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R. Soo
Moderator of
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SC26 - Angiogenesis Inhibition: Advances & Perspectives (ID 350)
- Event: WCLC 2016
- Type: Science Session
- Track: Biology/Pathology
- Presentations: 4
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SC26.01 - Biology of Angiogenesis (ID 6709)
11:00 - 11:20 | Author(s): J. Heymach
- Abstract
- Presentation
Abstract not provided
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SC26.02 - Angiogenesis Inhibition in Lung Cancer: Recent Advances and Perspectives (ID 6710)
11:20 - 11:40 | Author(s): M. Boyer
- Abstract
- Presentation
Abstract:
Angiogenesis is an important process in the development and progression of tumours. Across a range of tumour types markers of angiogenesis, such as elevated VEGF levels or increased micro vessel density, have been shown to be associated with poorer patient outcomes. The recognition that VEGF mediated signalling is a key driver of angiogenesis within tumours led to the development of a range of anti-angiogenic approaches targeting this biological process. These approaches have included monoclonal antibodies (bevacizumab, ramucirumab), decoy receptors (aflibercept), and receptor tyrosine kinase inhibitors (nintedanib, sorafenib, sunitinib, motesanib, vandetanib, cediranib, pazopanib), all of which have been evaluated in lung cancer. Despite this volume of clinical research, only three of these agents have been shown to produce benefit in patients with advanced non-small cell lung cancer (NSCLC): bevacizumab, ramucirumab and nintedanib. No antiangiogenic agent has to date been shown to be of benefit in small cell lung cancer. Bevacizumab, an anti-VEGF monoclonal antibody, was the first antiangiogenic therapy to be evaluated in NSCLC. Early studies identified that patients with squamous cancers were at risk of increased toxicity due to haemorrhage so randomised trials have been restricted to patients with non-squamous tumours. The ECOG 4599 randomized trial evaluated treatment with carboplatin and paclitaxel with or without bevacizumab[1]. In this study, as in most other studies of antiangiogenics, bevacizumab was continued in a maintenance phase following the conclusion of chemotherapy. The study demonstrated an improvement in overall survival (HR 0.79, 95% CI 0.67 – 0.92 p = 0.003). A second phase 3 study, AVAiL, evaluated the addition of two different doses of bevacizumab to the combination of gemcitabine and cisplatin, in a double blind manner[2]. The study demonstrated an improvement in progression free survival, but with no difference in overall survival. Based on the results of these two trials, bevacizumab received approval in several jurisdictions, but there remained some doubts over the benefit to patients given the lack of a confirmatory trial showing improved overall survival. A recent meta-analysis[3] incorporating these and other randomised studies has shown that bevacizumab produces a modest, but statistically significant improvement in overall survival (HR 0.90, 95% CI 0.81 – 0.99; p=0.03). Subsequently, a further randomised trial, BEYOND[4], has been published, with bevacizumab added to the combination of carboplatin and paclitaxel in a purely Asian population. This trial showed an improvement in overall survival (HR 0.68, 95% CI 0.50 – 0.93 p=0.015), with median OS increasing from 17.7 to 24.3 months. Bevacizumab has also been evaluated in the second line setting in combination with erlotinib (in patients unselected for EGFR mutations), without significant impact on overall survival in the BeTa study[5]. Ramucirumab is a monoclonal antibody directed against the VEGFR2 receptor. It has been evaluated in a randomised trial in the second line setting. Patients were randomised to receive treatment with docetaxel with or without ramucirumab[6]. Treatment was continued till progression, with monotherapy ramucirumab continued if toxicity developed to docetaxel (and vice versa). The primary endpoint of the study was overall survival, and the results indicated an improvement in overall survival for patients receiving ramucirumab (HR 0.86, 95% CI 0.75 – 0.98; p=0.023), with median survival increasing from 9.1 to 10.5 months. By contrast to the various studies of bevacizumab, this study included patients with squamous cell cancer, as well as those with non-squamous tumours, with the magnitude of benefit being similar in both histologic types. Addition of ramucirumab resulted in an increase in toxicity, with more hypertension, bleeding, and febrile neutropenia. However the rate of serious adverse events and of deaths due to adverse events were similar between the two study arms. The results of this study led to the approval of ramucirumab for patients with previously treated in NSCLC in some parts of the world, including the USA and Europe. However, subsequently, the results of trials of immune checkpoint inhibitors in the same patient population has resulted in many of these patients not receiving docetaxel chemotherapy, making it difficult to assess the appropriate role for this agent. The addition of a tyrosine kinase inhibitor to chemotherapy has been evaluated extensively in patients with advanced NSCLC in both the first and second line settings. The results of these trials have been disappointing, with none of them demonstrating an overall survival benefit. Many, however, did show some improvement in progression free survival. Only one of these agents, nintedanib, is approved (in Europe) for the treatment of patients with NSCLC. This is based on the results of the LUME-1 study, which compared treatment with docetaxel alone with docetaxel plus nintedanib in patients with previously treated NSCLC[7]. In this study, progression free survival (the primary endpoint) was longer with the addition of nintedanib (3.4 vs. 2.7 months, HR 0.79, 95% CI 0.68 – 0.92; p=0.0019). Although there was no difference in overall survival in the whole study population, in the predefined subset of patients with adenocarcinoma and progression within 9 months of initial therapy median overall survival increased from 7.9 to 10.9 months (HR 0.75, 95% CI 0.60 – 0.92; p=0.007). Similar, though less extreme results occurred in all patients with adenocarcinoma. There was no effect on survival of patients with squamous histology. The combination resulted in an increase in the rate of adverse events, predominantly diarrhoea, liver function abnormalities and vomiting. To date, no biomarker of angiogenesis that allows the selection of patients for treatment with has been identified. As a consequence, patient selection (for bevacizumab) is based on the avoidance of toxicity, by excluding groups of patients known to be at higher risk (e.g. those with squamous cell histology, or a history of haemoptysis). Furthermore the inability to identify those patients most likely to benefit, along with the relatively small improvements in survival means that from an economic viewpoint, the cost per life year gained is high. This has resulted in antiangiogenics not being widely used in some countries. References 1. Paclitaxel Carboplatin alone or with bevacizumab for non-small-cell lung cancer. Sandler et al. N Engl J Med 2006; 355: 2542 – 2550 2. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for non-squamous non-small-cell lung caner: AVAiL. Reck et al. J Clin Oncol 2009; 27: 1227 – 1234 3.Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum based chemotherapy as first-line treatment in patients with advanced non-small cell lung cancer. Soria et al. Ann Oncol 2013; 24: 20 – 30. 4. BEYOND: A randomized, double-blind, placebo-controlled, multicentre phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent non-squamous non-cell lung cancer. Zhou et al. J Clin Oncol 2015; 33: 2197 – 2204 5. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind placebo-controlled phase 3 trial. Herbst et al. Lancet 2011; 377: 1846 – 1854 6. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre double-blind randomised phase 3 trial. Lancet 2014; 384: 665 – 673 7. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-1): a phase 3 double blind , randomised controlled trial. Reck et al. Lancet Oncol 2014; 15: 143- 155
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SC26.03 - Predictive Biomarkers for Angiogenesis Inhibitors: An Update (ID 6711)
11:40 - 12:00 | Author(s): M. Reck
- Abstract
- Presentation
Abstract:
The concept of tumor-induced neoangiogenesis has been shown to be a relevant factor for tumor proliferation and metastasis already a couple of years ago (1). Therefore interaction with proangiogenic pathways appears to be a promising therapeutic target across several solide tumors. In eligible patients with advanced non-squamous NSCLC the addition of the anti vascular endothelial growth factor (anti VEGF) antibody bevacizumab to platinum based chemotherapy has shown consistent improvement of response, progression free survival (PFS) and overall survival. However also the combination did increase the incidence of characteristic adverse events like hypertension, arterial and venous vascular events, bleeding events, proteinuria and other (2). Recently two large randomised phase III trials revealed a significant increase in efficacy by the combination of antiangiogenic agents and chemotherapy in pretreated patients with advanced NSCLC. In the LUME 1 trial the combination of the oral angiokinase inhibitor nintedanib and docetaxel revealed a significant improvement of PFS (median PFS 3.4 vs 2.7 months, HR 0.79, 95% CI 0.68-0.92) and OS in patients with adenocarcinoma histology (median OS 12.6 vs 10.3 months, HR 0.82, 95% CI 0.7-0.99) compared to docetaxel (3). The combination of the anti VEGF receptor 2 antibody ramucirumab and docetaxel did show a significant improvement of response (response rate: 23% versus 14%, p<0.0001), PFS (median PFS 4.5 versus 3.0 months, HR 0.76, 95% CI 0.68-0.86) and OS (median OS 10.5 versus 9.1 months, HR 0.86, 95% CI 0.75-0.98) compared to docetaxel in pretreated patients with NSCLC regardless of histology (4). The identification of potential predictive biomarkers remains a challenge due to the complexity of angiogenesis, the interaction between the tumor and the host and due to dynamic changes of the system. In a very large trial (Abigail), specifically designed to identify potential tissue based or blood based markers of efficacy, no predictive markers could be determined. However the relevant prognostic nature of angiogenesis marker could be confirmed (5). Recent analyses revealed that besides molecular markers clinical factors like rapid progressive diseases or tumors refractory to conventional chemotherapy could be associated with improved outcomes of angiogenesis inhibitors. Preplanned as well as exploratory analyses did show pronounced efficacy for the combination of antiangiogenic agents like nintedanib, ramucirumab and bevacizumab compared to chemotherapy alone supporting the hypothesis that fast progressing tumors are more dependant on neo angiogenesis. The translational exploration of these clinical findings is on the way in several programs and trials. The understanding of this correlation will be important for the optimal placement of antiangiogenic agents e.g. in the combination with immunotherapies. Folkman J, Merler E, Abernathy C et al. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133: 275-288 Soria JC, Mauguen A, Reck M et al. Systematic review and meta-analysis of randomised phase II/III trials adding bevacizumab to platinum based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2013; 24: 20-30 Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double blind, randomised controlled trial. Lancet Oncol 2014; 15: 143-50 Garon E, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665-773 Mok T, Gorbunova V, Juhasz E et al. A correlative biomarker analysis of bevacizumab and carboplatin-based chemotherapy for advanced nonsquamous non-small cell lung cancer: results of the phase II randomized ABIGAIL study (BO21015). J Thorac Oncol 2014; 9: 848-55.
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SC26.04 - Novel Imaging Technique (ID 6712)
12:00 - 12:20 | Author(s): S. Schönberg
- Abstract
- Presentation
Abstract:
Lung cancer is still the leading cause of cancer-related death in both men and women with 80% to 85% of cases being non-small-cell lung cancer (NSCLC).[1]The past fifteen years have brought significant breakthroughs in the understanding of the molecular biology of lung cancer. Signalling pathways and genetic driver mutations that are vital for tumour growth have been identified and can be effectively targeted by novel pharmacologic agents, resulting in significantly improved survival of patients with lung cancer.[2]Parallel to the progress in lung cancer treatment, imaging techniques aiming at improving diagnosis, staging, response evaluation, and detection of tumour recurrence have also considerably advanced in recent years.[3]However, standard morphologic computed tomography (CT) and magnetic resonance imaging (MRI) as well as fluor-18-fluorodeoxyglucose ([18]F-FDG) positron emission tomography CT (PET-CT) are still the currently most frequently utilized imaging modalities in clinical practice and most clinical trials.[4,5]Novel state-of-the-art functional imaging techniques such as dual-energy CT (DECT), dynamic contrast enhanced CT (DCE-CT), diffusion weighted MRI (DW-MRI), perfusion MRI, and PET-CT with more specific tracers that visualize angiogenesis, tumour oxygenation or tumour cell proliferation have not yet been broadly implemented, neither in clinical practice nor in phase I–III clinical trials [6]. In this context, Nishino et al.[4] published an article on personalized tumour response assessment in the era of molecular treatment in oncology. The authors showed that the concept of personalized medicine with regard to cancer treatment has been well applied in therapeutic decision-making and patient management in clinical oncology. With regard to imaging techniques, however, it was criticized that the developments in tumour response assessment that should parallel the advances in cancer treatment are not sufficient to produce state-of-the-art functional information that directly reflect treatment targets. Functional information on tumour response is highly required because there is growing evidence that the current objective criteria for treatment response assessment may not reliably indicate treatment failure and do not adequately capture disease biology. Molecular-targeted therapies and novel immunotherapies induce effects that differ from those induced by classic cytotoxic treatment including intratumorale haemorrhage, changes in vascularity, and tumour cavitation. Thus, conventional approaches for therapy response assessment such as RECIST or WHO criteria that exclusively focus on the change in tumour size are of decreasing value for drug response assessment in clinical trials.[7,8] Parallel to the development of novel imaging techniques automated and more detailed analysis of standard images is currently highly investigated and has led to the introduction of the term Radiomics. Radiomics refers to the comprehensive quantification of tumour phenotypes by applying a large number of quantitative image features that are standardized collected with specific software algorithms. Radiomics features have the capability to further enhance imaging data regarding prognostic tumour signatures, detection of tumour heterogeneity as well as the detection of underlying gene expression patterns which is of special interest in patients with metastatic disease. The aim of of this presentation is to provide an overview on state-of-the-art imaging techniques for the initial staging, response evaluation as well as surveillance in patients with lung cancer. The various techniques will be discussed regarding their pros and cons to further provide functional information that best reflects specific targeted therapies including anti-angiogenetic treatment, immunotherapies and stereotactic body radiation therapy. Moreover, imaging techniques and optimal time points after local minimally invasive treatments with microwave ablation or novel irreversible electroporation will be discussed. The second part of the presentation will focus on Radiomics and its potential value in lung cancer imaging. Literature: 1. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009;15:4-9. 2. Rengan R, Maity AM, Stevenson JP, Hahn SM. New strategies in non-small cell lung cancer: improving outcomes in chemoradiotherapy for locally advanced disease. Clin Cancer Res 2011;17:4192-9. 3. Miles K. Can imaging help improve the survival of cancer patients? Cancer Imaging 2011;11 Spec No A:S86-92. 4. Nishino M, Jackman DM, Hatabu H, Janne PA, Johnson BE, Van den Abbeele AD. Imaging of lung cancer in the era of molecular medicine. Acad Radiol 2011;18:424-36. 5. Nishino M, Jagannathan JP, Ramaiya NH, Van den Abbeele AD. Revised RECIST guideline version 1.1: What oncologists want to know and what radiologists need to know. AJR Am J Roentgenol 2010;195:281-9. 6. Henzler T, Goldstraw P, Wenz F, et al. Perspectives of novel imaging techniques for staging, therapy response assessment, and monitoring of surveillance in lung cancer: summary of the Dresden 2013 Post WCLC-IASLC State-of-the-Art Imaging Workshop. J Thorac Oncol 2015;10:237-49. 7. Oxnard GR, Morris MJ, Hodi FS, et al. When progressive disease does not mean treatment failure: reconsidering the criteria for progression. J Natl Cancer Inst 2012;104:1534-41. 8. Stacchiotti S, Collini P, Messina A, et al. High-grade soft-tissue sarcomas: tumor response assessment--pilot study to assess the correlation between radiologic and pathologic response by using RECIST and Choi criteria. Radiology 2009;251:447-56.
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Author of
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OA06 - Prognostic & Predictive Biomarkers (ID 452)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:F. Shepherd, Y. Yatabe
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 1
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OA06.04 - Discussant for OA06.01, OA06.02, OA06.03 (ID 6962)
14:50 - 15:05 | Author(s): R. Soo
- Abstract
- Presentation
Abstract not provided
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-030 - Performance Evaluation of ALK/ROS1 Dual Break Apart FISH Probe Kit (RUO) in Non-Small-Cell Lung Cancer (ID 5233)
14:30 - 14:30 | Author(s): R. Soo
- Abstract
Background:
ALK and ROS1 gene rearrangements are distinct molecular subsets of non-small-cell lung cancer (NSCLC), and they are strong predictive biomarkers of response to ALK/ROS1 inhibitors, such as crizotinib. Thus, it is clinically important to detect patients who will benefit from such treatment and develop an effective screening strategy. In this study, we aim to evaluate the diagnostic performance of ALK/ROS1 RUO FISH probes which can concurrently detect ALK and ROS1 rearrangements.
Methods:
The study populations were composed of three patient cohorts with histologically confirmed lung adenocarcinoma (ALK rearrangement, ROS1 rearrangement and both wild type). Patient specimens consisted of 12 ALK-positive, 9 ROS1-positive and 21 ALK/ROS1-wild type formalin-fixed paraffin-embedded samples obtained from surgical resection or excisional biopsy. ALK rearrangement status was determined by Vysis LSI Dual Color Break Apart Rearrangement Probe (Abbott Molecular, Abbott Park, IL, USA) and ROS1 rearrangement status was assessed by ZytoLight SPEC ROS1 dual color break apart probe (Zytovision. Bremerhaven, Germany). All specimens were re-evaluated by ALK/ROS1 Break Apart FISH RUO 4-color kit. FISH images were scanned via the BioView Duet and interpreted remotely via BioView SoloWeb.
Results:
A total of 42 patient samples were evaluated. The concordance of results obtained from ALK/ROS1 Break Apart FISH RUO 4-color kit was evaluated relative to the ALK and ROS1 rearrangement status of the specimen, as previously determined. One ROS1-positive and 2 wild-type samples were excluded from analysis due to high background. Regarding 12 ALK-positive samples, 12 were ALK-positive by ALK/ROS1 RUO FISH, showing 100% (n=12/12) sensitivity to predict ALK rearrangement. Regarding 8 ROS1-positive samples, 6 cases were ROS1-positive by ALK/ROS1 RUO FISH, showing 75% (n=6/8) sensitivity to predict ROS1 rearrangement. Two cases showed weak ROS1 signals that could not be enumerated. Regarding 19 wild type cases, 18 cases were negative by ALK/ROS1 RUO FISH, showing 95% (n=18/19) specificity, while one case showed poor ROS1 signals which could not be properly enumerated.
Conclusion:
ALK/ROS1 RUO FISH can detect ALK and ROS1 rearrangements simultaneously in NSCLC. The fluorescence of ROS1 signal may be weakened by slide shipment and remote scoring.
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P1.02-059 - Evaluation of Plasma DNA Extraction, Droplet PCR and Droplet next Generation Sequencing Methods for Liquid Biopsy Analysis (ID 6407)
14:30 - 14:30 | Author(s): R. Soo
- Abstract
Background:
The ability to detect tumour mutations from blood and other bodily fluids promises many sample access, convenience, and monitoring benefits. However, the extremely rare levels at which mutations are present in these fluids obliges the use of optimal extraction and detection methods. Here, the performance of two extraction, two droplet PCR (dPCR) and a droplet next generation sequencing (dNGS) method for blood plasma analysis was systematically evaluated.
Methods:
Limits of detection were assessed using 15 blinded healthy donor blood samples spiked with equivolume mixtures of H1975 (containing EGFR L858R and T790M mutations) and H1650 (EGFR exon 19 deletion, e19del) cells at 10%, 1%, 0.1%, 0.01%, 0.001% H1650 cells in triplicate. A series of 32 blinded blood plasma samples from non-small cell lung cancer (NSCLC) patients with known tumour EGFR mutation status was also tested. Samples were processed for plasma, and 1ml plasma each underwent Qiagen Circulating Nucleic Acid and Promega Maxwell Circulation Cell Free DNA extraction processing. The plasma DNA samples were analysed using the Biorad dPCR and Raindance Raindrop dPCR method for L858R and exon 19 deletion mutations, and the 50-gene Raindance Thunderbolts dNGS protocol.
Results:
No significant difference in DNA yield and detection patterns was observed between the two extraction methods. L858R mutations were detected by both dPCR methods at 0.001% in 1/3 replicates and 0.01% in 3/3 replicates. Of 4 cases with L858R tumour mutations, mutations were detected in the same 3 plasma samples by both Biorad and Raindance dPCR (sensitivity 75%). “False positive” L858R mutations were identified in 2 (specificity 92%) and 7 (75%) cases respectively. For 8 tumour e19del mutations, the sensitivities were 38% and 25%, and specificities were 96% and 75% respectively. Of 16 clinical samples analysed by dNGS, an average of 20 mutations per sample were identified after filtering for quality, non-synomyous, and non-germline variant status. The sensitivity and specificity for detecting 2 L858R tumour mutation was 100% and 50%, and 1 e19del tumour mutation was 100% and 55% respectively. The allele frequencies for the majority of “false positives” for dPCR and dNGS were less than 5%, although some “true positives” were also detected at that level.
Conclusion:
dPCR and dNGS methods can enable detection of tumour mutations in blood, albeit imperfectly. Future work to determine optimal detection thresholds will help to maximize sensitivity and specificity.
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P1.03 - Poster Session with Presenters Present (ID 455)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.03-054 - Quantitative Accuracy and Lesion Detectability of Low-Dose FDG-PET for Lung Cancer Screening (ID 3839)
14:30 - 14:30 | Author(s): R. Soo
- Abstract
Background:
Low-dose computed tomography (CT) screening for high-risk patients can reduce lung cancer mortality, but false-positivity rates are high. Positron emission tomography (PET)/CT is more accurate compared to CT alone, but typically is associated with a higher radiation exposure. We investigate a low radiation dose PET/CT solution without compromising quality.
Methods:
Twenty lung cancer patients were scanned with PET/CT after an uptake period of 60 min, following injection of 5.9±0.14 mCi 18F-Fluorodeoxyglucose. All were scanned with 2 beds covering the lungs at 10 min each, resulting in 120±25 x106 mean true coincident counts per bed. Reduced doses were simulated by randomly discarding events in the PET list mode according to 9 predefined true count levels, from 20 to 0.25 x10[6]. For each patient & simulated dose, the highest possible number of independent realizations was generated & reconstructed, up to 50. The reconstruction algorithm was OP-OSEM, using TOF and PSF, with 2 iterations, 21 subsets & 5mm smoothing, producing 400x400 image matrices with voxel size 2.04x2.04x2.03mm. At each simulated dose, lesions consistent with those of early lung cancer were identified & classified by metabolic volume, signal-to-background contrast, mean & max SUV, lesion-to-background SNR, & Hotelling observer SNR. Bias & stability of the lesion activity measurements were evaluated across all simulated dose levels, and detectability was determined by various human-trained, numerical observer models.
Results:
Twelve isolated lung lesions (mean volume 2.61±2.86 cm[3] on CT) were studied in detail. Analyses of bias & reproducibility in the lesion activity values showed that measurements were stable until the count levels approached extreme conditions. Bias in the lesion VOI mean & max SUV were relatively negligible until true count level was decreased to 1 million. Variance on reproducibility of lesion values showed a more dramatic trend, but standard deviation was still around 10% at 5 million counts.
Conclusion:
We show that simulated images with accurate lesion characteristics can be obtained at 1/12 of a typical radiotracer dose.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-027 - A Comparison of Five Different Immunohistochemistry Assays for Programmed Death Ligand-1 Expression in Non-Small Cell Lung Cancer Samples (ID 4414)
14:30 - 14:30 | Author(s): R. Soo
- Abstract
Background:
Randomised trials have shown treatment with programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors can provide a survival benefit to patients with advanced stage non-small cell lung cancer (NSCLC). PD-L1 expression, determined by immunohistochemistry (IHC) using different protocols, antibodies and thresholds for positivity for different inhibitors, has been reported to be potentially predictive of clinical outcome. The objective of this study was to compare the staining patterns of prominent PD-L1 IHC assays in clinically relevant NSCLC samples.
Methods:
Consecutive full sections of 20 NSCLC samples, comprising five each of resection, core biopsy, cytology, and pleural fluid samples, underwent IHC with the following anti-PD-L1 antibodies/autostainers: 22C3/Link 48, 28-8/Bondmax, SP142/Bondmax, SP263/Benchmark XT, E1L3N/Benchmark XT according to publicly-available protocols. PD-L1 expression were scored manually by pathologists according to the percentage of tumour cells (%TC) stained on a continuous scale.
Results:
Using published tumour cell percentage thresholds for 22C3, 28-8, SP142 and SP263 of ≥50%, ≥1%, ≥5%, and ≥25%, the frequency of PD-L1 positive cases were 10%, 15%, 70%, and 15% of cases respectively. When a ≥1% threshold was applied, the corresponding frequencies were 70%, 15%, 95%, 65% respectively, and 55% for E1L3N. Using published thresholds, cases were positive according to 1, 2, 3, 4 and 5 antibodies in 15%, 25%, 25%, 0% and 5% of cases respectively. Sorting of cases according to increasing %TC staining revealed a similar order of cases between antibodies, albeit with differences in %TC quanta and occasional exceptions to the order. Spearman rho analysis indicated %TC staining significantly (p<0.05) correlated between most antibody pairs, except 28-8 and 22C3, 28-8 and SP142, and 28-8 and E1L3N. Unsupervised hierarchical clustering revealed two subgroups, comprising of SP142/SP263 and 22C3/28-8/E1L3N.
Conclusion:
The classification of cases as PD-L1 positive can vary significantly according to the antibody and protocol used. Differences were more likely due to protocol dependent staining intensities and nominated thresholds for positivity, rather than differences in antibody affinity for different epitopes.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-117 - Phase Ib Results from a Study of Capmatinib (INC280) + EGF816 in Patients with EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 5012)
14:30 - 14:30 | Author(s): R. Soo
- Abstract
Background:
Among patients with EGFR-mutant NSCLC who progress on EGFR tyrosine kinase inhibitors (EGFR-TKIs), the most common (50%) resistance mechanism is secondary T790M mutation. cMET dysregulation is the second most common mechanism, with amplification occurring in 5‒22% of resistant patients. This study evaluates targeting these two mechanisms to overcome acquired resistance to EGFR-TKIs. Capmatinib (INC280) is a highly selective, potent cMET inhibitor with clinical activity in patients with cMET dysregulation. EGF816 is an irreversible EGFR-TKI that selectively inhibits T790M and EGFR-activating mutations, with antitumor activity in EGFR[T790M]-mutated NSCLC. In this open-label Phase Ib/II study, capmatinib was combined with EGF816 in patients with EGFR-mutated, EGFR-TKI resistant NSCLC.
Methods:
The Phase Ib primary objective is estimation of the maximum tolerated dose (MTD)/recommended Phase II dose (RP2D) of the combination using an adaptive Bayesian logistic regression model. Eligible patients (≥18 years; ECOG PS ≤2) must have documented EGFR-mutated (exon19del and/or L858R) NSCLC and documented progression (RECIST v1.1) while on EGFR-TKI treatment. Patients received capmatinib (starting dose 200 mg BID) plus EGF816 (starting dose 50 mg QD).
Results:
At the data cut-off (Aug 1, 2016), 33 patients were enrolled at five capmatinib BID/EGF816 QD mg dose levels (200/50 [n=4]; 200/100 [n=5]; 400/75 [n=3]; 400/100 [n=16]; 400/150 mg [n=5]); 18/33 (55%) patients discontinued treatment, mainly (13 [39%] patients) due to disease progression. Dose-limiting toxicities (DLTs) occurred in 4 patients: in 1 patient at the 200/50 dose level (increased alanine aminotransferase), 1 patient at the 400/100 dose level (anaphylactic reaction), and 2 patients at the 400/150 dose level (pyrexia, maculopapular rash, and allergic dermatitis). The most frequent (≥30%) any-grade adverse events (AEs), regardless of causality, were nausea (55%), peripheral edema (45%), increased amylase (42%), increased blood creatinine (36%), decreased appetite and diarrhea (both 30%). The most frequent (>10%) Grade ≥3 AEs were maculopapular rash (18% [mainly in the 400/150 cohort]) and increased amylase (12%). Capmatinib and EGF816 exposure increased with dose; preliminary data indicate a ~35% increase in EGF816 exposure (AUC) at steady state when co-administered with the capmatinib RP2D, compared with single-agent exposure. The investigator-assessed overall response rate was 42% (2/33 complete responses; 12/33 partial responses) across all dose levels and 50% (8/16 patients) at the 400/100 dose level, regardless of molecular status of resistance.
Conclusion:
The RP2D of the combination was declared as capmatinib 400 mg BID + EGF816 100 mg QD. Preliminary antitumor activity was observed across dose levels, independent of T790M status.
