2013 Research Highlights
inhibitor or an H2 blocker at time of enrolment had a smaller decrease in forced vital capacity at 40 weeks (p=0·05). Despite the enthusiasm in response to this finding, there are many important questions that remain to be addressed; these include which IPF phenotypes benefit from anti-acid treatment, and treatment duration and doses that should be used to optimise clinical effect and minimise side-effects.10 Until recently, research in IPF has lagged behind other fields, including oncology, in applying genomics to discover disease-causing mutations, biomarkers that accurately predict disease progression and treatment responsiveness, and therapeutic agents. In this context, 2013 is a watershed year for IPF, the year that discoveries of gene variants and changes in gene expression that predict outcome opened the door for implementing personalised medicine in this disease. The studies discussed suggest that creating algorithms that combine physiological and genomic information will revolutionise our approach to diagnosis, prognosis, and treatment of IPF and other fibrotic lung disorders. There is only one way for these concepts to become applicable in everyday clinical practice—carefully designed replication and validation through sufficiently powered, multicentre clinical trials enrolling carefully phenotyped patients with IPF.
*Demosthenes Bouros, Argyris Tzouvelekis Department of Pneumonology, Medical School, Democritus University of Thrace and University Hospital of Alexandroupolis, Alexandroupolis, 68100, Greece (DB); and Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA (AT) [email protected] We declare that we have no conflicts of interest. 1
2
3
4 5
6
7
8
9
10
Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788–824. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188: 733–48. Fingerlin TE, Murphy E, Zhang W, et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet 2013; 45: 613–20. Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med 2011; 364: 1503–12. Peljto AL, Zhang Y, Fingerlin TE, et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA 2013; 309: 2232–39. Noth I, Zhang Y, Ma S-F, et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med 2013; 1: 309–17. Herazo-Maya JD, Noth I, Duncan SR, et al. Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med 2013; 5: 205ra136. Raghu G, Behr J, Brown KK, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med 2013; 158: 641–49. Lee JS, Collard HR, Anstrom KJ, et al. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med 2013; 1: 369–76. Tzouvelekis A, Bouros D. Anti-acid treatment for idiopathic pulmonary fibrosis. Lancet Respir Med 2013; 1: 348–49.
In 2011, the US National Lung Screening Trial (NLST) group reported a 20% reduction in lung cancer mortality when screening with low-dose spiral CT compared with chest radiography. The overall results of the initial screening of 53 439 eligible participants were recently described.1 A total of 7191 of 26 309 participants (27·3%) in the low-dose CT group and 2387 of 26 035 participants (9·2%) in the radiography group had a positive screening result. Lung cancer was diagnosed in 292 participants (1·1%) in the low-dose CT group and in 190 (0·7%) in the radiography group. The sensitivity and specificity were 93·8% and 73·4% for low-dose CT and 73·5% and 91·3% for chest radiography, respectively. Results of another recent study showed that low-dose CT screening identifies more early cancers but had a lower positive predictive value compared with radiography.2 www.thelancet.com/respiratory Vol 2 January 2014
The NLST was done to establish whether three annual screening rounds (prevalence round T0 and incidence rounds T1 and T2) with low-dose spiral CT can reduce mortality from lung cancer compared with chest radiography in an asymptomatic highrisk population of individuals aged 55–74 years with at least 30 pack-years of smoking. At both T1 and T2, the use of low-dose CT produced more positive results than radiography, leading to more patients in the low-dose CT group being diagnosed with lung cancer. Interestingly, there was a higher proportion of stage 1A lung cancers diagnosed in the low-dose CT group than in the radiography group, which had a higher proportion of stage III-IV tumours. This difference in stage distribution between the two groups persisted at T2. Thus, the increase in early stage lung cancer in the CT screened group was associated
Sciepro/Science Photo Library
Progress in research on screening and genetics in lung cancer
Published Online December 23, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70264-9
19
2013 Research Highlights
with a decrease in late-stage disease. Over the course of the study, the incidence of stage IV lung cancer was 138 cases per 100 000 person-years in the CT group versus 204 per 100 000 person-years in the radiography group. The NLST investigators concluded that the detection of lung cancer over the two intervals of screening in the spiral CT arm was increased 2·7-times compared with radiography, and this finding resulted in a corresponding three-times decrease in the rate of screen-negative (“missed”) lung cancers. The results from the NLST study are consistent with other recent screening reports, which led to a favourable recommendation by the US Prevention services Task Force3 for national implementation in highrisk individuals aged 55–74 years. The US Prostate, Lung, Colorectal, and Ovarian cancer screening study4 reported a lung cancer risk-prediction model, which included age, level of education, body-mass index, family history of lung cancer, chronic obstructive pulmonary disease, chest radiography in the previous 3 years, smoking status (present vs former), history of cigarette smoking in pack-years, duration of smoking, and time since quitting. In a recent report,4 this risk model was modified to assess risk of a diagnosis of lung cancer in 6 years of follow-up; the area under the curves were 0·803 for smokers and 0·797 in the interventional group, which suggest high and consistent predictive discrimination. Such a predictive model might be of value in providing individual-level screening programmes.4 The definition of a positive result needs to be continually prospectively assessed and updated, in view of emerging evidence from ongoing screening programmes, to reduce unnecessary surgery for non-malignant nodules and reduce harm from the diagnostic work-up, while maximising the diagnosis and treatment of curable cases of lung cancer.5 Important therapeutic developments in advanced lung cancer in 2013 have been made in several areas: the identification of driver oncogenes and pathways that are constitutively activated by mutation, amplification, translocation, or fusion in all histological types of lung cancer;6 the discovery that orally delivered small molecule tyrosine kinase inhibitors (ie, EGFR and ALK inhibitors) of these oncogenes produce high response rates and relatively long duration of response in defined subgroups and are superior to standard therapy in 20
randomised studies;7 the description of mechanisms of resistance to EGFR, ALK, and ROS1 tyrosine kinase inhibitors and development of second-generation and third-generation EGFR and ALK tyrosine kinase inhibitors;8 and the discovery that inhibition of immune checkpoint inhibitors can cause durable remissions in advanced lung cancers.9 Although identification of clinically relevant molecular targets (EGFR mutations and ALK-gene rearrangements) and the pronounced effects of specific targeted agents (EGFR tyrosine kinase inhibitors and ALK inhibitors) were limited previously to subpopulations of patients with lung adenocarcinomas, studies reported in 2013 identified molecular abnormalities in squamous cell carcinoma (SCC) and small-cell lung cancer (SCLC) that are probable drivers and targets for currently available therapeutics.6 The FGFR gene is amplified in 10–15% of SCC and in 5–10% of SCLC; FGFR inhibitors are being assessed for the treatment of these tumours. Crizotinib, the first ALK inhibitor approved in lung cancer, was approved on the basis of a single arm phase 1/2 study.10 In 2013, the first randomised study comparing crizotinib with standard chemotherapy showed superior efficacy of crizotinib with reduced toxic effects and improved quality of life.7 Based on approved agents for biomarker specific targeted therapy in NSCLC, international guidelines prescribing molecular testing before therapy were established.11 Adenocarcinomas with mutations in BRAF and ROS1 fusion proteins were reported to respond to specific tyrosine kinase inhibitors.12,13 These studies suggest that, in the future, multiple oncogene abnormalities should be tested before institution of therapy. Despite the encouraging results of new targeted therapies in lung cancer, which have produced improvements in progression-free survival of months to years in defined subgroups, all patients with lung cancer relapse sooner or later. Some resistance mechanisms for EGFR and ALK have been reported,8 but further work is needed. Resistance mechanisms include secondary gatekeeper mutations in the activated oncogene and activation of other pathways, such as EGFR, MET, FGFR and AXL, Her2 amplification, and epithelial to mesenchymal transition. New tyrosine kinase inhibitors that bind to the resistance mutation T790M, but not to wild-type EGFR receptors, were developed and promise www.thelancet.com/respiratory Vol 2 January 2014
2013 Research Highlights
improved results.8 Second-generation ALK tyrosine kinase inhibitors produced high response rates in patients progressing on crizotinib. Inhibition of immune checkpoint proteins causes durable remissions in advanced lung cancers.14 Antibodies to the programmed cell death receptor 1 (PD1) produce responses in lung cancer and melanoma.15 Many of these responses have been of long duration (ie, >1 year). Monoclonal antibodies to the PD1 ligand (anti-PDL1) have also been shown to produce responses and prolonged outcome in patients with lung cancer.9 In summary, much progress in lung cancer research has occurred over recent years, which gives rise to great optimism for reducing lung cancer mortality and improved substantially the prospect of long-term survival or even cure for subgroups of patients with advanced lung cancer.
1
2 3
4 5
6
7 8 9
10 11
*Fred R Hirsch, Paul A Bunn Jr Division of Medical Oncology, School of Medicine, University of Colorado Denver, Research Center 1 South Tower, 12801 E 17th Avenue, 8th Floor, Campus Box 8117, Aurora, CO 80045, USA [email protected]
12
FRH has been a consultant and served on advisory boards for Roche/Genentech, Pfizer, Lilly, Boehringer-Ingelheim, Celgene, Novartis, Amgen, and Synta; and has received research grants (through the University of Colorado) from Ventana, Lilly/Imclone, Celgene, and Amgen. PAB has been a consultant and served on advisory boards for Amgen, Astellas, Astra-Zeneca, Bayer, Boehringer-Ingelheim, Celgene, Daichi Sankyo, Eisai, GlaxoSmithKline, Lilly, Merck, Merck Serono, Myriad, Pfizer, Roche/Genentech, Sanofi, and Synta.
14
13
15
National Lung Screening Trial Research Team. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med 2013; 368: 1980–91. Aberle DR, DeMello S, Berg CD, et al. Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med 2013; 369: 920–31. Humphrey LL, Deffebach M, Pappas M, et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the US Preventive services task force recommendation. Ann Intern Med 2013; 159: 411–20. Tammemägi MC, Katki HA, Hocking WG, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013; 368: 728–36. Henschke CI, Yip R, Yankelevitz DF, Smith JP. Definition of a positive test result in computed tomography screening for lung cancer: a cohort study. Ann Intern Med 2013; 158: 246–52. Buettner R, Wolf J, Thomas RK. Lessons learned from lung cancer genomics: the emerging concept of individualized diagnostics and treatment. J Clin Oncol 2013; 31: 1858–65. Shaw AT, Kim D-W, Nakagawa K, et al, Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368: 2385–94. Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol 2013; 31: 3987–96. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455–65. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363: 1693–703. Lindeman NI, Cagle PT, Beasley MB et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013; 8: 823–59. Peters S, Michielin O, Zimmermann S. Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma. J Clin Oncol 2013; 31: e341–44. Davies KD, Doebele RC. Molecular pathways: ROS1 fusion proteins in cancer. Clin Cancer Res 2013; 19: 4040–45. Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1–2 study. Lancet Oncol 2013; 14: 590–98. Drake CG, Lipson EJ, Brahmer JR. Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat Rev Clin Oncol 2013; published online Nov 19. http://dx.doi.org/10.1038/nrclinonc.2013.208.
Changing perceptions in pulmonary hypertension Pulmonary hypertension is characterised by raised pulmonary arterial pressure at rest due to a reduction of the functional pulmonary vascular bed. New science has emerged in 2013 that fundamentally shifted the understanding of pulmonary hypertension. First, notions about the treatments for chronic thromboembolic pulmonary hypertension (CTEPH), the major-vessel mechanical subset of pulmonary hypertension, have been challenged by innovation. CTEPH is surgically curable by pulmonary endarterectomy (PEA), which removes major-vessel obstructions from the pulmonary arteries. However, according to the European CTEPH registry, 37% of all patients with CTEPH are classified as non-operable,1 creating a large unmet need for alternative treatments. The new-in-its-class guanylate www.thelancet.com/respiratory Vol 2 January 2014
cyclase stimulator riociguat was tested in patients with non-operable CTEPH or persistent or recurrent pulmonary hypertension in a phase 3, multicentre, randomised, double-blind, placebo-controlled trial.2 Medical treatment of this major-vessel obstructive disease has been justified by a small-vessel disease component in CTEPH. 261 patients were randomly assigned (1:2) to receive placebo or riociguat. After 16 weeks, significant placebocorrected improvements in 6 min walking distance, WHO functional class, haemodynamics, and quality of life were recorded in the riociguat group.2 The drug received FDA approval on Oct 8, 2013. With the refinement of balloon pulmonary angioplasty by Japanese pulmonary vascular interventionists3 the treatment framework of only PEA for CTEPH might soon be changed to a triad
Published Online December 23, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70287-X
21
inhibitor or an H2 blocker at time of enrolment had a smaller decrease in forced vital capacity at 40 weeks (p=0·05). Despite the enthusiasm in response to this finding, there are many important questions that remain to be addressed; these include which IPF phenotypes benefit from anti-acid treatment, and treatment duration and doses that should be used to optimise clinical effect and minimise side-effects.10 Until recently, research in IPF has lagged behind other fields, including oncology, in applying genomics to discover disease-causing mutations, biomarkers that accurately predict disease progression and treatment responsiveness, and therapeutic agents. In this context, 2013 is a watershed year for IPF, the year that discoveries of gene variants and changes in gene expression that predict outcome opened the door for implementing personalised medicine in this disease. The studies discussed suggest that creating algorithms that combine physiological and genomic information will revolutionise our approach to diagnosis, prognosis, and treatment of IPF and other fibrotic lung disorders. There is only one way for these concepts to become applicable in everyday clinical practice—carefully designed replication and validation through sufficiently powered, multicentre clinical trials enrolling carefully phenotyped patients with IPF.
*Demosthenes Bouros, Argyris Tzouvelekis Department of Pneumonology, Medical School, Democritus University of Thrace and University Hospital of Alexandroupolis, Alexandroupolis, 68100, Greece (DB); and Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA (AT) [email protected] We declare that we have no conflicts of interest. 1
2
3
4 5
6
7
8
9
10
Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788–824. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188: 733–48. Fingerlin TE, Murphy E, Zhang W, et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet 2013; 45: 613–20. Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med 2011; 364: 1503–12. Peljto AL, Zhang Y, Fingerlin TE, et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA 2013; 309: 2232–39. Noth I, Zhang Y, Ma S-F, et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med 2013; 1: 309–17. Herazo-Maya JD, Noth I, Duncan SR, et al. Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med 2013; 5: 205ra136. Raghu G, Behr J, Brown KK, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med 2013; 158: 641–49. Lee JS, Collard HR, Anstrom KJ, et al. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med 2013; 1: 369–76. Tzouvelekis A, Bouros D. Anti-acid treatment for idiopathic pulmonary fibrosis. Lancet Respir Med 2013; 1: 348–49.
In 2011, the US National Lung Screening Trial (NLST) group reported a 20% reduction in lung cancer mortality when screening with low-dose spiral CT compared with chest radiography. The overall results of the initial screening of 53 439 eligible participants were recently described.1 A total of 7191 of 26 309 participants (27·3%) in the low-dose CT group and 2387 of 26 035 participants (9·2%) in the radiography group had a positive screening result. Lung cancer was diagnosed in 292 participants (1·1%) in the low-dose CT group and in 190 (0·7%) in the radiography group. The sensitivity and specificity were 93·8% and 73·4% for low-dose CT and 73·5% and 91·3% for chest radiography, respectively. Results of another recent study showed that low-dose CT screening identifies more early cancers but had a lower positive predictive value compared with radiography.2 www.thelancet.com/respiratory Vol 2 January 2014
The NLST was done to establish whether three annual screening rounds (prevalence round T0 and incidence rounds T1 and T2) with low-dose spiral CT can reduce mortality from lung cancer compared with chest radiography in an asymptomatic highrisk population of individuals aged 55–74 years with at least 30 pack-years of smoking. At both T1 and T2, the use of low-dose CT produced more positive results than radiography, leading to more patients in the low-dose CT group being diagnosed with lung cancer. Interestingly, there was a higher proportion of stage 1A lung cancers diagnosed in the low-dose CT group than in the radiography group, which had a higher proportion of stage III-IV tumours. This difference in stage distribution between the two groups persisted at T2. Thus, the increase in early stage lung cancer in the CT screened group was associated
Sciepro/Science Photo Library
Progress in research on screening and genetics in lung cancer
Published Online December 23, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70264-9
19
2013 Research Highlights
with a decrease in late-stage disease. Over the course of the study, the incidence of stage IV lung cancer was 138 cases per 100 000 person-years in the CT group versus 204 per 100 000 person-years in the radiography group. The NLST investigators concluded that the detection of lung cancer over the two intervals of screening in the spiral CT arm was increased 2·7-times compared with radiography, and this finding resulted in a corresponding three-times decrease in the rate of screen-negative (“missed”) lung cancers. The results from the NLST study are consistent with other recent screening reports, which led to a favourable recommendation by the US Prevention services Task Force3 for national implementation in highrisk individuals aged 55–74 years. The US Prostate, Lung, Colorectal, and Ovarian cancer screening study4 reported a lung cancer risk-prediction model, which included age, level of education, body-mass index, family history of lung cancer, chronic obstructive pulmonary disease, chest radiography in the previous 3 years, smoking status (present vs former), history of cigarette smoking in pack-years, duration of smoking, and time since quitting. In a recent report,4 this risk model was modified to assess risk of a diagnosis of lung cancer in 6 years of follow-up; the area under the curves were 0·803 for smokers and 0·797 in the interventional group, which suggest high and consistent predictive discrimination. Such a predictive model might be of value in providing individual-level screening programmes.4 The definition of a positive result needs to be continually prospectively assessed and updated, in view of emerging evidence from ongoing screening programmes, to reduce unnecessary surgery for non-malignant nodules and reduce harm from the diagnostic work-up, while maximising the diagnosis and treatment of curable cases of lung cancer.5 Important therapeutic developments in advanced lung cancer in 2013 have been made in several areas: the identification of driver oncogenes and pathways that are constitutively activated by mutation, amplification, translocation, or fusion in all histological types of lung cancer;6 the discovery that orally delivered small molecule tyrosine kinase inhibitors (ie, EGFR and ALK inhibitors) of these oncogenes produce high response rates and relatively long duration of response in defined subgroups and are superior to standard therapy in 20
randomised studies;7 the description of mechanisms of resistance to EGFR, ALK, and ROS1 tyrosine kinase inhibitors and development of second-generation and third-generation EGFR and ALK tyrosine kinase inhibitors;8 and the discovery that inhibition of immune checkpoint inhibitors can cause durable remissions in advanced lung cancers.9 Although identification of clinically relevant molecular targets (EGFR mutations and ALK-gene rearrangements) and the pronounced effects of specific targeted agents (EGFR tyrosine kinase inhibitors and ALK inhibitors) were limited previously to subpopulations of patients with lung adenocarcinomas, studies reported in 2013 identified molecular abnormalities in squamous cell carcinoma (SCC) and small-cell lung cancer (SCLC) that are probable drivers and targets for currently available therapeutics.6 The FGFR gene is amplified in 10–15% of SCC and in 5–10% of SCLC; FGFR inhibitors are being assessed for the treatment of these tumours. Crizotinib, the first ALK inhibitor approved in lung cancer, was approved on the basis of a single arm phase 1/2 study.10 In 2013, the first randomised study comparing crizotinib with standard chemotherapy showed superior efficacy of crizotinib with reduced toxic effects and improved quality of life.7 Based on approved agents for biomarker specific targeted therapy in NSCLC, international guidelines prescribing molecular testing before therapy were established.11 Adenocarcinomas with mutations in BRAF and ROS1 fusion proteins were reported to respond to specific tyrosine kinase inhibitors.12,13 These studies suggest that, in the future, multiple oncogene abnormalities should be tested before institution of therapy. Despite the encouraging results of new targeted therapies in lung cancer, which have produced improvements in progression-free survival of months to years in defined subgroups, all patients with lung cancer relapse sooner or later. Some resistance mechanisms for EGFR and ALK have been reported,8 but further work is needed. Resistance mechanisms include secondary gatekeeper mutations in the activated oncogene and activation of other pathways, such as EGFR, MET, FGFR and AXL, Her2 amplification, and epithelial to mesenchymal transition. New tyrosine kinase inhibitors that bind to the resistance mutation T790M, but not to wild-type EGFR receptors, were developed and promise www.thelancet.com/respiratory Vol 2 January 2014
2013 Research Highlights
improved results.8 Second-generation ALK tyrosine kinase inhibitors produced high response rates in patients progressing on crizotinib. Inhibition of immune checkpoint proteins causes durable remissions in advanced lung cancers.14 Antibodies to the programmed cell death receptor 1 (PD1) produce responses in lung cancer and melanoma.15 Many of these responses have been of long duration (ie, >1 year). Monoclonal antibodies to the PD1 ligand (anti-PDL1) have also been shown to produce responses and prolonged outcome in patients with lung cancer.9 In summary, much progress in lung cancer research has occurred over recent years, which gives rise to great optimism for reducing lung cancer mortality and improved substantially the prospect of long-term survival or even cure for subgroups of patients with advanced lung cancer.
1
2 3
4 5
6
7 8 9
10 11
*Fred R Hirsch, Paul A Bunn Jr Division of Medical Oncology, School of Medicine, University of Colorado Denver, Research Center 1 South Tower, 12801 E 17th Avenue, 8th Floor, Campus Box 8117, Aurora, CO 80045, USA [email protected]
12
FRH has been a consultant and served on advisory boards for Roche/Genentech, Pfizer, Lilly, Boehringer-Ingelheim, Celgene, Novartis, Amgen, and Synta; and has received research grants (through the University of Colorado) from Ventana, Lilly/Imclone, Celgene, and Amgen. PAB has been a consultant and served on advisory boards for Amgen, Astellas, Astra-Zeneca, Bayer, Boehringer-Ingelheim, Celgene, Daichi Sankyo, Eisai, GlaxoSmithKline, Lilly, Merck, Merck Serono, Myriad, Pfizer, Roche/Genentech, Sanofi, and Synta.
14
13
15
National Lung Screening Trial Research Team. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med 2013; 368: 1980–91. Aberle DR, DeMello S, Berg CD, et al. Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med 2013; 369: 920–31. Humphrey LL, Deffebach M, Pappas M, et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the US Preventive services task force recommendation. Ann Intern Med 2013; 159: 411–20. Tammemägi MC, Katki HA, Hocking WG, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013; 368: 728–36. Henschke CI, Yip R, Yankelevitz DF, Smith JP. Definition of a positive test result in computed tomography screening for lung cancer: a cohort study. Ann Intern Med 2013; 158: 246–52. Buettner R, Wolf J, Thomas RK. Lessons learned from lung cancer genomics: the emerging concept of individualized diagnostics and treatment. J Clin Oncol 2013; 31: 1858–65. Shaw AT, Kim D-W, Nakagawa K, et al, Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368: 2385–94. Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol 2013; 31: 3987–96. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455–65. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363: 1693–703. Lindeman NI, Cagle PT, Beasley MB et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013; 8: 823–59. Peters S, Michielin O, Zimmermann S. Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma. J Clin Oncol 2013; 31: e341–44. Davies KD, Doebele RC. Molecular pathways: ROS1 fusion proteins in cancer. Clin Cancer Res 2013; 19: 4040–45. Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1–2 study. Lancet Oncol 2013; 14: 590–98. Drake CG, Lipson EJ, Brahmer JR. Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat Rev Clin Oncol 2013; published online Nov 19. http://dx.doi.org/10.1038/nrclinonc.2013.208.
Changing perceptions in pulmonary hypertension Pulmonary hypertension is characterised by raised pulmonary arterial pressure at rest due to a reduction of the functional pulmonary vascular bed. New science has emerged in 2013 that fundamentally shifted the understanding of pulmonary hypertension. First, notions about the treatments for chronic thromboembolic pulmonary hypertension (CTEPH), the major-vessel mechanical subset of pulmonary hypertension, have been challenged by innovation. CTEPH is surgically curable by pulmonary endarterectomy (PEA), which removes major-vessel obstructions from the pulmonary arteries. However, according to the European CTEPH registry, 37% of all patients with CTEPH are classified as non-operable,1 creating a large unmet need for alternative treatments. The new-in-its-class guanylate www.thelancet.com/respiratory Vol 2 January 2014
cyclase stimulator riociguat was tested in patients with non-operable CTEPH or persistent or recurrent pulmonary hypertension in a phase 3, multicentre, randomised, double-blind, placebo-controlled trial.2 Medical treatment of this major-vessel obstructive disease has been justified by a small-vessel disease component in CTEPH. 261 patients were randomly assigned (1:2) to receive placebo or riociguat. After 16 weeks, significant placebocorrected improvements in 6 min walking distance, WHO functional class, haemodynamics, and quality of life were recorded in the riociguat group.2 The drug received FDA approval on Oct 8, 2013. With the refinement of balloon pulmonary angioplasty by Japanese pulmonary vascular interventionists3 the treatment framework of only PEA for CTEPH might soon be changed to a triad
Published Online December 23, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70287-X
21
