Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
presentation will review the highlights of the radiologic methods for
evaluating pulmonary nodules with a focus on current guidelines and future
directions. Reference: 1. Frank L, Quint LE. Chest CT incidentalomas: thyroid
lesions, enlarged mediastinal lymph nodes, and lung nodules. Cancer imaging :
the official publication of the International Cancer Imaging Society 2012;12:41-
8. 2. Jacobs PC, Mali WP, Grobbee DE, van der Graaf Y. Prevalence of incidental
findings in computed tomographic screening of the chest: a systematic
review. Journal of computer assisted tomography 2008;32:214-21. 3. Lung CT
Screening Reporting and Data Systen (Lung-RADS). 2014. (Accessed March
27, 2015, at www.acr.org/Quality-Safety/Resources/LungRADS ) 4. Munden
RF, Erasmus JJ, Wahba H, Fineberg NS. Follow-up of small (4 mm or less)
incidentally detected nodules by computed tomography in oncology patients:
a retrospective review. J Thorac Oncol 2010;5:1958-62. 5. McMahon PM, Meza
R, Plevritis SK, et al. Comparing benefits from many possible computed
tomography lung cancer screening programs: extrapolating from the National
Lung Screening Trial using comparative modeling. PloS one 2014;9:e99978.
6. McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in
pulmonary nodules detected on first screening CT. N Engl J Med 2013;369:910-
9. 7. Revel MP, Merlin A, Peyrard S, et al. Software volumetric evaluation
of doubling times for differentiating benign versus malignant pulmonary
nodules. AJR Am J Roentgenol 2006;187:135-42. 8. Talwar A, Gleeson FV,
Rahman NM, Pickup L, Gooding M, Kadir T. A Review Of The Use Of 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
SESSION SC26: ANGIOGENESIS INHIBITION: ADVANCES &
PERSPECTIVES
WEDNESDAY, DECEMBER 7, 2016 - 11:00-12:30
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
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
Keywords: angiogenesis
SC26: ANGIOGENESIS INHIBITION: ADVANCES & PERSPECTIVES
WEDNESDAY, DECEMBER 7, 2016 - 11:00-12:30
SC26.03 PREDICTIVE BIOMARKERS FOR ANGIOGENESIS
INHIBITORS: AN UPDATE
Copyright © 2016 by the International Association for the Study of Lung Cancer
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