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Jin-Haeng Chung
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MA11 - Biomarkers of IO Response (ID 912)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
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MA11.02 - Increased CD3+ TIL Infiltration and Low FOXP3+/CD8+ TIL Ratio Can Predict Anti-PD-1 Therapeutic Response in Non-Small Cell Lung Cancer Patients (ID 12553)
10:35 - 10:40 | Author(s): Jin-Haeng Chung
- Abstract
- Presentation
Background
To determine whether distinct tumor microenvironments differentially affect the clinical response to anti-PD-1 therapy in non-small cell lung cancer (NSCLC), we investigated the expression level of PD-L1 and tumor infiltrating lymphocytes (TILs) and elucidate their predictive role.
a9ded1e5ce5d75814730bb4caaf49419 Method
Forty pretreated specimens (including 21 resected and 19 biopsied tissues) from 36 advanced, treatment-refractory NSCLC patients who underwent PD-1 blockade therapy were analyzed. PD-L1 expression by tumor cells and the distribution of CD3, CD8, CD4, FOXP3 and PD-1 positive TILs were immunohistochemically assessed. The mean number of cells positive for each marker in covered total fields was expressed in density per mm2 using digital image analyzer. In addition, CD8+/CD3+, CD8+/CD4+, FOXP3+/CD8+, and PD-1+/CD8+ ratios were calculated for each specimen using the mean number of total fields.
4c3880bb027f159e801041b1021e88e8 Result
CD3+ and CD8+ TILs were distributed more in PD-L1 positive group compared to PD-L1 negative group. Inversely, EGFR mutant group showed fewer CD3+ TILs than EGFR-naïve group. The patients in the clinical benefit group with PD-1 blockade showed a higher number of CD3+, CD8+ TILs and a higher CD8+/CD3+ TIL ratio (p=0.003, p=0.001, and p =0.042) and a lower FOXP3+/CD8+ TIL ratio compared to non-responders (p=0.001). We analyzed the effects of TIL, PD-L1 and clinicopathologic factors in PD-1 blockade therapeutic response using logistic regression. In multivariate analysis, increased CD3+ TIL infiltration and low FOXP3+/CD8+ TIL ratio were found to be independent predictors of clinical benefit with PD-1 blockade. (p=0.014 and p=0.03, respectively). Using receiver operating characteristic curves, levels of CD3+ TIL and FOXP3+/CD8+ TIL ratio that provide the best distinguishing point between responder versus non-responder to PD-1 blockade were 617.5/mm2 and 25%, respectively (p=0.007 and p=0.003). Considering that 1 mm2 is about 5 high power fields (HPF), a good response to the PD-1 blockade can be expected when CD3 + TIL is observed in 120 per 1 HPF and CD8 + TIL : FOXP3 + TIL are greater than 4 : 1. In addition, there were no difference between sample acquisition method (resection vs. biopsy) and duration (3, 6, and 12 months before PD-1 blockade treatment), and TIL expression.
8eea62084ca7e541d918e823422bd82e Conclusion
Based on our results, TIL is an independent predictive factor of response to PD-1 blockade and we suggested a cutoff value of TIL to predict responder group. In addition, properly sampled small biopsy tissue and well preserved archival specimens are feasible to evaluate TIL status.
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MA11.07 - Expression of LAG-3 and NY-ESO-1 In Tumor Cells is Promising Biomarker Predicting Durable Clinical Benefit of PD-1 Blockade in Advanced NSCLC (ID 12403)
11:10 - 11:15 | Author(s): Jin-Haeng Chung
- Abstract
- Presentation
Background
Anti-PD-1 antibodies are currently used in treating advanced non-small cell lung cancer (NSCLC). PD-L1 expression in tumor cell or immune cell is the only available predictive biomarker in the clinic. Lymphocyte activation gene-3 (LAG-3) is an inhibitory checkpoint in immune cells and NY-ESO-1 is an antigen expressed in tumor cells. We investigated LAG-3 and NY-ESO-1 protein expression and its relationship to response to anti-PD-1 therapy in NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively reviewed the medical records of 38 patients with advanced NSCLC who were enrolled in prospective clinical trials of nivolumab or pembrolizumab monotherapy (NCT01295827, NCT01905657, and NCT02175017) between October 2013 and April 2016 at Seoul National University Hospital and Seoul National University Bundang Hospital. Immunohistochemial staining (IHC) of NY-ESO-1(E978, Invitrogen), and PD-L1 (22C3, Dako) in tumor cell and LAG-3(EPR4392, Abcam) in immune cell was performed to determine protein expression.
4c3880bb027f159e801041b1021e88e8 Result
LAG-3 and NY-ESO-1 protein expression were assessed in 38 patients. LAG-3, NY-ESO-1 and PD-L1 were expressed in 76.3% (29/38), 50% (19/38) and 18.5% (7/36, 50% cut-off value), respectively. Sixteen patients with durable clinical benefit (DCB, anti-PD-1 therapy more than 6-month) were grouped as responder. NY-ESO-1 expression (DCB 11/19 vs 5/19, p= .05) and LAG-3 expression (DCB 16/29 vs 0/9, p= .003) were significantly correlated with the DCB to Anti-PD-1 therapy, while PD-L1 expression was identified in 5 patients with DCB (5/7 vs 11/29, p= .12). Patients with both NY-ESO-1 and LAG-3 expression had high rate of DCB (73.3%, 11/15 pts). With the results of the interaction with DCB, the calculation of positive predictive value and negative predictive value about durable clinical benefit is assessed and the significance of each measurement was proven by Fisher’s exact test. As a result, NPV of LAG-3 expression in tumor cell was 100% and PPV of each protein expression was LAG-3 (55.17%), NY-ESO-1(57.89%) and PD-L1 (71.43%) respectively. In survival analysis, LAG-3 expression was a significant predictor for PFS (HR 0.170; CI 0.066-0.437; p< .0001) and OS (HR 0.250; CI 0.140-0.599; p= .002).
8eea62084ca7e541d918e823422bd82e Conclusion
NY-ESO-1 expression on tumor tissue and LAG-3 expression on tumor microenvironment may be useful for identifying advanced NSCLC patients for the treatment of anti-PD-1 therapy. These protein markers seem quite promising and warrant further investigation in large sample size.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MTE20 - Molecular Testing in Small Samples (Ticketed Session) (ID 830)
- Event: WCLC 2018
- Type: Meet the Expert Session
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 07:00 - 08:00, Room 202 BD
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MTE20.02 - Molecular Testing in Small Samples (ID 11582)
07:30 - 08:00 | Presenting Author(s): Jin-Haeng Chung
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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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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OA03.03 - Phase 2B of Blueprint PD-L1 Immunohistochemistry Assay Comparability Study (ID 14530)
10:50 - 11:00 | Author(s): Jin-Haeng Chung
- Abstract
- Presentation
Background
PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. a9ded1e5ce5d75814730bb4caaf49419 Method
Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. 4c3880bb027f159e801041b1021e88e8 Result
The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. 8eea62084ca7e541d918e823422bd82e Conclusion
The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible. 6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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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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P2.01-106 - A Comparative Analysis of Genomic Alterations by Tumor Tissue and Circulating Tumor DNA in Advanced Non-Small Cell Lung Cancer (ID 13524)
16:45 - 18:00 | Author(s): Jin-Haeng Chung
- Abstract
Background
Genomic profiling of lung cancers using circulating tumor DNA (ctDNA) in the blood of patients is rapidly becoming established as a useful source of information to aid clinical decision-making. We evaluated the concordance of genomic alterations by ctDNA and tumor tissue DNA in Advanced Non-Small Cell Lung Cancer (NSCLC).
a9ded1e5ce5d75814730bb4caaf49419 Method
Tumor tissue DNA from formalin-fixed, paraffin-embedded (FFPE) samples and ctDNA from plasma samples were obtained at the time of diagnosis or at the time of progressive disease after receiving targeted therapy in 41 patients with stage IIIB or IV NSCLC in this prospective study (NCT03235765). Hybrid-capture based genomic profiling (Axen Cancer Panel, Macrogen) was performed to sequence 170 genes in both samples. Concordance is defined as the number of genomic alteration present in both samples divided by the number of genomic alteration in FFPE. Tumor mutation burden (TMB) was also measured.
4c3880bb027f159e801041b1021e88e8 Result
Most patients were adenocarcinoma (n=34, 82.9%). The total number of genomic alteration identified in FFPE and ctDNA were 751 and 561, respectively. Median concordance was 50% (8.0% – 100%). Among the clinical factors including smoking history, tumor size, PD-L1 status, EGFR mutation, TMB of tumor DNA, and concentration of ctDNA, concordance was negatively correlated with TMB of tumor DNA (Spearman's r= -0.504, P=0.001). When we divide low TMB (TMB-L) and high TMB (TMB-H) by the cut-off of 15/MB (median value), average concordance was 38.7% in TMB-H (N=20) and 59.7% in TMB-L (N=21) (Mann-Whitney, P=0.007). TMB by FFPE was significantly associated with the number of genomic alterations in FFPE (P<0.0001), but was not with the number of genomic alterations in ctDNA (P=0.128) or PD-L1 status (P=0.574).
8eea62084ca7e541d918e823422bd82e Conclusion
This study suggests that ctDNA genomic profiling may replace tissue-based genomic profiling in NSCLC patients with low TMB. However, both tissue and blood-based genomic profiling may be necessary for NSCLC patients with high TMB.
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