Entrectinib, a potent inhibitor of multiple receptor tyrosine kinases including tropomyosin receptor kinases (Trk) A, TrkB, TrkC, c-ros oncogene-1 ( ROS-1 ), and anaplastic lymphoma kinase (ALK), is an antineoplastic agent.1, 4
Entrectinib is used for the treatment of c-ros oncogene-1 ( ROS-1 )-positive metastatic non-small cell lung cancer (NSCLC) in adults.1, 8 The presence of ROS-1 rearrangement in tumor or plasma specimens should be confirmed by an FDA-approved test prior to initiation of therapy.1 Testing with plasma specimens is only appropriate for patients for whom tumor tissue is not available.1 Entrectinib has been designated an orphan drug by FDA for the treatment of tropomyosin receptor kinase (Trk) A-positive, TrkB-positive, TrkC-positive, ROS-1 -positive, and anaplastic lymphoma kinase (ALK)-positive NSCLC.2
The indication for entrectinib in the treatment of ROS-1 -positive metastatic NSCLC is based principally on pooled results for a cohort of 92 adults with metastatic NSCLC harboring a ROS-1 fusion in 3 multicenter, open-label, noncomparative phase 1 and 2 studies (ALKA-372-001, STARTRK-1, and STARTRK-2).1, 8 Patients who previously received a ROS-1 inhibitor were excluded from the primary efficacy analysis.1, 8 ROS-1 fusion was determined using fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), or polymerase chain reaction (PCR) and was confirmed by a central laboratory using a validated NGS test in 25% of patients.1 Patients enrolled in the NSCLC cohort received varying dosages of entrectinib;1, 3 however, 90% of patients received entrectinib 600 mg orally once daily.1 The primary efficacy end points were objective response rate (as evaluated by a blinded independent review committee) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response; an additional outcome measure was intracranial response.1 The median age of patients included in the NSCLC cohort was 53 years; 96% had adenocarcinoma histology, 88% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 48% were white, 45% were Asian, 65% were female, and 65% had received prior platinum-containing therapy for metastatic or recurrent disease.1 No patients had disease progression within 6 months of adjuvant or neoadjuvant platinum-based chemotherapy.1, 3 Most patients (94%) had metastatic disease; CNS metastases were present in 43% of patients.1, 3
At the time of data analysis, the objective response rate for patients receiving entrectinib for the treatment of metastatic ROS-1 -positive NSCLC was 74%; complete response was achieved in 15% of patients.1 At the time of analysis, 75, 57, or 38% of patients had durable responses of at least 9, 12, or 18 months, respectively.1 Intracranial response was achieved in 7 of 10 patients with measurable CNS metastases at baseline (as assessed by a blinded independent review committee) who had not received prior radiation therapy to the brain within 2 months of receiving entrectinib.1, 3 The most common ROS-1 fusion was CD74-ROS-1 .3 The objective response rate in patients with tumors harboring CD74-ROS-1 , SLC34A2-ROS-1 , SDC4-ROS-1 , EZR-ROS-1 , or TPM3-ROS-1 was 85, 57, 67, 100, or 50%, respectively.3 Among patients with tumors harboring an unknown ROS-1 fusion, the objective response rate was 83%.3
Solid Tumors with Neurotrophic Tyrosine Receptor Kinase Gene Fusion
Entrectinib is used in adults and pediatric patients >1 month of age for the treatment of solid tumors harboring a neurotrophic tyrosine receptor kinase ( NTRK ) gene fusion (without a known acquired mutation for resistance), in patients who have metastatic disease or may experience severe morbidity following surgical resection, and whose disease progressed following prior therapy or those who are not candidates for other treatment options.1, 10 The presence of NTRK fusion should be confirmed in tumor or plasma specimens by an FDA-approved test prior to initiation of therapy.1 Testing using plasma specimens is only appropriate for patients for whom tumor tissue is not available.1 Entrectinib has been designated an orphan drug by FDA for the treatment of these cancers.2 The accelerated approval of entrectinib for this indication is based on objective response rate and duration of response.1 Continued approval for this indication may be contingent on verification and description of clinical benefit of entrectinib in confirmatory studies.1
The incidence of solid tumors harboring activating NTRK fusions has not been fully characterized; however, 1500-5000 cases are estimated per year in the US.3 Although a relatively small subset (less than 1%) of patients with common solid tumors (e.g., cancers of the lung, colon, or prostate) harbor NTRK fusions, such fusions have been frequently reported in certain rare cancers (i.e., 91-100% of mammary analogue secretory carcinomas, secretory breast carcinomas, or infantile fibrosarcomas; 61% of congenital mesoblastic nephromas; 12-15% of papillary thyroid cancers).3, 14, 15
The indication for entrectinib in the treatment of solid tumors harboring a NTRK fusion is based principally on pooled results for a cohort of patients with unresectable or metastatic solid tumors harboring a NTRK fusion in 3 multicenter, open-label, noncomparative phase 1 and 2 studies (ALKA-372-001, STARTRK-1, and STARTRK-2).1, 10 This cohort of patients included the initial 54 adults enrolled in the ALKA-372-001, STARTRK-1, and STARTRK-2 studies with solid tumors harboring a NTRK fusion.1 Patients were included in the NTRK fusion-positive solid tumor cohort if they experienced disease progression following prior systemic therapy, if available, or if severe morbidity following surgical resection for locally advanced disease was expected.1 Patients were also required to have at least 2 years of follow-up from first post-treatment tumor assessment.1 Patients who previously received a tropomyosin receptor kinase (Trk) inhibitor were excluded from the primary efficacy analysis.1 NTRK fusion was detected using NGS or other nucleic acid-based tests; confirmation of NTRK fusion was detected by a validated NGS test in a central laboratory in 83% of patients.1 Patients enrolled in the NTRK fusion-positive solid tumor cohort received varying dosages of entrectinib;1 however, 94% of patients received entrectinib 600 mg orally once daily.1 Treatment was continued until disease progression or unacceptable toxicity occurred.1 The primary efficacy end points were objective response rate according to RECIST 1.1 (as evaluated by a blinded independent review committee) and duration of response; an additional outcome measure was intracranial response.1 The median age of patients included in the NTRK fusion-positive solid tumor cohort was 58 years, 89% had an ECOG performance status of 0 or 1, 80% were white, and 59% were female.1 Most patients (96%) had metastatic disease and 4% had unresectable locally advanced disease.1 All patients in the NTRK fusion-positive solid tumor cohort had received prior therapy for their disease (i.e., surgery, radiation therapy, systemic therapy); 74 or 17% of patients had received a median of 1 or at least 3 prior systemic therapies for metastatic disease, respectively.1 CNS metastases were present in 22% of patients.1 The most common cancers in the NTRK fusion-positive solid tumor cohort were sarcoma (24%), lung cancer (19%), salivary gland tumors (13%), breast cancer (11%), thyroid cancer (9%), and colorectal cancer (7%).1
At the time of data analysis, the objective response rate in the NTRK fusion-positive solid tumor cohort was 59%; complete response was achieved in 13% of patients.1, 10 At the time of analysis, 72, 66, or 56% of patients had durable responses of at least 6, 9, or 12 months, respectively.1 Intracranial response was achieved in 3 of 4 patients with measurable CNS metastases at baseline (as assessed by a blinded independent review committee) who had not received prior radiation therapy to the brain within 2 months of receiving entrectinib.1 Among patients with previously treated metastatic disease, the objective response rate was 53%.1 The objective response rate in patients with mammary analogue secretory carcinoma, breast cancer, NSCLC, sarcoma, colorectal cancer, or thyroid cancer was 86, 83, 60, 46, 25, or 60%, respectively.1 All patients with pancreatic cancer, gynecologic cancers, or cholangiocarcinoma achieved partial responses.1 All patients with neuroendocrine cancers achieved complete responses.1 The most common documented NTRK fusion was ETV6-NTRK3 .1 The objective response rate in patients with tumors harboring TPR-NTRK1 , ETV6-NTRK3 , or TPM3-NTRK1 was 100, 72, or 50%, respectively.1 Although SQSTM1-NTRK1 fusion was detected in 2 patients and CD74-NTRK1 , PLEKHA6-NTRK1 , CDC42BPA-NTRK1 , EPS15L1-NTRK1 , and RBPMS-NTRK3 fusions were detected in one patient each, most patients with tumors harboring these NTRK fusions achieved partial responses.1
The efficacy of entrectinib was also evaluated in 33 pediatric patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in 1 of 2 multicenter, open-label clinical trials: STARTRK-NG and TAPISTRY.1 Patients were administered entrectinb 20 to 600 mg [dosing based on body surface area (BSA)] orally or via enteral feeding tube once daily in 4-week cycles until unacceptable toxicity or disease progression.1 The primary efficacy outcome measure was overall response rate.1 The median age of enrolled patients was 4 years (range: 2 months to 15 years).1 About half (52%) of patients were male; 58% were white, 30% Asian, 9% Hispanic or Latino, and 3% Black or African American.1 Locally advanced disease was present in 71% of patients and 29% had metastatic disease; a majority (85%) received prior treatment for their cancer including surgery, radiotherapy, and/or systemic therapy.1
Results revealed an overall response rate of 70% for the 33 evaluable pediatric patients, with a complete response observed in 42% of patients and a partial response in 27%.1 A duration of response was assessed in 23 patients with a median duration of 25.4 months.1 The most common tumor types were primary CNS in 17 patients, infantile fibosarcoma in 8 patients, and spindle cell in 6 patients.1 The overall response rates for these tumor types were 53%, 88%, and 100%, respectively.1
Administer entrectinib orally without regard to food.1
Entrectinib is commercially available as oral capsules and oral pellets; clinicians should prescribe the most appropriate dosage form based on the dose required and patient needs.1
The capsules may be swallowed whole or made into an oral suspension (for oral or enteral tube administration).1 If swallowed whole, the capsules should not be crushed or chewed.1
The oral pellets should be swallowed with soft food.1 The pellets should not be chewed or crushed in order to avoid a bitter taste.1
If a dose of entrectinib is missed, the missed dose should be taken as soon as it is remembered unless the next dose is due within 12 hours.1 If a dose is vomited immediately after administration, an additional dose should be administered to make up for the vomited dose.1
Whole capsules are intended for use in patients who can swallow a whole capsule and whose doses are in multiples of 100 mg.1
Capsules prepared as an oral suspension are intended for use in patients who have difficulty or inability to swallow whole capsules or patients who require enteral (e.g., gastric or nasogastric tube) administration.1 Capsules prepared as a suspension should also be used for those patients who require dose increments of 10 mg.1 The oral suspension is compounded by carefully opening the appropriate number of capsules and pouring the contents into room temperature drinking water or milk.1 The suspension should sit for 15 minutes after preparation and then be administered immediately.1 Patients should drink water after taking the oral suspension to ensure the drug has been completely swallowed.1
If enteral administration is necessary, the oral suspension should be administered via a gastric or nasogastric tube.1 For dosing volumes ≥3 mL, an enteral tube that is 8 FR or higher is required for administration.1 Patients should divide dosing volumes ≥3 mL into at least 2 aliquots and a dosing volume of 30 mL into at least 3 (10 mL aliquots).1 The tube should be flushed with an equivalent volume of water or milk after administration of each aliquot.1
Refer to the entrectinib prescribing information for more specific information on the preparation of entrectinib capsules as a suspension for oral or enteral tube administration.1
Store entrectinib capsules at 20-25°C (excursions permitted between 15-30ºC) in the original container and keep the bottle tightly closed to protect from moisture.1 If the capsules are prepared as an oral suspension using drinking water or milk, store at <30°C for no more than 2 hours.1 Discard any unused suspension if not used within the 2 hours following preparation.1
The pellet formulation is intended for patients who have difficulty or inability to swallow whole capsules, but can swallow soft foods, and whose doses are in multiples of 50 mg.1
The pellets should be sprinkled on 1 or more spoonfuls of soft food (e.g., applesauce, yogurt, pudding) and administered within 20 minutes of preparation, followed by water to ensure the drug has been completely swallowed.1
The pellets should not be used to prepare an oral suspension.1 Partial quantities of pellets from a packet should not be used to prepare a dose.1 The pellet formulation should not be used for enteral administration as the pellets may clog the tube.1
Store entrectinib pellets at 20-25°C (excursions permitted between 15-30ºC) in the original container in order to protect from moisture.1
For the treatment of ROS-1 -positive metastatic NSCLC, the recommended adult dosage of entrectinib is 600 mg orally once daily.1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
Solid Tumors with Neurotrophic Receptor Tyrosine Kinase Gene Fusion
For the treatment of solid tumors harboring a NTRK fusion (without a known acquired mutation for resistance) in patients who have metastatic disease or may experience severe morbidity following surgical resection and whose disease progressed following prior therapy or those who are not candidates for other treatment options, the recommended dosage of entrectinib in adults and pediatric patients with a body surface area (BSA) 1.51 m 2 is 600 mg once daily.1 The recommended dosage in pediatric patients >1 month to 6 months of age is 250 mg/m2 once daily.1 Table 1 presents the recommended dosage for pediatric patients >6 months of age , which is based on BSA.1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
Body Surface Area (BSA)a | Recommended Dosage |
|---|---|
≤0.50 m2 | 300 mg/m2 once daily |
0.51 to 0.80 m2 | 200 mg once daily |
0.81 to 1.10 m2 | 300 mg once daily |
1.11 to 1.50 m2 | 400 mg once daily |
aBSA categories and recommended dosage are based on closely matching exposures to a target dose of 300 mg/m2.
Dosage Modification for Toxicity
Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of entrectinib may be necessary in patients experiencing certain adverse effects.1 When necessary, the dosage of entrectinib should be reduced as described in Table 2.1 Permanently discontinue entrectinib in patients who are unable to tolerate therapy after 2 dose reductions.1
Starting Dose (once daily) | First Dose Reduction | Second Dose Reduction |
|---|---|---|
250 mg/m2 or 300 mg/m2 | Reduce dose to two-thirds of the starting dose | Reduce dose to one-third of the starting dose |
200 mg | 150 mg once daily | 100 mg once daily |
300 mg | 200 mg once daily | 100 mg once daily |
400 mg | 300 mg once daily | 200 mg once daily |
600 mg | 400 mg once daily | 200 mg once daily |
Table 3 indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for certain adverse effects according to severity.1
Adverse Reaction and Severity | Modification |
|---|---|
Heart Failure | |
Grade 2 or 3 | Withhold therapy; when toxicity resolves to grade 1 or less, resume at reduced dosage |
Grade 4 | Permanently discontinue therapy |
CNS Effects |
|
Grade 2 (intolerable) | Withhold therapy; when toxicity resolves to baseline or grade 1 or less, resume at same or reduced dosage |
Grade 3 | Withhold therapy; when toxicity resolves to baseline or grade 1 or less, resume at reduced dosage |
Grade 4 | Permanently discontinue therapy |
Hepatotoxicity |
|
Grade 3 | Withhold therapy. If toxicity resolves to baseline or grade 1 or less within 4 weeks, resume at same dosa if toxicity does not resolve within 4 weeks, permanently discontinue therapy. Resume at a reduced dose for recurrent grade 3 events that resolve within 4 weeks |
Grade 4 | Withhold therapy. If toxicity resolves to baseline or grade 1 or less within 4 weeks, resume at reduced dosa if toxicity does not resolve within 4 weeks, permanently discontinue therapy. Permanently discontinue therapy for recurrent grade 4 events |
Elevated ALT or AST concentrations >3 times the ULN with concomitant total bilirubin concentrations >1.5 times the ULN in absence of cholestasis or hemolysis | Permanently discontinue therapy |
Hyperuricemia |
|
Symptomatic | Withhold therapy and initiate urate-lowering therapy; when toxicity improves, resume at same or reduced dosage |
Grade 4 | Withhold therapy and initiate urate-lowering therapy; when toxicity improves, resume at same or reduced dosage |
Prolongation of QT Interval |
|
QTc interval >500 msec | If other etiology of QT-interval prolongation is present: Withhold therapy and correct other causes of QT-interval prolongation; resume at same dosage when toxicity resolves to baseline If no other etiology of QT-interval prolongation is present: Withhold therapy; resume at reduced dosage when toxicity resolves to baseline |
Torsades de pointes, polymorphic ventricular tachycardia, or signs and/or symptoms of serious arrhythmia | Permanently discontinue therapy |
Visual Disturbances |
|
New visual symptoms, including changes that interfere with activities of daily living | Withhold therapy; when toxicity improves or stabilizes, resume at same or reduced dosage |
Grade 2 or greater | Withhold therapy; when toxicity improves or stabilizes, resume at same or reduced dosage |
Hematologic Toxicity |
|
Grade 3 or 4 anemia or neutropenia | Withhold therapy; when toxicity improves to grade 2 or less, resume at same or reduced dosage |
Other Toxicity |
|
Grade 3 or 4 (clinically significant) | Withhold therapy. If toxicity resolves to baseline or grade 1 within 4 weeks, resume at same or reduced dosa if toxicity does not resolve within 4 weeks, permanently discontinue therapy Permanently discontinue therapy for recurrent grade 4 events |
Concomitant Use with CYP3A Inhibitors
Concomitant use of entrectinib with moderate or strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A should be avoided.1 If concomitant use cannot be avoided in adults and pediatric patients 2 years of age or older, the manufacturer recommends reducing the dosage of entrectinib as shown in Table 4 and limiting coadministration to 14 days or less.1 After discontinuing the strong or moderate CYP3A inhibitor for 3-5 elimination half-lives, resume the entrectinib dose that was taken prior to initiating the CYP3A inhibitor.1
Starting Dosea | Moderate CYP3A Inhibitor | Strong CYP3A Inhibitor |
|---|---|---|
200 mg | 50 mg once daily | 50 mg on alternate days |
300 mg | 100 mg once daily | 50 mg once daily |
400 mg | 200 mg once daily | 50 mg once daily |
600 mg | 200 mg once daily | 100 mg once daily |
aFor pediatric patients with a starting dose <200 mg, avoid coadministration with a strong or moderate CYP3A inhibitor.
No dosage adjustment is necessary in patients with mild hepatic impairment (total bilirubin concentration 1.5 times or less the ULN).1
No dosage adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance of 30 to less than 90 mL/minute).1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Heart failure has been reported in patients receiving entrectinib.1 In clinical trials, heart failure occurred in 12 (3.4%) of 355 patients receiving the drug and was grade 3 in 2.3% of patients.1 The median time to onset of heart failure was 2 months (range: 11 days to 12 months).1 Entrectinib was interrupted in 6 patients with heart failure (50%) and discontinued in 2 patients (17%).1 Heart failure resolved in 6 patients (50%) following interruption or discontinuation of entrectinib and initiation of appropriate medical management.1 Myocarditis in the absence of heart failure also was reported in 0.3% of patients receiving the drug.1 Routine cardiac function assessment (except electrocardiograms [ECGs]) prior to and during therapy was not performed during these studies.1
Patients with symptomatic heart failure, myocardial infarction (MI), unstable angina, or those who underwent coronary artery bypass graft (CABG) within 3 months were excluded from clinical trials.1
In patients with symptoms or known risk factors for heart failure, left ventricular ejection fraction (LVEF) should be assessed prior to initiation of entrectinib.1 Patients should be monitored for signs and symptoms of heart failure (e.g., dyspnea, edema).1 For patients with myocarditis with or without decreased ejection fraction, magnetic resonance imaging (MRI) or cardiac biopsy may be necessary to confirm the diagnosis of myocarditis.1 If new onset or worsening heart failure occurs, appropriate therapy for heart failure should be initiated and assessment of left ventricular function should be repeated.1 Dosage reduction or permanent discontinuance of therapy may be necessary depending on the severity of heart failure or left ventricular dysfunction.1
Entrectinib can cause a wide variety of adverse CNS effects, including cognitive impairment, mood disorder, dizziness, and sleep disturbance.1 The overall incidence of adverse CNS effects was similar in patients with or without CNS metastases; however, the incidence of dizziness, headache, paresthesia, balance disorder, and confusional state appeared to be higher in patients who received prior radiation therapy to the brain for the treatment of CNS metastases compared with those who had not received prior radiation therapy to the brain.1
In clinical trials, 27% of 355 patients receiving entrectinib experienced cognitive impairment, which was grade 3 in 4.5% of patients.1 Most patients (77%) experienced cognitive impairment within 3 months of initiating the drug.1 Cognitive impairment included cognitive disorders, confusional state, disturbance in attention, memory impairment, amnesia, aphasia, mental status change, hallucination, and delirium.1 Dosage interruption, dosage reduction, or drug discontinuance was required in 18, 13, or 1%, respectively, of entrectinib-treated patients experiencing cognitive impairment.1
In clinical trials, 10% of 355 patients receiving entrectinib experienced mood disorders, which were grade 3 in 0.6% of patients.1 The median time to onset of mood disorders was 1 month (range: 1 day to 9 months).1 Mood disorders included anxiety, depression, and agitation.1 Suicidality (i.e., completed suicide) was reported in one patient 11 days following discontinuance of entrectinib.1 Among patients experiencing mood disorders, 6% required dosage reduction and 6% required interruption of therapy.1 Discontinuance of entrectinib therapy was not required in patients who experienced mood disorders.1
In clinical trials, 38% of 355 patients receiving entrectinib experienced dizziness, which was grade 3 in 2.2% of patients.1 Dosage reduction, dosage interruption, or drug discontinuance was required in 10, 7, or 0.7%, respectively, of entrectinib-treated patients experiencing dizziness. 1
In clinical trials, 14% of 355 patients receiving entrectinib experienced sleep disturbances and was grade 3 in 0.6% of patients.1 Sleep disturbances included insomnia, somnolence, hypersomnia, and sleep disorder.1 Dosage reduction was required in 6% of entrectinib-treated patients experiencing sleep disturbance.1 Discontinuance of entrectinib therapy was not required in patients who experienced sleep disturbance.1
Patients and their caregivers should be informed of the risk of adverse CNS effects associated with entrectinib therapy.1 Temporary interruption of entrectinib therapy, dosage reduction, or permanent discontinuance of therapy may be necessary in patients experiencing adverse CNS effects during therapy with the drug, and such patients should be advised not to drive or operate machinery.1
Fractures have been reported in patients receiving entrectinib.1 In an expanded safety population, fracture occurred in 5% of 338 adults and 25% of 76 pediatric patients receiving the drug; the median time to onset of fracture was 3.8 months (range: 0.3-18.5 months) in adults and 4.3 months (range: 2-28.7 months) in pediatric patients.1 In both adult and pediatric patients, mostfractures were hip or other lower extremity fractures.1 In 2 pediatric patients, bilateral femoral neck fractures occurred.1 A total of 41 fracture events were reported in 19 pediatric patients; 13 patients experienced more than one occurrence of fracture.1 Among the 19 pediatric patients who experienced fractures, 17 patients were <12 years of age.1 Entrectinib therapy was interrupted in 41% of adults and16% of pediatric patients who experienced fractures.1 Five pediatric patients discontinued treatment due to fractures.1
Patients experiencing signs or symptoms of fracture (e.g., pain, changes in mobility, deformity) should be promptly evaluated.1 Effect of entrectinib on healing of known fractures or long-term fracture risk is unknown.1
Hepatotoxicity has been reported in patients receiving entrectinib.1 In clinical trials, elevations of serum AST or ALT concentrations were reported in 42 or 36%, respectively, of 355 patients receiving entrectinib; grade 3-4 elevations in AST or ALT concentrations occurred in 2.5 or 2.8%, respectively, of patients.1 Because posttreatment liver function tests were not available for 4.5% of patients, the reported frequency may underestimate the drug's potential to cause elevated aminotransferase concentrations.1 The median time to onset of elevated ALT or AST concentrations was 2 weeks (range: 1 day to 29.5 months).1 Dosage interruption, dosage reduction, or drug discontinuance was required in 0.8, 0.8, or 0.8%, respectively, of entrectinib-treated patients who developed elevated ALT or AST concentrations.1
Liver function tests (e.g., ALT and AST concentrations) should be monitored every 2 weeks during the first month of therapy, monthly thereafter, and as clinically indicated.1 Temporary interruption of entrectinib therapy, dosage reduction, or permanent discontinuance of therapy may be necessary in patients experiencing hepatotoxicity.1
Hyperuricemia has been reported in patients receiving entrectinib.1 In clinical trials, 9% of 355 patients receiving entrectinib experienced symptomatic hyperuricemia-associated adverse reactions.1 Grade 4 hyperuricemia occurred in 1.7% of patients receiving the drug, including one fatal case of tumor lysis syndrome.1 Urate-lowering therapy, dosage reduction, and interruption of therapy were required in 34, 6, and 6%, respectively, of patients who experienced symptomatic hyperuricemia.1 Hyperuricemia resolved in 73% of patients following initiation of urate-lowering therapy without interruption of therapy or dosage reduction.1 Discontinuance of entrectinib therapy was not required in patients experiencing hyperuricemia.1
Serum uric acid levels should be assessed prior to initiating entrectinib and periodically during treatment.1 Patients should be monitored for signs and symptoms of hyperuricemia.1 In patients who develop signs or symptoms of hyperuricemia, urate-lowering therapy should be initiated as clinically indicated.1 Temporary interruption of therapy or dosage reduction may be necessary.1
Prolongation of the corrected QT (QTc) interval has been reported in patients receiving entrectinib.1 In clinical trials, an increase in the QTc interval (corrected for heart rate using Fridericia's formula [QTcF]) exceeding 60 msec from baseline occurred in 3.1% of entrectinib-treated patients, and QTcF intervals exceeding 500 msec occurred in 0.6% of entrectinib-treated patients.1
QT interval and electrolyte concentrations should be monitored at baseline and periodically during therapy.1 More frequent monitoring may be necessary in patients with preexisting QTc-interval prolongation and those with risk factors for developing QTc-interval prolongation (e.g., long QT syndromes, clinically important bradyarrhythmia, severe or uncontrolled heart failure, electrolyte abnormalities, concomitant use of drugs known to prolong the QTc interval).1 Temporary interruption of entrectinib therapy, dosage reduction, or permanent discontinuance of therapy may be necessary in patients experiencing QTc-interval prolongation.1
Visual disturbances (i.e., blurring, photophobia, diplopia, visual impairment, photopsia, cataract, vitreous floaters), generally mild in severity, have been reported in patients receiving entrectinib.1 In clinical trials, vision changes occurred in 21% of 355 patients receiving the drug.1
In patients who report new visual symptoms, including changes that interfere with activities of daily living, an ophthalmologic evaluation should be performed as clinically appropriate.1 Temporary interruption of therapy or dosage reduction may be necessary depending on the severity of the visual disturbance.1
Entrectinib may cause fetal harm in humans based on its mechanism of action and animal findings; embryofetal toxicity and teratogenicity have been demonstrated in animals.1 There are no available data regarding use of entrectinib in pregnant women.1 In animal reproduction studies, body closure defects (omphalocele, gastroschisis) and malformations of vertebrae, ribs, and limbs (micromelia, adactyly) were observed in rats receiving entrectinib at exposure levels up to 2.7 times the human exposure at the recommended dosa reduced fetal weight and reduced skeletal ossification were observed in rats receiving the drug at exposure levels approximately 0.2 and 0.9 times the human exposure, respectively, at the recommended dosage.1 Literature reports in individuals with congenital mutations in the tropomyosin receptor kinase (Trk) pathway suggest an association between decreased Trk-mediated signaling and obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.1
Pregnancy should be avoided during entrectinib therapy.1 The manufacturer states that a pregnancy test should be performed prior to initiation of entrectinib therapy in women of reproductive potential and states that such women should be advised to use effective contraceptive methods while receiving entrectinib and for at least 5 weeks after the last dose.1 Men who are partners of such women should use effective methods of contraception while receiving entrectinib and for 3 months after the last dose.1 Patients should be apprised of the potential hazard to the fetus if entrectinib is used during pregnancy.1
Entrectinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
It is not known whether entrectinib or its metabolites are distributed into human milk.1 The effects of the drug on nursing infants or on the production of milk are unknown.1 Because of the potential for adverse reactions to entrectinib in nursing infants, women should be advised not to nurse while receiving the drug and for 1 week after the last dose.1
Females and Males of Reproductive Potential
Verify the pregnancy status of females of reproductive potential prior to starting entrectinib therapy.1 Advise female patients of reproductive potential to use effective contraception during treatment and for at least 5 weeks following the last dose.1 Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the last dose.1
Safety and efficacy of entrectinib for the treatment of c-ros oncogene-1 ( ROS-1 )-positive non-small cell lung cancer (NSCLC) have not been established in pediatric patients.1
Safety and efficacy of entrectinib have been established in pediatric patients older than 1 month of age with solid tumors harboring a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion.1 Efficacy of entrectinib in pediatric patients is supported by evidence from adequate and well-controlled studies in adults and pediatric patients with additional population pharmacokinetic data demonstrating that the exposure of drug substance in pediatric patients >1 month of age is expected to be in the adult range, and that the course of disease is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients.1
In clinical trials, 25% of patients receiving entrectinib were 65 years of age or older, while 5% were 75 years of age or older.1 There is insufficient experience in patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of entrectinib are not substantially altered in patients with mild hepatic impairment (total bilirubin concentration 1.5 times or less the upper limit of normal [ULN]).1 Following administration of a single oral dose of entrectinib 100 mg (1/6 of the recommended dose), AUCINF was increased by 39%, 39%, and 23% in patients with mild, moderate, and severe hepatic impairment, respectively, compared to individuals with normal hepatic function.1 The combined AUClast of entrectinib and its M5 metabolite was increased by 16% for the mild, 16% for the moderate, and 4% for the severe hepatic impairment groups compared to the normal hepatic function group.1 Substantial variability in systemic exposure of entrectinib was observed in these hepatic impairment groups.1
The effect of moderate hepatic impairment (total bilirubin > 1.5 - 3 times ULN with any aspartate aminotransferase) or severe hepatic impairment (total bilirubin >3 times ULN with any aspartate aminotransferase) on the safety of entrectinib at the recommended dosage is unknown.1
Consider the risk/benefit profile of entrectinib prior to use in patients with moderate to severe hepatic impairment.1 Monitor for adverse reactions in patients with hepatic impairment more frequently since these patients may be at increased risk for adverse reactions.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of entrectinib are not substantially altered in patients with mild to moderate renal impairment (creatinine clearance of 30 to less than 90 mL/minute).1
The effect of severe renal impairment (creatinine clearance less than 30 mL/minute) on the pharmacokinetics of entrectinib has not been established.1
Adverse effects reported in at least 20% of patients receiving entrectinib include fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia, and vision disorders.1
Entrectinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1, 17
In vitro, entrectinib is not a substrate of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP), but its major active metabolite M5 is a substrate of both P-gp and BCRP.1 Neither entrectinib nor M5 is a substrate of organic anion transport protein (OATP) 1B1 or 1B3.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of entrectinib with moderate or strong inhibitors of CYP isoenzyme 3A may increase systemic exposure to entrectinib and possible toxicity.1 When the strong CYP3A inhibitor itraconazole was administered concomitantly with entrectinib (single 100-mg dose), peak plasma concentration and AUC of entrectinib were increased 1.7- and 6-fold, respectively.1 Simulations using physiologically based pharmacokinetic models suggest that concomitant use of the moderate CYP3A inhibitor erythromycin (500 mg three times daily) and entrectinib (200 mg once daily) may increase steady-state peak plasma concentration and AUC of entrectinib 2.9- and 3.4-fold, respectively.1, 3
In adults and pediatric patients 2 years of age or older , concomitant use of entrectinib with moderate or strong CYP3A inhibitors (e.g., itraconazole, grapefruit juice) should be avoided.1 If concomitant use of a strong CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of entrectinib as noted in Table 4 and limiting coadministration to 14 days or less.1 When concomitant use of the moderate or strong CYP3A inhibitor is discontinued, the entrectinib dosage should be returned (after 3-5 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the moderate or strong CYP3A inhibitor.1
In pediatric patients less than 2 years of age , concomitant use of moderate or strong inhibitors of CYP3A should be avoided.1
Concomitant use of entrectinib with moderate and strong inducers of CYP3A may decrease systemic exposure to entrectinib and reduce entrectinib efficacy.1 When the strong CYP3A inducer rifampin (600 mg once daily for 14 days) was administered concomitantly with entrectinib (single 600-mg dose), peak plasma concentration and AUC of entrectinib were decreased by 56 and 77%, respectively.1, 3 Simulations using physiologically-based pharmacokinetic models suggest that concomitant use of the moderate CYP3A inducer efavirenz (600 mg once daily) and entrectinib (600 mg once daily) may decrease the steady-state peak plasma concentration and AUC of entrectinib by 43 and 56%, respectively.1, 3
Concomitant use of entrectinib with moderate or strong CYP3A inducers should be avoided.1
Drugs Metabolized by Hepatic Microsomal Enzymes
When the sensitive CYP3A substrate midazolam was administered concomitantly with entrectinib (600 mg once daily), peak plasma concentration of midazolam was decreased by 21% and AUC of midazolam was increased by 50%.1
Substrates of P-glycoprotein Transport Systems
When the sensitive P-gp substrate digoxin was administered concomitantly with entrectinib (single 600-mg dose), peak plasma concentration and AUC of digoxin were increased by 28 and 18%, respectively.1
Drugs Affecting Gastric Acidity
When the proton-pump inhibitor lansoprazole was administered concomitantly with entrectinib (single 600-mg capsule dose), peak plasma concentration and AUC of entrectinib were decreased by 23 and 25%, respectively.1 When lansoprazole was concurrently administered with entrectinib (single 600-mg dose as oral suspension in water), peak plasma concentration and AUC of entrectinib increased by 17 and 25%, respectively.1
Drugs that Prolong the QT Interval
Concomitant use of entrectinib with other drugs known to prolong the QT interval should be avoided.1
Entrectinib, a potent inhibitor of multiple receptor tyrosine kinases, including tropomyosin receptor kinases (Trk) A, TrkB, TrkC, c-ros oncogene-1 ( ROS-1 ), and anaplastic lymphoma kinase (ALK), is an antineoplastic agent.1, 4 The Trk family of tyrosine kinases (encoded by the neurotrophic receptor tyrosine kinase genes NTRK1 , NTRK2 , and NTRK3 ) is involved in the initiation of various cascades of intracellular signaling events (i.e., Ras/MAPK/ERK, PI3K/Akt, and PLCγ1/Pkc signal transduction pathways), which leads to cell proliferation, differentiation, apoptosis, and regulation of processes critical to neuron survival in the central and peripheral nervous systems.1, 4, 6, 9, 11 Chromosomal rearrangements of the NTRK1 , NTRK2 , and NTRK3 genes result in fusions with an unrelated gene.6, 9 These NTRK gene fusions encode a constitutively active chimeric Trk oncogenic fusion protein resulting in dysregulation of Trk signaling and subsequent tumorigenesis.4, 6, 9 Similarly, fusion proteins, including ROS-1 or ALK kinase domains, activate tumorigenesis through hyperactivation of downstream signaling pathways.1, 4 In vitro and in vivo, entrectinib has demonstrated inhibition of cancer cell lines derived from multiple tumor types harboring NTRK , ROS-1 , and ALK fusion genes.1 In vitro, entrectinib is 10- to 100-fold more potent than crizotinib in its activity against ROS-1 , and 7- to 8-fold more potent than crizotinib in its activity against ALK.18, 19, 20 Entrectinib also has demonstrated inhibition of Janus kinase 2 (JAK2) and tyrosine kinase nonreceptor 2 (TNK2).1
Based on limited data, clinical resistance to entrectinib has been attributed to secondary point mutations of the NTRK kinase domain (i.e., G595R and G667C point mutations in the TrkA kinase domain; G623R point mutation in the TrkC kinase domain).3, 12, 13, 16, 17
Entrectinib and its active metabolite exhibit linear and time-independent pharmacokinetics over the oral dosage range of 100-400 mg/m2 when coadministered with food.1, 4 Following oral administration of a single 600-mg dose, peak plasma concentration of the drug is achieved in 4-6 hours.1 Entrectinib exposure following a single oral dose (600 mg) of oral pellets did not differ to a clinically significant extent compared to exposure following capsule administration with a light meal (250 calories; 25% fat) in healthy subjects.1 Additionally, exposure following a single oral dose (600 mg) of entrectinib capsules as a suspension with water or milk given through a nasogastric or gastric tube did not differ to a clinically significant extent compared to exposure following capsule administration under fasted conditions in healthy subjects.1 A high-fat, high-calorie meal did not affect the systemic exposure of entrectinib capsules.1 Steady-state concentrations of entrectinib and its active metabolite are achieved within 1 and 2 weeks, respectively, of daily dosing; systemic accumulation of entrectinib and its active metabolite is approximately 2- and 1.6-fold, respectively.1, 3, 4 Entrectinib crosses the blood-brain barrier in preclinical models.3, 17, 18 Entrectinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 to form its major active metabolite, M5, which exhibits similar inhibitory activity for TrkA, TrkB, TrkC, ROS-1 , and ALK to that of the parent drug in vitro.1, 3 Entrectinib and M5 are more than 99% bound to plasma proteins.1 Following oral administration of a single radiolabeled dose of entrectinib, 83% of the dose was recovered in feces (36% as unchanged drug and 22% as M5) and 3% of the dose was recovered in urine.1 The elimination half-lives of entrectinib and M5 are 20 and 40 hours, respectively.1, 4
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web]
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Obtain entrectinib through designated specialty pharmacies and distributors.5
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 100 mg | Genentech | |
200 mg | Rozlytrek® | Genentech | ||
Pellets | 50 mg | Rozlytrek® |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions July 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Genentech USA, Inc. Rozlytrek® (entrectinib) capsules prescribing information. South San Francisco, CA; 2024 Jan.
2. Food and Drug Administration. FDA Application: Search orphan drug designations and approvals. Silver Spring, MD. From FDA web site. [Web]
3. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 212725Orig1s000 and 212726Orig1s000: Multi-discipline review. From FDA website. [Web]
4. Drilon A, Siena S, Ou SI et al. Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov . 2017; 7:400-409. [PubMed 28183697]
5. Genentech. Rozlytrek® Distribution: Genentech BioOncology Access Solutions for Rozlytrek®. From Genentech for US Healthcare Professionals website. Accessed 2024 May 20. [Web]
6. Lange AM, Lo H. Inhibiting TRK Proteins in Clinical Cancer Therapy. Cancers . 2018; 10:1-15.
7. Robinson GW, Gajjar AJ, Gauvain KM. Phase 1/1b trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors. J Clin Oncol . 2019; 37:100009.
8. Drilon A, Siena S, Dziadziuszko R et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol . 2019; [PubMed 31838015]
9. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov . 2015; 5:25-34. [PubMed 25527197]
10. Doebele RC, Drilon A, Paz-Ares L et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol . 2019; [PubMed 31838007]
11. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open . 2016; 1:e000023. [PubMed 27843590]
12. Russo M, Misale S, Wei G et al. Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer. Cancer Discov . 2016; 6:36-44. [PubMed 26546295]
13. Drilon A, Li G, Dogan S et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann Oncol . 2016; 27:920-6. [PubMed 26884591]
14. Hong DS, Bauer TM, Lee JJ et al. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol . 2019; 30:325-31. [PubMed 30624546]
15. Hsiao SJ, Zehir A, Sireci AN et al. Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy. J Mol Diagn . 2019; 21:553-571. [PubMed 31075511]
16. Fuse MJ, Okada K, Oh-Hara T et al. Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged Cancers. Mol Cancer Ther . 2017; 16:2130-2143. [PubMed 28751539]
17. Liu D, Offin M, Harnicar S et al. Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK , ROS1 , and ALK fusion-positive solid tumors. Ther Clin Risk Manag . 2018; 14:1247-1252. [PubMed 30050303]
18. Rolfo C, Ruiz R, Giovannetti E et al. Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert Opin Investig Drugs . 2015; 24:1493-500. [PubMed 26457764]
19. Pacenta HL, Macy ME. Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma. Drug Des Devel Ther . 2018; 12:3549-3561. [PubMed 30425456]
20. Ardini E, Menichincheri M, Banfi P et al. Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther . 2016; 15:628-39. [PubMed 26939704]