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F. Skoulidis
Moderator of
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PD-L1 expression and tumor microenvironment in advanced lung cancer (ID 59)
- Event: ELCC 2018
- Type: Proffered Paper session
- Track:
- Presentations: 6
- Moderators:G. Scagliotti, F. Skoulidis
- Coordinates: 4/12/2018, 16:45 - 18:15, Room B
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Invited Discussant 1O and 2O (ID 692)
16:45 - 18:15 | Presenting Author(s): F. Skoulidis
- Abstract
- Presentation
Abstract not provided
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Invited Discussant 78O and 130O (ID 691)
16:45 - 18:15 | Presenting Author(s): K. Kerr
- Abstract
- Presentation
Abstract not provided
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130O - Real-world prevalence of PD-L1 expression in locally advanced or metastatic non-small cell lung cancer (NSCLC): The global, multicentre EXPRESS study (ID 619)
16:45 - 18:15 | Presenting Author(s): M. Dietel | Author(s): N. Savelov, R. Salanova, P. Micke, G. Bigras, T. Hida, B. Piperdi, T. Burke, S. Khambata-Ford, A. Deitz
- Abstract
- Presentation
Background:
PD-L1 expression on tumour cells has been associated with improved clinical benefit from immunotherapies targeting the PD-1 pathway. We conducted a global, multicentre, retrospective observational study to determine real-world prevalence of tumour PD-L1 expression in patients with advanced NSCLC.
Methods:
Patients ≥18 years with histologically confirmed stage IIIB/IV NSCLC and a tumour tissue block (≤5 years old) obtained before treatment at or after this stage were identified in 45 centres across 18 countries. PD-L1 tumour expression was evaluated at each institution using the PD-L1 IHC 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). The percentages of patients with PD-L1 tumour proportion score (TPS) ≥50%, TPS ≥1%, and TPS <1% were described overall and by relevant clinicopathologic characteristics.
Results:
Of 2634 patients who met inclusion criteria, 2435 (92%) had PD-L1 data; 540 (22%) of these were TPS ≥50%, 1256 (52%) were TPS ≥1%, and 1179 (48%) were TPS <1% (Table). The percentage of patients with PD-L1 TPS ≥50% and TPS ≥1%, respectively were: 22%/51% in Europe; 22%/53% in Asia Pacific; 22%/47% in the Americas, and 24%/54% in other countries. The prevalence of EGFR mutations (19%) and ALK alterations (3%) was consistent with prior reports in metastatic NSCLC. Among 1088 patients negative for both EGFR mutation and ALK alteration, the percentage of patients with PD-L1 TPS ≥50% and TPS ≥1%, respectively, were 26% and 53%.
aThe number of patients with the specific characteristic (row total) is the denominator for percentages in TPS columns.bIncludes Argentina, Canada, and Colombia.cIncludes Russian Federation, Saudi Arabia, and Turkey.Characteristic, n (%)[a] N TPS ≥50% TPS ≥1% TPS <1% All patients 2435 540 (22.2) 1256 (51.6) 1179 (48.4) Age, years ≥75 457 107 (23.4) 227 (49.7) 230 (50.3) <75 1977 433 (21.9) 1029 (52.0) 948 (48.0) Sex Female 925 191 (20.6) 477 (51.6) 448 (48.4) Male 1509 348 (23.1) 778 (51.6) 731 (48.4) Region Asia Pacific 691 152 (22.0) 366 (53.0) 325 (47.0) Europe 849 183 (21.6) 431 (50.8) 418 (49.2) The Americas[b] 369 80 (21.7) 175 (47.4) 194 (52.6) Other[c] 526 125 (23.8) 284 (54.0) 242 (46.0) Specimen type Surgical resection 618 127 (20.6) 330 (53.4) 288 (46.6) Biopsy 1743 400 (22.9) 895 (51.3) 848 (48.7) Specimen source Primary 1735 377 (21.7) 892 (51.4) 843 (48.6) Metastases 632 143 (22.6) 321 (50.8) 311 (49.2) Histology Squamous 507 114 (22.5) 288 (56.8) 219 (43.2) Nonsquamous 1906 420 (22.0) 956 (50.2) 950 (49.8) Smoking status Never 553 100 (18.1) 255 (46.1) 298 (53.9) Former 660 159 (24.1) 358 (54.2) 302 (45.8) Current 762 187 (24.5) 401 (52.6) 361 (47.4) ALK translocation status Positive 77 15 (19.5) 50 (64.9) 27 (35.1) Negative 1470 352 (23.9) 765 (52.0) 705 (48.0) EGFR mutation status Positive 464 60 (12.9) 200 (43.1) 264 (56.9) Negative 1286 324 (25.2) 682 (53.0) 604 (47.0)
Conclusions:
This is the largest real-world study in advanced NSCLC to date evaluating PD-L1 tumour expression using the 22C3 pharmDx kit. Testing failure rate was low despite local evaluation of PD-L1 TPS across a large number of sites. Prevalence of PD-L1 TPS ≥50% and TPS ≥1% was similar across geographic regions and broadly consistent with central testing results from clinical trial screening populations (Aggarwal et al. Ann Oncol 2016;27:1060P).
Clinical trial identification:
Legal entity responsible for the study:
Merck & Co., Inc., Kenilworth, NJ, USA
Funding:
This study and medical writing assistance were funded by Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure:
G. Bigras: Advisory board member for Merck. T. Hida: Grants and personal fees from AstraZeneca, Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly, Novartis, Taiho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim, Pfizer, Bristol-Meyers Squibb, Clovis Oncology, MSD, and Kissei; grants from Eisai, Takeda Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma, Abbvie, Merck Serono, Kyowa Hakko Kirin, Daiichi Sankyo, Astellas, Ignyta, and Servier. B. Piperdi, T. Burke, S. Khambata-Ford, A. Deitz: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA. All other authors have declared no conflicts of interest.
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1O - Integration of tissue and circulating parameters identifies a favorable immune profile in NSCLC patients treated with nivolumab (ID 421)
16:45 - 18:15 | Presenting Author(s): G. Mazzaschi | Author(s): F. Facchinetti, D. Madeddu, S. Buti, F. Gelsomino, A. Ardizzoni, F. Aversa, G. Missale, F. Quaini, M. Tiseo
- Abstract
- Presentation
Background:
To define prognostic and potentially predictive immune profiles in NSCLC patients receiving nivolumab, an integrated analysis of tissue and circulating parameters was performed.
Methods:
Peripheral blood (PB) from 31 advanced NSCLC patients was analyzed by FACS to assess CD3, CD8, CD4, NK, Treg, and MDSC (CD14[pos]/CD33[pos]/DR[neg]) number, function (PD-1, CD3ζ, Granzyme B, Perforin) and proliferation (Ki67). Data were collected at baseline (T0), and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. PD-L1 (H-score) and TILs subpopulations were immunohistochemically investigated. Merged tissue and circulating parameters were correlated to clinico-pathological features, response to treatment (RECIST 1.1) and survival outcomes.
Results:
T cells were more represented in PB from ADC patients (p < 0.01 vs SqCC), while KRAS mutation conditioned higher number of CD3, CD8, CD4, and NK, and lower MDSC (p < 0.05). Active smoking and BPCO directly correlated with T and NK cells proliferation (p < 0.05). Additionally, steroid naïve patients had increased effector and reduced immune suppressive (p < 0.05) phenotypes. Clinical benefit (CB, n = 19) group, compared to non-responder (NR, n = 12), displayed a distinctive PB immune profile at baseline, including higher NK (tot, CD3ζpos, Pfnpos, GrzBpos) and CD8pos/PD-1pos cells (p < 0.01). These CB immune features were maintained during nivolumab, while MDSC progressively rose in NR (p < 0.05). Prolonged OS (p < 0.05) and PFS (p < 0.01) were recorded in cases with high NK and CD8pos/PD-1pos number at T0. At tissue level, while high PD-L1 score had a modest clinical impact, low PD-1 expression in CD8pos TILs was a distinctive feature of CB (p < 0.001 vs NR) and correlated with better OS (ns) and PFS (p < 0.01). Strikingly, the combination of predetermined PB (high NK and CD8pos/PD-1pos) and tissue (low CD8pos/PD-1pos) positive prognostic factors characterized an immune privileged context provided by significantly prolonged PFS (p < 0.001) and OS (p < 0.01).
Conclusions:
A divergent PD-1 expression in blood and tissue cytotoxic cells associated with a preserved functional pool of circulating NKs portrays an immune profile prone to nivolumab efficacy.
Clinical trial identification:
Legal entity responsible for the study:
University of Parma, Italy
Funding:
Has not received any funding
Disclosure:
All authors have declared no conflicts of interest.
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2O - MET activation in lung cancer up-regulates PD-L1 expression independently of JAK-STAT pathway, promoting an immunosuppressive phenotype (ID 356)
16:45 - 18:15 | Presenting Author(s): M. Saigí | Author(s): J.J. Alburquerque-Béjar, A. Mc Leer-Florin, C. Pereira, E. Pros, O.A. Romero, N. Baixeras, E. Nadal, E. Brambilla, M. Sánchez-Céspedes
- Abstract
- Presentation
Background:
The ability of tumors to avoid immune surveillance has emerged as therapeutically approachable in several types of cancer, especially through the blockade of immune checkpoints such as PD-L1/PD-1. Our purpose is to determine the contribution of somatic genomic alterations in lung cancer (LC) to the capability of tumour cells to escape the immune surveillance checkpoints.
Methods:
The mutation status of recurrent driver genes in lung cancer (e.g. EGFR, KRAS, MET) and the expression of immune-related molecules (PD-L1, HLA-complex, and tumour infiltrating lymphocytes CD8+, TILs) were assessed in a cohort of 155 primary resected non-small cell lung cancer (NSCLC). Correlations between genomic alterations and immune markers were determined by Chi-square test and validated in genetically characterized cancer cell lines. Functional assays were performed using appropriate treatments, including IFNγ, to modulate selected pathways. RNA-Seq analysis was performed to analyse differential gene expression with these treatments.
Results:
MET activation, comprising MET exon 14 skipping mutations and MET amplification, was found in 3% of samples in our cohort and these tumors were more likely to have positive immunostaining (≥5%) of PD-L1 (p = 0.05), with no specific TILs CD8+ pattern. In MET altered cancer cell lines, PD-L1 was upregulated through MET activation, independently of JAK-STAT pathway. Interestingly, we reported JAK2 loss of function mutations in LC cell lines that co-occurred with MET alterations, and abrogated the response to IFNγ. RNA-Seq analysis showed that both MET activated signature (MA-Sign) and IFNγ treatment (IFN-Sign), included genes involved in negative regulation of immune response such as CD274 (PD-L1), PDCD1LG2 (PD-L2), SOCS1 and SOCS3. However, none of the pro-immune response genes commonly found in IFN-Sign were upregulated in MA-Sign.
Conclusions:
MET oncogenic is not mutually exclusive with JAK2 inactivating mutations in LC and promotes the intrinsic expression of several negative checkpoints of the immune response, including PD-L1. Both genetic alterations are likely to promote tumor growth by enabling immune tolerance.
Clinical trial identification:
Legal entity responsible for the study:
IDIBELL
Funding:
Has not received any funding
Disclosure:
All authors have declared no conflicts of interest.
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78O - Immune microenvironment of small cell lung cancer (SCLC): Distribution of PD-L1 expression and prognostic role of FOXP3-positive tumor infiltrating lymphocytes (ID 370)
16:45 - 18:15 | Presenting Author(s): A. Pavan | Author(s): M. Fassan, M.V. Dieci, I. Attili, G. Pasello, F. Calabrese, F. Rea, M. Rugge, P.F. Conte, L. Bonanno
- Abstract
- Presentation
Background:
SCLC represents one of the most aggressive lung malignancies, characterized by a high growth fraction and early metastatic spread. New therapeutic options are badly needed and immunotherapy might represent a promising approach. Unfortunately, so far, no molecular prognostic markers have been validated for clinical practice and data on immune microenvironment are limited.
Methods:
We have retrospectively analyzed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 (22C3 clone, DAKO) was performed on tumor cells (TCs) and on tumor-infiltrating lymphocytes (TILs): positivity was defined as PD-L1 expression on 1% or more TCs or TILs. Immunohistochemistry for CD8 (C8/144B clone, DAKO) and FOXP3 (236A/E7 clone, ABCAM) was also performed. A semiquantitative score was used and CD8 and FOXP3 TILs categorized as positive versus negative.
Results:
The analysis included 104 patients: 48 surgically resected, 18 patients treated with radical-intent chemo-radiotherapy and 38 metastatic. In overall study population, PD-L1 was expressed in TCs in 25% of cases. The expression of PD-L1 was significantly correlated with stage disease (32% stage I-III; 13% metastatic stage; p:0.034 for TCs and p:0.002 for TILs) and with outcome: median OS 46.8 months (m) (95% CI: 22.6 to 71.0) versus (vs) 10.9 m (95% CI: 6.2 to 15.7; p = 0.047) PD-L1 positive vs negative respectively; the relation with outcome however, was not confirmed in multivariate analysis. CD8-positive TILs and FOXP3-positive TILs were present in 59% and 72% of samples respectively. Neither the presence of CD8+ TILs nor that of FOXP3+ TILs was correlated to stage. The presence of FOXP3-positive TILs was associated with improved prognosis among non-metastatic patients: median OS 52.5 m (95% CI: 21.4 to 83.7) vs 20.5 m (95% CI: 0 to 49.2; p = 0.027) FOXP3-positive vs negative TILs, a relation confirmed in multivariate analysis.
Conclusions:
Expression of PD-L1 is reduced in advanced stage SCLC patients. Further studies are needed to understand if down-regulation of PD-L1 is linked to a more aggressive phenotype. The prognostic role of FOXP3 TILs in stage I-III SCLCs warrants further confirmation in larger series of patients.
Clinical trial identification:
Legal entity responsible for the study:
Istituto Oncologico Veneto (IOV), Padua, Italy
Funding:
Università degli Studi di Padova
Disclosure:
All authors have declared no conflicts of interest.
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Author of
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Immune checkpoint blockade: Basic mechanisms, preclinical evaluation and mechanisms of resistance (ID 25)
- Event: ELCC 2018
- Type: Educational session
- Track:
- Presentations: 1
- Moderators:O. Michielin, L. Rivoltini
- Coordinates: 4/13/2018, 11:00 - 12:30, Room C
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Genomic background and immune landscape (ID 104)
11:00 - 12:30 | Presenting Author(s): F. Skoulidis
- Abstract
Abstract not provided
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PD-L1 expression and tumor microenvironment in advanced lung cancer (ID 59)
- Event: ELCC 2018
- Type: Proffered Paper session
- Track:
- Presentations: 1
- Moderators:G. Scagliotti, F. Skoulidis
- Coordinates: 4/12/2018, 16:45 - 18:15, Room B
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Invited Discussant 1O and 2O (ID 692)
16:45 - 18:15 | Presenting Author(s): F. Skoulidis
- 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.
