Disease history:

Mariam K. is a 61-year-old Caucasian female who presents with c/o fatigue, productive cough with pink-tinged sputum, pain in R shoulder, and DOE X 3.5 months. She denies dysphagia or appetite loss. No hx of allergies, TB (latent or active), or exposure to environmental toxins (eg, asbestos, radiation). Pt was light (1-2 packs/wk) cigarette smoker X 20 y, but quit 15 y ago. She describes herself as normally fit and active, but states that fatigue and DOE have forced her to cut back on her activities.

Additional clinical features of this patient include:

PE:

• Gen: Afebrile, A&OX3, NAD

• Resp: 17 breaths/min; diminished breath sounds at the R lung base upon auscultation; + dullness to percussion at R lung base; possible effusion

• GI: mild hepatomegaly

• Remaining ROS WNL

PMH:

• Exercise-induced asthma

• Uterine fibroids; had partial hysterectomy in 1995 r/t DUB

• Osteoarthritis of L knee

SH:

• Married; mother of 3

• Retired school teacher

• Recent travel to South America for vacation

FH:

• Negative for malignancy

Differentials:

• TB

• Pneumonia

• COPD

• Non-Hodgkin’s Lymphoma

• Primary mediastinal B-cell lymphoma

• Lung malignancy (small cell or non-small cell)1

Challenge your knowledge of biomarker testing in advanced NSCLC. Consider this case study of disease progression following chemotherapy, with insightful commentary from Dr Rex Yung, The Johns Hopkins Hospital, Baltimore, MD, and Dr David Spigel of the Sarah Cannon Cancer Center.

Recommendations in this hypothetical case study are based on clinical guidelines and practice standards. These recommendations do not take the place of independent assessment or medical judgment.

*Not an actual patient.

Questions:

1. In addition to blood work, which tests would you order in the initial work-up of this patient?

Initial work-up on this patient showed the following:

•CBCnormal,exceptformildanemia(Hgb10.4g/dL;Hct28%)

•Comprehensivemetabolicpanelabnormal:prolongedPT/increasedPTT;elevatedASTandALT

•Contrast-enhancedchestCTreveals2.0cmX2.2cmlesioninRlowerlobewithcontralateralmediastinal node involvement

•AbdominalCTrevealslivermetastasis;PETindicatespositiveuptakeinregionalhepaticnodes

•Remaininganatomicimagingstudiesnegativeforbrainorbonemetastasis

2. If histologic diagnosis of nonsquamous advanced NSCLC is confirmed, should the pathologists reflexively test for specific biomarkers?

3. With the goal of biomarker testing in mind, what type of lung biopsy would you perform on this patient?

4. TRUE OR FALSE: When performing a biopsy, it is important to the future care and management of the patient to obtain a tissue sample of sufficient quantity and quality.

2

Questions:

EBUS-TBNA biopsy of the tumor is performed. Histology confirms adenocarcinoma and IHC stains indicate TTF-1 immunoreactivity and Napsin A expression, suggestive of primary pulmonary carcinoma. Subsequent molecular biomarker studies indicate that the tumor is positive for a point mutation in exon 21 (L858R). Mariam K. is diagnosed with a Stage IV NSCLC adenocarcinoma and is referred to an oncologist at your center.

5. In your opinion, should the pulmonologist continue to play a key role in the care of this patient following her referral to an oncologist?

Mariam K. has her initial consultation with an oncologist. In addition to her previously described clinical features, the oncologist notes the following:

•Patientischemotherapynaive

•Performancestatus1

•Patientdesirestoreturntopreviouslyactivelifestyle

6. What is the preferred first-line therapy for this patient?

7. TRUE OR FALSE: Having this patient’s EGFR mutation status available at the time of initial consultation was beneficial in creating the treatment plan and discussing it with the patient.

8. If reflex testing for EGFR mutations and ALK rearrangements were not performed in this case, would this delay the results you require in order to make a treatment decision?

3

Answers:

A) PPD

Rationale: It is important to r/o TB given this patient’s recent hx of travel to South America, where

there could be endemic areas of disease. However, other clinical signs point to the need for more comprehensive imaging studies.

B) Contrast-enhanced chest CT

Rationale: Contrast-enhanced CT is warranted to look for volume loss in the chest that may suggest a

space-occupying lesion or pleural effusion as well as to rule out TB granuloma. Additional anatomic imaging scans (PET scan, bone scan) are also useful to detect metastatic involvement if a malignancy is diagnosed.1-4

C) Targeted anatomic imaging studies (PET scan, bone scan, brain MRI)

Rationale: NCCN guidelines recommend imaging studies in patients with advanced NSCLC to help

evaluate the extent of the disease and provide more accurate staging. It should be noted that use of routine bone scans is not recommended.5

D) All of the above

Preferred answer commentary from Dr Rex Yung: Over the last 5 years the diagnosis of advanced NSCLC (non-small cell lung cancer) has

made pretty impressive leaps. There’s been a number of different advances both in the diagnostic approaches of imaging (such as PET scans, CT scans), which really helps us in making the diagnosis of knowing which lymph nodes stations or which lung nodules we should definitely biopsy.

A) No

Rationale: Testing for biomarkers may provide more information on which to base treatment decisions, as

patients with specific genetic alterations may then be able to receive optimal therapy.5,6 NCCN and Draft CAP/IASLC/AMP guidelines recommend testing of all nonsquamous tumors for EGFR mutations and ALK rearrangements, as both have been shown to have prognostic and predictive value. Both sets of guidelines recommend that testing should be performed immediately after establishing histology or before initiating targeted therapy in a patient.5,6 It is preferable to have tumor tissue from the first biopsy available for biomarker testing, so as to minimize the need for a second biopsy as well as potential patient risks and associated costs.7

B) Yes

Preferred answer commentary from Dr Rex Yung: In our approaches to diagnosing advanced NSCLC there are several aspects. We certainly

still count on so-called “clinical staging” by looking at the CT scan, by looking at lab tests,

1Question

2Question

4

Answers (cont’d): PET scan, MRIs of the brain, bone scans and so forth. But, ultimately, it really has to do

with getting sufficient tissue for us to understand the specifics of that particular patient’s tumor such that we can understand the molecular markers and driver mutations. Only by doing so would we be able to really personalize therapy and again improve for that particular patient their own prognosis. Early identifications of tumors harboring EGFR mutations or ALK rearrangements may predict patients’ response to treatment with targeted therapy. As evidence by the predictive and prognostic significance established in multiple clinical trials.

A) Bronchial washing

Rationale: Reference laboratories likely require a higher minimum tumor percentage/number of tumor

cells than those typically available through bronchial washing. In general, according to Draft CAP/IASLC guidelines, larger tumor samples (e.g., resections) are preferred for mutational assays because of greater amount of material and greater capacity to enrich the malignant content by dissection. While the minimum percentage of tumor cells for samples will depend onthemethodofanalysis,aminimummutantallelefrequencyof25%(50%cancercellfrequency, assuming heterozygosity and disomy) may be required (eg, for unmodified Sanger sequencing). The usefulness of different molecular assays for bronchoalveolar lavage is also still under investigation.6,8-12

B) Bronchoscopy/brushing

Rationale: While bronchial brushing is a procedure supported by the NCCN and Draft CAP/IASLC

guidelines for collecting tissue used in biomarker analysis, it is important for physicians performing biopsies (i.e., pulmonologists, interventional radiologists, and thoracic surgeons), to understand that tissue requirements for biomarker analysis may exceed those for cytologic or histologic analysis.13-17

C) Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)

Preferred answer commentary from Dr Rex Yung: In diagnosing advanced non–small-cell lung cancer, I do depend on EBUS—that’s

endobronchial ultrasound—a lot. The big advantage is that, once again, this is a real-time image-guided intervention. So it enhances accuracy because I can see a “real-time” punctured needle entering the suspect nodule and/or lymph node. Secondly, of course, it is a safety issue: very often lymph nodes reside in a “busy space” together with blood vessels, airways, and so forth. So, by again having a “real-time” guidance, we are lessening the risk of complications, such as bleeding or puncturing. And also very often, actually using the imaging system itself to guide, to look at the pattern of the lymph node: whether or not it is so-called “homogeneous” or “heterogeneous” in its densities; whether or not there are blood vessels within the EBUS and the lymph node. And this way, again, we can sample different areas and hence improved our yield.

3Question

5

Answers (cont’d):

D) CT-guided core needle biopsy

Rationale: CT-guided core needle biopsy may be an optimal procedure, as it ensures collection of

adequate quantity and quality of lung tissue.14,17,18 Use of CT-guided core needle biopsy has been utilized in the BATTLE clinical trial program (up to 3 passes per biopsy).19

A) True

Preferred answer commentary from Dr Rex Yung:

When performing a bronchoscopy biopsy, it is very important to get adequate tissue sample because we are being asked to provide more and more material to answer more and more questions. With the advance of this science of understanding the driver mutations and of the whole process of carcinogenesis—and especially of what makes an aggressive advanced non-small cell lung cancer so advanced—we are beginning to appreciate the many different pathways. And with the pathways being understood, we’re very fortunately working with the scientists also coming up with potential therapeutic solutions.

It has often been said that we should avoid areas of necrosis when performing a biopsy. One of the great solutions in, again, developing the partnership with our pathology colleagues, is that they can come to the bedside and help us provide a “first-look” evaluation. With their input, we are able to go back and get more material when we’ve provided nondiagnostic vs second passes. And when we do have the right material and know where to go, that’s when we begin to collect/harvest more material for the needed molecular studies for clinical use to personalized therapy.

B) False

Rationale: For purposes of molecular analysis, good-quality cytologic tissue samples are of greater

utility in molecular evaluation than necrotic tissue, so ensuring the quality and quantity of tissue specimens is critical.20,21 Evaluation of tissue by a pathologist onsite when lung biopsy is being performed has been demonstrated to help ensure tissue quality and minimize the need for additional biopsy.22,23

A) Yes

Preferred answer commentary from Dr Rex Yung: The role of the pulmonologist in diagnosing lung cancer is fairly central. We, of course, can

be one of the main conduits of providing the tissue diagnosis, but very often these patients also have risks for COPD and infection. The pulmonologist most often will also assess the overall pulmonary status of the patient, and obtain sufficient material during bronchoscopy to rule out an active infection that can be doing a lot of harm to the patient. Once the patient has been diagnosed with non–small cell lung cancer—and especially in advanced stage—then the pulmonologist continues to have a role even though the treatment phase by and large might be handed off to the team of oncologists, radiation oncologists. As mentioned,

4Question

6

5Question

Answers (cont’d):

we of course take interest in the overall lung health of the patients so we may be helpful in maintaining the pulmonary function. In a small percentage of patients, some pulmonologists, such as myself, who also perform interventional bronchoscopy, will also have the role in maintaining the airway patency of treated symptoms. So, I think in the future, also as we further advance the therapeutics, our role may even increase.

B) No

Rationale: After referral to the oncologist, the pulmonologist may prefer to stay involved in the

patient’s care and monitor her overall lung health. Communication among multiple disciplines is an important factor in the management of patients with advanced NSCLC.24 A multidisciplinary approach to early identification of tumors harboring EGFR mutations or ALK rearrangements may predict patient response to treatment with targeted therapy, as evidenced by the predictive and prognostic significance established in clinical trials.25-30

A) Carboplatin/paclitaxel

Rationale:

NCCN guidelines recommend an EGFR TKI (i.e., erlotinib) for patients with metastatic disease in whom an EGFR mutation is discovered prior to first-line chemotherapy.5 Additionally, Draft CAP/IASLC/AMP guidelines state that patients with advanced NSCLC who have EGFR mutations “demonstrate superior outcomes when targeted therapies are administered as first-line agents.”6 (Overall survival benefit has not yet been established.)

B) Carboplatin/pemetrexed

Rationale: NCCN guidelines recommend an EGFR TKI (i.e., erlotinib) for patients with metastatic

disease in whom an EGFR mutation is discovered prior to first-line chemotherapy.5

Additionally, Draft CAP/IASLC/AMP guidelines state that patients with advanced NSCLC who have EGFR mutations “demonstrate superior outcomes when targeted therapies are administered as first-line agents.”6 (Overall survival benefit has not yet been established.)

C) EGFR TKI (i.e., erlotinib)

Preferred answer commentary from Dr David Spigel: The treatment of advanced non–small cell lung cancer has really changed over the last

few years. Really for about 20 years, the standard approach to somebody with stage IV lung cancer was to give them chemotherapy, and it was kind of a “one size fits all” approach to care. That has all really changed in the last few years with the development of some novel oral agents, specifically some agents we call EGFR TKIs.

Now, it is not a “one size fits all.” It’s more of an individualized or personalized approach to cancer care. In the case of EGFR TKIs, we are looking for something specific in the lung cancer. I tell patients this is a “switch” and, when turned on, it makes the cancer cells aggressive and behave the way we don’t want them to behave.

6Question

7

Answers (cont’d):

This is what we mean by finding biomarkers on lung cancer: trying to discover does the patient’s lung cancer harbor these switches, these mutations, or gene rearrangements? If we discover those, then we know that up-front therapy with one of these oral agents can be quite remarkable for those patients.

In fact, all of our guidelines have changed. Our NCCN, or National Conference of Cancer Network, guidelines now specifically state that in the management of somebody with stage IV lung cancer, “You should find out if your patient has one of these switches.”

A) True

Preferred answer commentary from Dr David Spigel: As soon as you have a patient you know has lung cancer you need to think in your head: “Had EGFR mutation testing been performed? Had ALK testing been performed?”

I don’t know if there’s anything acceptable in delay. You want to know that information right away. Often patients are in your clinic, not only scared about their diagnosis and their family scared, but sick and struggling with the symptoms of a lung cancer. It’s dishearteningtohavetositthereandsay,“We’regoingtohavetowait21daysor28days to get these results back before I can tell you if you’re going to be offered one of these therapies.” Unfortunately, today it takes sometimes 2 weeks or 3 weeks or more to get those results back. I believe that testing with technology is going to improve. We are going to get better about shortening that window. It’s not going to be an hour or a day, but it’s hopefully not going to be 3 weeks before I can sit and tell a patient what we’re going to offer them.

B) False

Rationale: Testing for biomarkers, such as EGFR mutations and ALK rearrangements, may provide

information on which to base treatment decisions. Patients with specific genetic alterations may benefit by receiving optimal therapy.5,6 Leading oncology organizations have recognized the importance of biomarker testing for appropriate treatment selection in advanced NSCLC. The NCCN Clinical Practice Guidelines for NSCLC were revised in January 2011 to incorporate EGFR testing into the evaluation process for systemic therapy in all patients with advanced disease, exclusive of squamous cell carcinoma, after determination of histologic subtype.5 EGFR testing received a category 1 recommendation, signifying uniform NCCN consensus based upon high-level evidence, i.e., significantly greater responses to EGFR TKI therapy (erlotinib) demonstrated in patients with EGFR mutation-positive tumors in randomized clinical trials of gefitinib and erlotinib.5 The NCCN Guidelines have since been expanded to include ALK testing.5 In May 2011, ASCO issued a Provisional Clinical Opinion based on the results of five phase 3 randomized controlled trials of EGFR TKIs (i.e., gefitinib and erlotinib)* recommending that oncologists order testing for EGFR mutations for any patient being considered for first-line therapy with an EGFR TKI (i.e., erlotinib).31

*4trialsofgefitinib(nolongeravailableintheUS)and1trialoferlotinib.31

7Question

8

Answers (cont’d):

A) Yes

Preferred answer commentary from Dr David Spigel: The advantage of reflex testing for everyone has been efficiency. Now you’re not meeting

a patient in your clinic say a week or two after they were diagnosed and saying, “You know what, Mr Smith? I now have to send off for biomarker testing for the EGFR mutation or the ALK gene rearrangement.” Now you’re sitting with them in their clinic and saying, “That testing has been sent. It was sent a week or two ago when your surgeon did the biopsy or your pulmonologist did the biopsy on the bronchoscopy—and we only have that much longer to wait.” Efficiency is so important. It’s not about saving money. It’s about doing the most with the amount of tissue you have to get the information to the patient the soonest, so you can make a treatment decision. If you can sit with a patient today and offer them an oral therapy that targets the cancer in a very specific way—you’re eventually benefitting that patient in a dramatic fashion, as opposed to waiting a month, 2 months, or 6 months to offer them that therapy. Efficiency is about getting the answer the soonest and offering the patient therapy up front.

B) No

Rationale: Draft CAP/IASLC/AMP guidelines recommend a routine turnaround time for EGFR and

ALK testing results of 1-2 weeks (5-10 working days).6 Although not always achievable, this goal recognizes the importance of molecular diagnosis in treatment decisions.13 Turnaround time includes preparing and sending out slides, testing, and reporting the results. Sending slides out to external labs quickly can help reduce the turnaround time. External labs usually have a clear range for turnaround time (e.g., 6 to 10 days).

8Question

9

Case summary:

This case study highlights how testing for molecular biomarkers (such as EGFR and ALK) at the time of an advanced NSCLC diagnosis enables physicians to offer tailored therapy to appropriate patients in the front-line setting. Both NCCN and Draft CAP/IASLC/AMP guidelines support the routine testing of all nonsquamous tumors for EGFR mutations and ALK rearrangements immediately after establishing histology.5,6

A key point in this case study is that physicians who perform biopsies (here, the pulmonologist) should order biomarker testing when a diagnosis of advanced NSCLC is confirmed. This facilitates integration of patient data by permitting tumor histology, stage, and molecular profile to be combined in one pathology report and in the patient’s medical records.13 This approach also minimizes the potential for a second biopsy, with associated patient risks and costs.7

Another point illustrated is that the biopsy method should provide tissue of sufficient quantity and quality for biomarker analysis.13-17 In the present case, the pulmonologist used EBUS-TNA, which permits extraction of multiple high-quality tissue cores with minimal complications, and has been demonstrated to be a feasible and effective method for collecting tissue.18,19

The results of biomarker testing help clinicians make individualized treatment decisions based on EGFR M+ or ALK+ status. In phase 3 randomized controlled trials involving patients with advanced NSCLC, EGFR M+ disease has been shown to be predictive for a significant clinical benefit from EGFR TKIs (i.e., gefitinib and erlotinib).25-29* EGFR M+ disease is also associated with superior clinical outcomes (specifically, higher PFS and ORR) compared with EGFR mutation-negative (EGFR M–) disease, regardless of treatment received (EGFR TKI [i.e., erlotinib] or chemotherapy).25,32 All specialties involved in biomarker testing have an opportunity to help expedite the biomarker testing process and to identify patients who may be appropriate for targeted therapy. Establishing reflex testing of EGFR mutations or ALK rearrangements can identify such patients earlier in the treatment algorithm, helping to promote personalized treatment at the front-line setting. In addition, reflex testing provides benefits including efficiency and consistency in tissue acquisition, diagnostic procedures, as well as treatment decisions.

*4trialsofgefitinib(nolongeravailableintheUS)and1trialoferlotinib.31

References on following page.

10

Copyright © 2012. Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (4/12) OC182910PROF

™

References:

1. Schaffler GJ, Wolf G, Schoellnast H, et al. Non-small cell lung cancer: evaluation of pleural abnormalities on CT scans with 18FFDGPET.Radiology.2004;231(3):858-865.2. Tateishi U, Kusumoto M, Akiyama Y, Kishi F, Nishimura M, Moriyama N. Role of contrast-enhanced dynamic CT in the diagnosis of active tuberculoma. Chest.2002;122(4):1280-1284.3. Jeong YJ, Lee KS. Pulmonary tuberculosis: up-to-date imaging and management. Am J Roentgenol.2008;191(3):834-844.4. Patz EF Jr, Erasmus JJ. McAdams HP, et al. Lung cancer staging and management: comparison of contrast-enhanced and non-enhanced helical CT of the thorax. Radiology. 1999;212(1):56-60. 5. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer, version 2/2012. http://www.nccn.org/professionals/physician_gls /pdf/nscl.pdf. Accessed December 29, 2011. 6. College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association of Molecular Pathology (AMP) expert panel. Lung cancer biomarkers guideline draft recommendations. http://capstaging.cap.org/apps/docs/membership/transformation/new/lung_public_comment_supporting_materials.pdf. Accessed December 29, 2011. 7. Wiener RS, Schwartz LM, Woloshin S, Welch HG. Population-based risk for complications after transthoracic needle lung biopsy of a pulmonary nodule: an analysis of discharge records. Ann Intern Med.2011;155(3):137-144.8. ResponseDx. Specimen Preparation & Requirements. Response Genetics website. www.responsegenetics.com. Accessed February 7, 2012. 9. Diagnostic Services Specimen Requirements. Clarient Inc. website. http://www.clarientinc.com/ordering.aspx. Accessed February 7, 2012. 10. Lung Cancer Mutation Panel. Quest Diagnostics website. http://www.questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=TS_LungCancerMutation_Panel.htm. Accessed February 7, 2012. 11. Ahrendt SA, Chow JT, Xu L-H, et al. Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer. J Natl Cancer Inst.1999;91(4):332-339.12. Topaloglu O Hoque MO, Tokumaru Y, et al. Detection of promoter hypermethylation of multiple genes in the tumor and bronchoalveolar lavage of patients with lung cancer. Clin Cancer Res.2004;10(7):2284-2288.13. Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629. 14. Felip E, Gridelli C, Baas P, et al. Metastatic non-small-cell lung cancer: consensus on pathology and molecular tests, first-line, second-line, and third-line therapy: 1st ESMO Consensus Conference in Lung Cancer; Lugano 2010. Ann Oncol. 2011;22(7):1507-1519. 15. Pham DK, Kris MG, Riely GJ, et al. Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. J Clin Oncol.2006;24(11):1700-1704.16. D’Angelo SP, Pietanza MC, Johnson ML, et al. Incidence ofEGFRexon19deletionsandL858Rintumorspecimensfrommenandcigarettesmokerswithlungadenocarcinomas. J Clin Oncol. 2011;29(15):2066-2070. 17. Shaw AT, Hayes DN, Martins R. The importance of histology and molecular testing (EGFRandEML4-ALK)intheinitialevaluationofadvancednon-smallcelllungcancer.http://www.asco.org/ASCOv2/Home /Education%20&%20Training/Educational%20Book/PDF%20Files/2011/zds00111000292.pdf.AccessedDecember28,2011. 18. Pao W, Kris MG, Iafrate AJ, et al. Integration of molecular profiling into the lung cancer clinic. Clin Cancer Res. 2009;15(17):5317-5322. 19. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discovery.2011;1(1):44-53.20. Nakajima T, Yasufuku K, Suzuki M, et al. Assessment of epidermal growth factor receptor mutation by endobronchial ultrasound-guided transbronchial needle aspiration. Chest. 2007;132(2):597-602. 21. Billah S, Stewart J, Staerkel G, Chen S, Gong Y, Guo M. EGFR and KRAS mutations in lung carcinoma: molecular testing by using cytology specimens. Cancer Cytopathol. 2011;119(2):111-117. 22. Baram D, Garcia RB, Richman PS. Impact of rapid on-site cytologic evaluation during transbronchial needle aspiration. Chest.2005;128(2);869-875.23. Diacon AH, Schuurmans MM, Theron J, et al. Utility of rapid on-site evaluation of transbronchial needle aspirates. Respiration.2005;72(2):182-188. 24. Horvath LE, Yordan E, Malhotra D, et al. Multidisciplinary care in the oncology setting: historical perspective and data from lung and gynecology multidisciplinary clinics. J Oncol Pract. 2010;6(6):e21-e26. 25. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med.2009;361(10):947-957.26. 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(25):2380-2388.27. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-celllungcancerharbouringmutationsoftheepidermalgrowthfactorreceptor(WJTOG3405):anopenlabel,randomised phase 3 trial. Lancet Oncol.2010;11(2):121-128.28. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy asfirst-linetreatmentforpatientswithadvancedEGFRmutation-positivenon-small-celllungcancer(OPTIMAL,CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol.2011;12(8):735-742.29. Rosell R, Gervais R, Vergnenegre A, et al. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the European erlotinib versus chemotherapy (EURTAC) phase III randomized trial. ASCO 2011, Abstract 7503. http://www.asco.org/ascov2/Meetings/ Abstracts?&vmview=abst_detail_view&confID=102&abstractID=78285.AccessedDecember9,2011.30. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med.2010;363(18):1693-1703.31. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non–small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011;29(15):2121-2127. 32. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol.2011;29(21):2866-2874.

11