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John V Heymach



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    MA06 - PDL1, TMB and DNA Repair (ID 903)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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      MA06.02 - Prospective Immunogenomic Profiling of Non-Small Cell Lung Cancer: Genomic and Immune Profiling Updates from Project ICON (ID 13523)

      13:35 - 13:40  |  Author(s): John V Heymach

      • Abstract
      • Presentation
      • Slides

      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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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.

      8eea62084ca7e541d918e823422bd82e 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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    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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      MA19.10 - Impact of STK11/LKB1 Genomic Alterations on Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (ID 14295)

      16:15 - 16:20  |  Author(s): John V Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      Chemo-immunotherapy with pemetrexed/carboplatin/pembrolizumab represents a standard of care for the first-line treatment of patients with metastatic non-squamous NSCLC, irrespective of tumor cell PD-L1 expression. Genomic determinants of response to chemo-immunotherapy in NSCLC have not been reported thus far. We previously identified STK11/LKB1 alterations as a major genomic driver of de novo resistance to PD-1/PD-L1 inhibitor monotherapy in NSCLC (Skoulidis et al., Cancer Discovery, 2018). Here, we examine the impact of STK11/LKB1 mutations on clinical outcomes with chemo-immunotherapy with pemetrexed/carboplatin/pembrolizumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with metastatic non-squamous NSCLC that received at least 1 cycle of pemetrexed/carboplatin/pembrolizumab at MD Anderson Cancer Center, were alive for ≥14 days thereafter and had available next generation sequencing- based comprehensive tumor genomic profiling were eligible. Response assessment was based on RECIST1.1. PD-L1 expression on tumor cells was evaluated using the FDA-approved 22C3 pharmDx assay. All patients consented to collection of clinical and molecular data as part of the GEMINI protocol.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 49 eligible patients (median age 61 years, 51% female, 96% adenocarcinoma histology, 34.7% KRAS-mutant) the objective response rate to pemetrexed/carboplatin/pembrolizumab was 51% (25/49) for the overall population. The disease control rate (PR+SD≥ 6 months) differed significantly between STK11/LKB1-mutant and STK11/LKB1-wild-type tumors (31.3% vs 72.7%, P=0.011, two-tailed Fisher’s exact test). The objective response rate was 31.3% for STK11/LKB1-mutant and 60.6% for STK11/LKB1 wild-type tumors (P=0.07, two-tailed Fisher’s exact test). 37.5% (6/16) of STK11/LKB1-mutant tumors exhibited progressive disease as best overall response to chemo-immunotherapy compared with 6.1% (2/33) STK11/LKB1-wild-type tumors (P=0.01, two-tailed Fisher’s exact test). Patients bearing STK11/LKB1-mutant tumors exhibited shorter progression-free survival with chemo-immunotherapy (median PFS 4.4 months vs 11.0 months, P=0.039, log-rank test). STK11/LKB1-mutant tumors were less likely to be positive for PD-L1 expression (PD-L1 TPS ≥ 1%), although the difference did not reach statistical significance (43.8% vs 72%, P=0.1, two-tailed Fisher’s exact test).

      8eea62084ca7e541d918e823422bd82e Conclusion

      STK11/LKB1 genomic alterations are associated with inferior clinical outcomes with chemo-immunotherapy in non-squamous NSCLC, with response rates comparable to those previously reported for platinum doublet chemotherapy alone. Assessment of STK11/LKB1 status may help refine treatment approaches in non-squamous NSCLC.

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    MA23 - Early Stage Lung Cancer: Present and Future (ID 926)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 105
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      MA23.02 - Circulating Tumor DNA Analysis with a Novel Variant Classifier for Recurrence Detection in Resected, Early-Stage Lung Cancer (ID 13498)

      10:35 - 10:40  |  Author(s): John V Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      ctDNA is a blood-based biomarker with promising potential in lung cancer for minimal residual disease (MRD) assessment and early detection of recurrence. However, data regarding feasibility are limited, especially for stage I-II disease.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed longitudinal plasma ctDNA profiling of early-stage lung cancer patients (pts) that underwent resection at MD Anderson Cancer Center from Apr 2016 to Jan 2017. Plasma ctDNA was analyzed from pre-operative and multiple post-operative time points until disease recurrence. ctDNA profiling was performed using a 30kb Digital Sequencing panel (Guardant Health) covering SNVs in 21 genes and indels in 9 genes that are commonly present in lung cancer. ctDNA profiles from ~30,000 lung cancer pts were used to train a classifier to exclude non-tumor related mutations.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 40 pts were included in this analysis, comprised of the first 17 pts with recurrence in the longitudinal study and 23 consecutive pts without recurrence. This cohort was primarily stage I and II (15 [38%], 16 [40%]). Histology included adenocarcinoma (29 [73%]), SCC (6 [15%]), and SCLC (2 [5%]). 58% had adjuvant therapy. Median follow-up was 17.7 (3.4 – 24.5) months and median time to recurrence was 7.1 (3.4 – 16.5) months in this selected cohort. At least one ctDNA alteration was detected in 55% (21/38) of pts with evaluable pre-op samples and in 22% (8/37) of pts at 4 weeks post-op. Presence of ctDNA at 4 weeks post-op heralded eventual recurrence with 43% sensitivity and 91% specificity (75% PPV, 73% NPV) and was significantly associated with worse recurrence free survival (p=0.022, HR 6.52; 95% CI 1.3 – 32.6), while also accounting for stage. In the absence of the variant classifier, an additional 7/37 pts had non-tumor alterations detected at 4 weeks post-op with a recurrence sensitivity and specificity of 57.1% and 69.6%. ctDNA was identified in 76% (13/17) of pts prior to or at the time of recurrence. The median interval between ctDNA detection and radiographic recurrence was 91 days.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Detection of post-op ctDNA, as early as 4 weeks after resection of early-stage lung cancer, is associated with significantly increased risk of recurrence. Accurate detection of ctDNA in this MRD setting is enabled by a highly sensitive sequencing platform that incorporates a novel variant classifier to enhance clinical specificity.

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    OA01 - Improving Outcomes in Locoregional NSCLC I (ID 892)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 107
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      OA01.06 - DETERRED:  Phase II Trial Combining Atezolizumab Concurrently with Chemoradiation Therapy in Locally Advanced Non-Small Cell Lung Cancer (ID 12842)

      11:25 - 11:35  |  Author(s): John V Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      While consolidation immunotherapy after chemoradiation (CRT) is the current standard of care for locally advanced NSCLC (LA-NSCLC), the effectiveness of immunotherapies may be enhanced when combined concurrently with CRT. We report on the safety and preliminary efficacy of combining PD-L1 blockade using atezolizumab (atezo) and concurrent CRT followed by consolidation full dose carboplatin/paclitaxel (CP) with atezo and maintenance atezo up to 1 year for LA-NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a single institution phase II study in LA-NSCLC assessing the safety and feasibility of adding atezo to CRT in two parts: I) sequentially (N=10) with CP after completing CRT, or II) concurrently (N=30) with CRT followed by consolidation atezo with CP. Atezo was given at 1200 mg IV Q3 weeks for up to one year from the first dose. Radiation dose at 60-66 Gy in 30-33 fractions was combined with weekly low dose CP, followed by 2 cycles of full dose CP. Severe adverse events (AEs) ≥ grade 3 are defined within 15 weeks of start of therapy or any immune-related AEs during atezo treatment. Evaluable patients (pts) have received at least one dose of atezo.

      4c3880bb027f159e801041b1021e88e8 Result

      From February 2016 to April 2018, we accrued 40 evaluable pts. For part 1, any grade 3+ AEs was seen in 6 pts (60%), with most common being pneumonia (2 of 10, 20%). Three grade 3+ AEs (30%) were attributed to atezo, including dyspnea, arthralgia and a grade 5 TE fistula. Grade 2 radiation pneumonitis (RP) was seen in 3 pts. Four progressed with disease during atezo maintenance and have died, ranging from 0.93 to 1.86 years. Four pts completed atezo and are in follow up without recurrence. For part 2, 17 of 30 pts had any grade 3+ AEs (57%), with pneumonia being the most common (6 of 30, 20%). Three (10%) were attributed to atezo (dyspnea, fatigue and heart failure). RP was seen in 3 pts, with 2 grade 2 and 1 grade 3, which led to atezo discontinuation. So far, 4 pts have progressed and 4 have died, 2 due to disease and 2 due to treatment (neutropenic sepsis and gastric hemorrhage). All others have completed CRT and are on maintenance atezo, ranging from 5 to 19 doses. Updated efficacy results will be presented.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Concurrent atezo with CRT followed by consolidation and maintenance atezo appears safe without increased toxicities compared to CRT alone followed by consolidation and maintenance atezo.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
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      OA02.06 - A Phase II Trial of Poziotinib in EGFR and HER2 exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 14277)

      11:25 - 11:35  |  Presenting Author(s): John V Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      Insertions/mutations in exon 20 of EGFR or HER2 occur in ~3% of all lung adenocarcinomas. These alterations are characterized by primary resistance to tyrosine kinase inhibitors (TKIs) with response rates of <12%. We previously showed that exon 20 insertions restrict the size of drug-binding pocket, limiting binding of most available TKIs. However, poziotinib can potentially circumvent these steric changes due to its smaller, flexible structure and is a potent inhibitor of EGFR and HER2 exon 20 mutants (Robichaux et al. Nat Med, 2018). Herein, we report the results of an investigator-initiated study of poziotinib in EGFR and HER2 exon 20 mutant NSCLC (NCT03066206).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients ≥18yrs with metastatic NSCLC bearing mutations/insertions in EGFR or HER2 exon 20 (except EGFR T790M) were eligible. Unlimited prior systemic and targeted therapies were permitted. Poziotinib 16mg PO daily was administered until progression, death, or withdrawal. The primary endpoint was objective response rate (ORR) based on RECIST v1.1. Response was evaluated every eight weeks. A Bayesian design was used with a plan to enroll patients in cohorts of 10 and to terminate the study if ORR was ≤20%. Secondary endpoints included DCR, PFS, OS and safety

      4c3880bb027f159e801041b1021e88e8 Result

      As of May 3, 2018, the planned EGFR cohort of 50 patients was fully enrolled, and 40 patients were evaluated for response. 65.1% of patients had received at least two prior lines of therapy for metastatic disease. 60% of patients had ≥grade 3 adverse events; most common were skin-rash (27.5%) and diarrhea (12.5%). 45.0% of patients required dose reduction to 12mg, while 17.5% required dose reduction to 8mg. One patient stopped treatment due to grade 3 skin rash. ORR at eight weeks was 58% (95%-CI 40.9-73.0) and the DCR was 90% (95%-CI 76.3-97.2). Among 23 patients who achieved partial response, 15 responses were confirmed with subsequent scans, five responses were unconfirmed, and three patients are pending confirmation. Responses were observed in 8/13 (62%) patients that were previously treated with TKI. Median PFS was 5.6mo (95%-CI 5.06-NA). Furthermore, 13 patients were enrolled in HER2 cohort. Toxicities were similar to EGFR cohort except one case of grade 5 pneumonitis, assessed to be possibly drug related. Twelve patients were evaluated for response with ORR of 50% (95% CI 21.1-78.9) at eight weeks and DCR of 83%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging antitumor activity in both TKI-naive and -refractory patients, and manageable toxicity profile.

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    OA03 - Advances in Lung Cancer Pathology (ID 897)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
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      OA03.05 - Characterization of the Immunologic Intra-Tumor Heterogeneity in Early Stages of Non-Small Cell Lung Cancer by Multiplex Immunofluorescence (ID 13334)

      11:15 - 11:25  |  Author(s): John V Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      Recurrence of non-small cell lung carcinoma (NSCLC) is associated with genetic and epigenetic intra-tumor heterogeneity (ITH). The interaction between malignant cells, stromal cells, and tumor-associated immune-cells (TAICs), such as T-cell lymphocytes (TCLs) and tumor-associated macrophages (TAMs), is important for progression of NSCLC and the characterization of the immunologic ITH might be relevant to predict recurrence in surgically treated patients at early stages of NSCLC. The aim of this study was to characterize the immunologic ITH of primary NSCLC tumors at early stages using image analysis and multiplex immunofluorescence (mIF) approaches.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eight cases of stage IA and 8 cases of stage IB surgically resected NSCLC (11 adenocarcinomas, ADCs; and 5 squamous-cell carcinomas, SCCs) with a history of early recurrence were selected for this preliminary analysis. FFPE blocks were obtained and consecutive sections were stained with two panels of mIF for immune profiling, panel 1: pan-cytokeratin (AE1/AE3), PD-L1, PD-1, CD3, CD8, and CD68; panel 2: AE1/AE3, CD3, CD8, granzyme-B (GB), CD45RO, and FOXP3. Three not adjacent, intra-tumor regions (3mm2 each) per case were randomly selected after gridding the whole tumor section. A total of 41 intra-tumor regions were scanned by Vectra multispectral-microscope and analyzed using InForm-software. TAICs were quantified in epithelial and stromal compartments from each intra-tumor region. G-Cross AUC (area under the curve) was computed for specific intervals of distances between TAICs and malignant cells. Median distance between TAICs and malignant cells within each region was calculated.

      4c3880bb027f159e801041b1021e88e8 Result

      The median density of TCLs and TAMs were 1527 cells/mm2 and 635 cells/mm2, respectively, without significant differences between histologic subtypes. TCLs were predominantly concentered in stromal compartment (median, 2222 cells/mm2) compared with epithelial compartment (median, 332 cells/mm2). Percentage and density of TCLs and TAMs varied 4 and 8 times, respectively, between cases and regions. Non-cytotoxic T-cells and inactive cytotoxic T-cells were the most prevalent phenotypes. Higher density of TAMs and antigen-experienced TCLs were observed in stage IB than stage IA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Characterization of immunologic ITH of NSCLC is able by mIF and image analysis with FFPE tumor tissue. There is variability of TAICs densities between regions from the same tumor and different subpopulations were observed. TAMs and exhausted T-cells were more prominent in stage IB (tumor >3cm) suggesting these cells may play an important role in recurrence. Ongoing studies with a larger cohort and comparison with non-recurrent surgically treated patients are warranted. Supported by CPRITRP160668 and UTLungSPORE grants

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    P1.03 - Biology (Not CME Accredited Session) (ID 935)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.03-12 - PD-L1 Expression is Predominant in CD68+ Tumor-Associated Macrophages in Stage I-III Non-Small Cell Lung Cancers (ID 13340)

      16:45 - 18:00  |  Author(s): John V Heymach

      • Abstract
      • Slides

      Background

      PD-L1 tumor expression is a leading biomarker in metastatic non-small lung cancer (NSCLC). Its role and expression in surgically resectable lung cancers is not yet defined. The association between PD-L1 expression on tumor and CD68+ tumor-associated macrophages (TAMs) and the inflammatory cells within the tumor microenvironment continues to be studied. We analyzed 97 surgically resected lung cancers utilizing immunofluorescence profiling and flow cytometry (n=47) with the aim of defining PD-L1 expression and its association with tumor inflammatory cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Multiplex immunofluorescence profiling of lung cancers was performed with the focus on malignant cells (MC), MC PD-L1%, CD3+, CD8+, PD-1+ cells, CD68+, CD68+ PD-L1%, and CD20+ cells. Data on cell populations were expressed as the number of cells per mm2, PD-L1 expression as percentage. Flow cytometry was performed on freshly disaggregated tumor samples. The associations of cell populations with clinical and pathologic characteristics were assessed using Spearman's rank correlation coefficient and Wilcoxon rank-sum test.

      4c3880bb027f159e801041b1021e88e8 Result

      97 patients, 55 (57%) female and 42 (43%) male, with median tumor size 4.0 cm underwent surgical resection for pathologic stage I (N=39), stage II (N=34), and stage III (N=24) NSCLC. 85 (88%) were former smokers, 12 (12%) never smokers. 62 (65%) had adenocarcinoma, 25 (25%) squamous cell carcinoma, 10 (10%) other histology. Neoadjuvant chemotherapy was administered in 16 (16%) patients. R0 resection was achieved in 89 (92%) patients. At the median follow-up duration of 16 months, 18 patients experienced recurrence.

      CD68+ cells were less abundant than MC within tumor environment (median 120 cell/mm2 vs 4699, p<0.0001). However, PD-L1% expression was significantly higher on CD68+ vs MC within the tumor (median 33% vs 0.02%, p<0.0001); this was true for all stages. CD68+ PD-L1% in SCC was higher compared to adenocarcinoma (median 55% vs 30%, p=0.26). Induction chemotherapy increased CD68+ PD-L1% (median 31% no chemo vs 58%, p=0.05) without affecting the proportion of effector CD8+ TIL expressing its receptor, PD-1 (p=0.757). Tumors with > median CD68+ PD-L1% expression were associated with higher CD3+ (p=0.006), CD8+ (p=0.06), and CD68+ (p=0.004) cell numbers within the tumor.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In early NSCLC PD-L1% expression appears to be predominant in CD68+ TAMs rather than in malignant cells. Higher than median PD-L1% expression on CD68+ is associated with increased in CD3+ and CD8+ T cells. Further studies are required to understand the role of CD68+PD-L1 cells within tumor microenvironment, the influence of neoadjuvant chemotherapy or immunotherapy regimens on these cells, and their effect on outcomes.

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      P1.03-13 - eIF2β, A Subunit of Translation-Initiation Factor EIF2, as a Potential Therapeutic Target for Non-Small Cell Lung Cancer (ID 11293)

      16:45 - 18:00  |  Author(s): John V Heymach

      • Abstract
      • Slides

      Background

      To identify potential therapeutic targets for non-small cell lung cancer (NSCLC), we recently performed a semi-genome wide shRNA screen in a NSCLC cell line H460 . Through this approach, we identified multiple potential targets for NSCLC (Kakumu et al. Cancer Sci, 2017). In the present study, to search for genes with more generalized potential as therapeutic targets, we did shRNA screen using the alternative NSCLC cell line H358 and combined its results with those of our previous screen.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      19 NSCLC cell lines, two cdk4/hTERT-immortalized normal human bronchial epithelial (HBEC) cell lines and primary NHBE culture were used. A semi-genome wide shRNA screen was performed with the DECIPHER library in H358, and its results were integrated with those of our previous screen in H460. Gene silencing was done with RNA interference followed by growth and cell cycle analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      24 genes overlapped between results of two shRNA screens in H460 and H358 and we identified these as more generalized targets. Gene-annotation enrichment analysis showed that the RNA transport pathway including three genes is one of the overrepresented pathways in the 24 genes. Among the three genes, we determined to focus on eIF2β, a subunit of translation-initiation factor EIF2 because other two genes included in the RNA transport pathway, XPO1 and RAN are well characterized therapeutic targets for human cancers including lung cancer. eIF2β protein was more abundantly expressed in all the 19 lung cancer cell lines analyzed than in NHBE used as a control. To determine the clinical relevance of eIF2β in lung cancer, we examined eIF2β mRNA expression in lung adenocarcinoma tissues using TCGA dataset. These analyses showed significantly higher expression of eIF2β mRNA in lung adenocarcinoma tissues than in normal adjacent tissues. Importantly, we found that expression of eIF2β mRNA correlated with worse prognosis in patients with lung adenocarcinoma in multiple independent datasets, suggesting its potential as a prognostic marker. Next, we examined the effects of eIF2β knockdown on the growth of the H460 and H1975. Colorimetric growth and colony formation assays showed that eIF2β knockdown in H460 and H1975 suppresses cell growth and colony formation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      eIF2β is highly expressed in NSCLC cells, and its expression correlates with poor prognosis in patients with lung adenocarcinoma. Knockdown of eIF2β caused G1 arrest in lung cancer cell lines. These results suggest that eIF2β is a potential therapeutic target for NSCLC and that it is a prognostic marker for lung adenocarcinoma.

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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: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.04-08 - Co-Residence of Patient-Derived Immune Cells in Patient-Derived Xenografts from Lung Cancer Patients (ID 11161)

      16:45 - 18:00  |  Author(s): John V Heymach

      • Abstract

      Background

      Patient-derived xenograft (PDX) models have been shown to recapitulate many characteristics of human tumors and have been increasingly used for anticancer drug development, molecular characterization of cancer biology, and development of precision therapies. However, because PDXs are grown in immunodeficient mouse strains, they are regarded as inappropriate for preclinical evaluation of anticancer immunotherapy. Here we evaluated whether patient-derived immune cells co-exist in PDXs derived from lung cancer patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      First-generation PDX (F1) was established by subcutaneously implanting human tumor tissue into non-obese diabetic-severe combined immunodeficiency (NOD-SCID) mice with a null mutation of the gene encoding for interleukin-2 receptor g (NSG). When the resulting tumors in these mice grew to about 1.5 cm in diameter, we passaged the tumors in NSG or nude mice for subsequent generations. A small piece of these PDX tissues (about 2-3 mm3) were minced into fragments and cultured in media containing human interleukin-2 (IL-2) (2000 -6000 units/ml) for up to 6 weeks. The proliferated lymphocytes for analyzed by fluorescence-activated cell sorting (FACS) with antibodies specific for human immune cell surface markers. The provenance of cultured cells was determined by DNA fingerprinting assay together with patients’ DNA samples from primary tumors and/or peripheral blood mononuclear cells (PBMC).

      4c3880bb027f159e801041b1021e88e8 Result

      The mean time of PDX growth in NSG mice before harvesting for culturing tumor-infiltrating lymphocytes (TILs) was 120 days (ranging from 63-292 days). TILs were successfully cultured from 8 of 25 PDXs samples (about 32%), with one from F2 PDXs and 7 from F1 PDXs. TILs from five of those PDXs were predominantly human CD3+CD8+ T cells (72% -99%), while the remaining three were predominantly human CD19+ B cells (77% - 95%). DNA fingerprint analysis showed that genotypes of TILs were identical to patients’ primary tumors and/or PBMC, demonstrating that the TILs were from the same patients as the PDXs. Further analysis showed that CD8+ T cells from PDXs were CD45RO+, with either CD62L+ or CD62L-.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patient-derived immune cells co-exist with PDXs in some lung cancer PDX models. Most of those immune cells were CD3+CD8+ and could be memory T cells. These results suggest that some PDXs might be used for evaluating functions of tumor resident immune cells and/or for evaluating anticancer immunotherapies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-37 - Clinical Evaluation of Plasma-Based (cfDNA) Genomic Profiling in Over 1,000 Patients with Advanced Non-Small Cell Lung Cancer (ID 14332)

      16:45 - 18:00  |  Author(s): John V Heymach

      • Abstract

      Background

      Tumor genomic information from a simple blood collection revealing actionable mutation can improve clinical outcome without the need for an invasive tissue biopsy. We report on the clinical utility of a cell-free DNA (cfDNA) next generation sequencing (NGS) blood test in our patients with non-small cell lung cancers (NSCLC) and the outcome of treatments with targeted therapies based on the reported mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From May 2015 to February 2017, 1078 blood samples from 1011 consecutive patients with a diagnosis of NSCLC were collected and analyzed using next-generation sequencing of cfDNA with a panel of up to 70 cancer-related genes at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA) with reported sensitivity of 0.02% mutant allele fraction with high specificity (> 99.9999%) (CCR 2018 (17):3831). Patients in this retrospective study received targeted therapy as indicated by cfDNA molecular profiling. Tumor response was evaluated by RECIST V1.1 and standard clinical evaluation.

      4c3880bb027f159e801041b1021e88e8 Result

      From 1011 patients, 1078 cfDNA tests sent (additional follow-up tests: 1 in 64 patients and 2 in 3 patients). In 223/1011 (22%) patients had cfDNA report with at least 1 targetable mutations; with 48/223 (22%) patients meeting criteria for this retrospective review. Study population were 31 female:17 male, median age of 63 years (ranged:31-94). The rationale for the blood test included: insufficient tissue or not available (32%), addition to tissue molecular analysis (17%), alternative to tissue biopsy(10%), on-going treatment evaluation/resistance (41%). Mutations included:EGFR T790M (15), EGFR exon 19del (12), EGFR L858R (9), EGFR exon 20 insertion (4), EGFR others (1), ALK gene fusions (5) and MET exon 14 skipping (2). The median line of therapy was 2(ranged:1-7) with 28 patients receiving TKI as 1st line of therapy based on cfDNA mutations. With targeted treatments based on ctDNA results, the responses (RECIST V1.1) were: CR(3), PR(26), SD(14) and PD(4); median PFS was 8.5 months (ranged:1-26mos) for the overall population with 4 patients still receiving targeted therapy. Median PFS was 9.5 months (ranged:1-20 months) for those receiving TKI as 1st line.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the largest analysis of response rates with cfDNA directed therapy in advanced NSCLC and demonstrates positive clinical outcomes in patients treated with targeted therapy based on plasma identified biomarkers.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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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: 2
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-33 - Open-Label, Biomarker-Directed Platform Study in NSCLC Patients Who Progressed on an Anti-PD-(L)1 Containing Therapy (HUDSON) (ID 13743)

      16:45 - 18:00  |  Author(s): John V Heymach

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitor (ICI)-containing regimens have significantly improved survival outcomes in first- and second-line NSCLC. However, the majority of patients do not respond or have non-durable responses to anti-programmed cell death-1/programmed cell death-ligand 1 (anti-PD-1/PD-L1) containing therapy (primary resistance) or progress during anti-PD-1/PD-L1 containing therapy (acquired resistance). HUDSON addresses the urgent need to identify treatments and understand ICI resistance for this emerging ICI-resistant population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      HUDSON is a multi-centre, international multi-arm umbrella study that will 1) evaluate therapies to reverse ICI resistance and 2) define mechanisms of ICI resistance in NSCLC patients who have progressed following standard-of-care platinum and ICI-based therapies. HUDSON is a platform study that consists of two groups; a biomarker matched and a biomarker non-matched group. Within the biomarker matched group, different cohorts will test 1) homologous recombination repair (HRR) defects and 2) LKB1 aberration for response to durvalumab and olaparib (PARP inhibitor), 3) ATM deficiency for response to durvalumab and AZD6738 (ATR inhibitor) and 4) RICTOR amplification for response to durvalumab and vistusertib (mTORC1/2 inhibitor). In the biomarker non-matched group, cohorts will test durvalumab in combination with either i) olaparib, ii) AZD9150 (STAT3 inhibitor) or iii) AZD6738, in patients with primary and acquired resistance to a prior ICI. Allocation to a cohort is informed by the tumour molecular profile according to a pre-specified assignment algorithm. New cohorts will be added as new translational hypotheses are established. Translational research will be performed on serial peripheral blood samples (including ctDNA) and tumour biopsies. HUDSON enrols ICI-resistant patients in a signal searching manner. Biomarker matched and non-matched groups will be opened simultaneously, and all eligible patients can be allocated a treatment option irrespective of their tumour profile. Enrolment is ongoing, clinical trial information: NCT03334617.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-87 - Profiling the Symptom Burden of Patients with Metastatic NSCLC Receiving Either Chemotherapy or Targeted Therapy: Real-World Data (ID 13348)

      16:45 - 18:00  |  Author(s): John V Heymach

      • Abstract
      • Slides

      Background

      An understanding of the patient experience is lacking for newly developed cancer treatments, such as targeted therapies. We profiled the patient-reported outcome (PRO)-measured symptom burden experienced by patients with metastatic non-small cell lung cancer (mNSCLC) during 6 months of conventional chemotherapy or targeted therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      During 2017, patients with mNSCLC at a single institution were recruited and completed the MD Anderson Symptom Inventory lung cancer module (MDASI-LC) at clinic visits. The MDASI-LC assesses the severity of 13 core and 3 lung-cancer-specific symptoms and 6 interference items on 0‒10 scales (0=no symptom or interference, 10=worst imaginable symptom or complete interference). Descriptive statistics for MDASI-LC scores over 6 months of treatment were summarized. Symptom trajectories for the chemotherapy patients versus the targeted-therapy patients were compared via linear mixed-effects models.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 65 patients receiving chemotherapy and 27 receiving targeted therapy, the targeted-therapy group had more women (74% vs. 49%, P=0.029) and younger patients (57.6±12.2 vs. 64.2±9.9 years, P=0.012). Before treatment, both groups reported similar symptom burden, although sadness was worse in the targeted-therapy group (2.4±1.6 vs. 0.8±1.5, P=0.021). During the first 60 days of treatment, patients receiving chemotherapy reported significant increase in pain (estimate (est)=0.03, P=0.037) and interference with walking (est=0.04, P=0.025). Compared with those receiving chemotherapy, patients receiving targeted therapy experienced significantly less severe pain (est=‒1.17, P=0.024), fatigue (est=‒1.16, P=0.019), and shortness of breath (est=‒1.23, P=0.028) and less interference with walking (est=‒1.23, P=0.042) (figure 1). More severe dry mouth was reported by patients undergoing targeted therapy (est=1.17, P=0.027).

      figure1_shi_quiling.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      This real-world data demonstrates that, compared with conventional chemotherapy, targeted therapy correlates with less impairment of physiological condition and functioning in patients with mNSCLC. Additional follow up will confirm and expand these findings about the patient experience relative to treatment response.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-09 - Driver Mutations are Associated with Distinct Patterns of Response to Immune Checkpoint Blockade in Non-Small Cell Lung Cancer (ID 13362)

      16:45 - 18:00  |  Author(s): John V Heymach

      • Abstract
      • Slides

      Background

      Immune checkpoint blockade (IO) has demonstrated durable clinical benefit in metastatic non-small cell lung cancer (NSCLC). Tumors with driver mutations such as EGFR exon 19 and 21 mutations and ALK translocation tend to have low response rates to IO. However, IO response in NSCLC patients with rare driver mutations, such as EGFR exon 20 (~2%), HER-2 (~2%) and BRAF (~3%), representing approximately 7% of lung adenocarcinomas, has been poorly addressed.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We queried GEMINI (MD Anderson Lung Cancer Moon Shot funded database for prospective collection of clinical information on NSCLC) for patients with mutations in EGFR exon 19, 20, 21, HER-2 and BRAF treated with PD-1/PD-L1 checkpoint inhibitors. We assessed progression-free survival (PFS), overall response rate (ORR) and overall survival (OS) in each molecular group.

      4c3880bb027f159e801041b1021e88e8 Result

      Between 2014-2018, 108 patients with classic EGFR mutations (exon 19 del + exon 21 L858R, n=37), EGFR exon 20 mutations (n=36; no T790M included), HER-2 mutations (n=22) and BRAF mutations (n=13; V600E: 3pts; non-V600E: 10pts) had been treated with PD-1/PD-L1 inhibitors. EGFR exon 20 mutants and BRAF mutants demonstrated significantly higher PFS (EGFR exon 20: HR 0.4, p<0.001; BRAF: HR 0.2, p<0.001), higher disease control rate at 6 and 12 months as well as higher ORR when compared to classic EGFR mutants (Table). These differences remained significant in multivariate analysis after adjusting for age, smoking, PD-L1 status, radiation prior to treatment initiation, treatment with concurrent agents and prior treatment with TKIs. HER-2 mutants had similar PFS compared to EGFR classic mutants (HR 0.8, p=0.35) (Table).

      table.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      EGFR exon 20 and BRAF mutations are associated with superior outcome from PD-1/PD-L1 checkpoint inhibitors compared to classic EGFR and HER-2 mutations. Further studies on co-mutational status and tumor mutation burden in these molecularly-defined groups are ongoing to address potential underlying mechanisms associated with these findings.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.04-25 - Randomized Clinical Trial Comparing Immunotherapy Plus SABR (I-SABR) Versus SABR Alone for Early Stage NSCLC (ID 12620)

      16:45 - 18:00  |  Author(s): John V Heymach

      • Abstract
      • Slides

      Background

      Section not applicable

      Stereotactic ablative radiotherapy (SABR), which delivers high biologically effective radiation doses, can kill cancer cells, release tumor-associated antigens, and activate tumor-specific T cells, thereby functioning as a cancer-specific vaccine in situ. The combination of the immune-triggering effects of ionizing radiation with immune check point PD-1inhibitor may leverage the effects of radiotherapy, transforming what was once considered a local therapy to a novel systemic treatment. Further, the combined effects of local tumor control plus systemic control may improve cure rate in early stage NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Section not applicable

      This is a randomized phase II trial (NCT03110978) designed to study SABR (biological effective dose >100 Gy) with or without concurrent and adjuvant Nivolumab for total of 7 doses in early stage or isolated recurrent NSCLC. Inclusion criteria: stage I disease (tumor size ≤5 cm, N0M0) OR selected cases of stage IIa disease (tumor size >5 cm but ≤7 cm, N0M0), including multiple primary tumors, OR isolated lung-parenchymal recurrent or persistent NSCLC suitable for SABR. Tumor tissue /blood/stool samples will be collected before/during/after treatment and at the time of recurrence. Primary endpoints: Event-free survival (EFS), defined as local recurrence, regional recurrence, distant metastasis, secondary malignancy and death; secondary endpoints: overall survival; toxicity; exploratory analyses of potential predictive markers and immunologic mechanisms of action.

      Statistical design: It is considered clinically significant with a decrease of the 4-year cumulative event rate from 46% to 23%. Assuming a one-sided type I error rate of 0.05, an accrual rate of 3.5 patients per month, and an additional 20 months of follow-up, a study with 70 patients in each arm will have 85% power to detect an improvement of 23% in 4-year EFS rate. One interim analysis will be done to allow early termination of the trial should evidence at that time reveal that I-SABR is superior to SABR-only or that no difference is found between the two treatment arms.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      Up to April 30, 2018, 36 of planned 140 patients have been enrolled.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      Phase II randomized clinical trial comparing immunotherapy plus Stereotactic Ablative Radiotherapy (I-SABR) versus SABR Alone for stage I, selected stage IIa or isolated lung parenchymal recurrent Non-Small Cell Lung Cancer is ongoing and met with anticipated enrolment rate.

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    P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.01-109 - Real-World Patient-Reported Outcome Assessment of Patients with Metastatic Non-Small Cell Lung Cancer  (ID 12213)

      12:00 - 13:30  |  Author(s): John V Heymach

      • Abstract
      • Slides

      Background

      Patient-Reported Outcomes (PROs) provide information on patient treatment experience. We have established a real-world Advanced Non-Small Cell Lung Holistic Registry (ANCHoR) to understand how the advent of immunotherapy impacts treatment choice, clinical outcomes, and PROs of metastatic non-small cell lung cancer (mNSCLC). The aim of this analysis is to report early results of baseline symptom status and quality of life among mNSCLC patients using the MD Anderson Symptom Inventory lung cancer module (MDASI-LC) and EuroQol-5D 5-level version (EQ-5D-5L).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      During 2017, patients with mNSCLC at a single institution were enrolled in ANCHoR and completed the PRO questionnaires at clinic visits. MDASI-LC consists of thirteen core and three lung cancer-specific symptom severity questions, and six interference items rated on 0-10 scales (0 = no symptom or interference, 10 = worst imaginable symptom or complete interference). EQ-5D-5L captures five health state dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression rated on a five-level scale (1= no problems, 5= extreme problems). A single visual analogue scale (VAS) on EQ-5D-5L records patient self-rated health between ”best imaginable” (100) and “worst imaginable” (0) health state. Descriptive statistics for PRO scores at baseline are summarized.

      4c3880bb027f159e801041b1021e88e8 Result

      Forty-two patients completed baseline PROs before the start of therapy. Mean patient age was 63 years and 45% were males. For MDASI-LC, the mean scores for the core symptom, lung cancer-specific symptom, and interference subscales at baseline were 2.2 (standard deviation [SD] = 2.80), 2.1 (SD = 2.80), and 2.8 (SD = 3.10), respectively. Fatigue was the most severe symptom reported at baseline (mean = 4.1, SD = 3.01), followed by shortness of breath (mean = 3.2, SD = 2.81) and pain (mean = 3.19, SD = 3.00). The highest percentages of patients reporting moderate to severe symptom levels (score of ≥5) were 38% for fatigue, 33% for pain, 31% for drowsiness, 29% for shortness of breath and disturbed sleep, and 26% coughing. For EQ-5D-5L, 91% of patient reported problems with self-care, 81% with mobility, 48% with usual activity and anxiety, and 33% with pain. Mean EQ-5D VAS was 73.9 (SD = 18.2).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Prior to the start of treatment, fatigue, pain, drowsiness, disturbed sleep, and coughing were the most common symptoms with fatigue, shortness of breath, and pain being the most severe. Additional follow up will confirm and expand these findings and will also allow us to examine change in PROs after first-line treatment is administered.

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      P3.01-91 - Computing the Impact of Immunotherapy on the Non-Small Cell Lung Cancer (NSCLC) Therapeutic Landscape (ID 12209)

      12:00 - 13:30  |  Author(s): John V Heymach

      • Abstract

      Background

      The Advanced Non-Small Lung Holistic Registry (ANCHoR) is established to examine the real-world impact of immunotherapy on choice of treatment, clinical outcomes, and patient reported outcomes of patients with Stage IV NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Stage IV NSCLC patients diagnosed or initiating treatment at MD Anderson from January 1, 2017 are enrolled in the ongoing ANCHoR study. Their demographic, clinicopathological, molecular, and treatment data were populated in a prospective database. Treatment patterns by line and PD-L1 status were summarized in this interim analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      At the time of data cut off (Dec 31, 2017) 182 patients were enrolled in the registry, of which 150 were tested for PD-L1. Number of patients initiating first-, second-, and third-line treatment were 163, 42 and 7, respectively. Of the 30 patients not tested for PD-L1, 10 did not have enough tissue and 8 had actionable mutations.

      table 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The emergence of immunotherapy has had a dramatic impact on the first-line treatment of patient with advanced NSCLC. As of December, 2017 up to 41% of patient received immunotherapy either singly (23%) or in combination with chemotherapy. Only 40% of the patients now receive chemotherapy alone. There has been dramatic decrease in the use of chemotherapy with an anti-angiogenesis agent (1.23%). In our dataset 16% of the patients were eligible for targeted therapy as initial treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.03 - Biology (Not CME Accredited Session) (ID 969)

    • 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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      P3.03-28 - LKB1 Mutation Status is Associated with Poor Radiation Outcome in Patients with Non-Small Cell Lung Cancer (ID 13591)

      12:00 - 13:30  |  Author(s): John V Heymach

      • Abstract

      Background

      Previously, we reported that the upregulation of the NRF2/KEAP1 pathway in non-small cell lung cancers (NSCLC) bearing co-mutations in KRAS and LKB1 is critical to maintain redox homeostasis which contribute to radiation resistance in these tumors. Here, we explore the role of the LKB1 mutation as a potential predictor radiation outcome in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed the patients undergoing definitive treatment for newly diagnosed NSCLC who were enrolled in the prospectively collected MD Anderson Lung Cancer Moon Shot GEMINI database according to LKB1 mutation status. Cox regression analysis and log-rank tests were used to correlate with radiation outcomes according to LKB1 mutation status and/or KRAS mutation subgroup. We then investigated the mechanisms of radiation resistance in these tumors in preclinical models.

      4c3880bb027f159e801041b1021e88e8 Result

      wclc 2018 picture.jpgOf the 173 patients with stage III NSCLC treated with definitive radiotherapy, with or without chemotherapy were analyzed according to LKB1 mutation status demonstrated that LKB1 mutation had statistically significantly higher rate of loco-regional recurrence, and shorter disease-free survival than in patients with wild type LKB1 (P = 0.013 and P = 0.037, respectively). Moreover, additional loss of either LKB1 or TP53 in KRAS-mutant tumors renders these tumors higher loco-regional recurrence after radiation (P interaction = 0.045). We identified that LKB1 loss is associated with radio-resistance in part by KEAP1/NRF2 pathway activation. Re-expression of LKB1 or NRF2 pathway suppression (via KEAP1 expression) enhanced radiotherapy sensitivity in vivo.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that LKB1 mutation is a potential predictive impact on radiation outcome of patients with NSCLC. The upregulation of the KEAP1/NRF2 pathway in NSCLC bearing co-mutations in KRAS and LKB1 is critical to maintain redox homeostasis and determine the sensitivity for radiation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.09 - Pathology (Not CME Accredited Session) (ID 975)

    • 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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      P3.09-27 - Histopathologic Parameters Define Features of Treatment Response to Neoadjuvant Chemotherapy in Non-Small Cell Lung Cancer (ID 14257)

      12:00 - 13:30  |  Author(s): John V Heymach

      • Abstract

      Background

      Previous studies indicate that neoadjuvant chemotherapy improves survival in patients with loco-regionally advanced non-small cell lung cancer (NSCLC). The amount of residual viable tumor has been associated with long-term overall survival. This histopathologic measure has potential to become a standard method for evaluation of the effectiveness of neoadjuvant therapy regimens. However, adequate comparison of chemotherapy-treated and untreated lung cancers is lacking. We analyzed histopathologic characteristics of resected NSCLC with and without prior neoadjuvant chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Histopathologic assessment was performed of specimens obtained from patients enrolled on the immunogenomic lung cancer study (ICON), which integrates clinical, pathologic, immune, genomic and outcome data from surgically resected NSCLC. Cases included material from 10 patients who underwent neoadjuvant chemotherapy and 10 patients treated with primary surgery (adenocarcinoma, n=5; squamous cell carcinoma, n=5; for each cohort). Hematoxylin and eosin-stained tumor sections (mean, 6; range, 3-10) were evaluated and semiquantitatively scored for parameters commonly attributed to treatment response. The percentage of viable tumor was estimated by comparison to the proportion of fibrosis and necrosis on each slide. Additional parameters analyzed included the presence of inflammation, tertiary lymphoid structures (TLS), macrophages, lymphovascular invasion (LVI), cholesterol clefts, giant cells and neovascularization (score 0-3). For each patient, the results for all slides were averaged to determine a mean value. P values were calculated using the Mann-Whitney test.

      4c3880bb027f159e801041b1021e88e8 Result

      All histopathologic parameters typically associated with treatment response could also be identified in untreated specimens, albeit in different proportions. Compared to the untreated cohort, samples after chemotherapy were characterized by lower proportion of viable tumor (42.4% vs 67.7%, p=0.04) and higher degrees of fibrosis (46.6% vs 26.6%, p=0.08), and necrosis (11.0 % vs 5.6%, p=0.35). Among the additional parameters, similar scores were seen for inflammation (1.54 vs 1.46, p=0.60), TLS (1.00 vs 0.80, p=0.47), LVI (0.16 vs 0.23, p=0.62), and neovascularization (both 0) while macrophages (0.94 vs 0.12, p=0.20), cholesterol clefts (0.92 vs 0.13, p= 0.03) and giant cells (0.80 vs 0.40, p=0.17) were more common among the neoadjuvant cohort.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Histopathologic variables commonly associated with chemotherapy treatment response can also be identified in treatment naïve lung cancers. However, the amount of viable tumor, fibrosis and cholesterol clefts are parameters strongly associated with neoadjuvant therapy. These results highlight the importance of assessing the type and extent of treatment response. Analysis of larger patient cohorts will reveal potential prognostic value in primary tumors, chemotherapy-treated, and eventually immunotherapy-treated tumors.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session) (ID 981)

    • 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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      P3.15-29 - Defining the Symptom Burden of Non-Small Cell Lung Cancer (ID 12361)

      12:00 - 13:30  |  Author(s): John V Heymach

      • Abstract
      • Slides

      Background

      Symptom burden is disease and treatment symptom severity and its impact on daily functioning. Symptom monitoring has demonstrated improved cancer patient outcomes, including quality of life, resource utilization, ability to continue treatment, and survival. The use of disease-specific patient-reported outcomes (PRO) measures facilitates individualized symptom monitoring and management. The purpose of this study was to describe symptom experience from the patient perspective and identify key symptoms for a PRO measure of non-small cell lung cancer (NSCLC) symptom burden.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with NSCLC described their symptom experience in single qualitative interviews. Content analysis was used to define the content for a PRO measure of NSCLC symptom burden.

      4c3880bb027f159e801041b1021e88e8 Result

      Mean age of the 40 patients interviewed was 66.1 years (standard deviation = 10.9); 60.0% were male, 77.5% were white, and 56.4% had stage IV disease. Content analysis found a total of 32 symptoms, 6 reported by ≥ 20% of participants (see Table 1). Symptoms varied based on treatment modality (chemotherapy versus radiation therapy), but not stage of disease. Numbness or tingling and sore mouth were described only by patients who had received chemotherapy. Patients volunteered ways in which symptoms impacted daily activities and relationships.

      Table 1. Patient quotes from qualitative interviews describing the 6 most common symptoms (reported by ≥ 20% of participants)
      Symptom Participant Quote
      Shortness of breath

      “The heaviness, it’s like a—wow, I don’t know how to explain it—like a rock and hard to breathe sometimes, just shortness of breath. Of course, the more I try to walk, or whatever, I’m more short of breath.”

      ‒ 67-year-old female
      Cough

      “I had a real bad cough. I think I actually even broke a couple of ribs coughing so much.”

      ‒ 52-year-old male

      Distress

      “Terrifying. There’s no ways about it. You know, it’s a terrifying experience, especially when it’s dropped in your lap and you have to deal with it. You go through a lot physically and mentally.”

      ‒ 67-year-old male
      Fatigue

      “I'm more tired. I take a lot of naps where I never had been a nap person. Before I had all my energy, and I was doing lots of things, and now I'm wore out. I wake up, and I'm wore out.”

      ‒ 53-year-old male
      Pain

      “You keep trying to move it to make it feel better and no matter where you put it, it doesn’t feel any better … most of the time it will bother me after I get out of bed in the morning for a while. And then if I go try to take a nap, I’ll go ahead and take something for pain because I can’t lay there and—I just keep moving it and moving it and nothing helps.”

      - 68-year-old male
      Constipation

      “I didn’t have a bowel movement. I had always taken the stool softeners because they told me to do that. And I kept thinking, “Well, it’s going to work. It’s going to work.” Finally, I was in so much pain that I couldn’t stand anymore, so I went to the hospital … and they ended up physically removing, which was horrible.”

      ‒ 68-year-old female

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients with NSCLC experience numerous symptoms related to disease and treatment. Shortness of breath, cough, distress, fatigue, pain, and constipation were commonly reported symptoms, suggesting that clinicians should routinely and proactively monitor the presence and severity of these symptoms in NSCLC clinical care. In patients receiving chemotherapy, attention to specific treatment-related symptoms, including symptoms of neuropathy and sore mouth, is needed. While stage of disease does not produce unique symptoms, the severity of the symptoms may possibly vary by stage of disease. Clinicians should also be aware that symptoms result in interference with daily activities, relationships, life plans, treatment adherence, and mood.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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