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F. Blackhall
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OA05 - Treatment Advances in SCLC (ID 373)
- Event: WCLC 2016
- Type: Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 2
- Moderators:A. Ardizzoni, J. Pujol
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 2
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OA05.06 - Compliance and Outcome of Elderly Patients Treated in the Concurrent Once-Daily versus Twice-Daily RadioTherapy (CONVERT) Trial (ID 4061)
15:15 - 15:25 | Author(s): F. Blackhall
- Abstract
- Presentation
Background:
A significant proportion of limited-stage small cell lung cancer are elderly. However, there is paucity of data on the efficacy and safety of concurrent chemo-radiotherapy in the elderly to guide treatment decision-making.
Methods:
Data from the CONVERT trial was retrospectively analysed to compare the outcome of patients 70 years or older to patients younger than 70 years. Patients were randomised 1:1 to receive 45Gy in 30 twice-daily fractions over 3 weeks or 66Gy in 33 once-daily fractions over 6.5 weeks starting on day 22 of cycle 1 chemotherapy (4 to 6 cycles of Cisplatin 25mg/m2 days 1-3 or 75mg/m2 day 1 with Etoposide 100mg/m2 days 1-3), followed by Prophylactic Cranial Irradiation if indicated. Radiotherapy planning was with a 3D conformal technique or intensity modulated radiotherapy.
Results:
Of 547 patients randomised between April 2008 and November 2013, 57 patients were excluded for the purposes of this analysis as they did not receive concurrent chemo-radiotherapy. Of the 490 included patients, 67 (13.7%) were age 70 years or older with median age of 73 years (70-82). Patients’ characteristics were well balanced apart from more male in the elderly group (p=0.02). There was no significant difference in the number of chemotherapy cycles administered in the two groups (p=0.24). A higher proportion of patients received 30 or 33 fractions of radiotherapy as per protocol in the younger group (85% vs. 73%; p=0.03). Neutropenia grade 3/4 occurred more frequently in the elderly group (84% vs. 70%; p=0.02) but there was no statistically significant difference in neutropenic sepsis (4% vs. 7%; p=0.07) and non-haematological acute/late toxicities. There were two vs. six treatment-related deaths in the elderly and younger group respectively (p=0.67). At median follow up of 46 months for those alive; two-year survival was 53% (95% CI 41-64) vs. 57% (95% CI 52-61), median survival was 29 months vs. 30 months in the elderly vs. younger group respectively. Hazard ratios for overall survival and progression free survival were 1.15 (95% CI 0.84-1.59; log-rank p=0.38) and 1.04 (95% CI 0.76-1.41; log-rank p=0.81) respectively. In the elderly group median survival was not significantly different in patients who received once vs. twice daily radiotherapy (p=0.91).
Conclusion:
Radiotherapy treatment delivery was higher in the younger group but toxicity and survival rates were similar in elderly compared to younger patients. Concurrent chemo-radiotherapy with modern radiotherapy techniques is a treatment option for elderly patients with good performance status.
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OA05.07 - Prognostic Value of Circulating Tumour Cells in Limited-Disease Small Cell Lung Cancer Patients Treated on the CONVERT Trial (ID 5431)
15:25 - 15:35 | Author(s): F. Blackhall
- Abstract
- Presentation
Background:
Circulating tumour cells (CTCs) are prevalent in patients with small cell lung cancer (SCLC) (Hou et al. JCO 2012) but their clinical utility is not known for patients with limited disease (LD) who receive concurrent chemoradiation. Here we report on a patient subgroup who underwent CTC analysis and treatment on the Concurrent ONce-daily (OD) VErsus Twice-daily (BD) RadioTherapy (CONVERT) trial (Faivre-Finn Proc. ASCO 2016) that demonstrated a non-significant difference in the primary endpoint of two-year survival for the OD (51%) and BD (56%) arms.
Methods:
Blood samples (7.5mls) were collected at baseline, prior to any treatment from patients who were enrolled to the CONVERT trial at The Christie Hospital site, Manchester, UK. CTCs were enumerated prospectively using the Cellsearch platform. Patients were randomised 1:1 to receive 45Gy in 30 twice-daily fractions over 3 weeks (Arm 1) or 66Gy in 33 once-daily fractions over 6.5 weeks (Arm 2) starting on day 22 of cycle 1 chemotherapy (4 to 6 cycles of Cisplatin 25mg/m2 days 1-3 or 75mg/m2 day 1 with Etoposide 100mg/m2 days 1-3), followed by prophylactic cranial irradiation if indicated. Radiotherapy planning was with a 3D conformal technique or intensity modulated radiotherapy. Staging by Positron Emission Tomography (PET) was permitted. Standard statistical methods were used to examine associations between CTC number (CTC#), clinical factors and outcomes.
Results:
Of 547 patients randomised between April 2008 and November 2013, 79 patients (41 in Arm1 and 38 in Arm 2) underwent CTC enumeration (CTC subgroup). The clinical demographics and median overall survival (OS) of the CTC subgroup did not differ significantly from the overall study population. The median number (range) of CTCs per 7.5mls blood for all 79 patients was 1 (0-3750) and for arm 1 and arm 2 patients respectively, 12 (0-164) and 158 (0-3750) (p=0.495). There was a trend for association of CTC# with higher TNM stage. CTC# was significant for survival in univariate and multivariate analysis. The median (95% CI) OS for ≥15 CTCs (n=18) was 6.01 (4.2-11.5) months compared to 30.77 (19.7-39.3) months for < 15 CTCs (n=61), p <0.001. The positive predictive value of CTC# ≥15 for survival ≤ 2 years is 100%, and ≤ 1 year is 72%. CTC# also predicted for worse outcome in patients who had undergone PET staging.
Conclusion:
CTC# is highly prognostic for poor survival in patients with LD-SCLC, treated with concurrent chemoradiotherapy, and could aid treatment decision making for this disease.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-025 - Evaluation of NGS and RT-PCR Methods for ALK Assessment in European NSCLC Patients: Results from the ETOP Lungscape Project (ID 5001)
14:30 - 14:30 | Author(s): F. Blackhall
- Abstract
Background:
The reported prevalence of ALK rearrangement in NSCLC ranges from 2%-7%, depending on population and detection method. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proven to be a reproducible and sensitive technique. Reverse transcriptase-polymerase chain reaction (RT-PCR) has been advocated and most recently the advent of targeted Next-Generation Sequencing (NGS) for ALK and other fusions has become possible. This is one of the first studies comparing all 4 techniques in resected NSCLC from the large ETOP Lungscape cohort.
Methods:
96 cases from the ETOP Lungscape iBiobank (N=2709) selected based on any degree of IHC staining (clone 5A4 antibody, Novocastra, UK) were examined by FISH (Abbott Molecular, Inc.; Blackhall, JCO 2014), central RT-PCR and NGS. H-score 120 is used as cutoff for IHC+. For both RT-PCR and NGS, RNA was extracted from the same formalin-fixed, paraffin-embedded tissues. For RT-PCR, primers were used covering the most frequent ALK translocations. For NGS, the Oncomine™ Solid Tumour Fusion Transcript Kit was used, allowing simultaneous sequencing of 70 ALK, RET and ROS1 specific fusion transcripts associated with NSCLC, as well as novel ALK translocations using 5’-3’ ALK gene expression ‘Imbalance Assay’.
Results:
NGS provided results for 90 cases, while RT-PCR for 77. Overall, 70 cases have results for all 4 methods, with fully concordant 60 (85.7%) cases (49 ALK-, 11 ALK+). Before employing the ‘Imbalance Assay', in 5 of the remaining 10 cases, NGS differs from the other methods (3 NGS-, 2 NGS+), while in the other 5, NGS agrees with RT-PCR in all, IHC in 2, and FISH in 1. Using the concordant result of at least two of the three methods as true negative/positive, the specificity and sensitivity of the fourth is 96/94/100/96% and 94/94/89/72% for IHC/FISH/RT-PCR/NGS, respectively (incorporating imbalance: NGS sensitivity=83%). Imbalance scores are presented here for 18 NGS- cases: 9 ‘NGS-/FISH+/IHC+’, 9 ‘NGS-/FISH-/IHC-‘. Among the ‘NGS-/FISH+/IHC+’, there is strong evidence of imbalance in 4 cases (score’s range: 0.0144-0.0555), uncertain in 5 (range: 0.0030-0.0087), and no evidence (scores≤0.0004) in the 9 negative cases.
Conclusion:
NGS is a useful screening tool for ALK rearrangement status, superior to RT-PCR when RNA yield is limited. When using NGS, it is critically important to integrate the 5’-3’ imbalance assay and to confirm with one or more additional methods in the ‘imbalance’ cases. Data further highlight the possibility of missing actionable rearrangements when only one screening methodology is available.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-031 - Impact of PD-L1 Status on Clinical Response in SELECT-1: Selumetinib + Docetaxel in KRASm Advanced NSCLC (ID 5040)
14:30 - 14:30 | Author(s): F. Blackhall
- Abstract
Background:
Anti-PD-1/PD-L1 immunotherapy has delivered clinical benefit for patients with NSCLC, and PD-L1 has emerged as a predictive biomarker. In the Phase III SELECT-1 trial (NCT01933932), selumetinib (AZD6244, ARRY-142886), an oral, potent and selective, allosteric MEK1/2 inhibitor with a short half-life, plus second-line docetaxel did not provide clinical benefit for patients with KRAS-mutant (KRASm) NSCLC compared with placebo plus docetaxel (PBO+DOC). Although no incremental benefit was observed, it is important to evaluate biomarkers, such as PD-L1, to understand more about the biology of patients with KRASm NSCLC.
Methods:
In total, 510 patients with a prospectively, centrally confirmed KRAS mutation (cobas® KRAS Mutation Test, Roche Molecular Systems) were randomised 1:1 to selumetinib 75 mg BID, plus docetaxel 75 mg/m[2] q21d (SEL+DOC), or PBO+DOC. Evaluations included progression-free survival (PFS) by investigator assessment (RECIST 1.1; primary endpoint), and overall survival (OS). Association of tumour PD-L1 status with clinical responses was assessed as an exploratory objective. PD-L1 status was centrally determined using the PD-L1 IHC 28-8 pharmDx test (Dako) for all patients with sufficient tumour sample. Samples with a pre-specified cut-off of ≥5% tumour cell staining were considered PD-L1 positive.
Results:
SEL+DOC did not improve PFS or OS compared with PBO+DOC. PD-L1 status was determined for 385 (75%) patients: 224 (58%) samples were PD-L1 <5%, and 161 (42%) samples were PD-L1 ≥5%; the remaining 125 patients had unknown PD-L1 status due to insufficient tumour sample. Subgroups were balanced across treatments. PD-L1 subgroup analysis of PFS and OS is presented below.Subgroup Events (%) in SEL+DOC group Events (%) in PBO+DOC group HR (95% CI) PFS PD-L1 <5% 94/112 (84%) 101/112 (90%) 0.89 (0.67, 1.18) PD-L1 ≥5% 65/79 (82%) 71/82 (87%) 0.70 (0.50, 0.99) PD-L1 unknown 59/63 (94%) 57/62 (92%) 1.24 (0.86, 1.79) OS PD-L1 <5% 73/112 (65%) 74/112 (66%) 0.94 (0.68, 1.30) PD-L1 ≥5% 55/79 (70%) 58/82 (71%) 0.89 (0.61, 1.28) PD-L1 unknown 48/63 (76%) 38/62 (61%) 1.57 (1.02, 2.41)
Conclusion:
Prevalence of PD-L1 positive status in this KRASm cohort was similar to that reported for a pan-NSCLC cohort (Borghaei, NEJM 2015). No significant PFS or OS differences were observed between treatments in either PD-L1 positive or negative tumours. Additional biomarker analyses are planned for different KRAS codon mutations, and LKB1 and TP53 status.
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P2.05 - Poster Session with Presenters Present (ID 463)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.05-058 - Blood Biomarkers of Inflammation, Tumour Burden and Proliferation Predict Radiotherapy Response and Toxicity in Lung Cancer (ID 5587)
14:30 - 14:30 | Author(s): F. Blackhall
- Abstract
Background:
There is an unmet need to develop non-invasive biomarkers that can be used to tailor radiotherapy and select patients for future mechanism-based therapy-radiotherapy combination trials. The aim of this study is to assess blood biomarkers of radiotherapy response and toxicity in patients with lung cancer.
Methods:
This is a prospective exploratory study conducted at the Christie NHS Foundation Trust (Manchester, UK). Blood samples were collected prior, during and post-radiotherapy and at the time of relapse. A panel of 26 biomarkers were evaluated; M30 and M65 (apoptosis/ cell death), CA-IX and Osteopontin (hypoxia), Ang-1, Ang-2, FGFb, IL-8, PDGFb, PIGF, Tie-2, VEGFA, VEGFC, VEGFR-1 and VEGFR-2 (angiogenesis), E-selectin, IL-1b, IL-6, IL-10, IL-12 and TNFα (inflammation), CYFRA 21-1, EGF, KGF and VCAM-1 (tumour burden, proliferation and invasion) and HGF (multiple processes). Clinical, demographic and treatment data as well as routine haematology and biochemistry test results were collected. Blood sampling and analysis were performed in a good clinical practice-compliant laboratory. Univariate analysis was performed on patients with small-cell and non-small cell lung cancer (NSCLC) while multivariate analysis focused on patients with NSCLC. All statistical analyses were performed in R v3.1.1.
Results:
Between March 2010 and February 2012, blood samples form 78 patients were analysed. Forty eight (61.5%) were treated with sequential chemo-radiotherapy, 61 (78.2%) harboured NSCLC while 66 (84.6%) had stage III disease. TNFα, IL-1b, KGF and IL-12 accounted for the bulk of the variability between patients at baseline. Of these, high TNFα (hazard ratio (HR); 2.27, 95% confidence interval (CI); 1.22-4.23, log-rank p=0.008) and IL-1b (HR; 4.02, 95% CI; 2.04-7.93, log-rank p<0.001) were the strongest covariates of survival. Of routinely-collected laboratory tests, neutrophil count was a significant covariate of survival (HR; 1.07, 95% CI; 1.02-1.11, log-rank p=0.017). A multivariate survival predication model for NSCLC was created by combining baseline IL-1b and neutrophil count. The addition of early-treatment (week 3) CYFRA 21-1 to this model modestly improved the survival prediction concordance probability (0.75; p=0.029 to 0.78; p=0.004). Chemotherapy was strongly correlated with acute oesophagitis (p<0.001) while KGF was weekly correlated (p=0.019). The addition of KGF did not improve a multivariate toxicity prediction model based on chemotherapy. None of the tested variables correlated with acute pneumonitis.
Conclusion:
Blood biomarkers of inflammation and proliferation and early-treatment tumour burden could provide additional information about radiotherapy response and toxicity in patients with lung cancer. Following independent validation, the proposed biomarkers could be integrated within future mechanism-based therapy-radiotherapy combination trials.
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.08 - Discussant for PL03.07 (ID 7155)
09:55 - 10:05 | Author(s): F. Blackhall
- Abstract
- Presentation
Abstract not provided
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