CAP/IASLC/AMP Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors

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1 Guideline Highlights CAP/IASLC/AMP Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors Guideline endorsed by the American Society of Clinical Oncology (ASCO) 1 This booklet does not reflect all the recommendations contained within the full guideline. The selected excerpts should not be used in place of the full guideline for clinical decision making. Abbreviations: ALK, anaplastic lymphoma kinase; AMP, Association for Molecular Pathology; ASCO, American Society of Clinical Oncology; CAP, College of American Pathologists; EGFR, epidermal growth factor receptor; IASLC, International Association for the Study of Lung Cancer. XALKORI (crizotinib) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test. Please see Important Safety Information on pages 8-1 and full Prescribing Information at the end of this document. For more information, please visit 1

2 Guideline Highlights Who should be tested? When should patients be tested? Clinical characteristics should not determine which patients are tested 2 Disease stage at diagnosis should be taken into account 2 W H O ALK molecular testing should be used to select patients for ALK-targeted tyrosine kinase inhibitor therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics (eg, age, sex, ethnicity, smoking history) (1.1b: Recommendation). Histology may determine which patients should be tested 2 In the setting of lung cancer resection specimens, EGFR and ALK testing Is recommended for adenocarcinomas and mixed lung cancers with an adenocarcinoma component, regardless of histologic grade (1.2: Recommendation) Is not recommended for fully excised lung cancer specimens that lack any adenocarcinoma component, such as pure squamous cell carcinomas, pure small cell carcinomas, or large cell carcinomas lacking any immunohistochemistry (IHC) evidence of adenocarcinoma differentiation (1.2: Recommendation) In the setting of more limited lung cancer specimens (biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases showing squamous or small cell histology, but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing (1.3: Recommendation). ALK rearrangement testing should be ordered at the time of diagnosis for patients presenting with advanced-stage disease (stage IV according to the 7th edition TNM staging system) 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 (2.1b: Suggestion). For these patients, timely diagnosis is critical and molecular testing should be initiated as soon as a diagnosis of adenocarcinoma is established (2.1b: Suggestion). Reflex testing, a testing policy that does not require a separate clinician order for each case, is appropriate if agreed on by the lung cancer care team and may help to ensure expedited and consistent routing of specimens for molecular testing (2.1b: Suggestion). ALK testing of tumors at diagnosis from patients presenting with stage I, II, or III disease is encouraged, but the decision to do so should be made locally by each laboratory, in collaboration with its oncology team (2.2b: Expert consensus opinion). Abbreviations: ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; TNM, tumor node metastasis. W H E N Please see Important Safety Information on pages 8-1 and full Prescribing Information at the end of this document. For more information, please visit XALKORI (crizotinib) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test. 2 3

3 Guideline Highlights What samples should be provided for ALK testing? How long should the testing process take? Sufficient tissue of adequate quality is necessary for testing 2 Results should be available within 2 weeks 2 To determine EGFR and ALK status for initial treatment selection, primary tumors or metastatic lesions are equally suitable for testing (1.4: Recommendation). EGFR and ALK results should be available within 2 weeks (1 working days) of receiving the specimen in the testing laboratory (3.1: Expert consensus opinion). W H A T Tissue should be prioritized for EGFR and ALK testing (2.3: Recommendation). It is critical to retain sufficient material for molecular analysis and to be judicious in the use of sections for IHC studies, histochemical stains, or deeper levels that may not be essential to establish a histopathologic diagnosis (2.3: Recommendation). A pathologist should be involved in the selection of sections for ALK FISH testing by assessing tumor architecture, cytology, and specimen quality (9.3: Expert consensus opinion). A TAT goal of 1 week (5 working days) should be established for EGFR and ALK testing, up to a maximum TAT of 2 weeks (1 working days). This TAT refers to the period from the receipt of suitable material by the molecular pathology laboratory where the testing is performed to the reporting of the final results to the clinical care team, and is not related to the period of time between when a patient undergoes a diagnostic procedure and when a specimen is submitted to the laboratory for testing (3.1: Expert consensus opinion). Laboratories with average TATs beyond 2 weeks need to make available a more rapid test either in-house or through a reference laboratory in instances of clinical urgency (3.2: Recommendation). T I M I N G Specimen requirements for ALK FISH are generally similar to those for EGFR mutation testing: formalin fixation is acceptable, specimens should have enough cancer cells to analyze clearly, and DNA-damaging fixatives or acidic decalcifying agents should be avoided, as should specimens with abundant necrosis. Unlike EGFR mutation testing, however, FISH testing can be problematic when performed on alcohol-fixed samples (9.3: Expert consensus opinion). Laboratory departments should establish processes to ensure that specimens that have a final histopathologic diagnosis are sent to outside molecular pathology laboratories within 3 working days of receiving requests and to intramural molecular pathology laboratories within 24 hours (3.3: Expert consensus opinion). Abbreviations: FISH, fluorescence in situ hybridization; TAT, turnaround time. Please see Important Safety Information on pages 8-1 and full Prescribing Information at the end of this document. For more information, please visit XALKORI (crizotinib) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test. 4 5

4 XALKORI provides a reason to test right from the start Biomarker testing is important to determine who may benefit from a biomarker-driven therapy ALK rearrangement, a therapeutic target in NSCLC, can contribute to cell proliferation and tumor survival 3-5 EGFR and ALK are associated with approved therapies 6-8 As an ALK inhibitor, XALKORI has been shown to block important growth and survival pathways in tumors, which may lead to regression or stabilization of tumors 9 XALKORI (crizotinib) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test. SELECTED SAFETY INFORMATION Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in.1% of patients treated with XALKORI across clinical trials (n=1719). Transaminase elevations generally occurred within the first 2 months. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of treatment, then once a month, and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Permanently discontinue for ALT/AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated. There is no one type of patient who has ALK-positive NSCLC In XALKORI studies, the ALK fusion gene was identified across ages, genders, and ethnicities It was identified predominantly in patients with adenocarcinoma but was found in other histologic types It was identified more frequently in never-smokers but was also seen in former and current smokers APPROXIMATELY 3%-5% OF PATIENTS WITH NSCLC HAVE AN ALK-POSITIVE TUMOR 3,9-15 Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK positivity in tumor specimens as detected by an FDA-approved test 3%-5% a a Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at InVitroDiagnostics/ucm31431.htm. Please see Important Safety Information on pages 8-1 and full Prescribing Information at the end of this document. For more information, please visit 6 7

5 IMPORTANT SAFETY INFORMATION (CONT D) IMPORTANT SAFETY INFORMATION 8 Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in.1% of patients treated with XALKORI across clinical trials (n=1719). Transaminase elevations generally occurred within the first 2 months. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of treatment, then once a month, and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Permanently discontinue for ALT/AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated. Interstitial Lung Disease (Pneumonitis): Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur. Across clinical trials (n=1719), 2.9% of XALKORI-treated patients had any grade ILD, 1.% had Grade 3/4, and.5% had fatal ILD. ILD generally occurred within 3 months after initiation of treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue XALKORI in patients with drug-related ILD/pneumonitis. QT Interval Prolongation: QTc prolongation can occur. Across clinical trials (n=1616), 2.1% of patients had QTcF (corrected QT by the Fridericia method) 5 ms and 5.% had an increase from baseline QTcF 6 ms by automated machine-read evaluation of ECGs. Avoid use in patients with congenital long QT syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc >5 ms or 6 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >5 ms on at least 2 separate ECGs until recovery to a QTc 48 ms, then resume at a reduced dose. Bradycardia: Symptomatic bradycardia can occur. Across clinical trials, bradycardia occurred in 12.7% of patients treated with XALKORI (n=1719). Avoid use in combination with other agents known to cause bradycardia. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 6 bpm, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 6 bpm. If concomitant medications can be adjusted or discontinued, restart XALKORI at 25 mg once daily with frequent monitoring. For more information, please visit Severe Visual Loss: Across clinical trials, the incidence of Grade 4 visual field defect with vision loss was.2% (n=1719). Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 2/2 in one or both eyes). Perform an ophthalmological evaluation. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume should consider the potential benefits to the patient. Vision Disorders: Most commonly visual impairment, photopsia, blurred vision or vitreous floaters, occurred in 63.1% of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions..8% of patients had Grade 3 and.2% had Grade 4 visual impairment. The majority of patients on the XALKORI arms in Studies 1 and 2 (>5%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact on daily activities. Embryo-Fetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to the fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 45 days (females) or 9 days (males) respectively, following the final dose of XALKORI. ROS1-positive Metastatic NSCLC: Safety was evaluated in 5 patients with ROS1-positive metastatic NSCLC from a single-arm study, and was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC. Vision disorders occurred in 92% of patients in the ROS1 study; 9% of patients had Grade 1 vision disorders and 2% had Grade 2. Adverse Reactions: Safety was evaluated in a phase 3 study in previously untreated patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=171) or chemotherapy (n=169). Serious adverse events were reported in 34% of patients treated with XALKORI, the most frequent were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% of patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Common adverse reactions (all grades) occurring in 25% and more commonly ( 5%) in patients treated with XALKORI vs chemotherapy were vision disorder (71% vs 1%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), constipation (43% vs 3%), upper respiratory infection (32% vs 12%), dysgeusia (26% vs 5%), and abdominal pain (26% vs 12%). Grade 3/4 reactions occurring at a 2% higher incidence with XALKORI vs chemotherapy were QT prolongation (2% vs %), esophagitis (2% vs %), and constipation (2% vs %). In patients treated with XALKORI vs chemotherapy, the following occurred: elevation of ALT (any grade [79% vs 33%] or Grade 3/4 [15% vs 2%]); Please see additional Important Safety Information on page 1 and full Prescribing Information at the end of this document. IMPORTANT SAFETY INFORMATION 9

6 IMPORTANT SAFETY INFORMATION 1 IMPORTANT SAFETY INFORMATION (CONT D) elevation of AST (any grade [66% vs 28%] or Grade 3/4 [8% vs 1%]); neutropenia (any grade [52% vs 59%] or Grade 3/4 [11% vs 16%]); lymphopenia (any grade [48% vs 53%] or Grade 3/4 [7% vs 13%]); hypophosphatemia (any grade [32% vs 21%] or Grade 3/4 [1% vs 6%]). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (5% vs 1%). Nausea (56%), decreased appetite (3%), fatigue (29%), and neuropathy (21%) also occurred in patients taking XALKORI. Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Avoid concomitant use of CYP3A substrates with narrow therapeutic range in patients taking XALKORI. If concomitant use of CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions. Lactation: Because of the potential for adverse reactions in breastfed infants, advise females not to breastfeed during treatment with XALKORI and for 45 days after the final dose. Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment. Renal Impairment: Decreases in estimated glomerular filtration rate occurred in patients treated with XALKORI. Administer XALKORI at a starting dose of 25 mg taken orally once daily in patients with severe renal impairment (CLcr <3 ml/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment. Please see additional Important Safety Information on pages 8 and 9 and full Prescribing Information at the end of this document. For more information, please visit The discovery and clinical relevance of EGFR and ALK have impacted how NSCLC is diagnosed and treated 2 Evidence-based guideline recommendations for the molecular testing of lung cancers are available from CAP/IASLC/AMP These guideline recommendations may aid in the implementation and standardization of biomarker testing in your institution. Clinical characteristics should not determine which patients are tested for EGFR and ALK Disease stage at diagnosis should be taken into account to determine when a patient s sample is tested Sufficient tissue of adequate quality is necessary for biomarker testing Biomarker test results should be available within 2 weeks See inside for more detailed recommendations from the CAP/IASLC/AMP Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors. Please see Important Safety Information on pages 8-1 and full Prescribing Information at the end of this document. References: 1. Leighl NB, Rekhtman N, Biermann WA, et al: Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guideline. J Clin Oncol. 214 Nov 1;32(32): 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. Arch Pathol Lab Med. 213;137(6): Mossé YP, Wood A, Maris JM. Inhibition of ALK signaling for cancer therapy. Clin Cancer Res. 29;15(18): Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 28;8(1): Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A. 28;15(5): Tarceva (erlotinib) Prescribing Information. Northbrook, IL: OSI Pharmaceuticals, LLC, an affiliate of Astellas Pharma US, Inc; Gilotrif (afatinib) Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; XALKORI (crizotinib) Prescribing Information. New York, NY: Pfizer Labs; Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 21;46(1): Garber K. ALK, lung cancer, and personalized therapy: portent of the future? J Natl Cancer Inst. 21;12(1): Palmer RH, Vernersson E, Grabbe C, Hallberg B. Anaplastic lymphoma kinase: signalling in development and disease. Biochem J. 29;42(3): Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-pcr screening for EML4-ALK fusion transcripts. Clin Cancer Res. 28;14(2): Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 28;14(13): Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 29;115(8): Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 27;448(7153): PP-XLK-USA Pfizer Inc. All rights reserved. XALKORI is a registered trademark of Pfizer Inc. September

7 CAP/IASLC/AMP Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors 1 Summary of Recommendations SECTION I. WHEN SHOULD MOLECULAR TESTING OF LUNG CANCERS BE PERFORMED? QUESTION 1. WHICH PATIENTS SHOULD BE TESTED FOR EGFR MUTATIONS AND ALK REARRANGEMENTS? 1.1a: Recommendation: EGFR molecular testing should be used to select patients for EGFR-targeted TKI therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics. 1.1b: Recommendation: ALK molecular testing should be used to select patients for ALK-targeted TKI, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics. 1.2: Recommendation: In the setting of lung cancer resection specimens, EGFR and ALK testing is recommended for adenocarcinomas and mixed lung cancers with an adenocarcinoma component, regardless of histologic grade. In the setting of fully excised lung cancer specimens, EGFR and ALK testing is not recommended in lung cancers that lack any adenocarcinoma component, such as pure squamous cell carcinomas, pure small cell carcinomas, or large cell carcinomas lacking any immunohistochemistry (IHC) evidence of adenocarcinoma differentiation. 1.3: Recommendation: In the setting of more limited lung cancer specimens (biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases showing squamous or small cell histology, but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing. 1.4: Recommendation: To determine EGFR and ALK status for initial treatment selection, primary tumors or metastatic lesions are equally suitable for testing. 1.5: Expert consensus opinion: For patients with multiple, apparently separate, primary lung adenocarcinomas, each tumor may be tested, but testing of multiple different areas within a single tumor is not necessary. QUESTION 2. WHEN SHOULD A PATIENT SPECIMEN BE TESTED FOR EGFR MUTATION OR ALK REARRANGEMENT? 2.1a: Recommendation: EGFR mutation testing should be ordered at the time of diagnosis for patients presenting with advanced-stage disease (stage IV according to the 7th edition TNM staging system) 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. 2.1b: Suggestion: ALK rearrangement testing should be ordered at the time of diagnosis for patients presenting with advanced-stage disease (stage IV according to the 7th edition TNM staging system) 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. 2.2a: Expert consensus opinion: EGFR testing of tumors at diagnosis from patients presenting with stage I, II, or III disease is encouraged, but the decision to do so should be made locally by each laboratory, in collaboration with its oncology team. 12

8 2.2b: Expert consensus opinion: ALK testing of tumors at diagnosis from patients presenting with stage I, II, or III disease is encouraged, but the decision to do so should be made locally by each laboratory, in collaboration with its oncology team. 2.3: Recommendation: Tissue should be prioritized for EGFR and ALK testing. QUESTION 3. HOW RAPIDLY SHOULD TEST RESULTS BE AVAILABLE? 3.1: Expert consensus opinion: EGFR and ALK results should be available within 2 weeks (1 working days) of receiving the specimen in the testing laboratory. 3.2: Expert consensus opinion: Laboratories with average turnaround times beyond 2 weeks need to make available a more rapid test either in-house or through a reference laboratory in instances of clinical urgency. 3.3: Expert consensus opinion: Laboratory departments should establish processes to ensure that specimens that have a final histopathologic diagnosis are sent to outside molecular pathology laboratories within 3 working days of receiving requests and to intramural molecular pathology laboratories within 24 hours. SECTION II. HOW SHOULD EGFR TESTING BE PERFORMED? QUESTION 4. HOW SHOULD SPECIMENS BE PROCESSED FOR EGFR MUTATION TESTING? 4.1: Expert consensus opinion: Pathologists should use formalin-fixed, paraffin-embedded (FFPE) specimens or fresh, frozen, or alcohol-fixed specimens for PCR-based EGFR mutation tests. Other tissue treatments (eg, acidic or heavy metal fixatives, or decalcifying solutions) should be avoided in specimens destined for EGFR testing. 4.2: Expert consensus opinion: Cytologic samples are also suitable for EGFR and ALK testing, with cell blocks being preferred over smear preparations. QUESTION 5. WHAT ARE THE SPECIMEN REQUIREMENTS FOR EGFR TESTING? 5.1: Expert consensus opinion: Pathologists should determine the adequacy of specimens for EGFR testing by assessing cancer cell content and DNA quantity and quality. 5.2: Expert consensus opinion: Each laboratory should establish the minimum proportion and number of cancer cells needed for mutation detection during validation. 5.3: Expert consensus opinion: A pathologist should assess the tumor content of each specimen and either perform, or guide a trained technologist to perform, microdissection for tumor cell enrichment as needed. QUESTION 6. HOW SHOULD EGFR TESTING BE PERFORMED? 6.1: Recommendation: Laboratories may use any validated EGFR testing method with sufficient performance characteristics. 6.2: Expert consensus opinion: Laboratories should use EGFR test methods that are able to detect mutations in specimens with at least 5% cancer cell content, although laboratories are strongly encouraged to use (or have available at an external reference laboratory) more sensitive tests that are able to detect mutations in specimens with as little as 1% cancer cells. 13

9 6.3: Expert consensus opinion: Clinical EGFR mutation testing should be able to detect all individual mutations that have been reported with a frequency of at least 1% of EGFR-mutated lung adenocarcinomas. 6.4: Recommendation: Immunohistochemistry for total EGFR is not recommended for selection of EGFR TKI therapy. 6.5: Recommendation: EGFR copy number analysis (ie, FISH or CISH) is not recommended for selection of EGFR TKI therapy. QUESTION 7. WHAT IS THE ROLE OF KRAS ANALYSIS IN SELECTING PATIENTS FOR TARGETED THERAPY WITH EGFR TKIs? 7.1: Recommendation: KRAS mutation testing is not recommended as a sole determinant of EGFR TKI therapy. QUESTION 8. WHAT ADDITIONAL TESTING CONSIDERATIONS ARE IMPORTANT IN THE SETTING OF SECONDARY OR ACQUIRED EGFR TKI RESISTANCE? 8.1: Recommendation: If a laboratory performs testing on specimens from patients with acquired resistance to EGFR kinase inhibitors, such tests should be able to detect the secondary EGFR T79M mutation in as few as 5% of cells. SECTION III. HOW SHOULD ALK TESTING BE PERFORMED? QUESTION 9. WHAT METHODS SHOULD BE USED FOR ALK TESTING? 9.1: Recommendation: Laboratories should use an ALK FISH assay using dual-labeled break-apart probes for selecting patients for ALK TKI therapy; ALK immunohistochemistry, if carefully validated, may be considered as a screening methodology to select specimens for ALK FISH testing. 9.2: Recommendation: RT-PCR is not recommended as an alternative to FISH for selecting patients for ALK inhibitor therapy. 9.3: Expert consensus opinion: A pathologist should be involved in the selection of sections for ALK FISH testing by assessing tumor architecture, cytology, and specimen quality. 9.4: Expert consensus opinion: A pathologist should participate in the interpretation of ALK FISH slides, either by performing the analysis directly or by reviewing the interpretations of cytogeneticists or technologists with specialized training in solid tumor FISH analysis. 9.5: Expert consensus opinion: Testing for secondary mutations in ALK associated with acquired resistance to ALK inhibitors is not currently required for clinical management. SECTION IV: SHOULD OTHER GENES BE ROUTINELY TESTED IN LUNG ADENOCARCINOMA? QUESTION 1. ARE OTHER MOLECULAR MARKERS SUITABLE FOR TESTING IN LUNG CANCER? 1.1a: Recommendation: Testing for EGFR should be prioritized over other molecular markers in lung adenocarcinoma. 1.1b: Suggestion: After EGFR testing, testing for ALK should be prioritized over other proposed molecular markers in lung adenocarcinoma, for which published evidence is insufficient to support testing guideline development at the present time. 14

10 SECTION V: HOW SHOULD MOLECULAR TESTING OF LUNG ADENOCARCINOMAS BE IMPLEMENTED AND OPERATIONALIZED? QUESTION 11. MUST ALL ADENOCARCINOMAS BE TESTED FOR BOTH EGFR AND ALK? 11.1: Expert consensus opinion: Laboratories may implement testing algorithms to enhance the efficiency of molecular testing of lung adenocarcinomas, provided the overall turnaround time requirements are met. QUESTION 12. HOW SHOULD EGFR AND ALK RESULTS BE REPORTED? 12.1: Expert consensus opinion: EGFR mutation testing reports and ALK FISH reports should include a results and interpretation section readily understandable by oncologists and by nonspecialist pathologists. QUESTION 13. HOW SHOULD EGFR AND ALK TESTING BE VALIDATED? 13.1: Expert consensus opinion: EGFR and ALK testing validation should follow the same guidelines as for other molecular diagnostics and FISH tests. QUESTION 14. HOW SHOULD QUALITY ASSURANCE BE MAINTAINED? 14.1: Expert consensus opinion: Laboratories should follow similar quality control and quality assurance policies and procedures for EGFR and ALK testing in lung cancers as for other clinical laboratory assays. In particular, laboratories performing EGFR and ALK testing for TKI therapy should enroll in proficiency testing, if available. Content is adapted from Table 3 of the Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors, with permission from the College of American Pathologists. Abbreviations: ALK, anaplastic lymphoma kinase; AMP, Association for Molecular Pathology; CAP, College of American Pathologists; CISH, chromogenic in situ hybridization; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; IASLC, International Association for the Study of Lung Cancer; KRAS, Kirsten rat sarcoma; PCR, polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction; TKI, tyrosine kinase inhibitor; TNM, tumor node metastasis. Reference: 1. 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 Mol Diagn. 213;15(4): PP-XLK-USA Pfizer Inc. All rights reserved. XALKORI is a registered trademark of Pfizer Inc. September 217

11 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use XALKORI safely and effectively. See full prescribing information for XALKORI. XALKORI (crizotinib) capsules, for oral use Initial U.S. Approval: RECENT MAJOR CHANGES Indications and Usage (1) 7/217 Dosage and Administration, Patient Selection (2.1) 7/ INDICATIONS AND USAGE XALKORI is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test DOSAGE AND ADMINISTRATION Recommended Dose: 25 mg orally, twice daily. (2.2) Renal Impairment: 25 mg orally, once daily in patients with severe renal impairment (creatinine clearance <3 ml/min) not requiring dialysis. (2.2) DOSAGE FORMS AND STRENGTHS Capsules: 25 mg and 2 mg. (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS Hepatotoxicity: Fatal hepatotoxicity occurred in.1% of patients. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.1) Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 2.9% of patients. Permanently discontinue in patients with ILD/pneumonitis. (5.2) QT Interval Prolongation: Occurred in 2.1% of patients. Monitor electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.3) Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.4) Severe Visual Loss: Reported in.2% of patients. Discontinue XALKORI in patients with severe visual loss. Perform an ophthalmological evaluation. (5.5) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.6, 8.1, 8.3) ADVERSE REACTIONS The most common adverse reactions ( 25%) are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy. (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at or FDA at 1-8-FDA-188 or DRUG INTERACTIONS CYP3A Inhibitors: Avoid concurrent use of XALKORI with strong CYP3A inhibitors. (7.1) CYP3A Inducers: Avoid concurrent use of XALKORI with strong CYP3A inducers. (7.2) CYP3A Substrates: Avoid concurrent use of XALKORI with CYP3A substrates with narrow therapeutic indices. (7.3) USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed while taking XALKORI. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 7/217 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Recommended Dosing 2.3 Dose Modification 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Interstitial Lung Disease (Pneumonitis) 5.3 QT Interval Prolongation 5.4 Bradycardia 5.5 Severe Visual Loss 5.6 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Drugs That May Increase Crizotinib Plasma Concentrations 7.2 Drugs That May Decrease Crizotinib Plasma Concentrations 7.3 Drugs Whose Plasma Concentrations May Be Altered By Crizotinib 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 1 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 ALK-Positive Metastatic NSCLC 14.2 ROS1-Positive Metastatic NSCLC 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. 1

12 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE XALKORI is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test [see Clinical Studies (14.1 and 14.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK or ROS1 positivity in tumor specimens [see Indications and Usage (1) and Clinical Studies (14.1, 14.2)]. Information on FDA-approved tests for the detection of ALK and ROS1 rearrangements in NSCLC is available at Recommended Dosing The recommended dose of XALKORI is 25 mg orally, twice daily until disease progression or no longer tolerated by the patient. The recommended dose of XALKORI in patients with severe renal impairment [creatinine clearance (CL cr ) <3 ml/min] not requiring dialysis is 25 mg orally, once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. XALKORI may be taken with or without food. Swallow capsules whole. If a dose of XALKORI is missed, make up that dose unless the next dose is due within 6 hours. If vomiting occurs after taking a dose of XALKORI, take the next dose at the regular time. 2.3 Dose Modification Reduce dose as below, if 1 or more dose reductions are necessary due to adverse reactions of Grade 3 or 4 severity, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.: First dose reduction: XALKORI 2 mg taken orally twice daily Second dose reduction: XALKORI 25 mg taken orally once daily Permanently discontinue if unable to tolerate XALKORI 25 mg taken orally once daily Dose reduction guidelines are provided in Tables 1 and 2. Table 1. XALKORI Dose Modification Hematologic Toxicities a Grade XALKORI Dosing Grade 3 Withhold until recovery to Grade 2 or less, then resume at the same dose schedule Grade 4 Withhold until recovery to Grade 2 or less, then resume at next lower dose a Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). 2

13 Table 2. XALKORI Dose Modification Non-Hematologic Toxicities XALKORI Dosing Criteria Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation greater than 5 times upper limit of normal (ULN) with total bilirubin less than or equal to 1.5 times ULN ALT or AST elevation greater than 3 times ULN with concurrent total bilirubin elevation greater than 1.5 times ULN (in the absence of cholestasis or hemolysis) Any grade drug-related interstitial lung disease/pneumonitis QT corrected for heart rate (QTc) greater than 5 ms on at least 2 separate electrocardiograms (ECGs) QTc greater than 5 ms or greater than or equal to 6 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Bradycardia a (symptomatic, may be severe and medically significant, medical intervention indicated) Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume at reduced dose. Permanently discontinue. Permanently discontinue. Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at reduced dose. Permanently discontinue. Withhold until recovery to asymptomatic bradycardia or to a heart rate of 6 bpm or above. Evaluate concomitant medications known to cause bradycardia, as well as antihypertensive medications. If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to asymptomatic bradycardia or to a heart rate of 6 bpm or above. Bradycardia a,b (life-threatening consequences, urgent intervention indicated) Visual Loss (Grade 4 Ocular Disorder) a Heart rate less than 6 beats per minute (bpm). b Permanently discontinue for recurrence. If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose modified, resume at reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of 6 bpm or above. Permanently discontinue if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at 25 mg once daily upon recovery to asymptomatic bradycardia or to a heart rate of 6 bpm or above, with frequent monitoring. Discontinue during evaluation of severe vision loss. Monitor complete blood counts including differential white blood cell counts monthly and as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs. 3

14 3 DOSAGE FORMS AND STRENGTHS 25 mg capsules: hard gelatin capsule, size, pink opaque cap and body, with Pfizer on the cap and CRZ 25 on the body. 2 mg capsules: hard gelatin capsule, size 1, white opaque body and pink opaque cap, with Pfizer on the cap and CRZ 2 on the body. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Drug-induced hepatotoxicity with fatal outcome occurred in 2 (.1%) of the 1719 patients treated with XALKORI across clinical trials. Concurrent elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to 3 times the upper limit of normal (ULN) and total bilirubin greater than or equal to 2 times the ULN, with normal alkaline phosphatase, occurred in 1 patients (<1%) treated with XALKORI. Elevations in ALT or AST greater than 5 times the ULN occurred in 187 (11.2%) and 95 (5.7%) patients, respectively. Seventeen patients (1.%) required permanent discontinuation due to elevated transaminases. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of treatment, then once a month, and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as described in Table 2 [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.2 Interstitial Lung Disease (Pneumonitis) Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=1719), 5 XALKORI-treated patients (2.9%) had ILD of any grade, 18 patients (1.%) had Grade 3 or 4 ILD, and 8 patients (.5%) had fatal ILD. Interstitial lung disease generally occurred within 3 months after the initiation of XALKORI. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-related ILD/pneumonitis [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.3 QT Interval Prolongation QTc prolongation can occur in patients treated with XALKORI. Across clinical trials, 34 of 1616 patients (2.1%) had QTcF (corrected QT for heart rate by the Fridericia method) greater than or equal to 5 ms and 79 of 1582 patients (5.%) had an increase from baseline QTcF greater than or equal to 6 ms by automated machine-read evaluation of ECGs. Avoid use of XALKORI in patients with congenital long QT syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking 4

15 medications that are known to prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc greater than 5 ms or greater than or equal to 6 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc greater than 5 ms on at least 2 separate ECGs until recovery to a QTc less than or equal to 48 ms, then resume XALKORI at a reduced dose as described in Table 2 [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2)]. 5.4 Bradycardia Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia occurred in 219 (12.7%) of 1719 patients treated with XALKORI. Grade 3 syncope occurred in 2.4% of XALKORI-treated patients and in.6% of the chemotherapy-treated patients. Avoid using XALKORI in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 6 bpm or above, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 6 bpm or above, and if concomitant medications can be adjusted or discontinued, restart XALKORI at 25 mg once daily with frequent monitoring [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.5 Severe Visual Loss Across all clinical trials, the incidence of Grade 4 visual field defect with vision loss was.2% (4/1719). Optic atrophy and optic nerve disorder have been reported as potential causes of vision loss. Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 2/2 in one or both eyes). Perform an ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT) and other evaluations as appropriate for new onset of severe visual loss. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume XALKORI should consider the potential benefits to the patient. 5.6 Embryo-Fetal Toxicity Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those observed with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days following the final dose [see Use in Specific Populations (8.1, 8.3)]. Advise male patients with female partners of reproductive potential to use condoms during treatment with XALKORI and for at least 9 days after the final dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Hepatotoxicity [see Warnings and Precautions (5.1)] 5

16 Interstitial Lung Disease (Pneumonitis) [see Warnings and Precautions (5.2)] QT Interval Prolongation [see Warnings and Precautions (5.3)] Bradycardia [see Warnings and Precautions (5.4)] Severe Visual Loss [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data in the Warnings and Precautions section reflect exposure to XALKORI in 1719 patients who received XALKORI 25 mg twice daily enrolled on Studies 1 (including an additional 19 patients who crossed over from the control arm), 2, 3, a single arm trial (n=163) of ALK-positive NSCLC, and an additional ALK-positive NSCLC expansion cohort of a dose finding study (n=154) [see Warnings and Precautions (5)]. The data described below is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 25 mg twice daily from 2 open-label, randomized, active-controlled trials (Studies 1 and 2). The safety of XALKORI was also evaluated in 5 patients with ROS1-positive metastatic NSCLC from a single-arm study (Study 3). The most common adverse reactions ( 25%) of XALKORI are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy. Previously Untreated ALK-Positive Metastatic NSCLC - Study 1 The data in Table 3 are derived from 34 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study 1). Patients in the XALKORI arm (n=171) received XALKORI 25 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 169 patients in the chemotherapy arm received pemetrexed 5 mg/m 2 in combination with cisplatin 75 mg/m 2 (n=91) or carboplatin at a dose calculated to produce an area under the concentration-time curve (AUC) of 5 or 6 mg min/ml (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression. The median duration of study treatment was 1.9 months for patients in the XALKORI arm and 4.1 months for patients in the chemotherapy arm. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 34 patients who were treated in Study 1, the median age was 53 years; 16% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian. Serious adverse events were reported in 58 patients (34%) treated with XALKORI. The most frequent serious adverse events reported in patients treated with XALKORI were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. 6