- Email: [email protected]
SC26.02 Angiogenesis Inhibition in Lung Cancer: Recent Advances and Perspectives
January 2017
Computer Aided Texture Analysis For Pulmonary Nodules Classification. American journal of respiratory and critical care medicine 2015;191. 9. El-Zein RA, Lopez MS, D’Amelio AM, Jr., et al. The cytokinesis-blocked micronucleus assay as a strong predictor of lung cancer: extension of a lung cancer risk prediction model. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2014;23:2462-70. 10. Gillies RJ, Kinahan PE, Hricak H. Radiomics: Images Are More than Pictures, They Are Data. Radiology 2016;278:563-77. Keywords: Radiomics, Incidental, nodules, CT
SC26.02 Angiogenesis Inhibition in Lung Cancer: Recent Advances and Perspectives Michael Boyer Department of Medical Oncology, Chris O’Brien Lifehouse, Camperdown/NSW/Australia Angiogenesis is an important process in the development and progression of tumors. Across a range of tumor 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 signaling is a key driver of angiogenesis within tumors 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 hemorrhage so randomized trials have been restricted to patients with non-squamous tumors. 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
Abstracts
S135
improvement in overall survival (HR 0.79, 95% CI 0.67 e 0.92 p ¼ 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-analysis3 incorporating these and other randomized studies has shown that bevacizumab produces a modest, but statistically significant improvement in overall survival (HR 0.90, 95% CI 0.81 e 0.99; p¼0.03). Subsequently, a further randomized 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 e 0.93 p¼0.015), 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 randomized trial in the second line setting. Patients were randomized 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 e 0.98; p¼0.023), 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 tumors, 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 was 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
S136
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 e 0.92; p¼0.0019). 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 e 0.92; p¼0.007). 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 e 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 cancer: AVAiL. Reck et al. J Clin Oncol 2009; 27: 1227 e 1234 3.Systematic review and metaanalysis of randomized, 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 e 30. 4. BEYOND: A randomized, double-blind, placebocontrolled, multicentre phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in
Journal of Thoracic Oncology
Vol. 12 No. 1S
Chinese patients with advanced or recurrent non-squamous non-cell lung cancer. Zhou et al. J Clin Oncol 2015; 33: 2197 e 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 e 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 randomized phase 3 trial. Lancet 2014; 384: 665 e 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, randomized controlled trial. Reck et al. Lancet Oncol 2014; 15: 143155. Keywords: angiogenesis
SC26.03 Predictive Biomarkers for Angiogenesis Inhibitors: An Update Martin Reck Lungen Clinic Grosshansdorf, Großhansdorf/ Germany 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, 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 randomized 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%
Computer Aided Texture Analysis For Pulmonary Nodules Classification. American journal of respiratory and critical care medicine 2015;191. 9. El-Zein RA, Lopez MS, D’Amelio AM, Jr., et al. The cytokinesis-blocked micronucleus assay as a strong predictor of lung cancer: extension of a lung cancer risk prediction model. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2014;23:2462-70. 10. Gillies RJ, Kinahan PE, Hricak H. Radiomics: Images Are More than Pictures, They Are Data. Radiology 2016;278:563-77. Keywords: Radiomics, Incidental, nodules, CT
SC26.02 Angiogenesis Inhibition in Lung Cancer: Recent Advances and Perspectives Michael Boyer Department of Medical Oncology, Chris O’Brien Lifehouse, Camperdown/NSW/Australia Angiogenesis is an important process in the development and progression of tumors. Across a range of tumor 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 signaling is a key driver of angiogenesis within tumors 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 hemorrhage so randomized trials have been restricted to patients with non-squamous tumors. 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
Abstracts
S135
improvement in overall survival (HR 0.79, 95% CI 0.67 e 0.92 p ¼ 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-analysis3 incorporating these and other randomized studies has shown that bevacizumab produces a modest, but statistically significant improvement in overall survival (HR 0.90, 95% CI 0.81 e 0.99; p¼0.03). Subsequently, a further randomized 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 e 0.93 p¼0.015), 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 randomized trial in the second line setting. Patients were randomized 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 e 0.98; p¼0.023), 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 tumors, 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 was 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
S136
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 e 0.92; p¼0.0019). 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 e 0.92; p¼0.007). 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 e 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 cancer: AVAiL. Reck et al. J Clin Oncol 2009; 27: 1227 e 1234 3.Systematic review and metaanalysis of randomized, 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 e 30. 4. BEYOND: A randomized, double-blind, placebocontrolled, multicentre phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in
Journal of Thoracic Oncology
Vol. 12 No. 1S
Chinese patients with advanced or recurrent non-squamous non-cell lung cancer. Zhou et al. J Clin Oncol 2015; 33: 2197 e 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 e 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 randomized phase 3 trial. Lancet 2014; 384: 665 e 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, randomized controlled trial. Reck et al. Lancet Oncol 2014; 15: 143155. Keywords: angiogenesis
SC26.03 Predictive Biomarkers for Angiogenesis Inhibitors: An Update Martin Reck Lungen Clinic Grosshansdorf, Großhansdorf/ Germany 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, 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 randomized 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%