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Young Kwang Chae



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    MA19 - Genomic Markers of IO Response (ID 922)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
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      MA19.04 - The Clinical Implication of Frameshift Indel Mutation Burden in Non-Small Cell Lung Cancer (NSCLC) (ID 12592)

      15:35 - 15:40  |  Presenting Author(s): Young Kwang Chae

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor mutational burden (TMB) has been proposed as a potential predictive marker for immune checkpoint inhibitor (ICI) response in many cancers, including NSCLC. Recently, research has revealed frameshift indel (fsindel) of all mutations to be significantly associated with ICI response in melanoma patients. However, little is currently known regarding its clinical implication in NSCLC patients treated with PD1/PD-L1 inhibitors (ICIs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Next generation sequencing of 324 genes (FoundationOneTM) was used to derive fsindel burden and TMB. A total of 128 patient data with NSCLC treated with ICIs were analyzed from Northwestern University (N=68) and the University of Miami (N=60). A total of 128 patients were divided into two groups with 0 fsindel (FS-) and more than 1 fsindel (FS+). Progression free survival (PFS) and overall survival (OS) were compared between FS+ and FS- groups. PFS and OS outcomes of TMB high group (H-TMB, upper¼) and TMB low group (L-TMB, lower¼) were also compared.

      4c3880bb027f159e801041b1021e88e8 Result

      figure 1.jpg

      Among 128 patients, 51.6% belonged to FS+ group (N=66). Between FS-/FS+ groups, there were no significant differences in mean age (66.2/66.0) and performance status (0.9/0.9). Lines of ICIs used in the FS-/FS+ groups were 1st (19/19%), 2nd (47/56%), 3rd (24/11%), and 4th line or more (10/14%). FS+ group had significantly longer PFS compared with FS- group (median 6.2/2.7 months, P=0.02, Figure 1). No significant difference in OS was seen between the two groups (median 16.8/11.2 months, P=0.70). In contrast, however, H-TMB did not show any significant difference in PFS (median 5.6/4.0 months, P=0.14) and OS (median 15.8/15.1 months, P=0.69) compared to L-TMB.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the first report to illustrate an association between fsindel and outcome in patients with NSLC treated with ICIs. Our findings suggest its potential role as a predictive marker for immunotherapy.

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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 4
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.04-01 - Impact of Chromatin Remodeling Genes Including SMARCA2 and PBRM1 on Neoantigen and Immune Landscape of NSCLC (ID 12593)

      16:45 - 18:00  |  Presenting Author(s): Young Kwang Chae

      • Abstract
      • Slides

      Background

      Epigenetic changes in tumors and their microenvironment immune cells have been the recent focus of cancer research. Aberrations in SWI/SNF complexes within the chromatin remodeling machine may play a major role in carcinogenesis. However, little is known about their impact on neoantigen and the immune landscape of NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were divided into two groups; Mut group (at least one mutation in 27 SWI/SNF complex subunit genes including SMARCA2 and PBRM1) and NoMut group (no SWI/SNF mutations). We analyzed genomic, transcriptomic data from the TCGA database including patients with adenocarcinoma (ADC, n=515) and squamous cell carcinoma (SQCC, n=501) of lung cancer. The tumor immune landscape was analyzed using the signatures derived from 812 ‘immune metagenes’ (Angelova, M. et al, 2015). We analyzed neoantigen burden and immune landscape between two groups. RNA expression of the above genes were compared. Patients were also divided by the expression levels of the above genes (1st quartile vs 4th quartile).

      4c3880bb027f159e801041b1021e88e8 Result

      figure1.jpg

      Mut group (142 samples, 14%) showed significant higher neoantigen burden compared with NoMut group in ADC and SQCC (mean 32.17/15.22 and 34.75/19.83 mutation/mbp, respectively, both P<0.01). In addition, the Mut group demonstrated higher infiltration of activated CD8 T cells compared with the NoMut group in ADC (39%/25%, P<0.01). However, there was no significant difference between two groups in SQCC (32%/27%, P=0.42).

      For two representative genes (SMARCA2 and PBRM1), lower expression of the two genes were associated with higher infiltration of activate CD8 T-cells in ADC (60%/6% and 37%/17%, respectively, both P<0.01) and SQCC (40%/21% and 43%/17%, respectively, both P<0.01). However, there was no difference in neoantigen burden with respect to gene expression in either ADC or SQCC.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Mutation or low expression of chromatin remodeling genes including SMARCA2 and PBRM1 were associated with higher neoantigen burden and higher tumor infiltration of activated CD8 T-cells in human NSCLC.

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      P1.04-12 - Mass Spectrometry-Based Serum Proteomic Signature as a Potential Biomarker for Survival in NSCLC Patients with Immunotherapy (ID 13444)

      16:45 - 18:00  |  Presenting Author(s): Young Kwang Chae

      • Abstract
      • Slides

      Background

      The Veristrat test is a serum biomarker using a mass spectrometry (MS)-based proteomic signature derived from machine learning. It is used as a prognostic marker for patients with NSCLC undergoing platinum-based chemotherapy. However, its role in patients undergoing immunotherapy has not been investigated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      47 patients with advanced stage NSCLC and no activating EGFR mutation underwent VeriStrat testing from 2016 to 2017. Patients were grouped into Veristrat ‘Good’ risk group (VS-G) or Veristrat ‘Indeterminate’ & Veristrat ‘Poor’ risk group (VS-IP). Kaplan-Meier survival analyses with log rank test were performed to compare the progression-free survival (PFS) and overall survival (OS) between the two groups. PFS of NSCLC patients treated with immunotherapy was derived from the time of the immunotherapy to disease progression or death.

      4c3880bb027f159e801041b1021e88e8 Result

      figure 1_pfs by nsclc population treated with immunotherapy.jpg

      47 patients had a mean age of 65.6 (range: 30 to 91). 26 patients were female (55%). 26 patients had diagnosis of adenocarcinoma (55%), while 18 patients had squamous cell carcinoma (38%). 32 patients (68%) underwent treatment with a PD-1 inhibitor (pembrolizumab or nivolumab), whereas 15 patients (32%) did not. 32 patients (68%) demonstrated VS-G trait while 15 patients (32%) demonstrated VS-IP trait (intermediate: 1, poor: 14). Overall, VS-G demonstrated significantly prolonged PFS compared to VS-IP for all NSCLC patients regardless of treatment (median PFS, 12.0 months vs. 6 months, p<0.05), though there was not a significant different in OS between VS-G and VS-IP. Among NSCLC patients treated with immunotherapy, VS-G classification trended towards increased PFS when compared to VS-IP (Figure 1, median PFS, 12.0 vs 4.2 months, p=0.054), while OS was not statistically different. Multivariate analysis revealed that Veristrat was an independent predictor of PFS in this patients, regardless of various clinical factors.

      8eea62084ca7e541d918e823422bd82e Conclusion

      MS-based serum proteomic signature may serve as a biomarker for survival outcome in patients with NSCLC, including patients undergoing immunotherapy.

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      P1.04-19 - Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios Predict Survival After Immunotherapy in Non-Small Cell Lung Cancer (ID 13650)

      16:45 - 18:00  |  Presenting Author(s): Young Kwang Chae

      • Abstract
      • Slides

      Background

      Effective use of immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) may be improved by identifying biomarkers that are easily measured and predictive of clinical outcomes. Peripheral complete blood counts are commonly obtained and can be indicative of systemic inflammatory response, which has been associated with poor prognosis in multiple cancer types. Here, we investigated the ability of peripheral cell counts to predict patient survival after treatment with immunotherapy for NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Complete blood counts were retrospectively collected for 274 patients and analyzed for absolute neutrophil count (ANC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). Values were obtained immediately prior to treatment initiation. Overall survival (OS) and progression-free survival (PFS) was assessed using Kaplan-Meier analyses with log-rank test and Cox regression analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      OS was significantly associated with ANC (HR 1.63, p<0.0001) and NLR>5 (HR 1.62, p<0.0001), as was PFS (HR 1.48, p=0.0008 and HR 1.48, p=0.0012, respectively). PLR>400 was not associated with OS but did have a significant association with PFS (HR 1.39, p=0.0388). Baseline elevation of both NLR and PLR identified a particularly high-risk population, with worse OS (HR 1.69, p=0.0020) and PFS (HR 1.58, p=0.0069) when compared to the patient group with low baseline NLR and PLR (Figure 1). High NLR and PLR as a combined marker remained an independent predictor of OS in multivariate analysis after adjusting for multiple clinical variables (HR 1.91, p=0.008).

      figure 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Increased baseline ANC, NLR, and PLR were associated with worse overall and progression-free survival, and the combination of both high NLR and PLR denoted a subgroup with especially poor outcomes. These findings will need to be validated in larger prospective studies to further assess their clinical utility.

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      P1.04-25 - The Implication of Frameshift Mutation Burden in Neoantigen and Immune Cell Landscape in Non-Small Cell Lung Cancer (NSCLC) (ID 11995)

      16:45 - 18:00  |  Presenting Author(s): Young Kwang Chae

      • Abstract
      • Slides

      Background

      Recent research has shown an association between enrichment of insertion and deletion (indel) mutations and tumor-specific neoantigens, which in turn correlated with T-cell activation in renal cell carcinomas. Furthermore, frameshift indel (fsindel) mutation counts were significantly associated with clinical response to immune checkpoint inhibitors (ICIs) in melanoma patients. However, little is currently known about such associations in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Neoantigen counts were based on CloudNeo, a cloud pipeline used for identifying patient-specific neoantigens. The immune cell signatures of 31 distinct immune cell types of samples were derived from RNA-sequencing of 812 immune metagenes obtained from The Cancer Genome Atlas. 511 lung adenocarcinoma (ADC) and 471 squamous cell carcinoma (SqCC) patient samples were divided into 4 quartiles (Q1-Q4) according to number of fsindel mutations in order to compare neoantigen counts and immune cell infiltration. Fsindel mutations were identified from mutation annotations generated by the Genomic Data Commons’ MuTect2 somatic variation calling workflow.

      4c3880bb027f159e801041b1021e88e8 Result

      figure 1_final.pngThe range of fsindel count of ADC and SqCC were 0-139 and 0-150, respectively, while the median fsindel count was 7 and 8, respectively. Neoantigen count showed a significant positive association with fsindel in both ADC and SqCC (p<0.0001, p<0.01 respectively). Furthermore, a higher number of fsindels was associated with significantly increased activated CD4 and CD8 T-cell infiltration in ADC (Figure 1. p<0.001, p<0.01, respectively), while a similar trend was observed in SqCC for CD4 and CD8 T-cells, although not significant (Figure 1. p=0.056, p=0.341, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      We report for the first time the association between fsindels and higher neoantigen burden and infiltration of activated CD4 and CD8 T-cells in human NSCLC. As the presence of immune cells has been shown to be an important factor in determining response to ICIs, our findings suggest that fsindels could potentially be used as a predictive marker for immunotherapy.

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-82 - Neutrophil-to-Lymphocyte Ratio Complements the Prognostic Ability of PD-L1 in Non-Small Cell Lung Cancer Treated with PD-1/PD-L1 Inhibitors (ID 14091)

      16:45 - 18:00  |  Author(s): Young Kwang Chae

      • Abstract
      • Slides

      Background

      PD-L1 expression is an imperfect predictor of outcomes for patients (pts) with advanced non-small cell lung cancer (aNSCLC) treated with PD-1/PD-L1 inhibitors (PD-1/L1i). This was demonstrated in the recent ARCTIC trial in which PD-L1 expression did not significantly correlate with outcomes. In the quest for additional markers, a high neutrophil-to-lymphocyte ratio (NLR) has been associated with poor outcomes and may reflect a higher myeloid-to-lymphoid balance. Here we show improved prognostic ability for response to PD-1/L1i when baseline NLR is added to PD-L1 expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We used a retrospective cohort of 146 aNSCLC pts from the authors’ institutions in the United States and Japan who received single-agent PD-1/L1i. We categorized patients into three groups; favorable: PD-L1 ≥ 1% and NLR < 5, intermediate: PD-L1 ≥ 1% or NLR < 5, and poor: PD-L1 < 1% and NLR ≥ 5. We correlated the outcome of each group with overall survival (OS) and progression free survival (PFS).

      4c3880bb027f159e801041b1021e88e8 Result

      Median follow-up was 11.1 months (M) (95% Confidence Interval [CI]: 9.1-13.1). 47 pts had PD-L1 <1% and 99 pts ≥1%, 81 pts had NLR <5 and 65 pts ≥5. There were 52, 76, and 18 pts in the favorable, intermediate, and poor groups, respectively. Median OS for the favorable group was not reached and it was 14.7 M (CI: 10.5-19.0) and 3.5 M (CI: 0-13.1), respectively for the intermediate and poor groups. Median PFS was 9.9 M (CI: 3.7-16), 3.2 M (CI: 2.1-4.3), and 1.1 M (CI: 0.8-1.4), respectively. The poor group (PD-L1 < 1% and NLR ≥ 5) was significantly associated with progressive disease (Odds ratio [OR]: 5.0, p=0.01) in comparison to the PD-L1 < 1% group (OR: 2.6, p=0.013).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Prognostic ability of PD-L1 expression is enhanced when combined with baseline NLR for aNSCLC pts treated with single-agent PD-1/L1i. This study raises the hypothesis that high NLR and low PD-L1 expression could serve to identify those pts less likely to benefit from these therapies.

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    P3.CR - Case Reports (Not CME Accredited Session) (ID 984)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.CR-14 - A Case of EGFR Tyrosine Kinase Inhibitor (TKI), Osimertinib Induced Pneumonitis in a Patient with Recurrent Fevers of Unknown Origin (ID 13731)

      12:00 - 13:30  |  Presenting Author(s): Young Kwang Chae

      • Abstract
      • Slides

      Background

      64-year-old female with stage IV EGFR exon 19 mutated adenocarcinoma of lung on osimertinib presented with recurrent fevers of unknown origin.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Section not aplicable.

      4c3880bb027f159e801041b1021e88e8 Result

      Ms. M presented to the hospital with fevers. Osimertinib was held on admission. Imaging showed a possible pneumonia and she started IV antibiotics. Her fevers subsided and she was discharged on IV antibiotics. She resumed osimertinib upon discharge.

      The following day, she spiked fevers to 103.9F. She was admitted to the hospital with fevers and new hypoxia requiring 4 liters of supplemental oxygen. Osimertinib was continued on admission.

      The results of her infectious workup, including bronchoscopy studies, were negative and she continued to spike high fevers despite broadened coverage for atypicals and fungi. Osimertinib was stopped on hospital day #4 due to QTc prolongation likely from its interaction with other QT prolonging antimicrobials. Given persistently high fevers despite broad antibiotics and a negative infectious workup, Osimertinib-induced pneumonitis became a likely explanation. Anti-microbials were stopped and prednisone 1mg/kg daily was started. She deferversed and had a rapid symptomatic improvement.

      screen shot 2018-05-04 at 3.45.43 am.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Osimertinib toxicity has been investigated in the literature. In the AURA3 trial, pneumonitis resulted in 1/4 reported fatal adverse events. ILD–like events were reported in 10 patients (4%, 9 events were grade 1 or 2, 1 death). The FLUARA trial showed similar findings, with ILD-like adverse events in 11 patients (4%) with 7 “recovered” and 4 “recovering”. There were no reported fatal outcomes from ILD.

      After stopping Osimertinib during her 2 hospitalizations, our patient defervesced after 4 days and 3 days, respectfully. This correlates with the 48-hour half-life of Osimertinib. Our case demonstrates that determining drug toxicity can be challenging, especially when other etiologies such as infection are more common. For Ms. M, her lack of improvement with anti-microbials coupled with a significant response to steroids makes the case for Osimertinib-induced pneumonitis.

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