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D. Ionescu
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ORAL 13 - Immunotherapy Biomarkers (ID 104)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:D. Kim, D. Grunenwald
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL13.05 - Predictive Biomarker Testing for Programmed Cell Death 1 Inhibition in Non-Small Cell Lung Cancer (ID 1081)
17:28 - 17:39 | Author(s): D. Ionescu
- Abstract
- Presentation
Background:
Lung cancer is the largest cause of cancer-related mortality in the developed world. Advances in molecular targeted therapies have led to improved survival in a subset of non-small cell lung cancer (NSCLC) patients. Recently, inhibitors of the programmed cell death receptor 1 (PD1) have proven clinical efficacy in NSCLC. Only a subset of patients respond to PD1 inhibitors, likely reflecting variation in tumor-expression of the PD1 ligand (PD-L1). Many clinical trials have evaluated PD-L1 as a possible predictive biomarker for immune therapy; however several parallel and uncoordinated efforts have led to a high amount of heterogeneity, uncertainty, and ambiguity in the literature around PD-L1 and its use as a biomarker. We aim to investigate the feasibility of PD-L1 biomarker testing in NSCLC using immunohistochemistry (IHC).
Methods:
Cases of stage II, surgically resected NSCLC, adenocarcinoma were identified retrospectively from the archives of the British Columbia Cancer Agency. A tissue microarray (TMA) was constructed with matched primary and metastatic lung tumors. IHC directed towards PD-L1 was performed with 3 different primary antibody clones: E1L3N (Cell Signaling Technology), SP142 (Spring Bioscience), and 28-8 (Dako), each stain was prepared using a unique protocol. Additional cases of NSCLC with available whole-genome sequence were also stained. Staining results were reviewed and scored by intensity of staining and the percentage of positive tumor cells. Cases with positive staining of any intensity in greater than 1% of tumor cells were considered positive (H score > 1). Clinical, pathological, and genomic features of PD-L1 positive cases were reviewed.
Results:
Eighty cases of NSCLC were identified and used in TMA construction. 78 cases had matched lymph node metastases included in the TMA. 29 cases (36%) were positive by the SP142 clone, 19 (24%) by E1L3N, and 27 (34%) by the 28-8 clone. The 3 clones showed concordant results in 61 (76%) of cases, 15 (19%) discordant cases showed low level staining with SP142/28-8 and no staining with E1L3N, 2 (2.5%) cases showed no staining by 28-8 with moderate staining by SP142/E1L3N. Lymph node metastases showed a concordant PD-L1 score in 65 (83%) cases, with no detectable trend in the discordance. Comparison of primary antibodies showed a high rate of concordance (κ=0.68). Exploratory analysis of 6 additional cases with whole-genome and transcriptome data showed no statistical correlation between PD-L1 IHC and tobacco-induced hypermutation signature (p=0.22), or PD-L1 mRNA expression (R[2] = 0.35) by linear regression.
Conclusion:
PD-L1 IHC is reproducible in the setting of an academic reference laboratory. There are small, but potentially clinically relevant, differences between commercially available PD-L1 diagnostic antibodies. Primary tumor PD-L1 status is generally reflective of metastatic tumor PD-L1 status. Molecular correlates of PD-L1 positive cases remain to be elucidated and warrant further investigation.
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ORAL 23 - Prevention and Cancer Risk (ID 121)
- Event: WCLC 2015
- Type: Oral Session
- Track: Prevention and Tobacco Control
- Presentations: 1
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ORAL23.01 - A Randomized Phase IIb Trial of Myo-Inositol in Smokers with Bronchial Dysplasia (ID 856)
10:45 - 10:56 | Author(s): D. Ionescu
- Abstract
- Presentation
Background:
Previous preclinical studies and a phase I clinical trial suggested myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled, phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia.
Methods:
Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once/day for two weeks, and then twice/day for 6 months. The primary endpoint was change in dysplasia rate after six months of intervention on a per participant basis. Other trial endpoints reported herein include Ki-67 labeling index and pro-inflammatory, oxidant/anti-oxidant biomarker levels in blood and bronchoalveolar lavage fluid (BAL).
Results:
Seventy four (n=38 myo-inositol, n=36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (p=0.76). The mean percent change in Ki67 labeling index in bronchial biopsies with dysplasia was -22.8% and -6.2%, respectively, in the myo-inositol and placebo arms (p=0.34). Compared with placebo, myo-inositol intervention significantly reduced IL-6 levels in BAL over 6 months (p=0.03) and had borderline significant effects on BAL myeloperoxidase (p= 0.06) level.
Conclusion:
The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-067 - Clinical Characteristics Associated with PDL1 Positive Status in Resected NSCLC (ID 1077)
09:30 - 09:30 | Author(s): D. Ionescu
- Abstract
Background:
Multiple different PD1 and PDL1 targeting antibodies have been developed for the treatment of NSCLC. Identifying the population most likely to benefit from PD1/PDL1 direct therapy has focused on PDL1 immunohistochemistry (IHC) of the tumor cells. However, each therapeutic agent has a different companion diagnostic test therefore it is difficult to consistently ascertain the PDL1 status of an individual patient. We proposed to evaluate clinical predictors of PDL1 positive status based on consensus PDL1 immunohistochemistry.
Methods:
Patients with resected Stage II lung adenocarcinoma who underwent adjuvant chemotherapy at the BC Cancer Agency were selected for this study. A tissue microarray (TMA) with matched primary and lymph node was constructed. IHC directed towards PD-L1 was performed with 2 different primary antibody clones: E1L3N (Cell Signaling Technology) and SP142 (Spring Bioscience). PDL1 consensus score was considered positive if there was concordance with both antibodies. Clinical characteristics were abstracted by retrospective chart review.
Results:
Eighty cases of NSCLC were identified and used in TMA construction. 19 primary tumors (24%) were PD-L1 positive by consensus scoring. Lymph node metastases showed a concordant PD-L1 score in 92% cases. Patients were categorized as PDL1 positive based on consensus score of the primary tumor. Baseline characteristics based on PDL1 primary tumor status negative/positive: female 64%/47%, median age 61/65 (NS). Current smoker at the time of diagnosis 34%/58% (p=0.07). The 7 EGFR mutation positive and 2 ALK positive patients were PDL1 negative. PDL1 positivity was examined by pack years of smoking: >10 pk yrs 69%/90% (p=0.13), >20 pk yrs 62%/79% (p=0.26), >30 pk yrs 39/63% (p=0.11) and tumor differentiation: well 13%/5%, moderate 48%/21%, poorly 39%/74% (p=0.03).
Conclusion:
PDL1 positive status is associated with poorly differentiated tumors and demonstrates a trend towards current smokers. This is consistent with the concept that smoking related malignancies and poorly differentiated tumors are more antigenic and therefore require immunosuppression via PDL1 to remain undetected by the immune system.
