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N. Watkins
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-004 - Updated Analysis of Phase II Study of HA-Irinotecan, a CD44-Targeting Formulation of Hyaluronic Acid and Irinotecan, in Small Cell Lung Cancer (ID 5868)
14:30 - 14:30 | Author(s): N. Watkins
- Abstract
Background:
Preclinical studies in small cell lung cancer cell (SCLC) have shown that hyaluronic acid (HA) can be effectively used to deliver irinotecan and selectively decrease CD44 expressing (stem cell-like) tumour cells. The current “proof of principle” study was aimed to replicate these findings by investigating the effect on clinical outcome according to CD44 expression. Final efficacy and bio-marker data on the study is presented.
Methods:
Patients with ESLC, having measurable disease, suitable for safe biopsy and able to give informed consent were screened for this study. First 5 patients were treated with HA-irinotecan (150mg/m[2]) and carboplatin (AUC 5), every 3 weeks to evaluate safety data. Subsequent patients were stratified as first line or second line. All second line patients receive open label HA-irinotecan, while first line patients are randomized to receive either HA-irinotecan/carboplatin or irinotecan/carboplatin. The response was measured by CT/PET at baseline, after 1 cycle and every 2 cycles subsequently. Baseline tumour samples were stained for CD44s (standard) and CD44v6 (variant 6). Blood samples for circulating tumour cells (CTCs) were also obtained at the baseline and before each treatment cycle till progression of disease.
Results:
Forty (40) patients, median age 66 (range 39-83) were enrolled treated on this study. Seven (7) patients either died or progressed before the first evaluation scan. Of 34 evaluable patients, the overall response rate was 50%, with 4 (12%) complete and 13 (38%) partial responses. Four patients (12%) achieved stable disease while 7 patients (20%) progressed during the treatment. There was no PFS difference in the two first line treatment arms (median 28 weeks in experimental vs 42 week in standard arm) (P = 0.892 HR=0.93, 95% CI 0.36-2042). Median PFS was 14.4 weeks in the second line cohort. The toxicity profile was similar to standard irinotecan, with the incidence of grade III/IV diarrhea seen in the experimental arm of 11% compared with 25% in the standard arm. Biomarker data was available in case of 24 patients, which suggested that there was no difference in response rates or survival according to baseline CD44s or CD44v6 expression. A possible correlation between the number of CTCs and tumour response and relapse was noticed.
Conclusion:
HA-irinotecan is well tolerated and has shown activity in the treatment of extensive stage small cell lung cancer. However, no improvement in efficacy was seen in CD44s+ or CD44v6+ SCLC treated with HA-irinotecan. Further strategies to combine HA with other chemotherapeutic agents may be warranted.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-004 - Genome-Wide Copy Number Aberrations in Mesothelioma and Its Correlation with Tumour Microenvironment including PD-L1 Expression (ID 4506)
14:30 - 14:30 | Author(s): N. Watkins
- Abstract
Background:
Recent clinical studies have demonstrated positive correlation between tumour mutational burden and response to immune checkpoint inhibitors (CPI) in several malignancies. Although initial reports of some CPI in Malignant Mesothelioma (MM) have shown promise, the rate of somatic mutations in MM is known to be low and copy number aberrations (CNA) are the prominent genetic alterations. Using a large cohort of MM patients, we investigated CNA, PD-L1 expression and the surrounding immune infiltrates and correlated these parameters to clinicopathological features.
Methods:
Tissue microarrays (TMA) were constructed and stained with PD-L1 (E1L3N,CST, Massachusetts), CD4, CD8 and Foxp3 antibodies. PD-L1 positivity (PD-L1+) was defined as >5% membranous staining regardless of intensity and high positive as >50%. Genomic DNA was obtained from tumour cores of a representative subset (100 patients) and used for genome-wide copy number analysis. Percent genome aberrated (PGA) was computed for each sample as the total number of base pairs within altered regions, divided by the total number of base pairs in each region included in the array. Correlations of PGA, CNA profile and individual aberration (loss/gain) frequency with parameters including PD-L1 expression and survival were explored.
Results:
Amongst 329 patients evaluated, the median age was 67 years and most were male 274(83.2%). Epithelioid histology (N=203; 62.9%) was the commonest. PD-L1 positivity was seen in 41.7% with high positivity in 9.6%. PD-L1+ correlated with non–epitheloid histology (P=<0.0001) and increased infiltration with CD4, CD8 and FOXP3 lymphocytes. High PD-L1 expression correlated with worse prognosis (HR=2.37; 95%CI: 1.57-3.56; P=<0.0001) on univariate analysis but the effect was found to be time dependent. Neither PGA (P=0.57) nor CNA profile (P=0.76) were found to be associated with PD-L1 expression. After correction for multiple testing, no individual CNA count was significantly associated with PD-L1 status. Although epithelioid histology had higher PGA (P=0.04), high PGA was associated with poorer survival (HR=2.01; 95% CI: 1.24-3.26; P=0.004). This was also true when only epithelioid tumours (n=63) were considered.
Conclusion:
Increased genomic alterations in MM did not correlate with PD-L1 expression but was associated with poorer survival. High PD-L1 expression was associated with non-epithelioid MM, poor clinical outcome and increased immunological infiltrates.
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P3.03-025 - Investigating Phenotypic and Genomic Heterogeneity in Malignant Pleural Mesothelioma (ID 5318)
14:30 - 14:30 | Author(s): N. Watkins
- Abstract
Background:
Phenotypic and genomic heterogeneity may contribute to the pathogenesis of Malignant Mesothelioma (MM). We have implemented a novel clinical study in which multiple samples of tumour and normal pleura are obtained from individual patients undergoing surgery for the management of MM.
Methods:
Patients undergoing routine video-assisted thoracoscopic surgery (VATS) undergo a baseline FDG-PET scan. Extra samples are taken from both PET positive and PET negative areas of pleura, along with normal pleural samples. Corresponding fresh and formalin fixed tissue samples are obtained. Patients are subsequently treated as per standard of care practice, along with detailed clinical follow up and serial PET imaging. Standard H&E will be performed on formalin fixed samples to look for morphological heterogeneity in tumour cells and stroma and the findings will be correlated with PET imaging.
Results:
Six (6) patients (4 epithelioid, 1 sarcomatoid and 1 biphasic subtype) with median age of 70 (62-81) have been recruited into the project so far. All patients underwent an FGD-PET scan prior to VATS procedure. Multiple samples from PET avid and PET non-avid areas were collected and stored from 5 out of 6 patients. Preliminary results show that high quality samples were obtained. The H&E analysis shows that tumours from PET avid area are morphologically different to PET not avid areas (Figure 1). Further IHC analysis of various MM specific markers is underway. Figure 1
Conclusion:
This preliminary data demonstrate the feasibility of our clinical approach. We therefore propose to create a unique research platform in which MM samples from multiple sites from each patient will be integrated with clinical, imaging and therapeutic response. Further proof-of-principle studies will explore: (i) regional heterogeneity and the response to therapies; (ii) variability in the detection of predictive biomarkers within the same patient; (iii) genomic heterogeneity within MM, and its relationship to mutational changes in normal pleura.
