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J. Adam
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.02 - Mutational Burden in Pulmonary Neuroendocrine Tumors (puNETs) (ID 6099)
14:26 - 14:32 | Author(s): J. Adam
- Abstract
- Presentation
Background:
Tumor mutational load (TML) by whole-exome sequencing (WES) is a potential determinant of response to immune checkpoint blockers. The use of PD-L1 as a predictive biomarker for use of PD-1/PD-L1 inhibitors is limited. To date, there are few data concerning TML in puNETs.
Methods:
WES was performed in fresh-frozen tumor-normal pairs from 35 typical carcinoid (TC), 4 atypical carcinoid (AC) and 9 large-cell neuroendocrine carcinoma (LCNEC) consecutively collected. Exome enriched libraries were sequenced on an Illumina HiSeq 2000 with a paired-end 2 x 100 bp protocol. Reads were aligned to the reference hg19 using an implementation of the Burrows-Wheeler Aligner, and a BAM file was produced for each tumor and normal sample using the Picard pipeline. The MuTect algorithm was used to identify SSNVs in WES data. We used a minimal allelic fraction cutoff of 0.1. Patients' characteristics and TML were described (median and interquartile for quantitative variables and frequencies for qualitative variables). To evaluate the effect of some factors on the TML, an analysis of variance was used. A log transformation was performed according to the distribution of the TML. The median follow-up was estimated using the Schemper's method. The number of relapses and deaths was reported.
Results:
Cohort included 24 male and 24 female. Median age at diagnosis was 57 [Q1= 46; Q3= 70] years, 38% of carcinoids (TC+AC) and 89% of LCNEC were smokers, 26 (54%) stage I, 16 (34%) stage II, 3 (6%) stage III and 3 (6%) stage IV. All patients underwent surgery and 5 (10%) received neoadjuvant treatment. Median follow-up was 32.6 (min= 4.4; max= 179.9) months; there were 8 (17%) relapses (6/9 LCNEC, 2/39 carcinoids) and 10 deaths. On average, 11.6 Gb of sequence were produced per sample, aiming a mean coverage of 72X. Overall median TML was 0.31/Mb [Q1= 0.22; Q3= 0.67], significantly lower in carcinoids tumors than LCNEC (0.28 [Q1= 0.20; Q3= 0.38]/Mb vs. 2.98 [Q1= 1.20; Q3= 4.84]/Mb, respectively, p<0.0001). Similar findings were observed among smoker vs. non-smoker patients (0.28 [Q1= 0.18; Q3= 0.38]/Mb vs. 0.60 [Q1= 0.28; Q3= 2.98]/Mb, respectively, p=0.04). Both variables were found to be independently correlated with TML within the ANOVA test (p=0.0016).
Conclusion:
Our findings provide a unique portrait of puNETs, revealing different histotype mutational burden. Continued work in harnessing immunological data in puNETs are needed for better understanding immunotherapy-treatment option in this orphan disease.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-031 - Immune Checkpoint Inhibitors (IC) and Paradoxical Progressive Disease (PPD) in a Subset of Non-Small Cell Lung Cancer (NSCLC) Patients (ID 5448)
14:30 - 14:30 | Author(s): J. Adam
- Abstract
Background:
In non-squamous NSCLC PD-L1 negative patients (pts), IC might increase the risk of early death compared to docetaxel in the phase III study Checkmate 057. Tumor Growth Rate (TGR) is calculated using 2 CTscans and the time interval between the 2 exams. It integrates tumor dynamics and kinetics. We hypothesized that TGR could identify a subset of pts named PPD, in which IC could accelerate tumor progression, leading to early death.
Methods:
We performed a retrospective case study of all NSCLC pts treated by IC in a single institution between Dec. 12 and Feb. 16. CT scan were centrally reviewed by a senior radiologist and assessed according to RECIST 1.1 criteria. We calculated TGR at baseline of IC (baseline CTscan (n) vs n-1 CTscan) and TGR during IC (n+2 CTscan vs n+1 CTscan). We further estimated the difference (deltaTGR) between TGR during IC and TGR at baseline. DeltaTGR>0 means IC speeds up tumor growth. PPD was defined as deltaTGR>50%, corresponding to an absolute increase in TGR greater than 50% per month. PDL1 expression was assessed with the SP142 clone.
Results:
89 pts were eligible. 58% were male, median age 60 (41-78); 15% never smokers. 62 pts had adenocarcinoma, 21 squamous and 6 other histologies. Mutational status was unknown for 14 pts; 36% wild type, 9 pts EGFRmut, 25 pts KRASmut. PDL1 expression was positive in 25 pts, unknown in 57 pts. 52 pts (58%) received nivolumab, 25 pembrolizumab and 12 atezolizumab. Treatement was received as 1-3[rd] line in 52 pts, and as ≥ 4[th] line in 37 pts. Overall, 25 pts (28%) had a response according to RECIST 1.1 criteria, 31 (35%) a stable disease. Median OS was 14.7 months. During IC, deltaTGR was <0 in 79 pts and >0 in 20 pts. Among the 20 pts with deltaTGR>0, 9 had a PPD. Characteristics (age, sex, smoking status, pathology, number of previous line, PDL1 status) of the 9 pts were not different from other pts. None of the PPD were pseudoprogression. Median OS of PPD vs others was 3.2 and 23 months, respectively. PPD was not more frequent in tumors with high baseline TGR.
Conclusion:
Our results suggest that PPD is a new subset of response criteria in which IC may increase tumor progression, leading to a poorer survival. Rapidly growing disease at study entry nor RECIST criteria could predict the occurrence of PPD.
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P3.02c-066 - HLA-A2 Status and Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients (ID 4774)
14:30 - 14:30 | Author(s): J. Adam
- Abstract
Background:
The class I human leucocyte antigen (HLA) molecules play a critical role in tumor recognition by T cells and the loss of expression seems to be an escape mechanism of antitumoral immunity. Novel immune-targeting cancer vaccines are currently developped in HLA-A2 positive patients for modulating the T cells immune response. We hypothesized that HLA-A2 status could influence the prognosis and response to immune checkpoints (IC) inhibitors.
Methods:
Advanced NSCLC patients treated with nivolumab or within clinical trials (with pembrolizumab or atezolizumab) were prospectively included from November 2013 to July 2016 in our institute. HLA-A2 status was analysed by flow cytometry; PDL1 was analysed by immunohistochemistry. Clinical and biological data were collected at baseline and after cycle 1. Statistical analysis was performed with R studio.
Results:
Out of 160 patients treated, HLA-A2 status was available for 65 patients. 40 patients (61.54%) were male, median age was 65 years (30-86); 55 (84.6%) were smokers and 57 (72.3%) had performance status 0-1. 42 patients (64.6%) had an adenocarcinoma, 17 (26.1%) squamous cell carcinoma and 6 (9.2%) others histologies. Molecular status was available in 55 patients: 6 (10.9%) were EGFRmut, 3 (5.4%) ALK positive, 13 (23.6%) KRASmut, 3 (5.4%) BRAFmut and 12 (21.8%) wildtype. PDL1 expression was positive in 13 patients (20%), negative in 5 (7.7%) and unknown in 47 (72.3%). The median of previous lines of treatment was 1 (1-8). HLA-A2 status was positive in 32 patients (49.23%) and negative in 33 (50.76%). HLA-A2 positivity was associated with higher number of metastases at baseline and the presence of liver metastasis (p=0.04 and p= 0.016, respectively). Other patient and tumor characteristics were well balanced between HLA-A2 + and - groups. The median progression free survival to immunotherapy (iPFS) was 4 months [0-40]. In HLA-A2 positive the median iPFS was 4 months vs 4 months in HLA-A2 negative (p=0.63). The median overall survival (OS) was 21 months [0-121]. The median OS was 18.5 months in HLA positive vs. 24 months in HLA-A2 negative patients (p=0.25). No significant difference between both HLA-A2 groups was identified.
Conclusion:
Our preliminary results suggest that HLA-A2 status has no predictive or prognostic value in NSCLC patients treated with immune checkpoint inhibitors. An updated analysis on 78 patients will be presented.
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PL04a - Plenary Session: Immune Checkpoint Inhibitors in Advanced NSCLC (ID 430)
- Event: WCLC 2016
- Type: Plenary
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:J. Soria, C. Zhou
- Coordinates: 12/07/2016, 08:45 - 09:40, Hall D (Plenary Hall)
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PL04a.04 - Multicentric French Harmonization Study for PD-L1 IHC Testing in NSCLC (Abstract under Embargo until December 7, 7:00 CET) (ID 4910)
09:15 - 09:25 | Author(s): J. Adam
- Abstract
- Presentation
Background:
PD-L1 immunohistochemistry (IHC) is considered as a predictive biomarker for most anti PD-1/PDL-1 therapies in non-small cell lung cancer, but different assays were used in clinical trials. Several studies have compared 4 assays (22C3, 28-8, SP142, SP263) performed in central laboratories on dedicated platforms. In order to harmonise and make PD-L1 testing widely available on most IHC platforms and centers, we compared PD-L1 Dako (22C3, 28-8) and Ventana (SP263) assays and laboratory-developed tests (LDT).
Methods:
IHC with five anti-PD-L1 clones (28-8, 22C3, E1L3N, SP142 and SP263) was performed concomitantly on 41 NSCLC surgical specimens in 7 centers. The IHC platforms used were Ventana BenchMark Ultra (2 centers), Leica Bond (2 centers) or Dako Autostainer Link 48 (3 centers). For each matching platform, 22C3, 28.8 and SP263 assays were performed. For non-matching platforms and other antibodies, LDT were developed in each center and harmonised based on tonsil tissue staining. A total of 35 stainings were performed across different platforms and antibodies for each case. Seven thoracic pathologists trained to PD-L1 scoring in expert courses participated. Each pathologist analysed 6 cases and compared the stainings obtained with the 5 antibodies on all platforms. Tumor cell and immune cell D-L1 stainings were scored semi-quantitatively as recommended in PD-L1 Dako and Ventana assays. For statistical analysis, 1, 5, 25, 50% and 1, 5, 10% thresholds were used for tumor cells and immune cells, respectively.
Results:
28-8, 22C3 and SP263 assays were highly concordant for tumor cell and immune cell stainings across the 5 Dako or Ventana platforms (R2=0.886 to 0.953). LDT demonstrated various levels of concordance as compared to those 3 assays. Notably, LDT using SP263 clone were the most concordant across all platforms for both immune cell and tumor cell stainings, whereas some selected LDT with clones 28-8, 22C3 and E1L3N, but not SP142, showed a good correlation with the 3 assays regarding tumor cells only.
Conclusion:
28-8, 22C3 and SP263 assays gave comparable results across dedicated platforms for tumor cells staining, as well as some selected LDT protocols using 28-8, 22C3, SP263 and E1L3N clones. These results will be further validated at the national level in order to provide recommendations for the use of assays and LDT for PD-L1 testing in NSCLC.
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PR04 - Press Conference: Advanced Care (ID 404)
- Event: WCLC 2016
- Type: Press Conference
- Track:
- Presentations: 1
- Moderators:C. Zielinski
- Coordinates: 12/07/2016, 10:30 - 11:45, Schubert 1
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PR04.04 - Multicentric French Harmonization Study for PD-L1 IHC Testing in NSCLC (ID 7216)
10:30 - 10:30 | Author(s): J. Adam
- Abstract
- Presentation
Abstract not provided
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