For Patients and Caregivers

How to test for ROS1 in NSCLC

NCCN Testing Recommendation

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend biomarker testing for ROS1+ disease in nonsquamous metastatic NSCLC3a

  • NCCN Guidelines® recommend molecular testing for targetable oncogenic driver mutations, including ROS1 rearrangements, in all patients with non-squamous metastatic NSCLC
  • NCCN Guidelines recommend at this time that, when feasible, testing be performed via a broad, panel-based approach, most typically performed by NGS. For patients, who in broad panel testing don’t have identifiable driver oncogenes, consider RNA-based NGS, if not already performed, to maximize detection of fusion events
aThe NCCN Guidelines provide recommendations for individual biomarkers that should be tested and recommend testing techniques, but do not endorse any specific commercially available biomarker assays.

ROS1 fusions were identified in ROZLYTREK clinical trials using NGS and FISH1

  • 71% of patients had a ROS1 fusion detected by NGS
  • 29% of patients had a ROS1 fusion detected by FISH

Learn more about FDA-approved tests for the detection of ROS1 rearrangement(s) in NSCLC.

Tests that can identify ROS1+ NSCLC

Information on Testing for ROS1+ mNSCLC Using NGS, FISH, and Other Testing Methods
FISH=fluorescence in situ hybridization; IHC=immunohistochemistry; NCCN=National Comprehensive Cancer Network® (NCCN®); NGS=next-generation sequencing; NSCLC=non-small cell lung cancer; ROS1=ROS proto-oncogene 1; RT-PCR=reverse transcription polymerase chain reaction.
NEXT: Dosing & Administration
ROZLYTREK Efficacy in Patients Bar Chart Icon

Efficacy in Patients with ROS1+ mNSCLC

View ORR, DOR, and IC-ORR data in patients with ROS1+ mNSCLC

View data
ROS1+ Study Design

Study Design

Learn how ROZLYTREK was studied in patients with ROS1+ mNSCLC

Learn more
ROZLYTREK Financial Resources

Financial Support

Learn more about financial assistance options for ROZLYTREK

Learn more

SELECT IMPORTANT SAFETY INFORMATION

INDICATIONS

ROS1-Positive Non-Small Cell Lung Cancer

ROZLYTREK is indicated for the treatment of adult patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.

NTRK Gene Fusion-Positive Solid Tumors

ROZLYTREK is indicated for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that:

  • have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, as detected by an FDA-approved test without a known acquired resistance mutation,
  • are metastatic or where surgical resection is likely to result in severe morbidity, and
  • have either progressed following treatment or have no satisfactory alternative therapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

WARNINGS and PRECAUTIONS

Congestive Heart Failure

  • Among the 355 patients who received ROZLYTREK across clinical trials, congestive heart failure (CHF) occurred in 12 patients (3.4%), including Grade 3 (2.3%). The median time to onset was 2 months (range: 11 days to 12 months). Of these 12 patients, ROZLYTREK was interrupted in 6 (50%) and discontinued in 2 (17%). CHF resolved in 6 patients (50%) following interruption or discontinuation of ROZLYTREK and institution of appropriate medical management. In addition, myocarditis in the absence of CHF was documented in 0.3% of patients
  • Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK in patients with symptoms or known risk factors for CHF. Monitor patients for clinical signs and symptoms of CHF, including shortness of breath and edema. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For patients with new onset or worsening CHF, withhold ROZLYTREK, institute appropriate medical management, and reassess LVEF. Based on the severity of CHF or worsening LVEF, resume ROZLYTREK at a reduced dose upon recovery to baseline or permanently discontinue

Central Nervous System Effects

  • A broad spectrum of central nervous system (CNS) adverse reactions occurred in patients receiving ROZLYTREK, including cognitive impairment, mood disorders, dizziness, and sleep disturbances
  • Among the 355 patients who received ROZLYTREK across clinical trials, 96 (27%) experienced cognitive impairment; symptoms occurred within 3 months of starting ROZLYTREK in 74 (77%). Cognitive impairment included cognitive disorders (8%), confusional state (7%), disturbance in attention (4.8%), memory impairment (3.7%), amnesia (2.5%), aphasia (2.3%), mental status changes (2%), hallucinations (1.1%), and delirium (0.8%). Grade 3 cognitive adverse reactions occurred in 4.5% of patients. Of the 96 patients with cognitive impairment, 13% required a dose reduction, 18% required dose interruption, and 1% discontinued ROZLYTREK due to cognitive adverse reactions
  • Among the 355 patients who received ROZLYTREK across clinical trials, 36 (10%) experienced mood disorders. Median time to onset of mood disorders was 1 month (range: 1 day to 9 months). Mood disorders occurring in ≥1% of patients included anxiety (4.8%), depression (2.8%), and agitation (2%). Grade 3 mood disorders occurred in 0.6% of patients. One completed suicide was reported 11 days after treatment had ended. Among the 36 patients who experienced mood disorders, 6% required a dose reduction, 6% required dose interruption, and no patients discontinued ROZLYTREK due to mood disorders
  • Dizziness occurred in 136 (38%) of 355 patients. In patients who experienced dizziness, Grade 3 dizziness occurred in 2.2% of patients. Ten percent of patients required a dose reduction, 7% required dose interruption, and 0.7% discontinued ROZLYTREK due to dizziness
  • Among the 355 patients who received ROZLYTREK across clinical trials, 51 (14%) experienced sleep disturbances. Sleep disturbances included insomnia (7%), somnolence (7%), hypersomnia (1.1%), and sleep disorder (0.3%). Grade 3 sleep disturbances occurred in 0.6% of patients. Among the 51 patients who experienced sleep disturbances, 6% required a dose reduction and no patients discontinued ROZLYTREK due to sleep disturbances
  • Incidence of CNS adverse reactions was similar in patients with and without CNS metastases; however, the incidence of dizziness (38% vs 31%), headache (21% vs 13%), paresthesia (20% vs 6%), balance disorder (13% vs 4%), and confusional state (11% vs 2%) appeared to be increased in patients with CNS metastases who had received prior CNS irradiation (N=90) compared to those who did not (N=48)
  • Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue ROZLYTREK based on severity

Skeletal Fractures

  • ROZLYTREK increases the risk of fractures. In an expanded safety population that included 338 adult patients and 30 pediatric patients who received ROZLYTREK across clinical trials, 5% of adult patients and 23% of pediatric patients experienced fractures. In adult patients, some fractures occurred in the setting of a fall or other trauma to the affected area, while in pediatric patients, all fractures occurred in patients with minimal or no trauma. In general, there was inadequate assessment for tumor involvement at the site of fracture; however, radiologic abnormalities, possibly indicative of tumor involvement, were reported in some patients
  • In both adult and pediatric patients, most fractures were hip or other lower extremity fractures (eg, femoral or tibial shaft). In a limited number of patients, bilateral femoral neck fractures occurred. The median time to fracture was 3.8 months (range: 0.3 to 18.5 months) in adults and 4.0 months (range: 1.8 months to 7.4 months) in pediatric patients. ROZLYTREK was interrupted in 41% of adults and 43% of pediatric patients due to fractures. No patients discontinued ROZLYTREK due to fractures
  • Promptly evaluate patients with signs or symptoms (eg, pain, changes in mobility, deformity) of fractures. There are no data on the effects of ROZLYTREK on healing of known fractures and risk of future fractures

Hepatotoxicity

  • Among the 355 patients who received ROZLYTREK, increased AST of any grade occurred in 42% of patients and increased ALT of any grade occurred in 36%. Grade 3–4 increased AST or ALT occurred in 2.5% and 2.8% of patients, respectively; the incidence may be underestimated as 4.5% of patients had no post-treatment liver function tests. Median time to onset of increased AST was 2 weeks (range: 1 day to 29.5 months). Median time to onset of increased ALT was 2 weeks (range: 1 day to 9.2 months). Increased AST or ALT leading to dose interruptions or reductions occurred in 0.8% and 0.8% of patients, respectively. ROZLYTREK was discontinued due to increased AST or ALT in 0.8% of patients
  • Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on the severity. If withheld, resume ROZLYTREK at the same or reduced dose

Hyperuricemia

  • Among 355 patients who received ROZLYTREK across clinical trials, 32 patients (9%) experienced hyperuricemia reported as adverse reactions with symptoms, as well as elevated uric acid levels. Grade 4 hyperuricemia occurred in 1.7% of patients, including one patient who died due to tumor lysis syndrome. Among the 32 patients with hyperuricemic adverse reactions, 34% required urate-lowering medication to reduce uric acid levels, 6% required dose reduction, and 6% required dose interruption. Hyperuricemia resolved in 73% of patients following initiation of urate-lowering medication without interruption or dose reduction of ROZLYTREK. No patients discontinued ROZLYTREK due to hyperuricemia
  • Assess serum uric acid levels prior to initiating ROZLYTREK and periodically during treatment. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume ROZLYTREK at same or reduced dose upon improvement of signs or symptoms based on severity

QT Interval Prolongation

  • Among the 355 patients who received ROZLYTREK across the clinical trials, 3.1% of patients with at least one post-baseline ECG assessment experienced QTcF interval prolongation of >60 ms after starting ROZLYTREK and 0.6% had a QTcF interval >500 ms
  • Monitor patients who already have or who are at significant risk of developing QTc interval prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, and those taking other medicinal products associated with QT prolongation. Assess QT interval and electrolytes at baseline and periodically during treatment, adjusting frequency based upon risk factors such as congestive heart failure, electrolyte abnormalities, or concomitant medications known to prolong the QTc interval. Based on the severity of QTc interval prolongation, withhold ROZLYTREK and then resume at same or reduced dose, or permanently discontinue

Vision Disorders

  • Among the 355 patients who received ROZLYTREK across clinical trials, vision changes occurred in 21% of patients, including Grade 1 (17%), Grade 2 (2.8%), and Grade 3 (0.8%). Vision disorders occurring in ≥1% included blurred vision (9%), photophobia (5%), diplopia (3.1%), visual impairment (2%), photopsia (1.1%), cataract (1.1%), and vitreous floaters (1.1%)
  • For patients with new visual changes or changes that interfere with activities of daily living, withhold ROZLYTREK until improvement or stabilization and conduct an ophthalmological evaluation as clinically appropriate. Upon improvement or stabilization, resume ROZLYTREK at same or reduced dose

Embryo-Fetal Toxicity

  • Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, ROZLYTREK can cause fetal harm when administered to a pregnant woman. Administration of entrectinib to pregnant rats resulted in malformations at exposures approximately 2.7 times the human exposure at the 600 mg dose based on area under the curve (AUC)
  • Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 5 weeks following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 3 months after the final dose

Most Common Adverse Reactions

  • The most common adverse reactions (≥20%) were fatigue (48%), constipation (46%), dysgeusia (44%), edema (40%), dizziness (38%), diarrhea (35%), nausea (34%), dysesthesia (34%), dyspnea (30%), myalgia (28%), cognitive impairment (27%), increased weight (25%), cough (24%), vomiting (24%), pyrexia (21%), arthralgia (21%), and vision disorders (21%)

DRUG INTERACTIONS

Effect of Other Drugs on ROZLYTREK

Moderate and Strong CYP3A Inhibitors

  • Adults and Pediatric Patients 12 Years and Older with BSA >1.50 m2. Coadministration of ROZLYTREK with a strong or moderate CYP3A inhibitor increases entrectinib plasma concentrations, which could increase the frequency or severity of adverse reactions. Avoid coadministration of strong or moderate CYP3A inhibitors
  • Pediatric Patients 12 Years and Older with BSA ≤1.50 m2. Avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors
  • Avoid grapefruit products during treatment with ROZLYTREK, as they contain inhibitors of CYP3A

Moderate and Strong CYP3A Inducers

  • Coadministration of ROZLYTREK with a strong or moderate CYP3A inducer decreases entrectinib plasma concentrations, which may reduce ROZLYTREK efficacy. Avoid coadministration of strong and moderate CYP3A inducers with ROZLYTREK

Drugs That Prolong QT Interval

  • QTc interval prolongation can occur with ROZLYTREK. Avoid coadministration of ROZLYTREK with other products with a known potential to prolong QT/QTc interval

ADDITIONAL IMPORTANT SAFETY INFORMATION

Lactation
Risk Summary

  • Because of the potential adverse reactions in breastfed children from ROZLYTREK, advise a lactating woman to discontinue breastfeeding during treatment with ROZLYTREK and for 7 days after the final dose

Pediatric Use

  • There is limited clinical experience with ROZLYTREK in pediatric patients. The safety of ROZLYTREK in pediatric patients 12 years of age and older was established based on extrapolation of data in adults and data from 30 pediatric patients enrolled in STARTRK-NG. Of these 30 patients, 7% were <2 years (n=2), 77% were 2 to <12 years (n=23), 17% were 12 to <18 years (n=5); 57% had metastatic disease (n=17), 44% had locally advanced disease (n=13), and all patients had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy. The most common cancers were neuroblastoma (47%), primary CNS tumors (30%), and sarcoma (10%). The median duration of exposure for all pediatric patients was 4.2 months (range: 0.2 to 22.7 months)
  • Due to the small number of pediatric and adult patients, the single arm design of clinical studies of ROZLYTREK, and confounding factors such as differences in susceptibility to infections between pediatric and adult patients, it is not possible to determine whether the observed differences in the incidence of adverse reactions to ROZLYTREK are related to patient age or other factors. The Grade 3 or 4 adverse reactions and laboratory abnormalities that occurred more frequently (≥5%) in pediatric patients (n=30) compared with adults (n=338) were neutropenia (27% vs 2%), bone fractures (23% vs 5%), increased weight (20% vs 7%), thrombocytopenia (10% vs 0.3%), lymphopenia (7% vs 1%), increased gamma-glutamyl transferase (7% vs 0%), and device-related infection (7% vs 0.3%). Three pediatric patients discontinued ROZLYTREK due to an adverse reaction (Grade 4 pulmonary edema, Grade 3 dyspnea, and Grade 4 pancreatitis)
  • The safety and effectiveness of ROZLYTREK in pediatric patients <12 years of age with solid tumors who have an NTRK gene fusion have not been established
  • The safety and effectiveness of ROZLYTREK in pediatric patients with ROS1-positive NSCLC have not been established

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see additional Important Safety Information in the full Prescribing Information.

    • ROZLYTREK [prescribing information]. South San Francisco, CA: Genentech USA, Inc. 2022.

      ROZLYTREK [prescribing information]. South San Francisco, CA: Genentech USA, Inc. 2022.

    • Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34.

      Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer (V.2.2023). © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer (V.2.2023). © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Soft Tissue Sarcoma (V.2.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Soft Tissue Sarcoma (V.2.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Head and Neck Cancers (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Head and Neck Cancers (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma (V.3.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma (V.3.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer (V.3.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer (V.3.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer (V.4.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer (V.4.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Central Nervous System Cancer (V.2.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Central Nervous System Cancer (V.2.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma (V.2.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma (V.2.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer (V.3.2023). © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer (V.3.2023). © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Vulvar Cancer (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Vulvar Cancer (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Cervical Cancer (V.1.2023). © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Cervical Cancer (V.1.2023). © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer (V.2.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer (V.2.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Esophageal and Esophagogastric Junction Cancer (V.1.2023). © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Esophageal and Esophagogastric Junction Cancer (V.1.2023). © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancer (V.5.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancer (V.5.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Small Bowel Adenocarcinoma (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Small Bowel Adenocarcinoma (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastrointestinal Stromal Tumors (V.2.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastrointestinal Stromal Tumors (V.2.2022). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Uterine Neoplasms (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Uterine Neoplasms (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Melanoma: Cutaneous (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Melanoma: Cutaneous (V.1.2023). © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Patil T, Smith DE, Bunn PA, et al. The incidence of brain metastases in stage IV ROS1-rearranged non-small cell lung cancer and rate of central nervous system progression on crizotinib. J Thorac Oncol. 2018;13(11):1717-1726.

      Patil T, Smith DE, Bunn PA, et al. The incidence of brain metastases in stage IV ROS1-rearranged non-small cell lung cancer and rate of central nervous system progression on crizotinib. J Thorac Oncol. 2018;13(11):1717-1726.

    • Park S, Ahn B, Lim SW, et al. Characteristics and outcome of ROS1-positive non-small cell lung cancer patients in routine clinical practice. J Thorac Oncol. 2018;13(9):1373-1382.

      Park S, Ahn B, Lim SW, et al. Characteristics and outcome of ROS1-positive non-small cell lung cancer patients in routine clinical practice. J Thorac Oncol. 2018;13(9):1373-1382.

    • Ou SI, Zhu VW. CNS metastasis in ROS1+ NSCLC: an urgent call to action, to understand, and to overcome. Lung Cancer. 2019;130:201-207.

      Ou SI, Zhu VW. CNS metastasis in ROS1+ NSCLC: an urgent call to action, to understand, and to overcome. Lung Cancer. 2019;130:201-207.

    • Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010;2(4):2100-2137.

      Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010;2(4):2100-2137.

    • Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94(10):2698-2705.

      Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94(10):2698-2705.

    • Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004;22(14):2865-2872.

      Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004;22(14):2865-2872.

    • Gainor JF, Tseng D, Yoda S, et al. Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non-small-cell lung cancer. JCO Precis Oncol. 2017. doi: 10.1200/PO.17.00063.

      Gainor JF, Tseng D, Yoda S, et al. Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non-small-cell lung cancer. JCO Precis Oncol. 2017. doi: 10.1200/PO.17.00063.

    • Lu S, Shen L. Clinical impact of crizotinib on brain metastases in patients with advanced ROS1-rearranged non-small cell lung cancer [abstract]. Presented at: 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan.

      Lu S, Shen L. Clinical impact of crizotinib on brain metastases in patients with advanced ROS1-rearranged non-small cell lung cancer [abstract]. Presented at: 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan.

    • Misra A, Ganesh S, Shahiwala A, Shah SP. Drug delivery to the central nervous system: a review. J Pharm Pharm Sci. 2003;6(2):252-273.

      Misra A, Ganesh S, Shahiwala A, Shah SP. Drug delivery to the central nervous system: a review. J Pharm Pharm Sci. 2003;6(2):252-273.

    • Levin VA, Tonge PJ, Gallo JM, et al. CNS Anticancer Drug Discovery and Development Conference white paper. Neuro Oncol. 2015;17(suppl 6):vi1-vi26.

      Levin VA, Tonge PJ, Gallo JM, et al. CNS Anticancer Drug Discovery and Development Conference white paper. Neuro Oncol. 2015;17(suppl 6):vi1-vi26.

    • Fischer H, Ullah M, de la Cruz C, et al. Entrectinib, a TRK/ROS1 inhibitor with anti-CNS tumor activity: differentiation from other inhibitors in its class due to weak interaction with P-glycoprotein. Neuro Oncol. 2020;22(6):819-829.

      Fischer H, Ullah M, de la Cruz C, et al. Entrectinib, a TRK/ROS1 inhibitor with anti-CNS tumor activity: differentiation from other inhibitors in its class due to weak interaction with P-glycoprotein. Neuro Oncol. 2020;22(6):819-829.

    • Data on file. Genentech, Inc.

      Data on file. Genentech, Inc.

    • Yun F, Drilon A, Chiu CH, et al. Entrectinib in patients with ROS1 fusion-positive NSCLC: updated efficacy and safety analysis. Poster presented at: 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria.

      Yun F, Drilon A, Chiu CH, et al. Entrectinib in patients with ROS1 fusion-positive NSCLC: updated efficacy and safety analysis. Poster presented at: 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria.

    • Lange AM, Lo HW. Inhibiting TRK proteins in clinical cancer therapy. Cancers (Basel). 2018;10(4):105.

      Lange AM, Lo HW. Inhibiting TRK proteins in clinical cancer therapy. Cancers (Basel). 2018;10(4):105.

    • Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731-747.

      Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731-747.

    • Marchiò C, Scaltriti M, Ladanyi M, et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019;30(9):1417-1427.

      Marchiò C, Scaltriti M, Ladanyi M, et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019;30(9):1417-1427.

    • Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. 2017;19(11):1511-1521.

      Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. 2017;19(11):1511-1521.

    • Norden AD, Wen PY, Kesari S. Brain metastases. Curr Opin Neurol. 2005;18(6):654-661.

      Norden AD, Wen PY, Kesari S. Brain metastases. Curr Opin Neurol. 2005;18(6):654-661.

    • Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13(6):1663-1674.

      Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13(6):1663-1674.

    • Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846.

      Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846.

    • Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19(11):1469-1472.

      Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19(11):1469-1472.

    • Harada T, Yatabe Y, Takeshita M, et al. Role and relevance of TrkB mutations and expression in non-small cell lung cancer. Clin Cancer Res. 2011;17(9):2638-2645.

      Harada T, Yatabe Y, Takeshita M, et al. Role and relevance of TrkB mutations and expression in non-small cell lung cancer. Clin Cancer Res. 2011;17(9):2638-2645.

    • Bishop JA, Yonescu R, Batista D, Begum S, Eisele DW, Westra WH. Utility of mammaglobin immunohistochemistry as a proxy marker for the ETV6-NTRK3 translocation in the diagnosis of salivary mammary analogue secretory carcinoma. Hum Pathol. 2013;44(10):1982-1988.

      Bishop JA, Yonescu R, Batista D, Begum S, Eisele DW, Westra WH. Utility of mammaglobin immunohistochemistry as a proxy marker for the ETV6-NTRK3 translocation in the diagnosis of salivary mammary analogue secretory carcinoma. Hum Pathol. 2013;44(10):1982-1988.

    • Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2(5):367-376.

      Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2(5):367-376.

    • Leeman-Neill RJ, Kelly LM, Liu P, et al. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer. 2014;120(6):799-807.

      Leeman-Neill RJ, Kelly LM, Liu P, et al. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer. 2014;120(6):799-807.

    • Okamura R, Boichard A, Kato S, Sicklick JK, Bazhenova L, Kurzrock R. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol. 2018.

      Okamura R, Boichard A, Kato S, Sicklick JK, Bazhenova L, Kurzrock R. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol. 2018.

    • Hechtman JF, Benayed R, Hyman DM, et al. Pan-trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol. 2017;41(11):1547-1551.

      Hechtman JF, Benayed R, Hyman DM, et al. Pan-trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol. 2017;41(11):1547-1551.

    • Takeda M, Sakai K, Terashima M, et al. Clinical application of amplicon-based next-generation sequencing to therapeutic decision making in lung cancer. Ann Oncol. 2015;26(12):2477-2482.

      Takeda M, Sakai K, Terashima M, et al. Clinical application of amplicon-based next-generation sequencing to therapeutic decision making in lung cancer. Ann Oncol. 2015;26(12):2477-2482.

    • Diaz LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32(6):579-586.

      Diaz LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32(6):579-586.

    • Zhou B, Xu K, Zheng Xi, et al. Application of exosomes as liquid biopsy in clinical diagnosis. Nature. 2020;5(144):1-14.

      Zhou B, Xu K, Zheng Xi, et al. Application of exosomes as liquid biopsy in clinical diagnosis. Nature. 2020;5(144):1-14.

    • Murphy DA, Ely HA, Shoemaker R, et al. Detecting gene rearrangements in patient populations through a 2-step diagnostic test comprised of rapid IHC enrichment followed by sensitive next-generation sequencing. Appl Immunohistochem Mol Morphol. 2017;25(7):513-523.

      Murphy DA, Ely HA, Shoemaker R, et al. Detecting gene rearrangements in patient populations through a 2-step diagnostic test comprised of rapid IHC enrichment followed by sensitive next-generation sequencing. Appl Immunohistochem Mol Morphol. 2017;25(7):513-523.

    • Abel HJ, Al-Kateb H, Cottrell CE, et al. Detection of gene rearrangements in targeted clinical next-generation sequencing. J Mol Diagn. 2014;16(4):405-417.

      Abel HJ, Al-Kateb H, Cottrell CE, et al. Detection of gene rearrangements in targeted clinical next-generation sequencing. J Mol Diagn. 2014;16(4):405-417.

    • Bubendorf L, Büttner R, Al-Dayel F, et al. Testing for ROS1 in non-small cell lung cancer: a review with recommendations. Virchows Arch. 2016;469(5):489-503.

      Bubendorf L, Büttner R, Al-Dayel F, et al. Testing for ROS1 in non-small cell lung cancer: a review with recommendations. Virchows Arch. 2016;469(5):489-503.

    • Su D, Zhang D, Chen K, et al. High performance of targeted next generation sequencing on variance detection in clinical tumor specimens in comparison with current conventional methods. J Exp Clin Cancer Res. 2017;36(1):121.

      Su D, Zhang D, Chen K, et al. High performance of targeted next generation sequencing on variance detection in clinical tumor specimens in comparison with current conventional methods. J Exp Clin Cancer Res. 2017;36(1):121.

    • Shan L, Lian F, Guo L, et al. Detection of ROS1 gene rearrangement in lung adenocarcinoma: comparison of IHC, FISH and real-time RT-PCR. PloS One. 2015;10(3):e0120422.

      Shan L, Lian F, Guo L, et al. Detection of ROS1 gene rearrangement in lung adenocarcinoma: comparison of IHC, FISH and real-time RT-PCR. PloS One. 2015;10(3):e0120422.