Clinically tolerable safety profile established in 355 patients across 4 clinical trials1

91% of patients treated with ROZLYTREK were able to stay on treatment without discontinuation due to adverse reactions1

  • The most frequent adverse reactions (<1% each) that resulted in permanent discontinuation were pneumonia, cardiorespiratory arrest, dyspnea, and fatigue
  • Dose interruptions due to adverse reactions occurred in 46% of patients
  • The most frequent adverse reactions (≥2%) that resulted in interruption were increased blood creatinine (4%), fatigue (3.7%), anemia (3.1%), diarrhea (2.8%), pyrexia (2.8%), dizziness (2.5%), dyspnea (2.3%), nausea (2.3%), pneumonia (2.3%), cognitive disorder (2%), and neutropenia (2%)
  • Dose reductions due to adverse reactions occurred in 29% of patients who received ROZLYTREK
  • The most frequent adverse reactions resulting in dose reductions (≥1%) were dizziness (3.9%), increased blood creatinine (3.1%), fatigue (2.3%), anemia (1.7%), and increased weight (1.4%)

Most common adverse reactions (≥10%) in patients treated with ROZLYTREK within 4 clinical trials1

ROZLYTREK Adverse Reactions
aGrades 3-5, inclusive of fatal adverse reactions, including 2 events of pneumonia and 2 events of dyspnea.1
bIncludes fatigue, asthenia.1
cIncludes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling.1
dIncludes abdominal pain upper, abdominal pain, lower abdominal discomfort, abdominal tenderness.1
eIncludes dizziness, vertigo, dizziness postural.1
fIncludes paresthesia, hyperesthesia, hypoesthesia, dysesthesia, oral hypoaesthesia, palmar-plantar erythrodysaesthesia, oral paresthesia, genital hypoaesthesia.1
gIncludes amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, visual hallucination, memory impairment, mental disorder, mental status changes.1
hIncludes neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy.1
iIncludes ataxia, balance disorder, gait disturbances.1
jIncludes hypersomnia, insomnia, sleep disorder, somnolence.1
kIncludes anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation.1
lIncludes musculoskeletal pain, musculoskeletal chest pain, myalgia, neck pain.1
mIncludes blindness, cataract, cortical cataract, corneal erosion, diplopia, eye disorder, photophobia, photopsia, retinal hemorrhage, vision blurred, visual impairment, vitreous adhesions, vitreous detachment, vitreous floaters.1
nIncludes lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection.1
oIncludes hypotension, orthostatic hypotension.1
pIncludes rash, rash maculopapular, rash pruritic, rash erythematous, rash papular.1
DOR=duration of response; IC-ORR=intracranial objective response rate; mNSCLC=metastatic non-small cell lung cancer; ORR=objective response rate; ROS1=ROS proto-oncogene 1.

The majority of laboratory abnormalities were grade 1/21q

Laboratory abnormalities (≥20%) worsening from baseline in patients receiving ROZLYTREK within 4 clinical trials1

Laboratory Abnormalities Table
qDenominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 111 to 346 patients.
rBased on NCI-CTCAE v5.0.
sNE=not evaluable. Grade 1 and 2 could not be determined per NCI-CTCAE v5.0, as fasting glucose values were not collected.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

Ongoing monitoring considerations with ROZLYTREK1

Ongoing monitoring considerations with Rozlytrek

This list reflects a subset of monitoring considerations. For additional important considerations, please see the full Prescribing Information.

ROS1+ Study Design

Study Design

Learn how ROZLYTREK was studied in patients with ROS1+ mNSCLC

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

ROZLYTREK Financial Resources

Financial and Other Resources

Learn more about financial and other resources for ROZLYTREK

INDICATIONS

ROS1-Positive Non-Small Cell Lung Cancer

ROZLYTREK is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive.

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 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 (e.g., 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 (e.g., 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 (82%), Grade 2 (14%), and Grade 3 (0.8%). Vision disorders occurring in ≥1% included blurred vision (8.7%), photophobia (5.1%), diplopia (3.1%), visual impairment (2%), photopsia (1.3%), 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 Greater than 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 Less Than or Equal to 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 less than 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 full Prescribing Information.

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