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Wilfried Ernst Erich Eberhardt

Moderator of

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    MA03 - Clinomics and Genomics (ID 119)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 12
    • Now Available
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      MA03.01 - The Impact of Early Steroids on Clinical Outcomes in Patients with Advanced NSCLC Treated with Immune Checkpoint Inhibitors- A Cancerlinq Cohort (Now Available) (ID 2807)

      10:30 - 12:00  |  Presenting Author(s): Nathan Pennell  |  Author(s): Pradnya Dinkar Patil, Xuefei Jia, Brian Hobbs

      • Abstract
      • Presentation
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm for patients with NSCLC, however only a fraction of patients have objective responses to these agents. Identifying clinical factors that influence efficacy of ICIs is crucial for optimal patient selection for treatment. Since ICIs produce anti-tumor responses by reinvigorating cytotoxic effector T cells, one can surmise that patients who receive steroids within a short interval of initiating ICIs will have less robust anti-tumor responses. Clinical trials usually exclude patients receiving steroids for this reason. In clinical practice, patients with NSCLC often receive corticosteroids for various indications such as brain metastases, appetite stimulation, autoimmune disorders, or COPD. By analyzing data obtained from a large real world cohort of patients with NSCLC, we aim to study the impact of early steroids (within 30 days) on clinical outcomes in patients with advanced NSCLC treated with ICIs.

      Method

      Using the Cancerlinq Discovery Database which consists of data aggregated from the electronic medical records of oncology practices, 11,143 patients with advanced NSCLC treated with ICIs were identified. Of these, 1581 patients were prescribed or administered ≥ 10 mg of prednisone or equivalent corticosteroid dose within the first 30 days of initiating ICIs. To account for prognostic heterogeneity within the population, we created matched cohorts of patients that exhibited similar prognostic clinical characteristics such as age (using 65 years as a cutoff) and gender. Association between time on treatment with ICIs and early steroid use was evaluated using the Student’s t-test. Overall survival (OS) was estimated using the Kaplan-Meier method and analyzed using the Cox proportional-hazards model.

      Result

      The cohort consisted of a predominantly white population (53.4%), with a median age of 76 years and a slight male predominance (54.9%). The median time on ICI treatment was 3.8 months. Patients who received steroids within the first 30 days had a shorter time on treatment- median of 3.36 months vs 3.86 months for those without steroid use (p= 0.023). Early steroid use was also associated with significantly worse overall survival [HR 1.16, 95% CI (1.05, 1.28) p<0.002].

      Figure: Kaplan-Meier survival analyses of patients with NSCLC treated with ICIs according to early steroid use

      p1.png

      Conclusion

      The use of ≥ 10 mg of prednisone equivalent corticosteroid dose within 30 days of initiating ICIs was associated with shorter time on treatment and worse overall survival in this large real world cohort of NSCLC patients. It is prudent that clinicians judiciously prescribe corticosteroids upon initiation of ICIs.

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      MA03.02 - Genetic Variants in ERAP1 and NCF2 in the MHC Class I Related Genes Are Associated with Non-Small Cell Lung Cancer Survival (Now Available) (ID 1491)

      10:30 - 12:00  |  Presenting Author(s): Sen Yang  |  Author(s): Qingyi Wei, David C Christiani, Qiming Wang

      • Abstract
      • Presentation
      • Slides

      Background

      Adaptive immunity, particularly the presence of tumor-infiltrating CD8+ T cells, is crucial in the control of tumor cells and preventing overall cancer progression. However, the process of CD8+ T cells recognizing and killing tumor cells depends on the expression of MHC class I (MHCI) complex presented on tumor cell surface.

      Method

      In the present study, we performed a two-phase analysis of two independently published genome-wide association studies (GWASs) to evaluate associations between genetic variants in the MHCI-related gene-set and overall survival (OS) of patients with non-small cell lung cancer (NSCLC). In the discovery GWAS dataset, we performed multivariate Cox proportional hazards regression with Bayesian false-discovery probability for multiple test corrections and evaluated associations between 9,718 single-nucleotide polymorphisms (SNPs) in 102 genes and survival of 1,185 NSCLC patients. After validation in another GWAS dataset, we performed linkage disequilibrium, function prediction and a multivariate stepwise Cox proportional hazards regression analysis.

      Result

      We found that two independent, potentially functional SNPs in two genes (ERAP1 rs469783 T>C and NCF2 rs10911362 C>T) were significantly associated with NSCLC survival, and their meta‐analysis showed an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) =0.77–0.89] and P meta =  8.2×10-7; 1.31 (1.06-1.73) and P meta = 0.0009; respectively. A genetic score of unfavorable genotypes of these two SNPs revealed a decreased OS in a dose–response manner (P trend < 0.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between the genotypes and mRNA expression levels. Furthermore, the expression levels of these genes in tumor and normal tissues were different and had an effect on patient survival as well.pdf转图片- 老版.jpgpdf转图片- 老版11.jpg

      Conclusion

      Taken together, the genetic variant of the ERAP1 rs469783 and NCF2 rs10911362 from the MHCI pathway genes may be a promising predictor of survival in NSCLC patients via ERAP1 and NCF2 expression alteration.

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      MA03.03 - CEA and CYFRA 21-1 as Prognostic Biomarkers of Benefit from Nivolumab and as a Tool in Treatment Monitoring in Advanced NSCLC (Now Available) (ID 1370)

      10:30 - 12:00  |  Presenting Author(s): Filippo Gustavo Dall'Olio  |  Author(s): Francesca Abbati, Francesco Facchinetti, Francesco Gelsomino, Barbara Melotti, Maria Massucci, Sebastiano Buti, Michele Veneziani, marcello Tiseo, Andrea Ardizzoni

      • Abstract
      • Presentation
      • Slides

      Background

      To assess the role of pre-therapy levels of Carcinoembryonic antigen (CEA) and Cytokeratin-19 Fragments (CYFRA 21-1) as prognostic marker in advanced NSCLC patients treated with nivolumab, and their change as an early predictor of treatment outcome.

      Method

      This is a retrospective cohort study including all patients with stage IIIB – IV NSCLC who received nivolumab after first-line chemotherapy in 2 Italian institutions. Median Overall Survival (OS), Overall Response Rate (ORR), Disease Control Rate (DCR) and Time to Treatment Failure (TTF) were chosen as endpoints.

      Result

      100 patients were included. Cyfra 21-1 > ULN resulted correlated with OS (FIG.1A) both in univariate (HR 2.77, 95% CI 1.53 – 5.30, p 0.001) and multivariate analysis (HR 2.72, 95% CI 1.44 – 5.16, p 0.002). The only other factor correlated with OS in multivariate was ECOG PS (0-1 vs 2) (HR 5.46, 95% CI 3.07 – 9.91, p< 0.001) (Table 1).

      ECOG PS (0-1 vs 2) and CYFRA 21-1 (≤ 3.5 vs > 3.5) where combined to create a prognostic score (FIG.1B). Median OS was 23.9 months for patients without risk factors, 6.3 months with one (HR 2.75, 95% CI 1.40 – 5.40 p 0.003) and 1.3 months with 2 risk factors (HR 14.50, 95% CI 6.35 – 33.09, p< 0.001).

      Early 20% reduction after 3rd cycle was correlated with OS for CEA, HR 0.05 (95% CI 0.01–0.41), p 0,003 and borderline for CYFRA 21-1, HR 0.29 (95% CI 0.09 – 1.01), p 0.052. (FIG.1C-1D)imm per abstr.jpg.

      Univariate

      Multivariate

      Covariate

      HR (95% CI)

      P value

      HR (95%CI)

      P value

      ECOG PS 2 vs 0-1

      5.40 (3.21 – 9.09)

      < 0.001

      5.46 (3.07 – 9.91)

      < 0.001

      Cyfra > vs ≤ ULN

      2.77 (1.53 – 5.03)

      0.001

      2.72 (1.44 – 5.16)

      0.002

      Liver metastasis yes vs no

      2.19 (1.26 – 3.78)

      0.005

      0.102

      Neutrophil/lymphocyte ratio ≥ 4 vs < 4

      1.99 (1.23 – 3.20)

      0.005

      0.105

      KRAS mutated vs wild type*

      0.39 (0.21 – 0.74 )

      0.004

      0.262

      Bone metastasis yes vs no

      1.75 (1.10 – 2.79)

      0.018

      0.362

      Response to previous therapy yes vs no

      0.51 (0.29 – 0.91)

      0.023

      0.376

      CEA > vs ≤ ULN

      1.41 (0.88 – 2-25)

      0.150

      0.418

      Stage IV vs IIIB

      1.63 (0.75 – 3.54)

      0.22

      0.449

      Squamous vs non squamous

      0.79 (0.48 – 1.28)

      0.334

      0.689

      Smoker vs never smoker

      0.88 (0.65 – 1.18)

      0.386

      0.694

      Second-line vs third or more

      0.94 (0.60 – 1.47)

      0.77

      0.843

      Brain metastasis yes vs no

      1.16 (0.66 – 2.04)

      0.603

      0.594

      Conclusion

      Our data suggests that Cyfra 21-1 pre-therapy assessment, both alone and in combination with other factors in a prognostic/predictive score, may provide clinicians with further information on the prognosis of patients treated with nivolumab.

      CEA and CYFRA 21-1 repeated measures could be useful as an early surrogate marker of clinical benefit.

      Further analysis are warranted to confirm these findings.

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      MA03.04 - Discussant - MA03.01, MA03.02, MA03.03 (Now Available) (ID 3723)

      10:30 - 12:00  |  Presenting Author(s): Nathan Pennell

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA03.05 - BRAF Mutations Are Associated with Increased Benefit from PD1/PDL1 Blockade Compared with Other Oncogenic Drivers in Non-Small Cell Lung Cancer (Now Available) (ID 1472)

      10:30 - 12:00  |  Presenting Author(s): Marcelo Vailati Negrao  |  Author(s): Ferdinandos Skoulidis, Meagan Montesion, Katja Schulze, Ilze Bara, Vincent Shen, Sylvia Hu, Yasir Elamin, Xiuning Le, Michael E Goldberg, Chang-Jiun Wu, Jianhua Zhang, David S Barreto, Waree Rinsurongkawong, George R Simon, Jack Roth, Stephen Swisher, Jack Lee, Anne Tsao, Vassiliki A Papadimitrakopoulou, Don Lynn Gibbons, Bonnie Glisson, Vincent A Miller, Brian Alexander, Garrett M Frampton, Lee A Albacker, David S Shames, Jianjun Zhang, John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      PD-1/PD-L1 immune checkpoint blockade (ICB) has revolutionized the treatment of non-small cell lung cancer (NSCLC), but only a minority of patients achieve durable clinical benefit. Although classic EGFR/ALK alterations are correlated with ICB resistance, it is unknown if patients with other molecular subtypes of NSCLC also derive poorer outcomes from ICB. We investigated if there are oncogene-driven NSCLC associated with higher response rates (RR) and progression-free survival (PFS) to ICB.

      Method

      Two independent retrospective cohorts of oncogene-driven NSCLC treated with ICB monotherapy were analyzed for clinical outcome: MD Anderson (MDACC) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-CGDB). PD-L1 expression (Dako 22C3 - FoundationCore) and tumor mutational burden (TMB - FoundationCore; TCGA and MSK-IMPACT – cbioportal.org) were compared across distinct molecular subtypes of NSCLC to determine differences in clinical outcome.

      Result

      Among five oncogene defined groups from the MDACC cohort, BRAF-mutant NSCLC had the highest response rate (RR) (RECIST 1.1) (P<0.01) and PFS (P<0.01) when treated with ICB (Table). These differences remained significant after adjusting for PD-L1 expression. Classic EGFR and HER-2 mutant NSCLC had the lowest RR and PFS (Table). Similar results were observed in the independent FH-CGDB cohort where BRAF-mutant NSCLC had longer real-world (rw) PFS and OS to ICB monotherapy (Table). PD-L1 expression (tumor score ≥1% and ≥50%) and TMB were higher in BRAF-mutant NSCLC compared to EGFR and HER-2 (P<0.01). BRAF V600E NSCLC had lower TMB compared to non-V600E (5.9 vs 13.7 mut/Mb, P<0.01), but both had high PD-L1 expression (≥1%: 72% vs 61%; ≥50%: 42% vs 32%).

      KRAS

      BRAF

      Classic EGFR

      EGFR exon 20

      HER2

      MDACC cohort

      Patients – N

      87

      10 (V600E 3 / non-V600E 7)

      28

      25

      15

      RR – %

      24.3

      62.5

      4.5b

      10b

      8.3

      Median PFS – mo (95% CI)

      2.76

      (2.23-3.30)

      7.37 (not estimable)a

      1.78 (1.18-2.37)

      2.73 (1.71-3.75)

      1.88 (1.63-2.12)

      FH-CGDB

      Patients – N

      503

      68 (V600E 32 / non-V600E 36)

      52

      42

      25

      Median rwPFS -

      mo (95% CI)

      3.55

      (3.15-4.24)

      6.0

      (2.89-11.6)

      2.17b

      (1.77-2.63)

      2.66b

      (2.23-5.13)

      1.87b (1.31-4.34)

      Median rwOS – mo (95% CI)

      10.28

      (8.51-12.02)

      16.07

      (8.64-NA)

      5.29b

      (3.25-17.68)

      9.89b

      (3.68-20.86)

      10.81

      (4.17-NA)

      FoundationCore cohort – N

      NA

      188 (V600E 74 / non-V600E 114)

      386

      96

      57

      TMB – mean (mut/Mb)

      NA

      10.6a

      3.7

      3.8

      5.8

      PD-L1 TPS ≥ 50% (%)

      NA

      36a

      19

      23

      16

      a: P<0.01 vs all groups; b: P<0.05 for pairwise comparison vs BRAF.

      Conclusion

      NSCLCs with BRAF mutations are associated with increased benefit from ICB when compared to tumors harboring other targetable oncogenic drivers. Oncogene driver mutations are associated with distinct patterns of TMB and PD-L1 expression. These findings highlight the importance of developing mutation-specific clinical trials in NSCLC.

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      MA03.06 - Efficacy Results of Selective AXL Inhibitor Bemcentinib with Pembrolizumab Following Chemotherapy in Patients with NSCLC (Now Available) (ID 2271)

      10:30 - 12:00  |  Presenting Author(s): Enriqueta Felip  |  Author(s): Paal Brunsvig, Åslaug Helland, Nuria Viñolas, Santiago Ponce Aix, Enric Carcereny, Manuel Dómine, Jose Manuel Trigo Perez, Edurne Arriola, Rosario Garcia Campelo, James Spicer, Jonathan Robert Thompson, Ana Laura Ortega Granados, Robert J. Holt, Dominic Smethurst, James B. Lorens, Muhammad Shoaib, Abdul Siddiqui, Julia Schoelermann, Katherine Lorens, Emmett V. Schmidt, Michael Jon Chisamore, Matthew Krebs

      • Abstract
      • Presentation
      • Slides

      Background

      The RTK AXL is implicated in epithelial-to-mesenchymal transition, negative regulation of anti-tumour immunity and resistance to multiple therapies including immune checkpoint inhibitors.

      Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy.

      Method

      This phase II trial (Cohort A, NCT03184571) enrolled 48 advanced lung adenocarcinoma patients with progression on or after no more than one prior line of platinum-based chemotherapy. Patients with EGFR/ALK mutations were included in this study and must have progressed on or after at least one standard targeted therapy. The primary endpoint was ORR according to RECIST v1.1. Additional endpoints included efficacy according to biomarker expression, DCR, PFS, OS, and safety. Tumour biopsies were analysed for PD-L1 expression (22C3 pharmDx), AXL by IHC, and infiltrating immune cells.

      Result

      As of April 2019, the trial was fully recruited: median age 65 (range 39-82) yrs, 61% male, 76% smokers or ex-smokers.

      At time of writing, a total of 210 treatment cycles had been completed by all patients. 17 patients were ongoing.

      17 of 32 biomarker-evaluable patients (53%) were PD-L1 negative, 13 (41%) had TPS 1-49%, and 2 (6%) had TPS >50%. Of 28 biomarker-evaluable patients, 14 (50%) expressed AXL on their tumours.

      Among patients who had at least 1 evaluable on-treatment scan: 5 responses were observed in 13 AXL positive patients (38%), and 7 in 30 patients with TPS 0-49% (23%). There were 10 responses observed among 34 evaluable patients overall (29%).

      In Stage 1, two of the 4 AXL positive responses are ongoing; mDoR is not mature in the AXL positive patients. mPFS was 5.9 mo in AXL positive patients (n=10, 3.0-NR) and 4.0 mo (95% CI 1.9-NR) overall (n=24). mOS was not mature.

      The most common TRAEs (occurring in >10% of patient in both stages) were transaminase increases (34%), asthenia/fatigue (30%), diarrhoea (26%), nausea (13%), anaemia (11%), decreased appetite (11%), and pruritus (11%). All cases of transaminase increase were reversible and resolved with concomitant administration of systemic corticosteroids and interruption of study treatments.

      Conclusion

      Patients had predominantly low or no PD-L1 expression; approximately half were AXL positive. The combination of bemcentinib and pembrolizumab was well tolerated and showed promising efficacy in previously treated IO-naïve NSCLC patients, particularly in those with AXL positive disease, including PD-L1 negative patients. Mature ORR for both stages, as well as 12-month OS for stage 1 will be presented at the meeting.

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      MA03.07 - First-Line Atezolizumab Chemoimmunotherapy in Advanced Non-Squamous NSCLC Patients Harboring EGFR/ALK Genetic Alterations (Now Available) (ID 1163)

      10:30 - 12:00  |  Presenting Author(s): Kyaw Zin Thein  |  Author(s): Nusrat Jahan, Aung Myint Tun, Anita Sultan, Sriman Swarup, Francis Mogollon-Duffo, Rachana Yendala, Miguel Quirch, Thura Win Htut, Nicholas D’cunha, Shabnam Rehman, Fred Hardwicke, Sanjay Awasthi, Lukman Tijani

      • Abstract
      • Presentation
      • Slides

      Background

      Management of advanced non-squamous non-small cell lung cancer (NSCLC) is an area in dire need of therapeutic innovation. In recent years, multiple randomized clinical trials (RCT) have combined atezolizumab, programmed death ligand 1 (PDL-1) antibody, with chemotherapy as first-line treatment of advanced non-squamous NSCLC. In patients with EGFR/ ALK genetic alterations, PDL-1 or programmed death receptor 1 (PD-1) inhibitors monotherapy previously failed to demonstrate survival benefits compared to standard chemotherapy. The purpose of our study is to explore the efficacy of atezolizumab in combination with chemotherapy for first-line treatment of advanced non-squamous NSCLC harboring EGFR or ALK genetic alterations.

      Method

      We conducted a comprehensive literature search using PUBMED, MEDLINE, EMBASE databases and meeting abstracts from inception through March 2019. RCTs utilizing first-line atezolizumab combination regimen in patients with advanced non-squamous NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied.

      Result

      3 RCTs (IMpower – 130, 132 and 150) including 2101 patients with advanced non-squamous NSCLC were eligible. The study arm used standard chemotherapy regimens in combination with atezolizumab while control arm used only standard chemotherapy regimens. The randomization ratio was 2:1 in IMpower130 study and 2:1 in other studies. The I2statistic for heterogeneity was 0, suggesting homogeneity among RCTs. 1949 patients were EGFR/ ALK wild type and 152 patients from Impower 130 and 150 were positive for EGFR/ ALK genetic alterations. The pooled HR for PFS was statistically significant at 0.62 (95% CI: 0.56- 0.69; P < 0.0001) in patients with EGFR or ALK genetic alterations, favoring first-line atezolizumab chemoimmunotherapy regimen. In the EGFR/ ALK wild type population, the pooled HR for PFS was 0.63 (95% CI: 0.43 to 0.94; P = 0.02).

      Conclusion

      Our meta-analysis demonstrated that atezolizumab in combination with chemotherapy significantly improved progression-free survival compared to standard chemotherapy in patients with advanced non-squamous NSCLC, regardless of the presence or absence of EGFR/ ALK genetic alterations.

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      MA03.08 - Discussant - MA03.05. MA03.06, MA03.07 (Now Available) (ID 3724)

      10:30 - 12:00  |  Presenting Author(s): Myung-Ju Ahn

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA03.09 - Dramatic Responses to Immune Checkpoint Inhibitors in MET Exon 14 Skipping Mutation (METex14mut) Non Small Cell Lung Cancers (Now Available) (ID 1621)

      10:30 - 12:00  |  Presenting Author(s): Marie Mayenga  |  Author(s): Isabelle Monnet, Marie-Ange Massiani, Jean-Baptiste Assié, Laure Tabeze, Sylvie Friard, Severine Fraboulet, Anne-Cécile Metivier, Christos Chouaid, Leila Zemoura, Elisabeth Longchampt, Samia Melaabi, Louis-Jean Couderc, Helene Doubre

      • Abstract
      • Presentation
      • Slides

      Background

      METex14 mutations occur in 2-3% of Non-Small-Cell Lung Cancers (NSCLC), with a higher prevalence in patients aged over 70-years-old, non-smokers.and women. Crizotinib, a MET-inhibitor, allows remarkable, but often short, tumor responses. Immune Checkpoint Inhibitors (ICIs) have become pivotal treatments in NSCLC but seem less efficient in non-smokers and in case of oncogenic addiction. We report durable strong responses in four non-smoker women (A, B, C, D) and two smokers (E, F) treated by ICIs in a second-line setting for NSCLC harboring METex14 mut.

      Method

      We studied the clinical and biological characteristics and the tumor response after ICIs for each patient. The complete DNA sequencing of the tumor was available after the beginning of ICIs (explaining why crizotinib was not proposed in second line). PDL1 expression on tumor cells was evaluated by antibody clone E1L3N (Cell signaling Technology).

      Result

      Table 1 summarizes patient and tumor characteristics, and the evolution during ICIs : Nivolumab for all patients except E (pembrolizumab). There were neither EGFR, BRAF, KRAS mutations, nor ALK or ROS translocations (except minority KRAS mutation for C). No concurrent MET amplification was found.

      tableau.jpeg

      Partial or complete response was rapidly (2 months) obtained in five patients, while pseudo-progression was first observed in D. After a grade 3 diarrhea and diabetic ketoacidosis, ICI was stopped in A but the reintroduction one year later did not cause any toxicity. The tolerance was excellent for the 5 other patients. Response was maintained from 16 to 40 months and treatment is ongoing in four patients. C stopped ICI after 26 months (Complete response on PETscan). B had an isolated bone progression after 7 months of ICI which benefited from a local radiotherapy. After almost 2 years of ICI, a multisite progression occurred and crizotinib was proposed.

      Conclusion

      ICIs should be discussed in the treatment of METex14 mut NSCLC.

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      MA03.10 - Prospective Evaluation of a Prognostic Clinico-Molecular Score (DEMo) to Predict Outcome of Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 1378)

      10:30 - 12:00  |  Presenting Author(s): Arsela Prelaj  |  Author(s): Claudia Proto, Giuseppe Lo Russo, Diego Signorelli, Roberto Ferrara, Mavis Mensah, Giulia Galli, Alessandro De Toma, Giovanni Randon, Filippo Pagani, MARTA Brambilla, Benedetta Trevisan, Monica Ganzinelli, Nicoletta Zilembo, Filippo Guglielmo Maria De Braud, VALTER Torri, Marina Chiara Garassino, Gabriella Sozzi, Mattia Boeri

      • Abstract
      • Presentation
      • Slides

      Background

      We have already reported three different molecular (MSC: plasma miRNA-signature classifier, Boeri, Clin Cancer Res 2019) and clinico-biochemical scores (DiMaio: Di Maio, EJC 2010; EPSILoN: Ann.Onco 2018 supp) able to differently predict prognosis in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy (IO). Exploiting the ability of each test we developed a combined clinico-biological composite score called DEMo (DiMaio EPSILoN MSC). Objective of the study is to prospectively evaluate the prognostic value of DEMo in aNSCLC patients treated with IO.

      Method

      We enrolled 127 consecutive aNSCLC patients treated with IO in first (n=37) and further-lines (n=90) at Istituto Nazionale dei Tumori, Milan. All patients had complete clinico-laboratoristic data necessary for both scores: DiMaio (ECOG-PS, sex, histology, stage, uses of platinum-based therapy at first-line and response to first-line) and EPSILoN (ECOG-PS, Smoke, Liver, LDH, NLRatio). MSC was prospectively evaluated in plasma samples collected prior starting IO and the risk level were assessed. Progression-free survival (PFS) and overall survival (OS) in strata of MSC/DiMaio/EPSILoN alone or DEMo and overall response rate (ORR), were considered as endpoints. Kaplan Meier were used to generate survival curves and Cox hazard model were employed to perform multivariate analyses.

      Result

      In multivariate analyses, adjusted for age, sex, pack/year and ECOG-PS, patients with high MSC and high DiMaio and EPSILoN scores reported a lower PFS (MSC: HR 1.72 CI95% 1.06 – 2.77, p=0.027; DiMaio: HR 2.63 CI95% 1.40 – 5.00, p=0.002; EPSILoN: HR 2.17 CI95% 1.16 – 4.16, p=0.014) and OS (MSC: HR 2.17 CI95% 1.29 – 3.70, p=0.003; DiMaio: HR 3.57 CI95% 1.66 – 7.69, p=0.001; EPSILoN: HR 2.50 CI95% 1.15 – 5.26, p=0.020). DEMo stratified patients into four risk groups according to the presence of 3–2–1–0 bad markers (High MSC/DiMaio/EPSILoN or none). Groups had 0%–0%–32.2%–53.3% 1-year PFS (p<0.0001) and 4.4%– 19.4% – 66.9% – 75.4% 1-year OS (p<0.0001). We further compared 0/1 to 2/3 combined groups. At the multivariate Cox model group 2/3 had a mPFS 1.9 vs 9.4 mo compared to group 0/1 (HR 3.70 CI95% 2.08 – 6.67, p<0.0001) and mOS 4.1 vs 22.4 mo (HR 4.76 CI95% 2.56 – 9.10, p<0.0001). Regarding ORR, DEMo group 0/1 had a 3.86 (CI95% 1.76-8.47) fold higher probability to respond compare to 2/3 group (p=0.0007).

      Conclusion

      DEMo composite biomarker is able to predict better prognosis compared to each single score and can be a useful tool for guiding IO treatment choices. In particular, DEMo allowed a good selection for those patients who are less likely to benefit from IO.

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      MA03.11 - Chemotherapy After PD-1 Inhibitors Versus Chemotherapy Alone in Patients with Non–Small Cell Lung Cancer (WJOG10217L) (Now Available) (ID 409)

      10:30 - 12:00  |  Presenting Author(s): Hirotsugu Kenmotsu  |  Author(s): Eriko Miyawaki, Ryoji Kato, Hidetoshi Hayashi, Yasutaka Chiba, Junichi Shimizu, Tomohiro Ozaki, Daichi Fujimoto, Ryo Toyozawa, Yuki Akazawa, Motoyasu Okuno, Sayako Morikawa, Tatsuo Ohira, Taishi Harada, Ryota Ushio, Akihito Kubo, Toshiyuki Harada, Nozomu Kimura, Hiroyuki Yamaguchi, Kazuo Nishikawa, Nobuyuki Yamamoto, Kazuhiko Nakagawa

      • Abstract
      • Presentation
      • Slides

      Background

      Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response in patients with non–small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of subsequent chemotherapy after PD-1 inhibitors (CAP) compared with chemotherapy alone.

      Method

      We conducted a multicenter retrospective cohort study for patients with advanced or recurrent NSCLC who were treated at 47 institutions across Japan between 1 April 2014 and 31 July 2017 with chemotherapy (docetaxel with or without ramucirumab; S-1; or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort). The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors, including age, sex, smoking status, performance status, histology, EGFR or ALK genetic alterations, brain metastasis, and recurrence after curative radiotherapy.

      Result

      A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics—including age, histology, EGFR or ALK alterations, and brain metastasis—differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 10.8% for the control cohort (ORR ratio, 1.75; 95% confidence interval [CI], 1.25–2.45; P = .001). Median PFS was 3.5 and 2.6 months for the CAP and control cohorts, respectively (hazard ratio [HR], 0.862; 95% CI, 0.743–0.998; P = .048). The PFS rate at 3, 6, and 12 months was 53.3%, 28.5%, and 4.6%, respectively, for the CAP cohort, and 44.3%, 19.7%, and 6.1% for the control cohort. Median OS was 9.8 months for the CAP cohort and 10.3 months for the control cohort (HR, 0.979; 95% CI, 0.813–1.179; P = .822).

      Conclusion

      After adjustment for selection bias using propensity score–weighted analysis, CAP showed a significantly higher ORR and longer PFS compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into an OS advantage, and no PFS benefit was apparent at 12 months despite the improvement observed at 3 and 6 months. Our findings suggest that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.

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      MA03.12 - Discussant - MA03.09, MA03.10, MA03.11 (Now Available) (ID 3725)

      10:30 - 12:00  |  Presenting Author(s): HOWARD WEST

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ES23 - Optimal Management of N2 Disease in the Era Of IO (ID 26)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      ES23.03 - Is CT/RT Followed by I/O the Standard of Care for All N2 and Selected N3 Patients? (Now Available) (ID 3283)

      11:30 - 13:00  |  Presenting Author(s): Wilfried Ernst Erich Eberhardt

      • Abstract
      • Presentation
      • Slides

      Abstract

      Background: Immunotherapy consolidation with PD-L1-Ab has changed the current standard treatment for unresectable patients with stage III NSCLC (in Europe with PD-L1-exp by IHC > or = 1%) who are not progressing following definitive chemoradiotherapy1,2,3. More and more issue comes up for which patients this new strategy should be adopted, and for whom these data do not represent the new standard. Here we will try to analyze current evidence of stage selection for this multimodality approach.

      Methods: We analyzed the existing evidence on outcome results of stage III NSCLC subsets based on the new 8th-version of the IASLC/UICC staging classification and expert consensus4,5 and current outcome data on stage III subsets within large landmark randomized trials,6,7,8,9,10 and possible permutations of chosen multimodality treatment approaches.

      Results: The PACIFIC Trial included only unresectable patients with stage IIIA and stage IIIB (based on the old UICC7 staging classification)1,2,3. No detailed data on T- and N-subgroups as well as transferring the data to the new UICC8 stage subsets IIIA/IIIB/IIIC were given in the manuscript1. Definition of "unresectable stage IIIA and IIIB" was probably best carried out as "individual local descision within tumor boards including thoracic surgeons to define disease resectability status". Nevertheless, no clear definition on selection for unresectable disease is given in the trial description of the PACIFIC publication. The overall two- and three-year-survival results were excellent and showed a significant and clinically meaningful benefit for patients receiving PD-1-antibody consolidation for one year2,3. Based on current evidence and consensus4,5 about 15 to 20% of stage III patients are still ocnsidered to be potentially resectable. The majority of these belong to the IIIA(N2) diasease subset. Only one recently published clinical phase-III trial included subgroups with T4N0 (stage IIIB UICC7/stage IIIA/UICC8)8. Outside of multimodality groups with specific expertise, stage IIIB(UICC8) and stage IIIC(UICC8) are considered unresectable and would definitely be put on definitive chemoradiotherapy protocols. Only three large randomized trials6,7,8 included resectable patients subsets of stage IIIA(N2)-disease (INTERGROUP 0137, SAKK, ESPATUE). The treatment strategies within these trials were induction chemotherapy followed by surgery versus induction chemotherapy followed by radiation and followed by surgery6, induction chemoradiotherapy followed by surgery versus definitive chemoradiotherapy7or induction chemotherapy followed by concurrent chemoradiotherapy and surgery versus induction chemotherapy followed by concurrent chemoradiotherapy and definitive chemoradiation boost8. All three trials including surgery in at least one of the randomization arms gave a detailed description of T- and N-subgroups in their overall patient characteristics. All three clinical trials had PET-CT and detailed mediastinal staging techniques included into the initial patient selection descision (either mediastinoscopy or recently EBUS). All three trials had excellent overall survival outcomes in each of their randomization arms. Five-year survival results were somewhere betweeen 20% and 44% observed in the three randomized trials. In all three trials no significant difference was noted for OS between the different randomization arms while the OS results in all treatment groups of the studies can be considered excellent. However, in all three trials a low accrual rate was generally noted, and the overall duration of the clinical trials was around six to eight years in all three, pointing to a considerable selection procedure of patient inclusion. The two large randomized clinical phase-III trials investigating modern chemoradiation techniques9,10 included per definition only "unresectable stage IIIA and IIIB patients subsets" (following the old UICC7/UICC6 classification). However, in both trials (PROCLAIM and RTOG 0617) no detailed TN-subgroups were given, but they included rather IIIA and IIIB definitions based on PET-CT staging as well as biopsy confirmation of N2- or N3-tumor-positive lymph nodes at staging work-up. FIve-year overall survival data turned out somewhere around 30% of the initially included patient groups within the two trials. The only group that showed a significantly worse outcome was that with the higher total radiation dose of 74 Gy in the RTOG study (no comment on this issue here). Nevertheless, all survival outcomes showed overall excellent five-year survival data in these two chemoradiation trials, too. Median OS data were between 25 and 29 months observed. There are considerable difficulties to compare all six randomized trials (PACIFIC, RTOG 0617, PROCLAIM, SAKK-TRIAL, INTERGROUP 0139, ESPATUE) based on the difficulties to compare patient selection and included TN-subgroups. Thus the above mentioned relevant differences in patient selection and accrual between the pure chemoradiation trials and the randomized trials including surgical arms cannot be overcome by comparing TN-data from these studies. All three definitive chemoradiation trials did only give IIIA and IIIB subset numbers of their patient population. However, patient accrual was much faster in all three definitive chemoradiation studies, pointing to a less selective patient inclusion into these trials. Some of the differences in the observed OS and PFS results noted could in fact be based on these different patient selection procedures rather than on differences between the individual treatment strategies.

      Conclusion: Based on a differential analysis of the recent five largest randomized phase-III trials with multimodality treatment of stage III NSCLC, we cannot readily compare the patient selection for "pure" concurrent chemoradiotherapy trials on one hand, to that within multimodality trials including surgery in at least one trial arm on the other side. This strongly points to the fact, that we cannot currently widen up any indication for an inclusion of immunotherapy for subsets of patients with potentiallly resectable stage III NSCLC. Patient with resectable stage III (mostly IIIA) should either be treated within multimodality protocols including surgery (based on the local expertise) or should be offered to participate within clinical trials that try to implement immunotherapy with PD-1 or PD-L1 antibodies into this multimodality setting including surgery. Several clinical studies wirth induction chemoimmunotherapy followed by surgery or induction chemoimmunotherapy/chemoradiationimmunotherapy followed by surgery are currenlty being performed by different multimodality treatment groups. The practice-changing results of the PACIFIC trial for unresectable stage III disease leave us very enthusiastic, that this new approach could also improve the results for potentially resectable stage III patients groups in NSCLC.

      1Antonia, NEJM 2017 2 Antonia, NEJM 2018 3 Gray, ASCO 2019 4Goldstraw, J Thorac Oncol 2016 5Eberhardt, Ann Oncol 2015 6Pless, Lancet 2015 7Albain, Lancet 2009 8Eberhardt, J Clin Oncol 2015 9Senan, J Clin Oncol 2016 10 Bradley, Lancet Oncol 2015

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): Wilfried Ernst Erich Eberhardt

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-27 - Processing Escapes: Novel Resistance Mechanisms Under Immune Checkpoint Inhibition in NSCLC (Now Available) (ID 1153)

      09:45 - 18:00  |  Author(s): Wilfried Ernst Erich Eberhardt

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibition, especially the blocking of PD-1 and PD-L1, has become one of the most thriving therapeutic approaches in modern oncology. Unfortunately, 60-80% of all patients will develop long-term resistances under immunotherapy. We believe immune evasion caused by altered tumour epitope processing may be one possibility to explain therapy resistance. In a previous work, we were able to establish these so-called processing escapes as an intrinsic immune escape mechanism in patients suffering from neuroendocrine lung cancers. In the present study, we aim to demonstrate the effects of processing escapes on immunotherapy outcome in NSCLC-patients.

      Method

      Whole exome sequencing data of 400 NSCLC-patients (AdC and SCC) were extracted from the TCGA database serving as a training cohort. The validation cohort was composed of primary tumour probes from 48 NSCLC-patients, who received Nivolumab treatment. Mutational characteristics of these patients were determined by targeted amplicon-based sequencing including hotspots and whole exomes of 22 genes. The effect of mutations on proteasomal processing was evaluated by deep learning methods previously trained on 1260 known MHC-I ligands. Cox-regression modelling was used to determine the influence on overall survival.

      Result

      In the training cohort, processing escapes were connected to decreased overall survival (p= 0.025) as well as lowered expression of immune factors including Granzyme K (p= 0.15), CD20 (p=0.05) and CD40L (p= 0.025). In the validation cohort, the group of patients showing high abundances of processing escapes in combination with high levels of PD-L1 (n=9/48) had a significantly decreased overall survival (figure 1). The predictive significance of processing escapes proved to be independent of mutational load or PD-L1 status in multivariate analysis.

      figure1.jpg

      Conclusion

      Based on our retrospective data, the impact of processing escapes and PD-L1 status as a composite predictive score for checkpoint inhibitor response in NSCLC should be further investigated in prospective studies.

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    P1.06 - Mesothelioma (ID 169)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.06-12 - Defects in Homologous Recombination Repair Indicates Susceptibility for Olaparib Treatment in Malignant Pleural Mesothelioma (Now Available) (ID 350)

      09:45 - 18:00  |  Author(s): Wilfried Ernst Erich Eberhardt

      • Abstract
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is a tumour with dismal prognosis. Chemotherapeutic treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy remain largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed expression levels of genes compiled under the term “BRCAness”. An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis.

      Method

      We evaluated the response of three MPM cell lines and lung fibroblasts, serving as a control to treatment, with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members.

      Result

      We observed a BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM.

      Conclusion

      Defects in HR compiled under the term BRCAness are a common event in MPM. The present data may improve the understanding of underlaying cellular mechanisms and open new possibilities for modern therapeutic approaches for this severe disease. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. This combination therapy might be effective for up to 2/3 of patients, promising to enhance patients’ clinical management and outcome.

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