bs_bs_banner

Asia-Pacific Journal of Clinical Oncology 2014; 10(Suppl. 2): 2–10

doi: 10.1111/ajco.12189

REVIEW PAPER

Preparing for tomorrow: Molecular diagnostics and the changing nonsmall cell lung cancer landscape Michael BOYER,1 Ming-Sound TSAO,2 Pasi JÄNNE,3 Suresh RAMALINGAM,4 Susan PITMAN LOWENTHAL5 and Mahmood ALAM6 1

The Chris O’Brien Lifehouse, 6Oncology Business Unit, Pfizer, Sydney, Australia, and 2Princess Margaret Cancer Centre, Toronto, Canada, and 3Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, 4Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia and 5Clinical Development and Medical Affairs, Pfizer Oncology, New York, New York, USA

Abstract Over the last 10 to 15 years, the landscape of lung cancer has changed dramatically. Where cancers were previously described rather simplistically according to histological subtype, now molecular understanding of tumors has particularly resulted in segmentation of nonsmall cell lung cancer into many different subtypes. A multidisciplinary approach integrating a molecular testing algorithm that ideally includes reflex testing at diagnosis is recommended. This offers clinicians the opportunity to target treatment according to subtype. Identifying patients with rearrangements, such as those associated with the echinoderm microtubuleassociated protein-like 4 (EML-4) anaplastic lymphoma kinase (ALK) fusion gene (the major focus of this paper) has allowed clinicians to tailor therapy to target these mutations. The challenge that faces clinicians treating lung cancer is how best to implement the science that sits behind these targeted therapies in clinical practice through the identification of appropriate patients. Precision medicine can lead to the choice of the right medicine for the right patients and is proving to be a better approach than treating unselected patients with systemic chemotherapy. Key words: anaplastic lymphoma kinase (ALK) fusion gene, carcinoma, epidermal growth factor receptor mutation, molecular testing, nonsmall cell lung, targeted therapy.

NSCLC SEGMENTATION BASED ON DRIVER MUTATIONS

that allowed treatment to be targeted. This trial showed that, compared with epidermal growth factor receptor (EGFR) mutation-negative tumors, patients with mutation-positive tumors had improved progression-free survival following first-line treatment with EGFR tyrosine kinase inhibitor (TKI) therapy versus chemotherapy. Conversely, and perhaps more importantly, it also demonstrated that treatment with EGFR-TKI therapy can be detrimental to patients with wild-type EGFR tumors.2

Lung cancer is a heterogeneous disease, with the World Health Organization classification recognizing 20 different types of malignant lung neoplasms.1 Prior to 2009, the most critical decision when diagnosing lung cancer and determining first-line treatment for advanced or metastatic disease was to distinguish between small cell and nonsmall cell lung cancer (NSCLC). The results of the IPASS trial have led to a shift in the diagnostic paradigm with the introduction of molecular markers

EGFR mutations

Correspondence: Dr Mahmood Alam FRACP Regional Medical Affairs Lead, Pfizer Oncology, Asia Pacific Region, 38-42 Wharf Road, West Ryde, NSW 2114, Australia. Email: [email protected] Accepted for publication 13 February 2014.

EGFR mutations that are sensitive to TKIs generally occur within exons 18 to 21.3 The classical way to detect EGFR mutations is by direct sequencing of these exons. Although direct sequencing can detect all types of mutations, it is limited by low sensitivity. However, newer methods are available that have significantly increased

© 2014 Wiley Publishing Asia Pty Ltd

3

Nonsmall cell lung cancer landscape

Table 1

Sensitivity of various molecular testing tools4

Method Direct sequencing PCR-SSCP TaqMan PCR Loop-hybrid motility shift assay Cycleave PCR PCR-RFLP (fragment length analysis MassARRAY genotyping LNA-PCR clamp Scorpion ARMS (DxS) dHPLC COLD-TaqMan PCR

Sensitivity 25% 10% 10% 7.5% 5% 5% 5% 1% 1% 1% 0.05%

Mutations identified Known Known Known Known Known Known Known Known Known Known Known

and new only only only only only only only only only only

Adapted from Pao W, Ladanyi M. Epidermal growth factor receptor mutation testing in lung cancer: searching for the ideal method. Clin Cancer Res 2007;13:4954–5. ARMS, amplification refractory mutation system; dHPLC, denaturing high performance liquid chromatography; LNAL, locked nucleic acid; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; SSCP, singlestrand conformation polymorphism.

sensitivity (Table 1),4 albeit with the limitation that only known mutations can be detected. EGFR mutations are primarily found in adenocarcinomas.5–12 Therefore, current recommendations for EGFR mutation testing are limited to adenocarcinomas or nonsquamous NSCLC with adenocarcinoma components. The likelihood of finding EFGR mutations is high among patients of East Asian origin and female nonsmokers; however, it is recognized that phenotype alone cannot be used to select for EGFR mutation testing.13

EML4-ALK fusion gene The EML4-ALK fusion gene in NSCLC is a fusion of the kinase domain of the ALK gene with the EML-4 gene. The resulting gene results in the constitutive activation of ALK kinase.14 Although more than 20 ALK rearrangements have been identified, more than 90% of them involve only three variants. Importantly, all of these variants can be detected by fluorescence in situ hybridization (FISH).15 Currently, histology and cytology are the main methods for diagnosing lung cancer. At present, FISH is the gold standard for identifying the presence of an ALK rearrangement, and deciding whether or not to use an ALK inhibitor, such as crizotinib. However, in many countries, immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (PCR) are being used. In ALK wild-type tumors, FISH involves using two probes, which are found to be very close together or

Asia-Pac J Clin Oncol 2014; 10(Suppl. 2): 2–10

fused. When there is a rearrangement, the two probes separate. This separation has been described as the “break apart signal.” When this signal is present in at least 15% or more of the tumor cells, the tumor is regarded as being ALK-positive. IHC, being fast and cost-effective, is used commonly by pathologists to characterize tumors and is an effective method of detecting ALK protein (not normally expressed by lung tissue). Although IHC identifies expression of ALK protein it does not identify the gene rearrangement. Thus, routine use of ALK IHC is not widespread at this stage. Although several studies have now been reported which show a good correlation between IHC and FISH,16–19 there remain cases where tumors are FISH-negative but IHC-positive. Indeed, there have been reports of patients with FISH-negative, IHC-positive tumors who have responded to the ALK inhibitor, crizotinib.20 FISH negativity may be due to variations in the scoring of FISH signals by different pathologists. A large number of studies have demonstrated very high sensitivity and specificity of optimized IHC in detecting ALK-positive lung cancers.21 Based on these findings, screening with IHC followed by confirmation with FISH is the preferred approach for determining ALK-positivity in many parts of the world.21

Recommendations for good pathology practice Recommendations for good pathology practice published by the International Association for the Study of

© 2014 Wiley Publishing Asia Pty Ltd

4

Lung Cancer (IASLC), the American Thoracic Society and the European Respiratory Society include22 • Maximizing the amount of tissue available for molecular studies. • Developing a multidisciplinary team that coordinates the optimal approach to obtaining and processing biopsy/cytology specimens to provide expeditious diagnostic and molecular results. • Preparation of cell blocks from cytology samples including pleural fluids. New guidelines for selection of lung cancer patients for EGFR and ALK TKIs have been published jointly by the College of American Pathologists, IASLC and the Association for Molecular Pathology.13 These guidelines are based on an extensive systematic review of the literature and suggest that at this time patients should only be tested routinely for EGFR and ALK rearrangements. However, as targeted therapies are shown to address other mutations, the guidelines may be revised accordingly. Molecular aberration is part of the pathology of lung cancer, thus clinicians should strive to incorporate molecular testing as part of the diagnostic process. The turnaround time for molecular testing is extremely important in order for patients to be treated in a timely manner, and therefore, it is essential to have efficient molecular testing platforms to achieve a quick result. However, in some cases, turnaround times can be particularly long. In most parts of the world, molecular testing is ordered by oncologists, whereas in an ideal world, testing should be performed by the pathologist at the time of initial diagnosis of lung cancer. In this way, the results would be available when a patient is first informed of the diagnosis. This is referred to as “reflex testing” and is the standard practice in areas such as hormone receptor and human epidermal growth factor receptor 2 (HER-2) testing in breast cancer. IASLC guidelines recommend that ALK rearrangement testing should be ordered at the time of diagnosis for patients presenting with advanced-stage disease (stage IV) who are suitable for therapy or at time of recurrence or progression in patients who originally presented with lower stage disease but were not previously tested.13 Many types of tissue samples can be used for molecular testing. The most common is tumor tissue from excision, resection or core biopsy which allows adequate specimen for performing various tests simultaneously or sequentially. Nevertheless, specimens from fine-needle aspiration, sputum, pleural fluid and blood are not infrequently used to extract tumor cells to perform these tests.

© 2014 Wiley Publishing Asia Pty Ltd

M Boyer et al.

Because most lung cancer biopsy samples are small, it is important to optimize the amount of tissue available for molecular testing.Ideally, EGFR and ALK testing should be performed in parallel. In the future, large panels of genes will be tested as markers for new targeted therapies. If testing is performed sequentially, tissue volume will become a real issue. Some centers have moved away from fine-needle aspirates for molecular testing and now use core needle aspirates as these are more amenable to testing. There is certainly a need for higher throughput and multiplex platforms for mutational profiling of tumors. Techniques that are already available in some centers include mass spectrometry, SNaPShot multiplex PCR and next-generation sequencing.

TARGETABLE MUTATION AND PRECISION MEDICINE: PUTTING KNOWLEDGE INTO PRACTICE How lung cancer is viewed in 2013 is quite different to how it was viewed in 2003. Over the last 10–15 years, there has been a revolution in the understanding of genomic alterations in lung cancer. Clinical trials demonstrate that targeting oncogene drivers is a better approach than using chemotherapy. Precision medicine means choosing the right medicine for the right patient. Testing for EGFR and ALK should guide selection of targeted therapies in NSCLC and be given priority over all other forms of molecular testing. Such testing should also be performed in patients with advanced adenocarcinoma.

EGFR inhibitors improve survival in EGFR-positive patients Patients with EGFR-positive NSCLC have better response rates when treated with EGFR inhibitors than with chemotherapy (Fig. 1).23,24 When looking at trials of EGFR TKIs as standard first-line therapy, in all cases, the response rate is significantly higher for these agents versus chemotherapy. In addition, progression-free survival (PFS) is significantly longer.2,23–28

Introduction to ALK inhibitors Approximately 5% of patients with NSCLC have an ALK rearrangement.14,29,30 ALK makes a very good therapeutic target because it is not normally expressed

Asia-Pac J Clin Oncol 2014; 10(Suppl. 2): 2–10

5

Nonsmall cell lung cancer landscape

outside of cancer, and thus, there is a wide potential therapeutic index.

Crizotinib – clinical trials Crizotinib is the first ALK inhibitor to be approved for use in NSCLC. Phase II studies suggested that the vast majority of patients have at least a partial response to this agent and very few patients had progression as their best response.31,32

Figure 1 Progression-free survival for EGFR-positive patients treated with an EGFR inhibitor versus those treated with chemotherapy.23 Adapted with permission from: Rosell R, Carcereny E, Gervais R, et al. Lancet Oncol 2012;13:239–46.

Previously treated NSCLC patients The definitive Phase III clinical trial which compared crizotinib to standard chemotherapy of crizotinib was a recently published phase III trial randomizing 318 previously treated patients with ALK-positive NSCLC to crizotinib 250 mg twice daily for a 21-day cycle versus pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, day 1, 21-day cycle. Patients in the chemotherapy group who progressed were allowed to cross over into another trial where they received crizotinib.33 There was a significant difference in median PFS in favor of crizotinib, the primary end point of this trial (7.7 months vs 3.0 months for chemotherapy; P < 0.001; Fig. 2).33 When patients were analyzed according to baseline characteristics and stratification factors, the treatment effect on PFS favored crizotinib in all cases. The response rate for crizotinib versus chemotherapy overall was significantly greater (65.3% vs 19.5%, respectively; P < 0.0001) and versus the individual chemotherapy regimens (65.7% vs 29.3% for pemetrexed and 6.9% for docetaxel; P < 0.0001). The vast majority of responses with crizotinib were partial.33 An interim analysis reveals that, to date, there is no difference between groups in overall survival rates. Potential reasons for this finding are (i) the data are not mature and (ii) of those chemotherapy patients who had progressed, 111 had crossed over to the parallel trial where they received crizotinib. Interestingly, the median survival in both groups was approximately 20 months,33 which compares favorably with the median survival rate of 6 to 8 months in the pivotal docetaxel trials.

Figure 2 Phase III trial of crizotinib versus chemotherapy in previously treated patients with NSCLC: progression-free survival.33 Adapted from: Shaw AT, Kim DW, Nakagawa K, et al. N Engl J Med 2013;368: 2385–94.

Asia-Pac J Clin Oncol 2014; 10(Suppl. 2): 2–10

© 2014 Wiley Publishing Asia Pty Ltd

6

The prolonged survival may be due to the fact that this patient population received targeted therapy as secondor third-line treatment. Although there were no real differences between the two groups of patients in the number of grade 3/4 adverse events, there were some differences in the type of events. For example, there were more grade 3/4 cases of elevated aminotransferase with crizotinib, whereas, with chemotherapy, there were more cases of grade 3/4 diarrhoea and nausea. It is important to determine if improved response rate and PFS translate into other clinical benefits for patients. One way to capture this is to look at quality of life (QoL). Extensive QoL analysis of the pivotal phase III trial of crizotinib revealed that on the whole, QoL was improved in patients taking crizotinib, whereas it deteriorated in patients on chemotherapy.33

Patients with brain metastases A retrospective analysis of patients with or without brain metastases in two crizotinib studies revealed that around 25% of patients with brain metastases at baseline had a response. Intracranial disease control rate was around 60% at 12 weeks. The systemic response rate in patients with metastases was around 49%. In patients with no detectable brain metastases at baseline, 9% developed symptomatic brain metastases after starting treatment with crizotinib.34

Treating beyond documented progression In the crizotinib studies, clinicians had the option of continuing treatment beyond the predefined markers of progression if they felt patients were benefitting from the drug. In a phase I study, 39 of 69 patients (56%) with investigator-documented progression received crizotinib for more than 2 weeks beyond progression, with 12 of these patients (17%) being treated for more than 6 months. A number of these patients have been found to have stable disease or a partial response when therapy was continued after documented progression.31 At this point in time, there is no data indicating when therapy should be discontinued. The decision should be based on patient status, how patients are progressing and whether or not they are symptomatic.

Ongoing study in treatment-naïve patients A phase III study is investigating the efficacy of crizotinib versus standard chemotherapy (pemetrexed plus cisplatin or carboplatin) in patients with treatment-

© 2014 Wiley Publishing Asia Pty Ltd

M Boyer et al.

naïve ALK-positive NSCLC. Enrollments for this study are closed and it is hoped the data will be forthcoming in 2014.

Other molecular rearrangements There are a number of other molecular rearrangements in NSCLC including ROS1 rearrangement and c-MET amplifications. The former are found in approximately 1% of patients with NSCLC and are non-overlapping with other oncogenic mutations found in this disease.ROS1 rearrangements are enriched in younger patients with adenocarcinoma who have never smoked or who are light smokers.35–37 Crizotinib targets both c-MET and ROS1. Clinical activity has been seen in patients with these mutations.38

Is there a role for radiotherapy with TKIs and ALK inhibitors? There are limited data available on the subject of combining radiotherapy with targeted therapy. There have been phase I/II studies in unselected patients with stage III disease where radiotherapy was administered in conjunction with EGFR inhibitors.39–41 These demonstrated efficacy but it is not clear whether this is the right approach in stage III patients.42 A phase II trial has just started in the United States in which patients with EGFR mutations or ALK rearrangements will receive 3 months of an EGFR TKI or crizotinib, respectively, and then will be administered chemoradiation. The decision to discontinue targeted therapy if localized progression and not widespread systemic progression of disease is seen resides with the physician and is determined by the likelihood of clinical benefit expected. In some situations where a patient progresses and local radiation is warranted, it is probably not necessary to discontinue targeted therapy, as in the setting of isolated bone metastases. However, if chest or brain radiation is necessary, it may be advisable to discontinue therapy and re-evaluate. Certainly, more information is needed to clarify this issue.

THERAPEUTIC OPTIONS FOR UNSELECTED NSCLC There is a significant subset of patients with lung cancer for whom targeted therapies may not be adequate to control their disease or improve their outcomes. Clinicians need to expand and maximize the role of existing therapies for this patient population.

Asia-Pac J Clin Oncol 2014; 10(Suppl. 2): 2–10

7

Nonsmall cell lung cancer landscape

Is chemotherapy the answer? In most settings, an efficacy plateau has been reached with chemotherapy. Novel strategies include combination of different agents to improve efficacy of standard agents, use of targeted therapies that have been shown to be effective in wild-type tumors and immunotherapy. In patients with nonsquamous histology, the addition of bevacizumab to standard chemotherapy regimens has gone some way toward moving beyond the chemotherapy efficacy plateau. This subset of patients also benefits more from treatment with the combination of cisplatin and pemetrexed versus cisplatin plus gemcitabine. On the other hand, in patients with squamous histology, the converse is true.43 Maintenance therapy improves survival in NSCLC. Commonly used agents include pemetrexed and erlotinib. However, the decision to use maintenance therapy should be based on a variety of factors, including the individual patient’s situation. In the salvage therapy setting, monotherapy with docetaxel, pemetrexed or erlotinib is the accepted approach. Combination regimens of cytotoxic agents may increase response rate, but they do not improve survival.

Combining new agents with chemotherapy Poly(ADP-ribose) polymerase (PARP) inhibition Many of the chemotherapy agents used depend on impaired DNA repair to exert a lethal effect on the cell. PARP enhances DNA repair.44 Thus, it has been hypothesized that the effectiveness of chemotherapy and even radiotherapy can be increased by inhibiting PARP. The PARP inhibitor veliparib has been studied in a phase II study in which patients with stage IV NSCLC and no prior exposure to chemotherapy were randomized to either carboplatin plus paclitaxel plus veliparib or carboplatin plus paclitaxel plus placebo. It is anticipated that results will be available at the next American Society of Clinical Oncology (ASCO) meeting. In another ongoing phase II trial, veliparib is being studied in combination with cisplatin plus etoposide versus cisplatin plus etoposide plus placebo in patients with small cell lung cancer.

Heat-shock protein (HSP)-9 inhibition HSP-90s are critical for more than 200 different oncoproteins. Inhibiting HSP-90 inhibits a variety of oncogenes that may be involved in NSCLC. In an ongoing phase III trial of the HSP-90 inhibitor ganetespib patients

Asia-Pac J Clin Oncol 2014; 10(Suppl. 2): 2–10

with advanced NSCLC and exposure to one prior chemotherapy regimen were randomized to ganetespib plus docetaxel versus docetaxel alone. Results are anticipated next year.

Programmed death (PD)-1 receptor inhibition When T-cells are activated, they need costimulation signals to attack tumors. PD-1 is one protective mechanism exhibited by tumor cells to evade T-cell attack. By blocking PD-1 or the PD-1 ligand, it is hypothesized that T-cell attack of tumor cells would be facilitated.45,46 The anti-PD-1 antibody, nivolumab, has been studied in patients with advanced NSCLC at three different doses, with some early data on efficacy presented at ASCO 2013.47 There are a number PD-1 inhibitors under investigation and they show great promise as potential therapies for lung cancer.

Improving efficacy of EGFR inhibitors The EGFR inhibitor erlotinib is broadly effective in patients with wild-type tumors. In a phase II trial erlotinib was given in combination with onartuzumab, a monoclonal antibody that inhibits c-MET. In this trial, there were no differences in outcomes for patients treated with the combination of erlotinib and onartuzumab and those treated with erlotinib alone. However, patients with MET-positive tumors received a clear benefit from combination therapy. A phase III trial is now underway in patients with c-MET-positive tumors. Another strategy is irreversible blockade of EGFR. Advantages associated with the use of irreversible EGFR inhibitors in NSCLC include48 • Permanent blockade of catalytic activity. • A shift in equilibrium between adenosine triphosphate (ATP) and kinase. • Noncompetitive inhibition. • A pharmacokinetic advantage in the presence of high intracellular ATP concentrations. • Potential to achieve higher specificity and selectivity. • TKI remains in tumor cells despite falling drug levels. Dacomitinib is an example of a pan irreversible EGFR inhibitor, which inhibits HER-1, −2 and −4.49 When EGFR is activated, dimerization occurs and the HER-1 receptor can either dimerize with itself or can heterodimerize with other members of the EGFR family. The advantage of a pan inhibitor that it offers a more extended spectrum of EGFR inhibitor activity. IC50 data reveal that dacomitinib is almost 10 times more potent than first-generation EGFR inhibitors against HER-2 and HER-4 (Table 2).49

© 2014 Wiley Publishing Asia Pty Ltd

8

M Boyer et al.

Table 2 IC50 comparison of dacomitinib, gefitinib and erlotinib49 IC50 (nM)

Dacomitinib Gefitinib Erlotinib

EGFR

HER-2

HER-4

6.0 3.1 0.56

45.7 343 512

73.7 476 790

In vitro kinase assay against wild-type HER receptors. Adapted from Engelman JA, Zejnullahu K, Gale CM et al. Cancer Res 2007;67: 11924–32.

In a phase II study comparing erlotinib with dacomitinib in patients with advanced NSCLC, PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/ EGFR wild-type and EGFR mutants.50 Dacomitinib is now being studied in an extensive clinical trial program with phase III trials underway in a treatment-refractory NSCLC population (vs placebo), as second-line therapy after standard chemotherapy (vs erlotinib) and in firstline EGFR mutation-positive NSCLC (vs geftinib).

CONCLUSIONS EGFR and ALK testing have the utility to be used in treatment decision making in nonsquamous NSCLC. Individual centers should develop a multidisciplinary approach to integrate a molecular testing algorithm that ideally includes reflex testing at diagnosis. Next generation sequencing can resolve much of the complexity of molecular testing, especially in situations where there is only a small amount of tissue available. It is critical to test for targetable oncogenic alterations. Clinical trials demonstrate that precision medicine can lead to choosing the right medicine for the right patient and is a better approach than treating unselected patients with systemic chemotherapy. A number of novel approaches are being studied for patients without known driver mutations. Improving the efficacy of existing agents remains a major research priority.

ACKNOWLEDGMENTS This manuscript is based on coverage of a Pfizer sponsored education symposium at the 15th World Lung Cancer Conference, held in Sydney on October 27, 2013. This symposium was organized and funded by Pfizer Oncology and was conducted in accordance with

© 2014 Wiley Publishing Asia Pty Ltd

Medicines Australia Code of Conduct. Attendance was limited to healthcare professionals registered to attend World Lung Cancer Conference. The symposium was chaired by Professor Michael Boyer, and included three independent presentations from Professors Ming-Sound Tsao, Pasi Janne and Suresh Ramalingam, followed by a panel discussion. Dr Susan Pitman Lowenthal and Dr Mahmood Alam from Pfizer designed the program, facilitated and reviewed the content of the presentations and the manuscript. Publication of this supplement has been supported through an independent educational grant from Pfizer Oncology. The authors Michael Boyer, Ming-Sound Tsao, Pasi Janne and Suresh Ramalingam have received honoraria and/or research funding from Pfizer Inc.

REFERENCES 1 Beasley MB, Brambilla E, Travis WD. The 2004 World Health Organization classification of lung tumors. Semin Roentgenol 2005; 40: 90–7. 2 Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–57. 3 Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007; 7: 169–81. 4 Pao W, Ladanyi M. Epidermal growth factor receptor mutation testing in lung cancer: searching for the ideal method. Clin Cancer Res 2007; 13: 4954–5. 5 Asahina H, Yamazaki K, Kinoshita I et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer 2006; 95: 998–1004. 6 Bell DW, Lynch TJ, Haserlat SM et al. Epidermal growth factor receptor mutations and gene amplification in nonsmall-cell lung cancer: molecular analysis of the IDEAL/ INTACT gefitinib trials. J Clin Oncol 2005; 23: 8081–92. 7 Douillard JY, Shepherd FA, Hirsh V et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 2010; 28: 744–52. 8 Eberhard DA, Johnson BE, Amler LC et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-smallcell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005; 23: 5900–9. 9 Rosell R, Moran T, Queralt C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361: 958–67. 10 Tamura K, Okamoto I, Kashii T et al. Multicentre prospective phase II trial of gefitinib for advanced non-small cell lung cancer with epidermal growth factor receptor

Asia-Pac J Clin Oncol 2014; 10(Suppl. 2): 2–10

9

Nonsmall cell lung cancer landscape

11

12

13

14

15

16

17

18

19

20

21

22

23

mutations: results of the West Japan Thoracic Oncology Group trial (WJTOG0403). Br J Cancer 2008; 98: 907–14. Yang CH, Yu CJ, Shih JY et al. Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol 2008; 26: 2745–53. Zhu CQ, da Cunha Santos G, Ding K et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2008; 26: 4268–75. 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. Soda M, Choi YL, Enomoto M et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448: 561–6. Ou SH, Bartlett CH, Mino-Kenudson M, Cui J, Iafrate AJ. Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist 2012; 17: 1351–75. Kim H, Yoo SB, Choe JY et al. Detection of ALK gene rearrangement in non-small cell lung cancer: a comparison of fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression. J Thorac Oncol 2011; 6: 1359–66. Minca EC, Portier BP, Wang Z et al. ALK status testing in non-small cell lung carcinoma: correlation between ultrasensitive IHC and FISH. J Mol Diagn 2013; 15: 341–6. Paik JH, Choe G, Kim H et al. Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: correlation with fluorescence in situ hybridization. J Thorac Oncol 2011; 6: 466–72. Yi ES, Boland JM, Maleszewski JJ et al. Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. J Thorac Oncol 2011; 6: 459–65. Sun JM, Choi YL, Won JK et al. A dramatic response to crizotinib in a non-small-cell lung cancer patient with IHCpositive and FISH-negative ALK. J Thorac Oncol 2012; 7: e36–8. Tsao MS, Hirsch FR, Yatabe Y (eds). IASLC Atlas of ALK Testing in Lung Cancer. International Association for the Study of Lunger Cancer, Aurora, CO 2013. Travis WD, Brambilla E, Noguchi M et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6: 244–85. Rosell R, Carcereny E, Gervais R et al. Erlotinib versus standard chemotherapy as first-line treatment for European

Asia-Pac J Clin Oncol 2014; 10(Suppl. 2): 2–10

24

25

26

27

28

29

30

31

32

33

34

35

36

patients with advanced EGFR mutation-positive non-smallcell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239–46. Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12: 735– 42. Han JY, Park K, Kim SW et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012; 30: 1122–8. Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362: 2380–8. Mitsudomi T, Morita S, Yatabe Y et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010; 11: 121–8. Sequist LV, Yang JC, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327–34. Camidge DR, Doebele RC. Treating ALK-positive lung cancer – early successes and future challenges. Nat Rev Clin Oncol 2012; 9: 268–77. Rikova K, Guo A, Zeng Q et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007; 131: 1190–203. Camidge DR, Bang YJ, Kwak EL et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012; 13: 1011–9. Kim D, Ahn M, Yang P et al. Updated results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer. Ann Oncol 2012; 23: ix402. Shaw AT, Kim DW, Nakagawa K et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368: 2385–94. Crino L, Ahn MJ, Ou SHI et al. Clinical experience with crizotinib in patients (pts) with advanced ALK+ non-small cell lung cancer (NSCLC) and brain metastases. Presented at the European Cancer Congress, Amsterdam, Netherlands, 2013. Bergethon K, Shaw AT, Ou SH et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012; 30: 863–70. Ou SH, Kwak EL, Siwak-Tapp C et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol 2011; 6: 942–6.

© 2014 Wiley Publishing Asia Pty Ltd

10

37 Takeuchi K, Soda M, Togashi Y et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18: 378–81. 38 Cui JJ, Tran-Dube M, Shen H et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 2011; 54: 6342–63. 39 Center B, Petty WJ, Ayala D et al. A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III non-small cell lung cancer. J Thorac Oncol 2010; 5: 69–74. 40 Chang CC, Chi KH, Kao SJ et al. Upfront gefitinib/ erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: a mono-institutional experience. Lung Cancer 2011; 73: 189–94. 41 Wang J, Xia TY, Wang YJ et al. Prospective study of epidermal growth factor receptor tyrosine kinase inhibitors concurrent with individualized radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011; 81: e59–65. 42 Chi A, Remick S, Tse W. EGFR inhibition in non-small cell lung cancer: current evidence and future directions. Biomark Res 2013; 1: 1–2. 43 Scagliotti GV, Parikh P, von Pawel J et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26: 3543–51.

© 2014 Wiley Publishing Asia Pty Ltd

M Boyer et al.

44 Beljanski V, Marzilli LG, Doetsch PW. DNA damageprocessing pathways involved in the eukaryotic cellular response to anticancer DNA cross-linking drugs. Mol Pharmacol 2004; 65: 1496–506. 45 Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677–704. 46 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252–64. 47 Brahmer JR, Horn L, Antonia SJ et al. Survival and longterm follow-up of the phase I trial of nivolumab (antiPD-1; BMS-936558; ONO-4538) in patients (pts) with previously treated advanced non-small cell lung cancer (NSCLC). Presented at 2013 ASCO Annual Meeting, Chicago, IL, May 31–June 4. 2013. 48 Kluter S, Simard JR, Rode HB et al. Characterization of irreversible kinase inhibitors by directly detecting covalent bond formation: a tool for dissecting kinase drug resistance. Chembiochem 2010; 11: 2557–66. 49 Engelman JA, Zejnullahu K, Gale CM et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007; 67: 11924– 32. 50 Ramalingam SS, Blackhall F, Krzakowski M et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2012; 30: 3337– 44.

Asia-Pac J Clin Oncol 2014; 10(Suppl. 2): 2–10

Preparing for tomorrow: molecular diagnostics and the changing nonsmall cell lung cancer landscape.

Over the last 10 to 15 years, the landscape of lung cancer has changed dramatically. Where cancers were previously described rather simplistically acc...
264KB Sizes 0 Downloads 3 Views