:35 - 14:45  |  Presenting Author(s): Brendon Stiles  |  Author(s): Mohamed Rahouma, Mohamed Kamel, Abu Nasar, Sebron Harrison, Benjamin Lee, Jeffrey L. Port, Nasser Altorki

      • Abstract

      Background

      Given perceived morbidity of lung cancer surgery, patients may instead pursue other treatment options, particularly in the current era of shared decision-making. We sought to determine predictors of refusal of surgery for clinical stage I non-small cell lung cancer (NSCLC) patients and to determine associated outcomes.

      Method

      The NCDB (2004-2014) was queried for clinical stage I NSCLC patients who underwent or were recommended to undergo surgery. A unique field in the NCDB allows identification of those patients who were recommended to have surgery, but refused. We only included cases in which surgery was refused “by the patient, patient’s family member or guardian”. We excluded patients with multiple primary tumors, unknown treatment modality/sequence, those who did not undergo recommended surgery for unknown reasons, and those initially not recommended to have surgery. Survival was compared using log rank test in Kaplan Meier curves. Logistic regression was performed to identify predictors of refusing surgery.

      Result

      We identified 118,0217 patients undergoing surgery and 3,210 (2.6%) who were recommended, but refused surgery. By multivariate analysis older age (HR=1.09, CI=1.08-1.09), non-white race (HR=2.18, CI=1.97-2.42), low income (HR=1.28,CI=1.16-1.41), lack of insurance (HR=2.62,CI=1.89-3.62), squamous histology (HR=1.40,CI=1.29-1.53), and larger tumor size (HR=1.57,CI=1.42-1.73) predicted refusal of surgery.Patients refusing surgery were treated with chemoradiation (n=249, 7.8%), radiation or chemotherapy alone (n=1,568, 48.8%), or no treatment (n=1393, 43.4%). Median survival was worse for patients who refused any treatment versus those who received other treatment modalities (19.8 vs 42.2 months, P<0.001). Among those patients refusing surgery who were treated with radiation, we identified 758 patients (23.6%) who received stereotactic body radiation therapy (SBRT). The proportion of patients who refused surgery and received SBRT increased over time, from 3.8% in 2004-2006, to 17% in 2007-2009, to 31.1% in 2010-2012, and to 37.9% in 2013-2014. Patients receiving SBRT had improved survival compared to other patients refusing surgery (47.9 vs. 25.2 months, p<0.001), although survival in the SBRT group was inferior to patients undergoing surgery as recommended (47.9 vs. 82.8 months, p<0.001).

      Conclusion

      Although patients may be reluctant to undergo surgery for early stage NSCLC, refusal of surgery when recommended comes at the expense of decreased survival. Socioeconomic factors may be associated with refusal of surgery. The use of SBRT is an effective and increasingly used alternative in these patients, which improves survival compared to no treatment but which is still not equivalent to surgery in this unmatched, retrospective cohort.

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      OA06.08 - Discussant - OA 06.05, OA 06.06, OA 06.07

      14:45 - 15:00  |  Presenting Author(s): Steven H Lin

      • Abstract

      Abstract not provided

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    PC02 - Debate on Local Therapies for Limited Small Cell Lung Cancer? Surgery PRO/CON and BID Radiation PRO/CON

    • Type: Pro-Con Session
    • Track: Small Cell Lung Cancer/NET
    • Moderators:
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      PC02.00 - Introduction with Poll Questions

      13:30 - 13:35  |  Presenting Author(s): Quincy Chu, Wilfried Eberhardt

      • Abstract

      Abstract not provided

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      PC02.01 - Surgery - PRO

      13:35 - 13:55  |  Presenting Author(s): Elliot Wakeam

      • Abstract

      Abstract

      Surgery in the treatment of small cell lung cancer (SCLC) was commonplace up until the mid-1970’s when the results of the medical research council (MRC) trial compared surgery to radiation and found no improvement with the addition of surgery. A later trial compared chemoradiation with adjuvant surgery to chemoradiation alone also failed to show an improvement with surgery. These two results have been used to justify nihilism amongst thoracic oncologists with respect to the use of surgery. However, modern screening, staging, minimally-invasive surgery and adjuvant therapy have changed the situation for the treatment of early SCLC. Modern evidence, albeit retrospective, supports a greater utility for surgery in the treatment of early SCLC than what may have been suggested by older randomized trials that are no longer applicable in the modern era. Surgery has much to offer in the treatment of early SCLC and this lecture will outline the potential utility of surgery - in particular anatomic resection and systematic lymph node dissection - as part of a multimodality treatment regimen.

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      PC02.02 - Surgery - CON

      13:55 - 14:15  |  Presenting Author(s): Cecile Le Pechoux

      • Abstract

      Abstract not provided

    • +

      PC02.02a - Poll Questions

      14:15 - 14:20  |  Presenting Author(s): Quincy Chu, Wilfried Eberhardt

      • Abstract

      Abstract not provided

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      PC02.03 - BID Radiation - CON

      14:20 - 14:40  |  Presenting Author(s): Ben Slotman

      • Abstract

      Abstract

      Thoracic radiotherapy for LS-SCLC: QD is just as good as BID ?!

      Most of the advances in outcome of small cell lung cancer (SCLC) in the past few decades can be attributed to improvements in radiotherapy, including better imaging and target selection, better treatment planning, better integration with chemotherapy, and use of prophylactic cranial irradiation.

      Thoracic radiotherapy plays an important role in the treatment of limited disease SCLC (LS-SCLC). Best results are obtained with twice daily (BID) radiotherapy, starting early and given concurrently with chemotherapy [1]. In addition, it was shown that a shorter time from start of chemotherapy to completion of radiotherapy was associated with longer survival [2]. Two meta-analyses demonstrated that use of thoracic radiotherapy led to improved local control and an absolute survival benefit at 3 years of 5% [3,4].

      Turrisi et al. [5] demonstrated in the Intergroup 0096 study that 45 Gy given BID in 30 fractions in 3 weeks was superior compared to the same dose delivered once-daily (QD) in 25 fractions over a 5 week period. Overall survival at 5 years was improved (26% vs 16%), but at the expense of more G3-4 oesophagitis (32 vs 16%). In spite of these results, BID radiotherapy is still used in a only a minority of SCLC patients [6,7]. In The Netherlands, early concurrent BID rasdiotherapy is given in about a quarter of the patients [7]. The radiotherapy dose in the QD arm of the Intergroup trial [5] was relatively low and some argued that a higher QD radiotherapy dose might be equivalent to or even better than the 45 Gy BID scheme. In the ongoing CALGB 30610 / RTOG 0538 study (NCT00632853) a dose of 70 Gy once-daily in 35 fractions in 7 weeks is compared with the 45Gy BD scheme. In this trial, radiotherapy starts with the first course of chemotherapy and includes elective nodal irradiation. Accrual is expected to continue for several years.

      In the recently published CONVERT trial (ISRCTN91927162), patients were randomized between 45 Gy BID in 3 weeks and 66 Gy QD in 33 fractions in 6.6 weeks starting with the second course of chemotherapy [8]. Treatment did not include elective nodal irradiation. The study was designed to investigate whether the higher QD regimen would lead to improved survival. Median overall survival was 30 months for the BID and 25 months for the QD arm. There were no statistically significant differences in the rates of local and metastatic progression. Survival in the control arm (BID) was 12% higher than expected when designing the study, possibly due to improvements in radiotherapy techniques. Based on the study, it can be concluded that a higher dose given QD does not lead to improved survival or better local control. There were no significant differences in acute toxicity, except for more G4 or higher neutropenia in the BID arm (49% vs 38%). The risk of Grade 3-4 oesophagitis was 19% with no significant differences between the two study arms.

      Based on the results of this trial, 45 Gy given BID in 3 weeks should remain the reference standard. This regimen leads to the best results in the shortest time with the fewest number of fractions. The CONVERT study also indicates that where delivery of a BED scheme is not feasible, a higher dose once-daily schedule does not compromise clinical outcomes. However, it Is surprising that the significantly higher biologically equivalent radiotherapy dose of the QD scheme in the CONVERT study did not translate into better outcome.Does the early distant dissemination of the disease preclude further improvements in local control and survival by local treatment? Or is the influence of the repopulation may greater than calculated in our radiobiological models?

      The possible benefit of shortened treatment time was evaluated in a phase II study from Norway in which 45 Gy BID in 3 weeks was compared with 42 Gy in 15 fractions in 3 weeks given QD. There was no significant difference in progression free survival at 1 year, the primary endpoint of this study in which 157 patients were enrolled (49% vs 45%). Although overall response rates were similar (88% and 92%), more complete responses were seen in the BID arm (33 vs 13%). In addition, although not statistically significant, overall survival was 25 months for the BID vs 19 months for the QD arm.

      In the BID scheme, treatment is completed in 3 weeks and a BED10 of 52 Gy is delivered, whereas the same BED10 is reached after about 22 fractions of 2 Gy delivered once-daily. The delivered BED during the last third of the QD treatment does not seem to contribute to outcome. This suggest that repopulation starts very early and that tumor doubling times may be much shorter than generally assumed and a shorter QD scheme may be preferable if treatmenti is not deliverded BID.. .

      References

      1. Fried DB. S J Clin Oncol 2004;22:4837–45.

      2. De Ruysscher D.et al., J Clin Oncol 2006;24:1057–63.

      3. Pignon JP, et al. N Engl J Med 1992;327:1618–24.

      4. Warde P, Payne D. J Clin Oncol 1992;10:890–5.

      5. Turrisi AT, ert al. et al. N Engl J Med 1999;340:265–71.

      6. Komaki R, et al. Int J Radiat Oncol Biol Phys 2013;85:1082-9.

      7. Damhuis R, et al. Clin Oncol 2018;30:17-22.

      8. Faivre-Finn C. et al. Lancet Oncol 2017;18:1116-25.

      9. Gronberg BH, Acta Oncol 2016;55:591-7.

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      PC02.04 - BID Radiation - PRO

      14:40 - 15:00  |  Presenting Author(s): Jeffrey Bogart

      • Abstract

      Abstract

      The optimal thoracic radiotherapy dose for treating limited stage small cell lung cancer remains to be defined. Given the radiosensitivity of small cell lung cancer cell lines in preclinical studies in the 1980's it was postulated that twice daily radiotherapy would result in improved efficacy. Subsequent clinical experience included the landmark Intergroup 0096 trial, which demonstrated improved overall survival for patients assigned to twice daily radiotherapy (45 Gy) compared with once daily radiotherapy to the same total dose. Despite being one of the few randomized trials showing that changing the radiotherapy regimen impacts overall survival, the twice-daily regimen was slow to be adopted in clinical practice and many NCI cooperative group studies continued to use once-daily radiotherapy. Reluctance to routinely use the twice-daily regimen likely relate to concerns with acute toxicity, logistic issues, and use of a modest radiotherapy dose of only 45 Gy on the standard arm. In addition, a contemporaneous study from NCCTG did not show an advantage to twice-daily radiotherapy, although a planned treatment break was included such that radiotherapy was not accelerated. Alternate strategies to improve the efficacy of thoracic radiotherapy have included the development of high dose once-daily regimens with a 70 Gy regimen utilized in several phase II trials from the Cancer and Leukemia Group B. These trials are somewhat difficult to interpret, as radiotherapy was not initiated until the 3rd cycle of chemotherapy and novel induction chemotherapy regimens were included. The RTOG has also studied a concomitant boost regimen, though overall survival was lower than expected in the phase II experience. Results from the CONVERT trial, comparing 45 Gy twice-daily and 66 Gy once-daily radiotherapy, were recently published. The trial was powered to show superiority of high dose daily radiotherapy and failed to do so, and thus the authors concluded that 45 Gy twice-daily remain the standard of care. The CALGB 30610 trial, which uses 70 Gy in the once-daily arm, is near completion and will provide further data regarding the therapeutic ratio of these regimens. For the time being it should be kept in mind that the long held assumption that increasing radiotherapy dose with conventional fractionation will result in improved outcomes may not be justified – particularly in the setting of concurrent chemotherapy. For example, increasing the radiotherapy dose from 50.4 Gy to 64.8 Gy, with cisplatin and 5-FU, did not improve outcomes for patients with esophageal cancer on the phase 3 Intergroup 0123 trial. Perhaps even more suprising are the results of RTOG 0617, where even in the era of advanced radiotherapy treatment planning raising the radiotherapy dose resulted in worse outcomes.

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    MA08 - Clinical Trials in Brain Metastases

    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Moderators:
    • +

      MA08.01 - Phase 3 Trial of Whole Brain Radiotherapy with Concurrent Erlotinib Versus WBRT Alone for NSCLC with Brain Metastases (ENTER)

      15:15 - 15:20  |  Presenting Author(s): ZhenZhou Yang  |  Author(s): Yan Zhang, RongQing Li, Abulimiti Yisikandaer, BiYong Ren, JianGuo Sun, JianJun Li, Long Chen, Ren Zhao, JuYing Zhang

      • Abstract

      Background

      Brain metastasis (BM) is a leading cause of death for non-small cell lung cancer (NSCLC). Whole Brain Radiotherapy (WBRT) is a standard-of-care treatment for NSCLC patients with multiple brain metastases. Elevated EGFR expression and activity are important causes of tumor resistance to radiotherapy. This phase 3 trial sought to determine if concurrent erlotinib with WBRT will benefit patients with multiple BM compared with WBRT alone.

      Method

      In this open-label, randomised, multicenter phase 3 study in China (NCT01887795), we enrolled NSCLC patients with at least two metastatic brain lesions who were naive to brain radiation and free from any EGFR-TKI for at least 4 weeks. Participants were randomly assigned (1:1) to receive either WBRT (2.0 Gy per day, 5 days per week, to 40 Gy) or WBRT plus concurrent oral erlotinib 150 mg daily (Erlotinib was given for 6 days then concurrently with WBRT). Subsequent treatments were maintenance therapy of erlotinib for EGFR-positive patients or standard chemotherapy for EGFR-negative patients until unacceptable adverse events or disease progression. The primary endpoint was intracranial progression-free survival (iPFS), defined as time from randomisation to either intracranial disease progression or death for any cause.

      Result

      Between August 7, 2013 and November 25, 2016, in total 222 patients from 11 centers across China were randomized to treatments: 115 with WBRT alone and 107 with WBRT and concurrent erlotinib. Median follow-up was 11.2 months (IQR 4.6-18.2). Median iPFS was 11.2 months (95% CI: 7.2-13.7) with WBRT and concurrent erlotinib versus 9.2 months (95% CI: 6.7-10.9) with WBRT alone (HR 0.926; 95% CI: 0.695-1.234; P=0.601). In the subgroup of 109 patients who were positive for the EGFR mutation, iPFS was not significantly longer among those who received WBRT with concurrent erlotinib than WBRT with sequential erlotinib (14.6 [95% CI 11.8-17.7] vs 12.8 [7.9-14.9] months; HR 0.743; 95% CI: 0.489-1.129; P=0.164). Median PFS of concurrent erlotinib arm was 5.3 months versus 4.0 of WBRT alone (HR 0.969; 95% CI: 0.735-1.277; P=0.825) and median overall survival (OS) was 12.9 versus 10.0 months (HR 0.913; 95% CI: 0.680-1.226; P=0.545).

      Conclusion

      This multi-institutional study demonstrated WBRT with concurrent erlotinib improved neither iPFS significantly than WBRT alone in the intention-to-treat population and the EGFR-positive subgroup, nor improved PFS or OS in intention-to-treat population, indicating that erlotinib played limited role when concurrently used with WBRT and for EGFR-positive NSCLC patients, WBRT with concurrent erlotinib was not significantly superior to WBRT with sequential erlotinib.

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      MA08.02 - Prophylactic Cranial Irradiation Reduces the Risk of Brain Metastases in High-Risk Lung Cancer Patients: EGFR and ALK Mutations

      15:20 - 15:25  |  Presenting Author(s): Oscar Arrieta  |  Author(s): Federico Maldonado, Laura-Alejandra Ramírez-Tirado, Feliciano Barron, Yelitza Esmeralda Campos-Salgado, Monica Blake, Andrés F. Cardona, Jaime G De La Garza

      • Abstract

      Background

      Prophylactic Cranial Irradiation (PCI) is considered standard-of-care for small-cell lung cancer, due to consistent findings of a reduced risk of developing brain metastases (BM) and a survival benefit. The role of PCI for patients with Non-small cell lung cancer (NSCLC) is less well established, since a clear survival benefit has not been identified, although high-risk subgroups have been identified, including patients with driver mutations and with elevated carcinoembryonic antigen (CEA) levels.

      Method

      We assessed the use of PCI compared to observation in patients with stage IV NSCLC (NCT01603849). PCI dose was set 25 Gy/10 f. An amendment to the original record was requested so that patients who received PCI after January 2016 had hippocampal sparing. Primary end point was Intracranial Progression-Free survival (IPFS), secondary was overall survival (OS).

      Result

      84 patients were included, 43 were randomized to observation and 41 to PCI. 83.3% had a driver mutation (DM). Baseline characteristics were well balanced among groups. Median IPFS was 21.0 months (95%CI 16.2-25.9). Factors which were independently, positively associated with IPFS included ECOG (p=0.012) and therapeutic arm (p=0.006). PCI was associated with lower odds of progression to CNS (OR:0.16 (0.04–0.53), p=0.006).Cumulative incidence of BM at 1-yr was higher among patients without PCI (22% vs. 3%, p<0.001). Relative risk for IPFS in patients with DM was 0.29 (0.10-0.82, p=0.01), HR for OS was 0.48 (0.20-1.16, p=0.098). Median OS was higher in the PCI group compared to control [42.8 (95%CI: 28.1–57.6) vs. 25.9 (95%CI: 17.7 – 34.2)] months. Last, PCI was associated with lower hazards of death, 0.47 (0.24–0.95), p=0.035.rt-prof figure.png

      Conclusion

      PCI significantly increases IPFS and decreases risk of death in patients with advanced NSCLC, without neurocognitive impairment or decreased QoL. This intervention appears to be particularly useful for patients with good performance status and driver mutations. PCI increased IPFS without neurocognitive impairment or decreased QoL.

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      MA08.03 - EGFR-TKI Plus Brain Radiotherapy Versus EGFR-TKI Alone in the Management of EGFR Mutated NSCLC Patients with Brain Metastases: A Meta-Analysis

      15:25 - 15:30  |  Presenting Author(s): Wenhua Liang  |  Author(s): Xiaojun Xia, Minzhang Guo, Jianxing He

      • Abstract

      Background

      It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) presented better efficacy than brain radiotherapy (brain RT) in the treatment of brain metastasis (BM) in EGFR mutated NSCLC patients. However, whether the combination of EGFR-TKI and brain RT is better than EGFR-TKI alone remains unclear. We aim to compare the benefit of adding brain RT to EGFR-TKI by a meta-analysis of currently available data.

      Method

      A systematic search for relevant articles was conducted in six databases (PubMed, EMBASE, Cochrane database, Medline, Web of Science, Google scholar). The primary outcome was overall survival (OS) between groups, and the secondary outcome was intra-cranial progression-free survival (icPFS), both being measured as hazard ratios (HRs). The data was synthesized by random-effects model using STATA 13.0.

      Result

      A total of four retrospective studies involving 507 EGFR mutated patients with BM at the first diagnosis were included, 209 patients received brain RT (predominantly whole brain RT). Combined therapy of EGFR-TKI and brain RT reduced 19% risk of deaths (OS HR=0.81, 95% CI 0.53-1.26; P=0.36) and 16% risk of intracranial progression (icPFS HR=0.84, 95% CI 0.55-1.27; P=0.40) compared with EGFR-TKI alone, however, no statistically significance was observed. Further subgroup analyses suggested that patients with 21 exon L858R mutation were more inclined to have greater icPFS benefit under combination therapy (HR 0.67, 95% CI 0.19-2.40) in contrast to 19 exon deletion patients (HR 1.35, 95% CI 0.88-2.09). In addition, patients older than 65 (HR 0.74, 95% CI 0.37-1.48) might benefit more from combination than those younger than 65 (HR 4.47, 95%CI 0.29-70.13).

      Conclusion

      This meta-analysis suggested that the combination of EGFR-TKIs and brain radiotherapy showed similar but potentially better OS and intracrnial control in EGFR-mutated NSCLC patients when compared to EGFR-TKI alone, especially for those with L858R mutations or older than 65. The current results underscore the importance of future randomized control trials and provide information for study design.

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      MA08.04 - Discussant - MA 08.01, MA 08.02, MA 08.03

      15:30 - 15:45  |  Presenting Author(s): Nasser Hanna

      • Abstract

      Abstract not provided

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      MA08.05 - Brain Penetration of Lorlatinib and Cumulative Incidence Rates for CNS and Non CNS Progression from a Phase 1/2 Study

      15:45 - 15:50  |  Presenting Author(s): Todd M. Bauer  |  Author(s): Alice T. Shaw, Melissa L. Johnson, Alejandro Navarro, Justin F Gainor, Holger Thurm, Yazdi K. Pithavala, Antonello Abbattista, Enriqueta Felip

      • Abstract

      Background

      The potent, selective, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) lorlatinib was designed to penetrate the blood-brain barrier (BBB). In a phase 1/2 study, lorlatinib showed robust clinical activity in patients with ALK-positive non-small cell lung cancer (NSCLC), most of whom had CNS metastases and failed ≥1 ALK TKI. In preclinical studies, lorlatinib demonstrated high BBB permeability with rapid brain uptake in vivo and significant activity against ALK-positive intracranial tumor models.1,2 To assess brain penetration of lorlatinib in a clinical setting, we report exploratory analyses from a phase 1/2 study (NCT01970865), evaluating CSF-to-plasma concentration ratios from a small sample of patients and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and deaths for pretreated patients with ALK-positive NSCLC ± baseline CNS metastases.

      Method

      Across the ongoing phase 1/2 study, 5 patients at lorlatinib 100 mg QD starting dose underwent CSF sampling. Patients with ALK-positive NSCLC with ≥1 prior ALK TKI were analysed for progressive disease, categorized as either CNS or non-CNS progression, based on independent central review. CIRs for patients in expansion cohorts EXP2–5 from the phase 2 portion of the phase 1/2 study (N=198) were calculated using competing risks methodology.

      Result

      In patients (n=5), mean CSF-to-plasma concentration ratio was 0.73 (SD 0.14). The table shows CIRs at 6 and 12 months.

      Months Cumulative Incidence Probability
      Patients with ≥1 prior ALK TKIa CNS Progression

      Non-CNS

      Progression

      Death
      All patients (n=198)

      6 mos

      12 mos

      0.13

      0.18

      0.25

      0.37

      0.05

      NE
      Patients with baseline CNS metastases (n=131)

      6 mos

      12 mos

      0.14

      0.22

      0.21

      0.31

      NE

      NE
      Patients with no baseline CNS metastases (n=67)

      6 mos

      12 mos

      NE

      NE

      0.32

      0.49

      0.05

      NE

      aPatients in expansion cohorts EXP2–5 from the phase 2 study

      NE, not evaluable
      Conclusion

      Lorlatinib showed high BBB permeability as evidenced by a high mean CSF-to-plasma concentration ratio, in line with preclinical rat studies showing CNS penetration. This translated into high activity against CNS metastases as suggested by the numerically higher probability of the first progression event being extracranial rather than intracranial, including in patients with a history of CNS metastases.

      References

      1. Collier, et al. Mol Imaging 2017;16:1–3.

      2. Zou, et al. Cancer Cell 2015;28:70–81.

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      MA08.07 - Real World Data of Osimertinib in Patients with Central Nervous System (CNS) Metastasis in ASTRIS Korean Subset.

      15:50 - 15:55  |  Presenting Author(s): Jin-Hyoung Kang  |  Author(s): Byoung Chul Cho, Dong-Wan Kim, Keunchil Park, Jong-Seok Lee, Seung soo Yoo, Sung Yong Lee, Cheol Hyeon Kim, Seung Hun Jang, Young-Chul Kim, Hyoung-Kyu Yoon, Sang-We Kim

      • Abstract

      Background

      More than 40% of non-small cell lung cancer (NSCLC) patients develop CNS metastasis in their lifetime. Osimertinib is a third-generation EGFR-TKI which selectively inhibits both EGFR-sensitizing and EGFR T790M resistance mutations. Clinical studies have shown superior efficacy of osimertinib in CNS compared to platinum chemotherapy. Treatment efficacy in patients with or without CNS metastasis were observed within the second interim analysis of ASTRIS (NCT02474355). Data cut-off (DCO) was 20 October 2017.

      Method

      In ASTRIS, advanced NSCLC patients with a locally confirmed T790M mutation, WHO performance status 0-2, prior EGFR-TKI therapy were enrolled. Patients with stable CNS metastases were allowed. The primary endpoint was overall survival (OS); other endpoints included investigator-assessed response rate (RR), progression-free survival (PFS), time to treatment discontinuation (TTD) and safety. These endpoints were also analyzed according to presence of CNS metastasis.

      Result

      A total of 466 patients received at least one dose of osimertinib 80mg from 31 Korean sites. CNS metastasis was evaluated in 310 patients and was present in 211 (68.1%) patients (CNS-met); 181 brain only, 1 leptomeningeal only, 29 both. 99 (31.9%) patients did not have CNS metastasis (CNS-no), and 155 patients were not evaluated (CNS-ne). At DCO, 236 patients (50.6%) were ongoing and median duration of exposure was 11.2 (0–19) months. In patients evaluable for response, defined as at least one dose of osimertinib and one response assessment, RR was 71.0% (320/451; 95% CI, 66.5–75.1): Patients with (N=211), without (N=99), and not-evaluated CNS metastasis (N=155) had RR of 68% (134/197; 95% CI, 61.0-74.5), 79.6% (78/98; 95% CI, 70.3-87.1), and 69.7% (108/155; 95% CI, 61.8-76.8), respectively. Median PFS was 12.4 months (95% CI, 11.1-13.6 months); 10.8 months (95% CI, 9.5-11.5) in CNS-met,11.0 months (95% CI, 9.2-14.5) in CNS-no, and 15.1 months (95% CI, 13.6-18.2) in CNS-ne. Median TTD was 16.5 months (95% CI, 14.1-NC); 11.2 months (95% CI, 9.4-14.8) in CNS-met, 14.7 months (95% CI, 12.2-NC) in CNS-no, and NC (95% CI, 15.5-NC) in CNS-ne. OS was not reached (data maturity: 19.7%). Serious adverse event (AE) regardless of causality were reported in 116 patients (24.9%) and AEs leading to death in 13 patients (2.8%). ILD/pneumonitis-like events were reported in 8 patients (1.7%), and QTc prolongation in 7 patients (1.5%).

      Conclusion

      In ASTRIS Korean subset, patients with or without CNS metastasis had comparable efficacy outcome. This data continues to support osimertinib’s clinical benefit on EGFRm T790M NSCLC patients with CNS metastasis.

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      MA08.08 - Discussant - MA 08.05, MA 08.07

      15:55 - 16:10  |  Presenting Author(s): Myung-Ju Ahn

      • Abstract

      Abstract not provided

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      MA08.09 - Impact of Brain Metastases in Immune Checkpoint Inhibitors (ICI) Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

      16:10 - 16:15  |  Presenting Author(s): Lizza Hendriks  |  Author(s): Clémence Henon, Eduard Auclin, Laura Mezquita, Roberto Ferrara, Clarisse Audigier-Valette, Julien Mazieres, Corentin Lefebvre, Sylvestre le Moulec, Sophie Cousin, Boris Duchemann, Cecile Le Pechoux, Angela Botticella, Samy Ammari, Anas Gazzah, Caroline Caramella, Julien Adam, David Planchard, Dirk De Ruysscher, Anne-Marie C. Dingemans, Benjamin Besse

      • Abstract

      Background

      Brain metastases (BM) are frequent in NSCLC. Unfortunately, patients with (untreated) BM are often excluded from ICI trials so that their outcome on ICI is largely unknown..

      Method

      Retrospective data collection of all consecutive advanced ICI treated NSCLC patients in 6 centers (5 French, 1 Dutch) (nov 2012 – march 2018). Active BM was defined as non-irradiated new and/or growing lesions on brain imaging < 6 weeks before ICI start. Progression free survival (PFS), overall survival (OS) and site of progression on ICI was collected.

      Result

      945 patients included: 63% male, 83% WHO PS 0-1, median age 64 years, 73% non-squamous, 4% targetable driver mutations, 33% known PD-L1 (65% ≥1% expression). ICI treatment was median 2nd line (range 1-12), 94% had monotherapy PD-(L)1 inhibition. 241 patients (26%) had BM, 68% had previous cranial irradiation, 40% had active BM. BM patients were significantly younger than others (61 vs 66 years), had more adenocarcinoma (78 vs 62%), more organs involved (median 3 vs 2), a poorer PS (0-1: 76 vs 85%) and more steroids at baseline (26 vs 9%). Median follow-up: 15 months. Median (95% CI) PFS and OS without and with BM were 2 (2-3) vs 2 (1-2) months and 13 (9-16) vs 9 (7-13) months, respectively. In multivariate analysis, > 2 metastatic sites, PS ≥2 and steroids use were associated with worse PFS and OS, BM were not (table 1). In univariate analysis of BM patients, active BM were not associated with worse outcome compared to stable BM (HR PFS 0.98 (p=0.66), HR OS 0.93 (p=0.92)). Progressing BM patients had more often brain PD and a dissociated response (not specifically brain dissociated) on ICI (40 vs 12% and 13 vs 7%, respectively).

      Factor PFS HR (95% CI) p-value OS HR (95% CI) p-value
      Age > 65 vs ≤ 65 1.02 (0.87-1.20) 0.79 1.11 (0.92-1.34) 0.29
      Smoking yes vs no 0.53 (0.41-0.69) <0.001 0.81 (0.59-1.12) 0.20
      Histology squamous vs adeno 1.07 (0.89-1.28) 0.78 1.24 (0.99-1.55) 0.12
      Nr of organs with metastases > 2 vs ≤ 2 1.28 (1.09-1.50) 0.003 1.48 (1.22-1.80) <0.001
      Immuno line > 2 vs ≤ 2 1.11 (0.94-1.30) 0.22 1.10 (0.91-1.33) 0.34
      WHO PS 0-1 vs ≥2 2.14 (1.75-2.62) <0.001 3.48 (2.78-4.36) <0.001
      Use of corticosteroids yes vs no 1.36 (1.10-1.69) 0.005 1.31 (1.03-1.68) 0.03
      BM yes vs no 1.05 (0.88-1.26) 0.58 0.96 (0.77-1.19) 0.70

      Conclusion

      BM, treated or active, do not negatively impact outcome on ICI although BM failure is more common in these patients.

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      MA08.10 - Real-Life Intracerebral Efficacy of Nivolumab in Non-Small Cell Lung Cancer Patients with Brain Metastases

      16:15 - 16:20  |  Presenting Author(s): Margaux Geier  |  Author(s): Renaud Descourt, Romain Corre, Guillaume Léveiller, Regine Lamy, Eric Goarant, Jean-Louis Bizec, Cyril Bernier, Gilles Quéré, Francis Couturaud, Gilles Robinet

      • Abstract

      Background

      Data regarding intracerebral efficacy of nivolumab in advanced non-small cell lung cancer (NSCLC) are lacking because of routinely exclusion of patients with active brain metastases (BMs) from clinical trials. We aimed at assessing intracranial activity of nivolumab in patients with BMs in a real-life setting and determining the potential role of prior radiotherapy.

      Method

      Between 01/09/2015 and 30/09/2016, all consecutive advanced NSCLC patients treated with nivolumab after failure of at least one line of chemotherapy were included. Nivolumab was administered at a dose of 3 mg/kg q2w until progression or unacceptable toxicity. Primary endpoint was intracerebral objective response rate (IORR) assessed by brain magnetic resonance imaging or brain computed-tomography scans. Secondary endpoints were overall response rate (ORR) and median duration of intracerebral response.

      Result

      259 patients were treated with nivolumab in 9 centers. Among them, 77 patients who presented BMs before nivolumab initiation were enrolled: 53 (20.5%) at diagnosis and 24 (9.3%) during the course of treatments. Median age at diagnosis was 57 years [29-78]. Most patients were males (72.7%) with smoking history (90.9%) and had adenocarcinoma (72.7%). 23 patients harbored a KRAS mutation. PD-L1 status was unknown. The median of prior lines was 1 [1-6]. BMs were pretreated in 48 (62.3%) patients: 16 received prior SBRT, 32 WBRT. Median time between prior radiotherapy and nivolumab initiation was 4 months [1-;27]. IORR and ORR were 10.4% and 20.8%, respectively. Among the 8 patients with intracerebral response, 5 (6.5%) had pretreated BMs, 3 (3.9%) had radiotherapy-naïve BMs. Median duration of intracerebral response was 11.5 months. No neurological adverse events occurred during nivolumab treatment. Among 259 patients, 36 (13.8%) developed BMs during nivolumab treatment.

      Conclusion

      Nivolumab intracerebral response achieved 10.4% in real-life with a satisfactory neurological safety profile. If prior radiotherapy improves IORR must be determined by further investigations.

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      MA08.11 - Early Safety Data of a Phase I/II Combining Nivolumab and Stereotactic Brain Radiosurgery for Treatment of Brain Metastases in Patients with NSCLC

      16:20 - 16:25  |  Presenting Author(s): Raafat Alameddine  |  Author(s): Philip Wong, Laura Masucci, David Roberge, Cynthia Menard, Bertrand Routy, Mustapha Tehfe, Normand Blais, Marie Florescu

      • Abstract

      Background

      Radiotherapy can stimulate the immune system through various means. Highly cytotoxic stereotactic radiosurgery (SRS) doses (>10Gy per fraction) may synergize with anti-PD1 to reduce intracranial disease progression or recurrence.

      Method

      Within a phase I/II trial evaluating the combination of nivolumab with SRS in the treatment of brain metastases from NSCLC and RCC (NCT02978404), 8 patients were enrolled (1 RCC and 7 NSCLC) in the first trial cohort. Herein, only the NSCLC cases are reviewed. Patients were eligible if their KPS ≥70, were minimally symptomatic (RTOG neurological function <2), and had ≤10cc of untreated brain metastases. Prophylactic corticosteroids were not given. Nivolumab (240mg IV q2 weeks) was started 2 weeks prior to SRS, and administered until RECIST progression. SRS (15-20Gy in 1 fraction) was given to each brain metastasis. The aim of the first patient cohort is to estimate the tolerability of the combined treatment strategy.

      Result

      The median follow-up of the three male and four female patients was 2 months. Median age was 63 years (55-84 years). Five NSCLC patients completed ≥1 cycle of nivolumab and SRS, and were evaluated for tolerability of the combination. One patient elected to withdraw before the first nivolumab dose and 1 patient died prior to SRS. Median baseline brain edema and total brain metastases volumes were 0.5cc (0-46.97cc) and 1.25 cc (0.1-3.46cc), respectively. To date, the median number of nivolumab cycles administered is 4.5 (1-15). Intracranial adverse effects were limited to apraxia and paresthesias in the patient who had the largest volume of peri-tumoral brain edema at baseline (46.97cc). Nivolumab was held and dexamethasone was given for 74 days at doses >1mg/day until neurological symptoms resolved. Systemic adverse events included one patient with grade 2 arthritis necessitating a 6-week treatment delay and 51 days of prednisone ≥10mg. At last follow-up, three patients had died of extracranial disease progression, including the two patients who did not receive protocol SRS. Among the three patients evaluable for intracranial response, there was one partial response and two stable diseases. All three patients had stable extracranial disease.

      Conclusion

      Combining SRS and immunotherapy is safe in regards to acute toxicity with a manageable side effect profile. Close monitoring may be required for patients with significant baseline brain edema. Evaluation for efficacy awaits further follow-up and completion of recruitment in the phase 2 component of the trial.

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      MA08.12 - Discussant - MA 08.09, MA 08.10, MA 08.11

      16:25 - 16:40  |  Presenting Author(s): Arjun Sahgal

      • Abstract

      Abstract not provided

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      MA08.12a - Q&A

      16:40 - 16:45

      • Abstract

      Abstract not provided