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A. Ardizzoni
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Epidemiology and innovations in biomarker development (ID 42)
- Event: ELCC 2017
- Type: Poster Discussion session
- Track:
- Presentations: 1
- Moderators:P. Boffetta, S. Lantuejoul, R.A. Stahel
- Coordinates: 5/06/2017, 16:45 - 17:45, Room W
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30PD_PR - Circulating immune-profile as predictor of outcome in NSCLC patients treated with nivolumab (ID 510)
16:45 - 17:45 | Author(s): A. Ardizzoni
- Abstract
Background:
PD-1/PD-L1 axis blockade is of pivotal interest in NSCLC, where the relative antibodies have shown relevant activity. Detection of markers able to predict the activity of these treatments is an importance issue. The predictive role of PD-L1 evaluated by IHC is debated in NSCLC, also, considering that small biopsies or cytological specimens represent often the only tumor material available. This study aimed to assess a circulating immuno-profile as predictor of outcome in NSCLC patients treated with nivolumab.
Methods:
A peripheral blood immuno-profile evaluation was performed at three different times: At baseline (T0), after 2 cycles (T1) and after 4 cycles (T2) of Nivolumab in 54 advanced pre-treated NSCLC patients treated in an Expanded Access Program in two Italian institutions. Tumor assessment was performed after 4 cycles and every 2 months. FACS analysis of lymphocyte subpopulations [CD3, CD4, CD8, NK (CD56) and Treg (FOXP3)] was performed. In addition to changes in absolute number and % of these populations, they were also characterized for their functional and proliferative activity. Quali-quantitative leucocyte composition at baseline and its change during therapy were correlated with tumor response and overall survival.
Results:
Baseline Neutrophil-to-Lymphocyte Ratio, baseline NK count, lymphocyte count and CD4 variations during therapy showed a statistically significant prognostic role (p < 0.001; p = 0.012; p < 0.001; p = 0.010, respectively). Preliminary results on 31 patients with all 3 time-points samples, showed: A significant increase of NK cells and a significant decrease of CD4% from T0 to T2; a significant increase from T0 to T2 of NK subpopulation CD56dim (with reduction of CD56bright); considering two groups of patients (19 responders vs. 12 non-responders), a NK increase (overall and of CD56dim) and CD4% decrease was observed in responders and non-responders, respectively; absolute number and % of NK at baseline was statistically different in the two groups; absolute number and % of CD8+/PD1+ at baseline was significantly higher in responders vs. non-responders.
Conclusions:
These data show that it is possible to identify predictive peripheral immuno-biomarkers, such as NK and CD8, for nivolumab therapy in advanced NSCLC.
Clinical trial identification:
NA
Legal entity responsible for the study:
University Hospital of Parma
Funding:
AIRC
Disclosure:
All authors have declared no conflicts of interest.
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Immunotherapies and targeted therapies in advanced NSCLC (ID 39)
- Event: ELCC 2017
- Type: Proffered Paper session
- Track:
- Presentations: 1
- Moderators:L. Paz-Ares, N. Reguart
- Coordinates: 5/06/2017, 14:45 - 16:15, Room B
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2O - Favorable clinical outcome and response to immunotherapy share a common PD-L1/PD-1 based NSCLC immune contexture (ID 400)
14:45 - 16:15 | Author(s): A. Ardizzoni
- Abstract
- Presentation
Background:
The success of PD-1/PD-L1 immune checkpoint inhibitors strengthens the notion that tumor growth and regression are immune regulated. According to PD-L1 status and number of Tumor Infiltrating Lymphocytes (TILs), the cancer microenvironment can be classified into four types reflecting immune resistance, ignorance, induction and tolerance. However, an extended tissue characterization of the immune contexture and its predictive/prognostic value in NSCLC remain elusive. The aim of the present investigation was to determine whether immunologically defined classes of NSCLC differentially impact on clinical outcome.
Methods:
Histologic sections of NSCLC samples surgically removed to untreated 51 ADC and 69 SCC and 8 ADC and 10 SCC patients receiving Nivolumab were included. PD-L1 (clones 28-8 and SP142) was measured by immunoperoxidase (H-score) and immunofluorescence (QIF). The n/mm[2] and intra-, peri-tumor or invasive margin localization of TILs subpopulations were computed establishing cut off values relative to each phenotype. Immunohistochemical data and clinical records were subjected to Kaplan Meier analysis.
Results:
ADC cases had 2-fold higher CD3[pos] and 1.8-fold lower CD4[pos] cells compared to SCC and TILs-rich ADC had 10 months’ increase in OS vs –poor (p < 0.01). EGFR mutation conditioned a lower intratumor density of TILs. The frequency of type I (PD-L1[high] TILs[high]) contexture was low (14.6%) while > 1/3 of NSCLC samples displayed type II (PD-L1[low/neg] TILs[low]), reflecting immune exhaustion. The proportion of type III (PD-L1[high] TILs[low]) and IV (PD-L1[low/neg] TILs[high]) immune categories, with relatively increased Nks and Tregs, was similar. NSCLC type III had the highest OS (35.5 mos.) and PFS (25.7) while in type II immune ignorant cases OS and PFS were respectively 21.7 and 12. Independently from immune categories, patients with PD-1[low] and high CD8/CD3 ratio had 11 mos. gain in OS (p < 0.01) compared to the reverse counterpart. Accordingly, PD-L1[high] and PD-1[low] characterized 86% of patients responsive to nivolumab.
Conclusions:
In a dynamic PD-L1 milieu a concomitant intrinsic or therapeutically induced decay of PD-1 receptor allows TILs to escape from PD-L1 pressure and delays tumor progression, improving OS.
Clinical trial identification:
Legal entity responsible for the study:
University Hospital of Parma, Medicine
Funding:
University of Parma
Disclosure:
All authors have declared no conflicts of interest.
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Poster Display Session (ID 63)
- Event: ELCC 2017
- Type: Poster Display Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 5/07/2017, 12:30 - 13:00, Hall 1
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102P - LUX-Lung 8 phase III trial: Analysis of long-term response to second-line afatinib in patients with advanced squamous cell carcinoma (SCC) of the lung (ID 355)
12:30 - 13:00 | Author(s): A. Ardizzoni
- Abstract
Background:
In LUX-Lung 8, afatinib (A; 40mg/day) significantly improved OS (median 7.9 vs 6.8 months, p = 0.008) and PFS (2.6 vs 1.9 months, p = 0.010) versus erlotinib (E; 150mg/day) in pts with pretreated SCC of the lung (n = 795). 12-month (36 vs 28%; p = 0.016) and 18-month survival (22 vs 14%; p = 0.013) were significantly higher with A than E, indicating that some pts derive prolonged benefit from A. This is a post-hoc analysis of baseline characteristics and efficacy/safety of A in long-term responders (LTRs; treatment for ≥12 months). Archived tumor samples and serum were analyzed to identify potential biomarkers.
Methods:
Tumor samples were retrospectively analyzed using next-generation sequencing (NGS); EGFR expression was determined by IHC. Pre-treatment serum samples were analyzed with VeriStrat[®] and classified as VeriStrat-Good or VeriStrat-Poor.
Results:
21/398 pts treated with A were LTRs. Six pts were still on treatment at the time of data cut-off. The median duration of treatment was 17.6 months (range: 12.3–27.6). Baseline characteristics were similar to the overall dataset (median age: 64 y [range: 54–81]; male: 76%; Asian: 29%; ECOG 0/1: 33%/67%; best response to chemotherapy CR or PR/SD: 48%/52%; current and ex-smokers: 90%). Median PFS was 16.6 months (range: 2.8–25.8); median OS was 21.1 months (12.9–31.6). The most common treatment-related AEs (all grade/grade 3) were: diarrhea (81%/5%); rash/acne (71%/5%); stomatitis (29%/5%). AEs generally occurred soon after treatment onset. Six pts had dose reductions due to related AEs. NGS data in ten LTRs will be presented. Genomic aberrations in the ErbB gene family were identified in 50% of these pts (overall dataset: 26.5%). Of 17 pts assessed by VeriStrat, 88% were VeriStrat-Good (overall dataset: 62%). IHC data were available for only one LTR (EGFR-).
Conclusions:
Baseline characteristics of LTRs to A were similar to the overall dataset. A conferred median OS of almost 2 years in this subgroup. A was well tolerated with predictable, transient AEs. Though biomarker data look promising, the cohort was too small to identify any clear NGS/VeriStrat predictive signals; further studies are required.
Clinical trial identification:
LUX-Lung 8: EudraCT No: 2011-002380-24
Legal entity responsible for the study:
Boehringer Ingelheim
Funding:
Boehringer Ingelheim
Disclosure:
J.C-H. Yang: Ad board and honoraria: BI, Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical Daiichi, Sankyo, and AZ. G. Goss: Participated on advisory boards for AstraZeneca, Boehringer Ingelheim, Pfizer, Eli Lilly, Bristol-Myers Squibb, and Celgene. E. Felip: Participated on advisory boards for Eli Lilly, Pfizer, Roche, MSD, and Boehringer Ingelheim. Felip has receieved lecture fees from AstraZeneca, Bristol-Myers Squibb, and Novartis. A. Ardizzoni: Received honoraria and participated on advisory boards for Bristol-Myers Squibb, MSD, Eli-Lilly, and Boehringer Ingelheim. Ardizzoni has received honoraria from Pfizer and Bayer. S.M. Gadgeel: Participated on advisory boards for Boehringer Ingelheim, Pfizer, Genentech, ARIAD, AstraZeneca, Bristol-Myers Squibb, and Roche. N. Dupuis: Employee of and owns stock in Biodesix. E. Ehrnrooth: Employee of Boehringer Ingelheim. J-C. Soria: Astrazeneca, Astex, GSK, Gammamabs, Lilly, MSD, Merus, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Symphogen, Takeda. All other authors have declared no conflicts of interest.
