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Entrectinib

Entrectinib, sold under the brand name Rozlytrek, is an oral, centrally active tyrosine kinase inhibitor approved for the treatment of solid tumors harboring neurotrophic tyrosine receptor kinase (NTRK) gene fusions and ROS1-positive non-small cell lung cancer (NSCLC).^[1]^[2] It selectively targets the proteins encoded by NTRK1, NTRK2, NTRK3 (collectively TRK), ROS1, and anaplastic lymphoma kinase (ALK), thereby inhibiting tumor growth driven by these oncogenic fusions or mutations.^[2]^[3] Developed by Ignyta (acquired by Roche in 2018), entrectinib received accelerated FDA approval on August 15, 2019, under the agency's breakthrough therapy, priority review, and orphan drug designations, marking it as the second TRK inhibitor approved for tumor-agnostic use based on genetic alterations rather than tumor histology. On October 20, 2023, the FDA expanded the NTRK indication to pediatric patients 1 month of age and older and approved an oral pellet formulation.^[1]^[2]^[4] The approval was supported by data from integrated analyses of phase 1 (ALKA) and phase 2 (STARTRK-2) trials, demonstrating an objective response rate (ORR) of 57% in NTRK fusion-positive solid tumors (with 68% of responses lasting at least 6 months) and 78% in ROS1-positive NSCLC (with 55% lasting at least 12 months).^[1]^[3] It is indicated for adults and pediatric patients 1 month of age and older with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are either metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following prior systemic therapy or for which there are no satisfactory alternative treatments or clinical trials, as well as for adults with ROS1-positive metastatic NSCLC; continued approval for the NTRK indication is contingent on confirmatory trials.^[1]^[2]^[5] The recommended dosage is 600 mg orally once daily for adults, with pediatric dosing based on body surface area (250 mg/m² once daily for ages 1 month to 6 months; BSA-tiered doses from 300 mg/m² to 600 mg for those older than 6 months), available as capsules or oral pellets, and the drug is metabolized primarily by CYP3A4, necessitating dose modifications with strong CYP3A inhibitors or inducers.^[1]^[2]^[5] Common adverse effects include fatigue, constipation, dysgeusia, edema, diarrhea, dizziness, nausea, and elevated liver enzymes, while serious risks encompass congestive heart failure, central nervous system effects (e.g., cognitive impairment), bone fractures, hepatotoxicity, hyperuricemia, QT interval prolongation, and vision disorders.^[1]^[2] Entrectinib's ability to penetrate the blood-brain barrier makes it particularly valuable for patients with central nervous system metastases, addressing a key unmet need in these rare, fusion-driven cancers.^[3]^[2]

Indications and Usage

Approved Indications

Entrectinib, marketed as Rozlytrek, received accelerated approval from the U.S. Food and Drug Administration (FDA) in August 2019 for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive, as detected by an FDA-approved test.^[5] This approval marked entrectinib as the second targeted therapy for ROS1-positive NSCLC following crizotinib.^[1] The drug also holds FDA approval for adult and pediatric patients older than 1 month with unresectable or metastatic solid tumors harboring NTRK gene fusions without known acquired resistance mutations, where the tumors have progressed following prior treatment or no satisfactory alternative therapies exist, as confirmed by an FDA-approved test.^[5] This NTRK indication represents a tumor-agnostic approval, the third such FDA designation after pembrolizumab for microsatellite instability-high cancers and larotrectinib for NTRK fusions, emphasizing genetic alterations over tumor histology.^[1] The pediatric expansion to patients older than 1 month for NTRK fusion-positive solid tumors was granted in October 2023 under accelerated approval, based on response rates and durability of response.^[4] In the European Union, the European Medicines Agency (EMA) approved entrectinib in 2020 for adult patients with advanced ROS1-positive NSCLC not previously treated with a ROS1 inhibitor.^[6] It is also indicated as monotherapy for adult and pediatric patients older than 1 month with solid tumors featuring NTRK gene fusions without satisfactory prior treatments, detected via validated tests.^[6] Use of entrectinib requires molecular testing of tumor or plasma specimens to confirm ROS1 or NTRK gene fusions prior to initiation.^[5] The drug should be avoided in patients with congenital long QT syndrome due to the risk of QT interval prolongation.^[6]

Dosage and Administration

Entrectinib is administered orally at a recommended dose of 600 mg once daily in adults with ROS1-positive non-small cell lung cancer or NTRK gene fusion-positive solid tumors, continued until disease progression or unacceptable toxicity.^[5] This dose may be taken with or without food.^[5] For pediatric patients older than 1 month with NTRK gene fusion-positive solid tumors, dosing is based on body surface area (BSA) and age.^[5] In patients aged 6 months to 12 years, the recommended doses are: 300 mg/m² once daily for BSA ≤ 0.50 m²; 200 mg once daily for BSA 0.51–0.80 m²; 300 mg once daily for BSA 0.81–1.10 m²; 400 mg once daily for BSA 1.11–1.50 m²; and 600 mg once daily for BSA ≥ 1.51 m².^[5] For patients aged 1 month to 6 months, the dose is 250 mg/m² once daily.^[5] In October 2023, the FDA approved an oral pellet formulation (50 mg per packet) to facilitate administration in infants and young children unable to swallow capsules, which can be sprinkled on soft foods or administered via enteral tubes.^[4] Capsules (100 mg or 200 mg) should be swallowed whole or prepared as a suspension if needed, but pellets must not be used for enteral tube administration.^[5] Dose modifications are required for adverse reactions, with reductions from 600 mg to 400 mg or 200 mg for grade 2 or 3 toxicities, and further to 100 mg if necessary; permanent discontinuation is recommended if toxicity persists after two dose reductions.^[5] Specific guidelines include withholding for grade 3 or 4 hepatotoxicity and resuming at the same or reduced dose upon resolution within 4 weeks, or discontinuing if unresolved; withholding for QTc prolongation >500 ms and resuming after correction; and withholding for intolerable CNS effects or vision disorders, resuming at the same or reduced dose after improvement.^[5] Monitoring includes baseline and periodic assessments of left ventricular ejection fraction (LVEF), serum uric acid, QT interval, electrolytes, and liver function tests (ALT/AST every 2 weeks for the first month, then monthly).^[5] Ophthalmologic examinations are recommended for patients reporting vision changes.^[5] In special populations, no dose adjustment is needed for mild to moderate renal impairment (CrCl ≥30 mL/min), but caution is advised for severe renal impairment due to limited data.^[5] For moderate hepatic impairment, the risk-benefit should be considered with close monitoring; data are insufficient for severe hepatic impairment.^[5] Concomitant use of strong CYP3A inhibitors requires dose reduction to 200 mg once daily in adults (avoid in pediatrics under 2 years); moderate CYP3A inhibitors necessitate reduction to 400 mg once daily.^[5] Strong or moderate CYP3A inducers should be avoided.^[5] Drugs that prolong the QT interval should also be avoided.^[5]

Pharmacology

Mechanism of Action

Entrectinib is a potent, ATP-competitive inhibitor of the tropomyosin receptor kinases (TRK) encoded by NTRK1, NTRK2, and NTRK3 (TRKA, TRKB, and TRKC, respectively), as well as ROS1 and ALK tyrosine kinases, with IC₅₀ values in the range of 0.1–2 nM for these primary targets.^[7] This inhibition occurs through binding to the kinase domains of both wild-type and fusion variant proteins, such as ETV6-NTRK3 and CD74-ROS1, preventing their autophosphorylation and constitutive activation.^[8] By blocking these oncogenic drivers, entrectinib disrupts downstream signaling cascades, including the MAPK/ERK and PI3K/AKT pathways, which are critical for tumor cell survival and proliferation, ultimately leading to apoptosis in fusion-positive cancer cells.^[8] A key feature of entrectinib's molecular pharmacology is its ability to penetrate the central nervous system effectively, facilitated by low affinity for efflux transporters such as P-glycoprotein at the blood-brain barrier.^[9] This property enables sustained therapeutic concentrations in the brain, addressing the challenge of treating intracranial metastases in patients with TRK, ROS1, or ALK fusion-driven tumors.^[7] Entrectinib exhibits high selectivity for its intended targets, with IC₅₀ values exceeding 1 μM against unrelated kinases like FGFR1 and VEGFR2, resulting in minimal off-target effects relative to broader-spectrum inhibitors such as earlier multi-kinase agents.^[8] This profile contributes to its efficacy across various fusion-driven solid tumors while limiting interference with normal cellular processes.^[10]

Pharmacokinetics

Entrectinib is rapidly absorbed following oral administration, with a time to maximum plasma concentration (T_max) of 4 to 6 hours after a 600 mg dose.^[5] Its absolute bioavailability is approximately 66%, and the pharmacokinetics are linear over the therapeutic dose range without time-dependent changes.^[11] Administration with a high-fat meal results in an approximately 15% increase in AUC and 6% in C_max, which is not considered clinically significant.^[12] The volume of distribution at steady state for entrectinib is large, approximately 551 L, indicating extensive distribution into tissues.^[5] It is highly bound to plasma proteins (>99%), primarily albumin and alpha-1-acid glycoprotein.^[5] Entrectinib demonstrates good penetration into the central nervous system, with animal studies showing brain-to-plasma ratios of 0.4 to 2.2 at steady state, supporting its activity against intracranial metastases.^[11] Entrectinib undergoes extensive hepatic metabolism, primarily via cytochrome P450 3A4 (CYP3A4), which accounts for about 76% of its biotransformation, along with minor contributions from other CYP enzymes such as CYP2C9, CYP1A2, CYP2C19, and UGT1A1.^[5] The major circulating metabolite is M5, formed through N-demethylation, which is pharmacologically active and contributes approximately 40% to the total exposure of entrectinib plus M5 at steady state.^[5] Elimination of entrectinib occurs mainly through feces, with 83% of the dose recovered unchanged or as metabolites and only 3% in urine.^[5] The terminal half-life is approximately 20 hours for entrectinib and 40 hours for M5, with steady-state concentrations achieved within 3 to 7 days of daily dosing and minimal accumulation thereafter.^[5] The apparent oral clearance is 19.6 L/h for entrectinib.^[5] Drug interactions involving CYP3A modulators significantly affect entrectinib exposure. Strong CYP3A inhibitors, such as ketoconazole or itraconazole, can increase AUC by up to 6-fold, necessitating dose reduction, while moderate inhibitors like fluconazole increase it by about 3-fold.^[5] Conversely, strong CYP3A inducers, such as rifampin, decrease AUC by approximately 77%, and coadministration should be avoided.^[5]

Adverse Effects

Common Side Effects

The most common adverse reactions to entrectinib, occurring in more than 20% of patients across integrated safety data from clinical trials involving approximately 355 adults, include fatigue (48%), constipation (46%), dysgeusia (altered taste; 44%), peripheral edema (40%), dizziness (38%), nausea (34%), and vomiting (24%).^[5] These effects are generally mild to moderate (Grade 1-2), with Grade 3 or higher incidences ranging from 0.3% to 5% for most, and they were observed in trials such as ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG.^[5] Management of these common side effects typically involves supportive care measures, such as antiemetics for nausea and vomiting, laxatives for constipation, and hydration or diuretics for peripheral edema, with most resolving upon dose interruption or reduction.^[5] Dose modifications were required in about 3-4% of cases for fatigue, dizziness, and nausea, emphasizing the drug's overall tolerability when effects are monitored proactively.^[5] In pediatric patients (n=76), the profile remains similar but with somewhat lower incidences for some effects, such as fatigue (30%) and constipation (41%), alongside higher rates of vomiting (38%); patients should be monitored for cumulative impacts like weight gain from edema.^[5]

Serious Adverse Effects

Entrectinib is associated with several serious adverse effects, primarily due to its potent inhibition of tropomyosin receptor kinases (TRK) and its ability to penetrate the central nervous system (CNS). CNS effects, such as confusion, hallucinations, cognitive impairment, and mood disorders, occur in up to 27% of patients overall, with severe manifestations like delirium or hallucinations reported in approximately 5-10% of cases; these are linked to the drug's high brain penetration and necessitate monitoring for symptoms including dizziness or sleep disturbances, which may precede more severe events.^[5]^[13] Hepatotoxicity is another key risk, with elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) observed in 36% and 42% of patients, respectively, including grade 3-4 events in 2.5-2.8%; regular liver function tests are recommended every two weeks initially, then monthly, with dose interruption or discontinuation for severe cases.^[5] QT interval prolongation affects 3.1% of patients (with changes >60 ms from baseline), carrying a risk of torsades de pointes, particularly in those with electrolyte imbalances or concomitant QT-prolonging drugs; baseline and periodic ECG monitoring is advised.^[5] Interstitial lung disease occurs rarely, in 1-2% of patients, often presenting as pneumonitis, and requires immediate evaluation for respiratory symptoms with potential drug discontinuation.^[14] Skeletal fractures represent a notable on-target effect from TRK inhibition, occurring in 5% of adults and up to 25% of pediatric patients, possibly through induction of osteoclastogenesis; patients should be assessed for bone health, and fractures warrant prompt orthopedic evaluation.^[5]^[15] Cardiac toxicity includes congestive heart failure in 3.4% of patients (2.3% grade 3), with left ventricular ejection fraction (LVEF) decreases >10% from baseline; a baseline echocardiogram is required, followed by monitoring every 3 months during treatment.^[5] Other serious risks encompass hyperglycemia in approximately 10% of patients (3.8% grade 3-4), necessitating glucose monitoring in at-risk individuals, and vision changes in 21% (0.8% grade 3), including potential retinopathy that may require ophthalmologic assessment if severe.^[5]^[16] Entrectinib can cause fetal harm based on animal studies showing malformations at exposures similar to human levels, and effective contraception is required for females of reproductive potential during treatment and for 5 weeks after, and for males for 3 months after.^[5] Post-marketing real-world data from a 2024 Japanese study in patients with ROS1 fusion-positive non-small cell lung cancer reported adverse event rates consistent with clinical trials, including CNS effects in 28.6% and hepatotoxicity in similar proportions, underscoring the need for vigilant monitoring.^[14] Recent 2025 updates on pediatric use from integrated trial analyses confirm overall tolerability in children with NTRK or ROS1 fusion-positive tumors, though with higher fracture incidence, supporting its application in this population with appropriate precautions.^[17]

Development and Approval

Preclinical and Early Development

Entrectinib, initially designated as RXDX-101 and previously known as NMS-E628 or NMS-01191372, was discovered through high-throughput screening of kinase-targeted compound libraries at Nerviano Medical Sciences, followed by medicinal chemistry optimization of a 3-amino-5-substituted-indazole scaffold to enhance potency and selectivity against TRK, ROS1, and ALK kinases.^[8] The compound was first synthesized as detailed in a 2009 patent application by Nerviano Medical Sciences and licensed exclusively to Ignyta in November 2013 for global development and commercialization.^[18]^[19] In preclinical studies, entrectinib demonstrated potent inhibition of wild-type and fusion variants of its target kinases in vitro, with IC₅₀ values ranging from 1 nmol/L for TRKA to 12 nmol/L for ALK.^[8] It induced G1 cell cycle arrest and apoptosis in fusion-driven cell lines, such as KM12 colorectal cancer cells harboring TPM3-TRKA (IC₅₀ 17 nmol/L) and NCI-H2228 non-small cell lung cancer cells with EML4-ALK (IC₅₀ 68 nmol/L).^[8] In vivo, oral administration led to significant antitumor activity in patient-derived and engineered xenograft models of NTRK-, ROS1-, and ALK-driven cancers; for example, in KM12 TRKA-fusion xenografts, doses of 15–60 mg/kg twice daily resulted in marked tumor regression (P < 0.0001), while 60 mg/kg twice daily achieved complete regressions in Ba/F3 TEL-ROS1 and NCI-H2228 EML4-ALK models, with 3 of 7 mice remaining tumor-free at day 97 in the latter (P < 0.0001).^[8] Entrectinib also penetrated the blood-brain barrier effectively, controlling intracranial tumor growth and prolonging survival in orthotopic NCI-H2228 models at 120 mg/kg twice daily.^[8] The first-in-human phase I trial, ALKA-372-001, was initiated in October 2012 as an open-label, multicenter dose-escalation study in adults with advanced or metastatic solid tumors, enrolling 54 patients across three dosing schedules to evaluate safety, tolerability, and preliminary antitumor activity.^[20] Using a standard 3+3 design, doses escalated from 100 mg/m² to 1600 mg/m² (later converted to flat dosing of 600–800 mg once daily), establishing 600 mg once daily under fed conditions as the maximum tolerated dose due to dose-limiting toxicities like elevated liver enzymes at higher levels.^[20] Early efficacy signals were promising, with an objective response rate of 100% (3 of 3 patients with measurable disease) observed in those with NTRK fusion-positive tumors, including cases of non-small cell lung cancer, mammary analogue secretory carcinoma, and colorectal cancer.^[20] The basket trial design for subsequent development was rationalized by the rarity of NTRK, ROS1, and ALK gene fusions, which occur at low frequencies (typically <1–5%) across diverse solid tumor types, necessitating enrollment across histologies to efficiently identify and treat responsive patients.^[20]

Clinical Trials

Entrectinib's clinical development has primarily relied on basket trials targeting rare fusion-positive tumors, with the pivotal STARTRK-2 phase II study (NCT02568267, initiated in 2015 and ongoing) evaluating its efficacy in adults with NTRK fusion-positive solid tumors and ROS1 fusion-positive non-small cell lung cancer (NSCLC). This multicenter, open-label basket trial enrolled 114 patients with NTRK fusion-positive tumors and 51 with ROS1 fusion-positive NSCLC, demonstrating an objective response rate (ORR) of 57.4% in the NTRK cohort and 77.4% in the ROS1 cohort, as assessed by blinded independent central review. Median progression-free survival (PFS) was 13.8 months for NTRK-positive patients and 19 months for ROS1-positive patients, highlighting durable responses in these molecularly defined populations.^[21]30690-4/fulltext) Integrated analyses across three phase I/II trials—STARTRK-1 (NCT02097810), STARTRK-2 (NCT02568267), and ALKA-372-001 (EudraCT 2012-000148-88)—supported the 2023 expansion of entrectinib's pediatric approval for patients over 1 month of age with NTRK fusion-positive solid tumors. These pooled data from 121 NTRK fusion-positive patients showed an updated ORR of 61.2% and median PFS of 13.8 months, with particular intracranial activity in 11 patients with measurable central nervous system (CNS) metastases, yielding a CNS ORR of 63.6%. In pediatric subsets, entrectinib induced rapid responses, contributing to regulatory endorsements based on tumor response durability.^[21]^[22] Recent real-world evidence and updates as of 2025 further affirm entrectinib's role. A post-marketing surveillance study in Japan (data collected 2020–2021, published 2025) involving 260 patients with ROS1 fusion-positive advanced NSCLC reported an overall ORR of 38.8%, with a notably higher 70.8% ORR in the 48 first-line patients, aligning with trial outcomes in this setting. At the 2025 American Society of Clinical Oncology (ASCO) meeting, updated pediatric data from integrated trials (including STARTRK-NG NCT02650401 and TAPISTRY NCT04589845) in 26 children with ROS1 fusion-positive extracranial solid or primary CNS tumors showed an ORR of 69.2%, with common adverse events like weight gain (37.2%) and anemia (36.3%) but no new safety signals. Ongoing studies, such as the phase I/II trial NCT02650401 evaluating entrectinib in pediatric relapsed or refractory solid tumors including infant brain tumors, continue to explore its utility in younger populations.^[23]^[17]^[24] Entrectinib's approvals, including the pediatric expansion, were granted under the U.S. Food and Drug Administration's accelerated approval pathway, relying on ORR and response duration as surrogate endpoints from these trials. Continued approval remains contingent on confirmatory trials verifying overall survival benefits, with ongoing efforts to address this requirement in fusion-positive malignancies.^[4]

Regulatory Approvals and History

Entrectinib received orphan drug designation from the U.S. Food and Drug Administration (FDA) in 2012 for the treatment of neuroblastoma.^[25] In 2015, it was granted orphan drug designation by the European Medicines Agency (EMA) for the same indication.^[26] That same year, the FDA awarded entrectinib Breakthrough Therapy designation for the treatment of ROS1-positive non-small cell lung cancer (NSCLC).^[27] In December 2017, Roche acquired Ignyta, the developer of entrectinib, for $1.7 billion in cash, which expedited the drug's global development and regulatory submissions.^[28] This acquisition integrated entrectinib into Roche's oncology portfolio, facilitating faster progression through late-stage trials and approval processes. The FDA granted accelerated approval to entrectinib (Rozlytrek) on August 15, 2019, for adult patients with solid tumors harboring NTRK gene fusions without a satisfactory prior treatment or metastatic ROS1-positive NSCLC.^[1] In May 2020, the Therapeutic Goods Administration (TGA) in Australia approved entrectinib for adults with advanced ROS1-positive NSCLC.^[29] The EMA followed with conditional marketing authorization on July 31, 2020, for adults and pediatric patients aged 12 years and older with NTRK fusion-positive solid tumors or ROS1-positive NSCLC.^[30] Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) approved entrectinib in January 2021 for similar indications in adults.^[31] On October 20, 2023, the FDA expanded accelerated approval to include pediatric patients over 1 month of age with NTRK fusion-positive solid tumors and approved a new oral pellet formulation to improve administration in young children.^[4] In 2024, the EMA extended entrectinib's authorization for additional pediatric uses in NTRK fusion-positive tumors, now including patients from 1 month of age.^[30] On November 17, 2025, China's National Medical Products Administration (NMPA) approved PanTRKare, an NGS-based companion diagnostic assay for detecting NTRK1/2/3 gene fusions to identify patients eligible for entrectinib treatment in solid tumors.^[32] As of November 2025, entrectinib has no major withdrawals, black-box warnings, or significant label restrictions beyond standard monitoring for adverse events.^[33]

Society and Culture

Legal Status

In the United States, entrectinib (marketed as Rozlytrek) is approved by the Food and Drug Administration (FDA) under accelerated approval for the treatment of adult and pediatric patients 1 month of age and older with solid tumors harboring NTRK gene fusions that are unresectable or metastatic, as well as for adults with ROS1-positive metastatic non-small cell lung cancer (NSCLC).^[4] It is not classified as a controlled substance and is available only by prescription.^[34] Although no Risk Evaluation and Mitigation Strategy (REMS) program is required, the prescribing information recommends electrocardiogram (ECG) monitoring for QT interval prolongation, particularly in patients with risk factors such as congenital long QT syndrome or concomitant use of QT-prolonging drugs. Entrectinib has received orphan drug designation in the US, which provides incentives such as market exclusivity to support development for rare diseases, including NTRK fusion-positive solid tumors.^[25] In the European Union, entrectinib (Rozlytrek) holds a conditional marketing authorization from the European Medicines Agency (EMA), centrally authorizing its use across member states for adult and pediatric patients 1 month of age and older with solid tumors expressing NTRK gene fusions that are unresectable or metastatic and for whom no satisfactory alternative treatments exist, as well as for adults with ROS1-positive advanced NSCLC not previously treated with a ROS1 inhibitor.^[30] Initial authorization limited pediatric use to those 12 years and older, but this was expanded based on efficacy data from pediatric studies showing response rates of approximately 73% in children with NTRK fusion-positive tumors.^[11] The conditional status requires ongoing submission of confirmatory data from studies evaluating long-term effectiveness and safety, with the next EMA review influencing product information scheduled for March 2025; no broader changes to authorization are anticipated as of late 2025, though assessments continue for expanded use in pediatric refractory solid tumors.^[30] Orphan drug status and PRIME designation in the EU further facilitate access and reimbursement for these rare indications.^[35] Entrectinib is approved in other regions, including Canada (authorized February 2020 for NTRK fusion-positive solid tumors), Japan (approved June 2019 for NTRK fusion-positive tumors, with subsequent focus on ROS1-positive NSCLC), and Australia (authorized May 2020 for ROS1-positive advanced NSCLC and NTRK fusion-positive solid tumors).^[36]^[37]^[38] However, availability remains limited in low-resource countries due to the necessity of companion diagnostic testing for NTRK or ROS1 fusions, such as the FDA-approved FoundationOne CDx assay, which identifies eligible patients but requires specialized laboratory infrastructure often unavailable in such settings.^[39] The orphan status in approving regions supports reimbursement efforts, improving access for patients with these rare genetic alterations.^[25]

Commercial Aspects

Rozlytrek (entrectinib) is marketed by Genentech, a member of the Roche Group, following Roche's $1.7 billion acquisition of Ignyta in 2018, which highlighted the drug's potential in treating rare cancers driven by NTRK gene fusions and ROS1 alterations.^[40] In the United States, the wholesale acquisition cost for Rozlytrek at the standard 600 mg daily dose is approximately $20,600 per month based on 90 capsules of 200 mg strength, reflecting premium pricing typical for targeted therapies in oncology.^[41] To address affordability, Genentech offers patient assistance through ROZLYTREK Access Solutions, including co-pay programs for commercially insured patients and the Genentech Patient Foundation for uninsured or underinsured individuals meeting financial criteria.^[42] Rozlytrek benefits from orphan drug exclusivity in the US, providing market protection until August 15, 2026, for adult and pediatric patients aged 12 years and older with NTRK fusion-positive solid tumors, and until October 20, 2030, for pediatric patients under 12 years with the same indication.^[25] Global sales reached 147 million Swiss francs (approximately $163 million USD) in 2023, with growth anticipated following the 2023 pediatric approval expanding access to younger patients and an oral pellet formulation.^[43] Key competitors include larotrectinib (Vitrakvi by Bayer/Loxo Oncology), another TRK inhibitor approved for similar NTRK-driven tumors, though Rozlytrek offers advantages in ROS1-positive non-small cell lung cancer.^[44] Manufacturing of Rozlytrek is handled by Genentech facilities under Roche oversight, with the drug product produced as hypromellose capsules and, since 2023, oral pellets for pediatric use.^[45] As of 2025, no supply chain disruptions or shortages have been reported, supporting stable availability for patients. The economics of Rozlytrek's development underscore the high-risk, high-reward nature of rare cancer therapies, where the $1.7 billion acquisition cost is offset by orphan status, regulatory incentives, and sustained revenue from premium pricing in a niche market projected to expand with broader indications.^[28]

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entrectinib. Trade Name: Rozlytrek. Marketing Approval Date: 08/15/2019 ... U.S. Food and Drug Administration. 10903 New Hampshire Avenue Silver Spring ...Missing: EU | Show results with:EU
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EU/3/15/1580 - orphan designation for treatment of neuroblastoma
Jan 6, 2016 · This medicine is now known as entrectinib. Please note that this product was withdrawn from the Community Register of designated Orphan ...Missing: drug | Show results with:drug
[26]
Rozlytrek (entrectinib) FDA Approval History - Drugs.com
Oct 25, 2023 · Rozlytrek (entrectinib) is a selective tyrosine kinase inhibitor for the treatment of patients with ROS1-positive, metastatic non-small cell lung cancer.
[27]
Roche and Ignyta reach definitive merger agreement
They have entered into a definitive merger agreement for Roche to fully acquire Ignyta at a price of US$ 27.00 per share in an all-cash transaction.
[28]
Rozlytrek | Therapeutic Goods Administration (TGA)
Rozlytrek is indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) whose tumours are ROS1-positive.
[29]
Rozlytrek | European Medicines Agency (EMA)
Rozlytrek as monotherapy is indicated for the treatment of adult patients with ROS1 positive, advanced non small cell lung cancer (NSCLC) not previously treated ...
[30]
Review Reports: Drugs - PMDA
The review reports were selected for translation among those of drugs with a new active ingredient that recently received marketing approval.
[31]
[PDF] 1 This label may not be the latest approved by FDA. For current ...
Oct 10, 2023 · Entrectinib exposure following a single oral dose (600 mg) of ROZLYTREK oral pellets was not clinically significant compared to ROZLYTREK ...
[32]
https://www.onclive.com/view/pantrkare-approved-in-china-as-companion-diagnostic-for-entrectinib-in-ntrk-solid-tumors
[33]
Japan becomes the first country to approve Roche's personalised ...
Jun 17, 2019 · Roche today announced that Japan's Ministry of Health, Labour and Welfare (MHLW) has approved Rozlytrek® (entrectinib) for the treatment of ...Missing: date | Show results with:date
[34]
Summary Basis of Decision for Rozlytrek
Hoffmann-La Roche Ltd. New Drug Submission Control Number: 227517. On February 10, 2020, Health Canada issued a Notice of Compliance under the Notice of ...
[35]
[PDF] Report on the Deliberation Results June 3, 2019 Pharmaceutical ...
Jun 3, 2019 · In tumors at 4 hours post-dose, entrectinib at either dose level inhibited the phosphorylation of TRKC, PLC-γ, ERK1/2, and STAT3. 3.1.3.
[36]
[PDF] AusPAR - ROZLYTREK - entrectinib - Roche Products Pty Ltd - PM
Dec 11, 2020 · Vision disorders. Vision changes were reported in 21% of patients treated with Rozlytrek in clinical trials (see section 4.8 Adverse effects ...
[37]
FoundationOne®Liquid CDx Receives FDA Approval as a ...
Jan 5, 2023 · FoundationOne Liquid CDx is the first and only blood-based companion diagnostic approved for Rozlytrek (entrectinib).Missing: issues orphan
[38]
Rozlytrek Prices, Coupons, Copay Cards & Patient Assistance
Compare Rozlytrek prices, print discount coupons, find manufacturer promotions, copay cards and patient assistance programs.Missing: 2024 | Show results with:2024
[39]
Explore ROZLYTREK Financial Assistance Programs
For eligible patients with commercial or public health insurance, ROZLYTREK Access Solutions offers referrals to independent co-pay assistance foundations.
[40]
[PDF] appendix-tables-fy-2023.pdf - Roche
Dec 31, 2023 · Quarterly sales and constant exchange rate sales growth by Division in 2023 and 2022 ... Rozlytrek. 86. 25. 45. 2. 16. 36. 8. 27. 17. 147.
[41]
Rozlytrek vs. Vitrakvi: How Do These Cancer Drugs Compare?
Roche's Rozlytrek (entrectinib) has been priced at about half the cost of its competitor, Vitrakvi (larotrectinib), according to reports.
[42]
[PDF] Product Quality Review(s) - accessdata.fda.gov
Oct 15, 2017 · ➢ MANUFACTURING SITES FOR THE PROPOSED DRUG PRODUCT: is identified as the manufacturing site for the commercial F06 hypromellose capsule product ...