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    ROS1 and ALK Testing

    Before selecting first-line therapy, NCCN Guidelines recommend molecular testing in all patients with metastatic nonsquamous NSCLC, if clinically feasible1*

    • Molecular testing should be conducted as part of broad molecular profiling that includes EGFR (Category 1), ALK (Category 1), ROS1, BRAF, MET exon 14 skipping, and RET
    • If there is insufficient tissue to allow testing for all of EGFR, ALK, ROS1, BRAF, MET, and RET, repeat biopsy and/or plasma testing should be done. If these are not feasible, treatment is guided by available results and, if unknown, these patients are treated as though they do not have driver oncogenes
      • For patients who, in broad panel testing don’t have identifiable driver oncogenes (especially in never smokers), consider RNA-based NGS if not already performed, to maximize detection of fusion events

    Molecular test results for EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, and RET should be negative before considering treatment with PD-L1 inhibitors, if clinically feasible.*

    “Although PD-L1 expression can be elevated in patients with an oncogenic driver, targeted therapy for the oncogenic driver should take precedence over treatment with an immune checkpoint inhibitor.”

    NCCN Guidelines® for NSCLC, Version 6.2020

    *The NCCN Guidelines® for NSCLC provide recommendations for individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays.
    The NCCN NSCLC Guidelines Panel recommends molecular testing and strongly advises broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is a key component of the improvement of care of patients with NSCLC.

    Test for ROS1 and ALK to inform initial treatment decisions

    In the US, ALK gene fusion occurs in 3% to 5% of patients with NSCLC, while incidence of ROS1 is estimated at 1% to 2%.2,3 ALK and ROS1 are most commonly associated with adenocarcinoma histology. However, ALK and ROS1 have been seen in squamous cell carcinomas and, in some cases, adenosquamous carcinomas.4-6 

    Testing Guidelines

    Available Tests

    Tissue Guidelines

    ROS1, ALK, and EGFR testing is recommended by the CAP/IASLC/AMP guideline5

    The CAP/IASLC/AMP Molecular Testing Guideline recommends EGFR, ROS1, and ALK testing for adenocarcinoma and mixed lung cancers with an adenocarcinoma component, regardless of histologic grade.

    • Clinical characteristics should not be used exclusively to determine which patients are tested for EGFR, ALK, and ROS1

    • 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 molecular testing

    • Molecular test results should be available within 2 weeks


    References:
    1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.6.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed August 31, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
    2. Garber K. ALK, lung cancer, and personalised therapy: portent of the future? J Natl Cancer Inst. 2010;102(10):672-675.
    3. Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist. 2013;18(7):865-875.
    4. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30(8):863-870.
    5. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn. 2018;20(2):129-159.
    6. Cai W, Li X, Su C, et al. ROS1 fusions in Chinese patients with non-small-cell lung cancer. Ann Oncol. 2013;24(7):1822-1827.
    7. Ion Torrent™ Oncomine™ Dx Target Test user guide. Waltham, MA: Thermo Fisher Scientific Inc.; 2017.
    8. Vysis ALK Break Apart FISH Probe Kit [package insert]. Des Plaines, IL: Abbott Molecular Inc.; 2015.
    9. VENTANA ALK (D5F3) CDx Assay [package insert]. Tucson, AZ: Ventana Medical Systems, Inc.; 2017.
    10. FoundationOne CDx™ (F1CDx™) diagnostic device [package insert]. Foundation Medicine, Inc.; 2017.
    11. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl 5):e142S-e165S. 

    XALKORI efficacy in ROS1+ metastatic NSCLC

    See ROS1+ efficacy data

    XALKORI safety profile

    See safety profile

    See experts and patients discuss ROS1+ metastatic NSCLC

    Watch the video series

    INDICATIONS

    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.

    Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of patients treated with XALKORI across clinical trials (n=1719). Increased transaminases 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 increased transaminases. 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, 1.0% had Grade 3/4, and 0.5% 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) ≥500 ms and 5% of 1582 patients had an increase from baseline QTcF ≥60 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 >500 ms or ≥60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >500 ms on at least 2 separate ECGs until recovery to baseline or a QTc <481 ms, then resume at next lower dosage.

    Bradycardia: Symptomatic bradycardia can occur. Across clinical trials, bradycardia occurred in 13% of patients treated with XALKORI (n=1719). Avoid use in combination with other medications known to cause bradycardia. Monitor heart rate and blood pressure regularly. If bradycardia occurs, re-evaluate for the use of concomitant medications known to cause bradycardia. 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 ≥60 bpm. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring.

    Severe Visual Loss: Across clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% of 1719 patients. Optic atrophy and optic nerve disorder have been reported as potential causes of visual loss. Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation. There is insufficient information to characterize the risks of resumption of XALKORI in patients with 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% of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. 0.8% of patients had Grade 3 and 0.2% had Grade 4 visual impairment. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) 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 90 days (males) respectively, following the final dose of XALKORI.

    ROS1-positive Metastatic NSCLC: Safety was evaluated in 50 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; 90% 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 10%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), constipation (43% vs 30%), 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 0%), esophagitis (2% vs 0%), and constipation (2% vs 0%). 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%]); 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 [10% vs 6%]). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (5% vs 1%). Nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%), and rash (11%) also occurred in patients taking XALKORI.

    Drug Interactions: Avoid concomitant use of XALKORI with strong CYP3A inhibitors as these increase XALKORI plasma concentrations. Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of XALKORI. Use caution with concomitant use of moderate CYP3A inhibitors. Concomitant use of XALKORI with strong CYP3A inducers decreases XALKORI plasma concentrations which may decrease the efficacy of XALKORI. Avoid concomitant use of strong CYP3A inducers. Concomitant use of XALKORI increases plasma concentrations of CYP3A substrates. Avoid concomitant use of XALKORI with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions. If concomitant use of XALKORI is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling.

    Lactation: Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with XALKORI and for 45 days after the final dose.

    Hepatic Impairment: Crizotinib concentrations increased in patients with pre-existing moderate (any AST and total bilirubin >1.5x ULN and ≤3x ULN) or severe (any AST and total bilirubin >3x ULN) hepatic impairment. Reduce XALKORI dosage in patients with moderate or severe hepatic impairment. The recommended dose of XALKORI in patients with pre-existing moderate hepatic impairment is 200 mg orally twice daily or with pre-existing severe hepatic impairment is 250 mg orally once daily.

    Renal Impairment: Decreases in estimated glomerular filtration rate occurred in patients treated with XALKORI. Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis.

    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.

    Please see Full Prescribing Information for XALKORI.