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Julien Adam
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MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:David R Spigel, Roberto Ferrara
- Coordinates: 9/08/2019, 13:30 - 15:00, Vancouver (2003)
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MA07.01 - Circulating Immature Neutrophils, Tumor-Associated Neutrophils and dNLR for Identification of Fast Progressors to Immunotherapy in NSCLC (Now Available) (ID 1618)
13:30 - 15:00 | Author(s): Julien Adam
- Abstract
- Presentation
Background
Neutrophils are active regulators of the antitumor immune response, with pro- and antitumor- properties, but generally are associated with progression (PD) and poor outcomes. We reported that pretreatment dNLR ((neutrophils/[leucocytes-neutrophils]; high>3) correlated with immune checkpoint inhibitor (ICI) outcomes in advanced (a) NSCLC pts. Although neutrophil population is heterogeneous, the immature neutrophils (i.e. CD15+CD244-CD16low, among others) seem to be a key subpopulation linked to PD. Tumor-associated neutrophils (TAN) can be also modulator on the microenvironment. We aimed to assess the role of pretreatment circulating immature-neutrophils and tissue-TAN, combined with dNLR, on ICI outcomes in aNSCLC pts.
Method
aNSCLC pts treated with ICI at our institution between 11/2012 and 08/2018 were eligible. Pretreatment immunophenotyping of monocytes, monocytic MDSC (mMDSC) and granulocytes (CD15, CD11b, CD33, CD244, CD16, CD14, CD32, CD64, HLA-DR) was prospectively performed by flow cytometry in fresh whole blood in 58 pts; we defined immature-neutrophils as CD15+CD244-CD16low. TAN in the stroma were assessed using H&E staining from archival specimen, available from 80 pts. dNLR was retrospectively collected; available from 343 pts. Correlation between baseline circulating neutrophils phenotype, TAN and dNLR was evaluated as well as their impact on outcomes: progression-free survival (PFS), overall (OS), including death before 12 weeks (12wk-death) (fast-PD)
Result
366 pts included; 320 (90%) smokers, median age 63; 280 (77%) nonsquamous, 117 (64%) ≥1%PDL1 and 183 missing. Median PFS (mPFS) was 1.93 months (m) [95%CI, 1.8-2.3] and mOS 8.8m [6.5-11.6]. Overall, 12wk-death rate was 31% [25.9-35.6].
Pretreatment high-dNLR (143/343; 42%) was correlated with poor PFS (P=0.002), OS P=0.0003) and a 12wk-death rate of 43% [34.5-50.9]. Pretreatment high immature-neutrophils (30/58; 53%), defined by logrank maximization method (>0.22%), were also associated with poor PFS (P=0.04), OS (P=0.0007) and a 12wk-death rate of 48.7% [26.7-64.1]. TAN (9/80; 11%) were not correlated with outcomes. There was not a correlation between immature-neutrophils, tissue-TAN and dNLR.
When evaluating pretreatment immature-neutrophils and dNLR together, we identified a fast-PD phenotype (high immature-neutrophils/high-dNLR, 10/58; 17%), with a mOS of 1.3m [0.73- not reached (NR)] and 12wk-death rate of 60% [14.5-81.3] compared to a responder-phenotype (low immature-neutrophils/low-dNLR, 12/58; 21%), associated with good outcomes: mOS NR [18.23-NR] (P=0.002).
Conclusion
Pretreatment high circulating immature-neutrophils (CD15+CD244-CD16low) correlate with early failure to ICI and fast-PD phenotype. The combination of circulating immature-neutrophils and dNLR could improve the identification of this population. The impact of immature-neutrophils on ICI should be more deeply explored.
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MA25 - Precision Medicine in Advanced NSCLC (ID 352)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Sebastian Defranchi, Karen Kelly
- Coordinates: 9/10/2019, 14:30 - 16:00, Dublin (1997)
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MA25.03 - Tumor-Infiltrating Lymphocytes (TIL) and Outcomes with Immunotherapy (ICI) or Chemotherapy in Advanced NSCLC (aNSCLC) Patients (Now Available) (ID 1374)
14:30 - 16:00 | Presenting Author(s): Julien Adam
- Abstract
- Presentation
Background
Tumor infiltrating lymphocytes (TIL) morphologically assessed is prognostic in early stages in several tumors. We previously reported the correlation of TIL with immune checkpoint inhibitors (ICI) outcomes in 98 advanced (a) NSCLC patients treated with ICI. We aimed to assess the role of TIL in a larger cohort treated with ICI, and in patients exclusively treated with chemotherapy (CT).
Method
aNSCLC patients with treated with single-agent ICI, with H&E stained sample available, were included between 11/2012 and 02/2017 in 3 cancer centers (immuno-cohort). Patient’s characteristics, biological data were retrospectively collected. The CT-cohort was extracted from the prospective MSN study (NCT02105168), between 06/2009 and 10/2016, enrolling aNSCLC patients treated with platinum-based CT, and tissue available. TIL in the stroma was evaluated in archival samples. High-TIL was defined as ≥10% density. Multivariate Cox model was used to study its prognostic values on overall and progression-free survival (OS, PFS).
Result
A total of 221 patients were included in the immuno-cohort: 142 (64%) male, with median (m) age of 63, 182 (84%) smokers, 161 (77%) PS≤1, 162 (63%) adenocarcinoma; 125 (57%) received ICI as second-line. High-TIL was observed in 49/221 (28%), non-assessable in 46. High-TIL had independent impact on OS and PFS (HR 0.40; 95% CI 0.25-0.63, P<0.0001). The mPFS and OS were 3.1months (mo.) (2.5-4.9) and 11mo. (7.0-13.2) respectively. The high-TIL group had mPFS of 13mo. (5.0-NR) vs. 2.2mo. (1.7-3.0) in low-TIL group (P<0.0001). High-TIL group had mOS not reached (NR) (12.2-NR) vs. 8.4 mo. (5.0-11.6) in low-TIL (P=0.007). The CT-cohort (N=189) had high-TIL in 103/189 (54%). The mPFS and mOS were 5.7mo. (4.9-6.7) and 11.7mo. (9.3-13.0) respectively, with no association with TIL.
OS, Immuno-cohort (n=221) OS, Chemo-cohort (n=188) Hazard ratio (HR)
95% confidence interval (CI)P-value HR
95% CIP-value TIL
≥10% (high)0.46 (0.28-0.81) 0.006 1.03 (0.76-1.41) 0.84 Age
≥65 y0.86 (0.50-1.46) 0.57 0.99 (0.72-1.38) 0.99 Line of treatment*
≥ second line0.69 (0.44-1.09) 0.11 0.84 (0.60-1.16) 0.29 N# metastatic sites
>21.40 (0.88-2.20) 0.16 1.50 (1.07-2.12) 0.02 Performance status
≥22.75 (1.73-4.37) <0.0001 1.94 (1.23-3.04) 0.004 Histology
Squamous1.13 (0.70-1.81) 0.62 1.09 (0.65-1.83) 0.75 *Line of treatment: lines of immunotherapy for the Immuno-cohort; lines of chemotherapy for the Chemo-cohort.
Conclusion
High-TIL (≥10%) is a simple and accessible marker associated with better ICI outcomes, but not with CT. This suggests a potential predictive value that must be validated in larger prospectively studies.
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P1.10 - Prevention and Tobacco Control (ID 175)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.10-06 - Pathological Characterization of Radon-Induced Lung Cancer in Rats (ID 1616)
09:45 - 18:00 | Author(s): Julien Adam
- Abstract
Background
Radon is a radioactive gas, considered the leading cause of lung cancer in non-smokers. Although the risk of lung cancer is linear, there is no safe level and even low dose can be associated with risk. In humans, no specific pathological subtypes of lung cancer have been clearly associated with radon. In animals, the French Atomic Energy Commission (CEA) exposed to low dose of radon (25 working level month, WLM) a large cohort of rats in a radon-exposure chamber, showing lung cancer induced by low exposure (Chameaud J, Radiation Prot Dosimetry 1984). We aimed to describe pathological features of radon-induced tumors in rats from the CEA’s cohort.
Method
Retrospective assessment of archival samples available of the rats exposed to low-dose radon in the Laboratoire de Pathologie Pulmonaire Experimentale, COGEMA (France), between 1989 and 1992. Autopsy reports were also reviewed. The pathological assessment was performed for a thoracic oncology pathologist (JA) in H&E staining slides according to the current WHO histological classification.
Result
Samples from 117 rats were collected. Among 104 tumors, to date the analysis has been performed in 94. Forty tumors (43%) were classified as malignant, 28 (30%) as uncertain malignant potential (UMP) and 26 (28%) benign. In 2 rats (2%) synchronous malignant and non-malignant tumors were observed.
Among the malignant tumors, 23 (58%) were epithelial and 17 (42%) non-epithelial. Lung carcinoma was the most common primary epithelial tumor (n=10, 43%), followed by abdominal area tumors (n=5, 22%), and thyroid (n=3, 13%). In the UMP group, 7 (25%) were epithelial and 21 (75%) non-epithelial, with no lung tumors observed. In the benign group, most of them (n=24, 92%) were epithelial, with 4 cases with lung atypical adenomatous hyperplasia-like lesions; 2 synchronous with other malignant tumors (n=1 lymphoma, n=1 cutaneous squamous cell carcinoma).
A total of 26 tumors (27%) had thoracic involvement: 4 (15%) primary lung non-malignant lesions, 11 primary lung malignancies (42%) and 11 with metastases from other tumors (42%). As primary malignant lung tumors, we observed: 7 (64%) adenocarcinoma in situ, one papillary adenocarcinoma, one undifferentiated large cell carcinoma with bilateral metastases, one metastatic squamous carcinoma and one metastatic undifferentiated tumor, compatible with sarcoma
Conclusion
In this cohort of radon-induced tumors in rats, we observed different tumor types, from non-malignant lesions to aggressive malignancies, with predominance of epithelial tumors. Lung carcinoma was the most common primary tumor and adenocarcinoma the histological subtype more observed, with histological similarities with humans.
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P2.09 - Pathology (ID 174)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.09-15 - PD-L1 Expression and Lymphocyte Infiltration in Resected Stage IIIAN2 NSCLC: Preliminary Data from a Lung ART Ancillary Study (ID 1344)
10:15 - 18:15 | Presenting Author(s): Julien Adam
- Abstract
Background
Patients with resectable stage IIIA N2 NSCLC, are at high risk of both systemic and loco-regional relapse following surgical resection, necessitating neo-adjuvant or adjuvant treatments. Prognostic biological markers are needed. Parameters from the immune microenvironment, including PD-L1 expression and lymphocytic infiltration, have been poorly described in this group of patients. Thus we assessed simultaneously PD-L1 expression and TIL density in a cohort of stage IIIA N2 Lung ART patients, and correlated the results with clinical and pathological features before adjuvant treatment.
Method
Formalin fixed paraffin-embedded tumor surgical specimens from 247 patients included in the Lung Adjuvant Radiotherapy Trial (NCT00410683) were studied. PD-L1 immunohistochemistry was performed centrally on whole slides using a validated clinical PD-L1 assay. Expression of PD-L1 in tumor cells (TC) and immune cell (IC) was scored by a trained pathologist. Morphological assessment of TIL density (percentage of tumor area) was performed on whole hematoxylin-eosin stained slides. Surgical and pathology reports were reviewed by an independent expert committee for tumor staging. Association between immune parameters and baseline clinical characteristics were assessed in exploratory analyses in order to provide insights on immune activity in resected NSCLC patients.
Result
PD-L1 expression in ≥1% TC, ≥50% TC, ≥1% IC, ≥10% IC was observed in 47.8%, 21.9%, 61.5%, 7.3% of patients, respectively. In univariate analysis, high PD-L1 expression in both tumor cells and immune cells for all cut points correlated strongly with a higher TIL density (p-values ≤0.001). In 41 (16.6%) patients with preoperative chemotherapy (CT), a higher TIL density was observed (mean 28.1 vs. 17.5%, p=0.0018) as compared to patients without preoperative CT, but no difference was noted for PD-L1 expression in both TC and IC,. Skip N2 metastases were associated with a higher TIL infiltration (mean 22.9% vs. 17.4% p=0.014). We found no significant correlation between PD-L1 or TIL infiltration with the number of mediastinal lymph nodes stations involved on pathological examination and with histological tumor subtypes (squamous cell carcinoma vs. adenocarcinoma).
Conclusion
PD-L1 expression levels in TC and IC appeared similar in stage IIIA N2 NSCLC as compared to other stages. Expression in both TC and IC strongly correlated with TIL infiltration, suggesting a prominently immune-induced expression mechanism. Preoperative chemotherapy was associated with a higher TIL infiltration but not higher PD-L1 expression. Patients with skip N2 metastases harbored a higher level of TIL density, a finding consistent with a more active immune microenvironment in this group of patients with better prognosis. These data will be subsequently updated on a larger number of patient and correlated to clinical follow-up.
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P2.09-17 - Real-World Concordance Across Pathologists for PD-L1 Scoring in Non-Small Cell Lung Cancer: Results from a Large Nationwide Initiative (ID 898)
10:15 - 18:15 | Presenting Author(s): Julien Adam
- Abstract
Background
PD-L1 immunohistochemistry (IHC) is an important routine biomarker in patients with metastatic and locally advanced non resectable non-small cell lung cancer (NSCLC). Currently, the thresholds of ≥1% and ≥50% of tumor cells stained are clinically relevant. Scoring concordance across pathologists was reported only in small groups of pathologists or across thoracic pathology experts. Here, we provide real-world concordance data in a large group of pathologists (n=161) with various experience of PD-L1 testing and practice in thoracic pathology.
Method
Twenty-nine NSCLC samples, mostly biopsies, stained in routine clinical pathology practice with PD-L1 IHC standardized assays (22C3, 28-8 and SP263), were selected to represent various PD-L1 expression levels. Slides were digitalized and scored for the percentage of tumor cells with membranous staining by 161 pathologists using an online digital platform. A consensus score was defined for each case by a group 15 expert pathologists. Data regarding experience, training and practice of PD-L1 testing were also collected for each pathologist.
Result
Consensus score determined by the expert group highly correlated with the median of scores for each case (correlation coefficient=0.992). Overall concordance across pathologists was moderate, higher for the ≥50% cutoff (K=0.64) than the ≥1% cutoff (K=0.58). A higher concordance was achieved in the expert group (15 pathologists) as compared to the other pathologists (146 pathologists), in particular for the ≥1% cutoff. Concordance across pathologists correlated with training to PD-L1 scoring as well as the number of PD-L1 tests evaluated weekly. No correlation was found with the number of years of thoracic pathology practice or the type of pathology practice (private laboratory, community hospital, university hospital). The issues observed in the most discrepant cases were evaluated and described.
Conclusion
Concordance across pathologists for PD-L1 scoring in NSCLC was higher in the expert group of pathologists as compared to other pathologists, in particular for the ≥1% cutoff. Training to PD-L1 scoring and experience in routine pathology practice correlated with higher concordance. These data emphasize the importance of training to achieve a high concordance across pathologists in the real-world setting.
