Comprehensive Clinical and Scientific Monograph: Repotrectinib (AUGTYRO®)

Introduction and Overview

Repotrectinib, marketed under the brand name AUGTYRO®, represents a significant advancement in the field of precision oncology. It is a potent, orally bioavailable, small-molecule therapeutic belonging to the class of tyrosine kinase inhibitors (TKIs).[1] As a next-generation agent, Repotrectinib was specifically engineered to target key oncogenic drivers of cancer cell growth and proliferation, including the proto-oncogene tyrosine-protein kinase ROS1, the family of Tropomyosin Receptor Kinases (TRKA, TRKB, and TRKC), and Anaplastic Lymphoma Kinase (ALK).[1] Its development and subsequent approval address critical unmet medical needs in patient populations whose tumors are driven by these specific genetic alterations.

The primary clinical value of Repotrectinib stems from its rational design, which was conceived to overcome the challenge of acquired resistance—a near-universal limitation of earlier-generation TKIs. Many patients treated with first-generation inhibitors, such as crizotinib for ROS1-rearranged non-small cell lung cancer (NSCLC), eventually experience disease progression due to the emergence of secondary mutations within the kinase domain of the target protein. A predominant mechanism of such resistance is the solvent-front mutation, exemplified by the ROS1 G2032R substitution, which accounts for up to 60% of crizotinib-resistant cases.[1] The development of Repotrectinib was not merely an incremental improvement over existing therapies but a direct and strategic response to this known mechanism of clinical failure. This "resistance-first" approach to drug design signifies a paradigm shift, where the molecular basis of treatment failure informs the foundational chemistry of the next therapeutic agent.

This strategic design is embodied in Repotrectinib's novel and compact azamacrocyclic chemical structure.[1] This three-dimensional architecture confers a conformational rigidity that allows the molecule to effectively bind to the ATP-binding pocket of the target kinase, even in the presence of bulky resistance mutations that sterically hinder larger, more flexible inhibitors.[1] This structural feature is fundamental to its potent activity against both wild-type and a wide array of mutant kinases, enabling durable clinical responses where previous therapies have failed.

Reflecting its significant clinical efficacy, Repotrectinib has secured landmark approvals from major global regulatory bodies. The U.S. Food and Drug Administration (FDA) first approved it for the treatment of adults with locally advanced or metastatic ROS1-positive NSCLC. This was followed by an expanded, tumor-agnostic approval for adult and pediatric patients aged 12 and older with solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion.[1] This dual utility highlights its importance in both a specific, biomarker-defined cancer type and a broader, histology-independent context. This report provides an exhaustive analysis of Repotrectinib, detailing its physicochemical properties, its complex pharmacological profile, the pivotal clinical trial data supporting its efficacy and safety, and its global regulatory journey, thereby contextualizing its established role in the modern armamentarium of targeted cancer therapies.

Physicochemical Properties and Formulation

A comprehensive understanding of Repotrectinib begins with its fundamental chemical and physical characteristics, which are essential for its identification, manufacturing, and formulation into a clinically effective oral therapeutic.

Chemical Identity

Repotrectinib is a synthetic organic compound classified as an azamacrocycle and a pyrazolopyrimidine derivative.[1] Its identity is defined by a consistent set of names and development codes used across scientific literature, clinical trials, and regulatory filings.

• International Non-proprietary Name (INN): Repotrectinib [1]
• Brand Name: AUGTYRO® [3]
• Developmental Codes: TPX-0005, BMS-986472 [1]
• Chemical Class: Tyrosine Kinase Inhibitor, Azamacrocycle [1]

Structural and Formulaic Data

The molecular structure of Repotrectinib is the basis for its unique mechanism of action and pharmacological properties. Its compact and rigid macrocyclic scaffold is a key feature of its design.

• Molecular Formula: C18​H18​FN5​O2​ [1]
• Molecular Weight: 355.373 g·mol−1 [3]
• CAS Number: 1802220-02-5 [3]
• DrugBank ID: DB16826 [1]

The molecule's properties, particularly its lack of rotatable bonds, reflect a highly constrained and optimized structure. This rigidity is a deliberate design feature, not an incidental property. The azamacrocyclic framework inherently limits conformational flexibility, which is confirmed by computational analyses showing zero rotatable bonds.[10] This structural constraint reduces the entropic penalty associated with binding to its target kinase, a factor that can contribute to higher binding affinity and, consequently, greater potency. Furthermore, this rigidity ensures the molecule maintains a precise three-dimensional shape, enabling it to fit within the ATP-binding pocket of the kinase while avoiding steric clashes with bulky amino acid residues that arise from resistance mutations. This sophisticated level of medicinal chemistry, where a physical property like rigidity is intentionally engineered to achieve a specific biological outcome—potency against resistant mutants—serves as an exemplar of modern, rational drug design.

The following table consolidates the key chemical identifiers and computed properties for Repotrectinib.

Property	Value	Source(s)
IUPAC Name	(3R,11S)-6-fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one	1
Brand Name	Augtyro®	3
Molecular Formula	C18​H18​FN5​O2​	1
Molecular Weight	355.373 g·mol−1	3
CAS Number	1802220-02-5	3
DrugBank ID	DB16826	1
SMILES	C[C@H]1CNC(=O)C2=C3N=C(C=CN3N=C2)NC@@HC
InChIKey	FIKPXCOQUIZNHB-WDEREUQCSA-N
XLogP	3.08
Hydrogen Bond Donors	2
Hydrogen Bond Acceptors	5
Rotatable Bonds	0

Pharmaceutical Formulation

Repotrectinib is formulated for oral administration, providing a convenient outpatient treatment option.

• Dosage Forms and Strengths: It is available as immediate-release hard-shell capsules in two strengths: 40 mg and 160 mg.
• Appearance: The capsules are distinct in appearance to prevent dosing errors. The 40 mg capsule is a white, opaque capsule imprinted with “REP 40” in blue ink. The 160 mg capsule is a blue, opaque capsule imprinted with “REP 160” in white ink.
• Excipients (Inactive Ingredients): The capsule contents include microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium. The capsule shell is composed of gelatin and titanium dioxide, with the 160 mg shell also containing brilliant blue dye. The printing ink contains shellac and food-grade dyes.

Clinical Pharmacology

The clinical utility of Repotrectinib is a direct result of its carefully engineered pharmacological profile, encompassing its potent mechanism of action, its predictable pharmacodynamic effects, and its well-characterized pharmacokinetic behavior in humans.

Mechanism of Action

Repotrectinib functions as a multi-targeted, ATP-competitive inhibitor of several key receptor tyrosine kinases that act as oncogenic drivers in various cancers. Its primary targets are ROS1, the TRK family (TRKA, TRKB, TRKC), and ALK. By binding to the ATP-binding site within the catalytic domain of these kinases, Repotrectinib blocks the phosphorylation of tyrosine residues, a critical step in kinase activation. This inhibition effectively halts the aberrant, constitutive signaling that drives tumor cell proliferation, survival, and migration. The downstream effects include the suppression of major oncogenic signaling cascades, such as the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways, which ultimately leads to cell cycle arrest and the induction of apoptosis (programmed cell death) in cancer cells.

A defining feature of Repotrectinib is its exceptional potency, with sub-nanomolar half-maximal inhibitory concentrations (IC50​) against its key targets. In cell-free assays, its IC50​ values were 0.07 nM for ROS1 and ranged from 0.05 to 0.83 nM for the TRK kinases. This high on-target potency translates into profound inhibition at clinically achievable concentrations.

The most critical aspect of its mechanism is its ability to overcome acquired resistance. The compact macrocyclic structure of Repotrectinib was rationally designed to maintain high-affinity binding even when bulky mutations arise in the kinase domain, particularly in the solvent-front region. This allows it to potently inhibit kinases with mutations such as

ROS1 G2032R, ALK G1202R, and TRKA G595R, which confer resistance to earlier-generation TKIs by sterically hindering their binding. This activity against a broad spectrum of both wild-type and mutant kinases is the molecular basis for its durable efficacy in both TKI-naïve and heavily pretreated patient populations.

Pharmacodynamics

The pharmacodynamic effects of Repotrectinib relate to the physiological and biochemical effects of the drug on the body. While comprehensive exposure-response relationships for efficacy and safety are not fully characterized, key pharmacodynamic properties have been established.

A significant safety feature is its lack of clinically relevant effects on cardiac repolarization. At the approved recommended dosage, Repotrectinib does not cause a mean increase in the corrected QT (QTc) interval greater than 20 milliseconds, mitigating a common safety concern associated with many TKIs.

Furthermore, Repotrectinib is a moderate inducer of the Cytochrome P450 3A4 (CYP3A4) enzyme system. This pharmacodynamic effect has important clinical consequences. It leads to the autoinduction of its own metabolism, influencing its pharmacokinetic profile over time. It also creates a potential for significant drug-drug interactions, as Repotrectinib can accelerate the clearance of other medications that are substrates of CYP3A4.

Pharmacokinetics

The pharmacokinetic profile of Repotrectinib describes its absorption, distribution, metabolism, and excretion (ADME). These parameters dictate the dosing regimen and inform the management of potential drug interactions. The pharmacokinetic properties of Repotrectinib are summarized in the table below.

PK Parameter	Value	Comment/Significance	Source(s)
Absolute Bioavailability	45.7%	Moderate oral absorption.
Tmax (single dose)	2–3 hours	Rapid absorption after oral administration.
Food Effect	No clinically significant effect	Can be taken with or without food, enhancing patient convenience.
Volume of Distribution (Vz/F)	432 L	Extensive distribution into tissues.
Plasma Protein Binding	95.4%	Highly bound to plasma proteins.
Primary Metabolic Pathway	CYP3A4 oxidation, followed by glucuronidation	High potential for drug interactions involving the CYP3A4 pathway.
Terminal Half-Life (single dose)	~50.6 hours	Long half-life supports once- or twice-daily dosing.
Terminal Half-Life (steady state)	~35.4 hours	Half-life decreases at steady state due to autoinduction.
Primary Route of Excretion	Feces (88.8%)	Primarily eliminated via the hepatobiliary system, with minimal renal clearance.

The unique pharmacokinetic property of CYP3A4 autoinduction directly dictates the approved dosing regimen. Repotrectinib is not only a substrate of CYP3A4 but also an inducer of the enzyme. This means that over the initial period of treatment, the drug increases the rate of its own metabolism. If treatment were initiated at the final maintenance dose of 160 mg twice daily, the initial plasma concentrations could be excessively high before the induction process is complete, potentially leading to increased toxicity. To mitigate this, a 14-day lead-in period with a lower dose of 160 mg once daily is employed. This lead-in phase allows the CYP3A4 enzyme system to gradually upregulate, increasing the drug's clearance to a new, higher steady state. After 14 days, when its clearance rate has stabilized, the dose can be safely increased to the 160 mg twice-daily maintenance level. This ensures that therapeutic concentrations are maintained for the duration of treatment while minimizing the risk of adverse events during initiation. This sophisticated dosing strategy is a direct clinical application of its pharmacokinetic profile and highlights the critical importance of understanding a drug's metabolic behavior to design safe and effective regimens.

Clinical Efficacy in Registrational Trials

The clinical efficacy and safety of Repotrectinib were established through a series of robust clinical trials, most notably the pivotal Phase 1/2 TRIDENT-1 study. The data from this trial formed the basis for its regulatory approvals and defined its role in treating patients with ROS1-positive NSCLC and NTRK fusion-positive solid tumors.

The TRIDENT-1 Study (NCT03093116): Design and Population

TRIDENT-1 was a global, multicenter, single-arm, open-label, first-in-human Phase 1/2 clinical trial designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of Repotrectinib. The Phase 1 portion of the study employed a dose-escalation design to determine the maximum tolerated dose (MTD) and establish the recommended Phase 2 dose (RP2D). The RP2D was determined to be 160 mg once daily for 14 days, followed by 160 mg twice daily thereafter.

The Phase 2 portion was designed to assess efficacy across six distinct expansion cohorts, which stratified patients based on their specific oncogenic driver (ROS1 or NTRK) and their prior treatment history with TKIs. The primary efficacy endpoint for Phase 2 was the objective response rate (ORR), as assessed by a Blinded Independent Central Review (BICR) using RECIST v1.1 criteria. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), and intracranial ORR.

Efficacy in ROS1-Positive NSCLC

The TRIDENT-1 trial demonstrated profound and durable clinical activity in patients with locally advanced or metastatic ROS1-positive NSCLC, both in those who were new to TKI therapy and in those who had developed resistance to prior inhibitors.

• TKI-Naïve Patients: In the cohort of 71 patients who had not previously received a ROS1 TKI, Repotrectinib demonstrated a confirmed ORR of 79% (95% CI, 68–88). The responses were remarkably durable, with a median DOR of 34.1 months (95% CI, 25.6–Not Evaluable) and a median PFS of 35.7 months. This exceptional durability establishes Repotrectinib as a highly effective first-line treatment option.
• TKI-Pretreated Patients: For patients who had progressed on a prior ROS1 TKI, a population with no approved targeted therapies, Repotrectinib offered a new standard of care. In a cohort of 56 patients who had received one prior ROS1 TKI (and no prior chemotherapy), the confirmed ORR was 38% (95% CI, 25–52). The responses remained clinically meaningful, with a median DOR of 14.8 months and a median PFS of 9.0 months.
• Efficacy Against Resistance Mutations: The trial provided direct clinical validation of Repotrectinib's rational design. In a subset of 17 patients with tumors harboring the ROS1 G2032R solvent-front resistance mutation, the ORR was 59% (95% CI, 33–82), confirming its ability to overcome this common mechanism of resistance.

Intracranial Efficacy

A critical challenge in the management of NSCLC is the high incidence of brain metastases. Many TKIs exhibit poor penetration of the blood-brain barrier, making the central nervous system (CNS) a common site of disease progression. Repotrectinib was specifically designed for favorable brain penetration, and the clinical data from TRIDENT-1 confirmed its potent intracranial activity.

• In TKI-naïve patients with measurable baseline CNS metastases, Repotrectinib achieved an intracranial ORR (icORR) of 89%.
• In TKI-pretreated patients with measurable CNS lesions, the icORR was 38%.

This robust activity within the CNS is a key differentiating feature of Repotrectinib, offering durable disease control in a sanctuary site where many other agents fail.

Efficacy in NTRK Gene Fusion-Positive Solid Tumors

The TRIDENT-1 trial also evaluated Repotrectinib in a tumor-agnostic setting for patients with NTRK gene fusion-positive solid tumors, another population where acquired resistance to first-generation inhibitors like larotrectinib is a significant clinical problem.

• TKI-Naïve Patients: In 40 patients who had not previously received a TRK inhibitor, the confirmed ORR was 58% (95% CI, 41–73).
• TKI-Pretreated Patients: In 48 patients who had progressed on at least one prior TRK inhibitor, Repotrectinib demonstrated a confirmed ORR of 50% (95% CI, 35–65). This result was particularly impactful, as it established Repotrectinib as the first effective second-line targeted therapy for this resistant patient population.

The efficacy data from TRIDENT-1 reveal a compelling dual-market positioning for Repotrectinib. For TKI-naïve patients with ROS1-positive NSCLC, its exceptional durability, with a median PFS approaching three years, supports its role as a potential "best-in-class" first-line agent. Simultaneously, for patients with

ROS1-positive or NTRK-positive tumors who have progressed on prior TKIs—a setting where no approved targeted therapies previously existed—its ability to induce meaningful and durable responses establishes it as a "first-in-class" treatment option. This capacity to serve both as a superior frontline therapy and as a salvage therapy for resistant disease allows Repotrectinib to span the entire treatment journey for patients with these specific biomarkers, a rare and significant clinical advantage.

The table below summarizes the pivotal efficacy outcomes from the TRIDENT-1 study across key patient populations.

Patient Cohort	N	Confirmed ORR (95% CI)	Median DOR (95% CI)	Median PFS (95% CI)	Intracranial ORR	Source(s)
ROS1+ NSCLC (TKI-Naïve)	71	79% (68, 88)	34.1 months (25.6, NE)	35.7 months (27.4, NE)	89%
ROS1+ NSCLC (1 Prior TKI)	56	38% (25, 52)	14.8 months (7.6, NE)	9.0 months (6.8, 19.6)	38%
NTRK+ Solid Tumors (TKI-Naïve)	40	58% (41, 73)	Not Evaluable	Not Reported	Not Applicable
NTRK+ Solid Tumors (TKI-Pretreated)	48	50% (35, 65)	9.9 months	Not Reported	Not Applicable

The CARE Study (NCT04094610) in Pediatric Patients

The CARE study is an ongoing Phase 1/2 trial evaluating the safety and efficacy of Repotrectinib in pediatric and young adult patients (up to age 25) with advanced solid tumors harboring ALK, ROS1, or NTRK alterations. Safety data from this study, combined with the robust efficacy data from the adult population in TRIDENT-1, provided the evidence needed to support the expanded approval of Repotrectinib for the treatment of

NTRK fusion-positive solid tumors in pediatric patients aged 12 and older. Early results from CARE demonstrated confirmed responses in TKI-naïve pediatric patients with

NTRK-positive tumors, validating its activity in this younger population.

Approved Indications and Patient Selection

The clinical development program for Repotrectinib has led to specific, biomarker-driven indications approved by major regulatory agencies worldwide. Proper patient selection through validated molecular testing is a prerequisite for its use.

ROS1-Positive Non-Small Cell Lung Cancer

Repotrectinib is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive. This indication covers both patients who are TKI-naïve and those who have been previously treated with a ROS1 inhibitor, a first for any approved therapy in this setting.

NTRK Gene Fusion-Positive Solid Tumors

In a tumor-agnostic indication, Repotrectinib is approved 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. This indication is further qualified by several criteria:

• The tumors must be locally advanced, metastatic, or in cases where surgical resection is likely to result in severe morbidity.
• Patients must have experienced disease progression following prior treatment or have no other satisfactory alternative therapeutic options.

This indication was granted under the FDA's accelerated approval program, which is reserved for drugs that treat serious conditions and fill an unmet medical need based on a surrogate endpoint—in this case, ORR and DOR. The regulatory strategy of targeting a high-unmet-need population, specifically those who have exhausted other options, was instrumental in expediting market access for this vulnerable group. This pathway allows promising drugs to reach patients faster, but it also places a requirement on the manufacturer to conduct confirmatory trials to verify and describe the clinical benefit, such as an improvement in survival, in post-marketing studies. This approach highlights the balance that regulatory bodies strike between providing early access to innovative therapies and ensuring a complete dataset on their long-term benefits.

Requirement for Biomarker Testing

The use of Repotrectinib is strictly limited to patients with a confirmed genetic alteration in their tumors. Before initiating therapy, the presence of a ROS1 gene rearrangement (for NSCLC) or an NTRK1, NTRK2, or NTRK3 gene fusion (for solid tumors) must be confirmed by a validated diagnostic test, such as next-generation sequencing (NGS) or fluorescence in situ hybridization (FISH). This requirement firmly establishes Repotrectinib as a precision medicine, where treatment is tailored to the specific molecular drivers of a patient's cancer.

Safety, Tolerability, and Risk Management

The clinical utility of any therapeutic agent is determined by the balance between its efficacy and its safety profile. The safety of Repotrectinib was extensively evaluated in the TRIDENT-1 clinical trial, which included a pooled safety population of 426 patients who received the drug.

Overview of Adverse Reactions

The safety profile of Repotrectinib is characterized by a high incidence of generally low-grade and manageable adverse events, but also includes a risk of less frequent but potentially severe toxicities that require careful monitoring and management.

The most common adverse reactions, occurring in ≥20% of patients, were primarily neurological and gastrointestinal in nature. These included dizziness, dysgeusia (alteration in the sense of taste), peripheral neuropathy, constipation, dyspnea (shortness of breath), fatigue, ataxia (impaired coordination and balance), cognitive impairment, muscular weakness, and nausea.

Serious adverse reactions were reported in 35% of patients, with the most frequent (occurring in ≥2% of patients) being pneumonia, dyspnea, pleural effusion, and hypoxia. Fatal adverse reactions occurred in 3.5% of patients and were attributed to a range of causes, including pneumonia, cardiac events, and respiratory failure.

The table below details the incidence of the most common adverse reactions observed in the pivotal clinical trial.

Adverse Reaction	Incidence (All Grades %)	Incidence (Grade 3–4 %)	Source(s)
Dizziness	65%	2.8%
Dysgeusia	54%	0%
Peripheral Neuropathy	49%	1.4%
Constipation	38%	0.2%
Dyspnea	30%	6%
Fatigue	30%	1.2%
Ataxia	28%	0.5%
Cognitive Impairment	25%	0.9%
Muscular Weakness	20%	2%
Nausea	20%	0.7%

Warnings and Precautions

The prescribing information for Repotrectinib includes several important warnings and precautions regarding clinically significant risks that require proactive monitoring and management.

• Central Nervous System (CNS) Effects: CNS adverse reactions are the most prominent toxicity associated with Repotrectinib, occurring in 77% of patients, with Grade 3 or 4 events in 4.5%. These effects encompass a broad spectrum of symptoms, including dizziness (65%), ataxia (28%), cognitive impairment (e.g., memory issues, confusion) (25%), mood disorders, and sleep disturbances. Patients must be counseled on these risks and advised to avoid driving or operating hazardous machinery if they experience these symptoms. Management may require dose interruption, reduction, or permanent discontinuation depending on severity.
• Interstitial Lung Disease (ILD)/Pneumonitis: A serious, potentially life-threatening pulmonary toxicity occurred in 3.1% of patients. Patients should be monitored for any new or worsening respiratory symptoms. If ILD/pneumonitis is suspected, Repotrectinib must be withheld immediately and permanently discontinued if the diagnosis is confirmed.
• Hepatotoxicity: Elevations in liver transaminases are frequent, with increased Alanine Aminotransferase (ALT) observed in 38% of patients and increased Aspartate Aminotransferase (AST) in 41%. Liver function tests must be monitored every two weeks for the first month of treatment and as clinically indicated thereafter to detect potential liver injury.
• Myalgia with Creatine Phosphokinase (CPK) Elevation: Myalgia (muscle pain) occurred in 13% of patients. Patients reporting unexplained muscle pain, tenderness, or weakness should have their serum CPK levels monitored.
• Hyperuricemia: Increased serum uric acid levels were reported in 5% of patients and can lead to conditions like gout. Uric acid levels should be monitored prior to and periodically during treatment.
• Skeletal Fractures: An increased risk of skeletal fractures was observed, occurring in 2.3% of patients. Fractures occurred with and without trauma. Any patient presenting with pain, changes in mobility, or deformity should be promptly evaluated for a fracture.
• Embryo-Fetal Toxicity: Based on its mechanism of action and animal studies, Repotrectinib can cause fetal harm. Stringent contraception measures are required. Females of reproductive potential must use effective non-hormonal contraception during treatment and for 2 months after the final dose. Male patients with female partners of reproductive potential must use effective contraception during treatment and for 4 months after the final dose.

The overall safety profile necessitates a proactive clinical management strategy. While the most common adverse events, such as dizziness and dysgeusia, are high in incidence but generally low in grade, the risk of rare but severe events like ILD/pneumonitis requires constant vigilance. The prescribing information mandates specific monitoring schedules for liver enzymes and other laboratory parameters, underscoring that the drug's "manageable" tolerability profile is contingent upon diligent oversight by the healthcare team. The absence of any absolute contraindications places the full responsibility of risk-benefit assessment and patient management squarely on the prescribing physician.

Contraindications and Use in Specific Populations

• Contraindications: There are no contraindications listed in the prescribing information for Repotrectinib.
• Renal and Hepatic Impairment: No dosage adjustments are required for patients with mild-to-moderate renal impairment or mild hepatic impairment. The drug has not been studied in patients with severe renal or moderate-to-severe hepatic impairment, and its use in these populations is not recommended.
• Pregnancy and Lactation: Repotrectinib is not recommended for use during pregnancy. Due to the potential for serious adverse reactions in a breastfed child, lactating women are advised not to breastfeed during treatment and for 10 days after the last dose.

Dosage, Administration, and Drug Interactions

Effective and safe use of Repotrectinib requires strict adherence to the recommended dosing schedule, proper administration techniques, and careful management of potential drug and food interactions.

Dosing and Administration

• Recommended Dosage: The recommended dosage for both approved indications is 160 mg taken orally once daily for the first 14 days, followed by an increase to 160 mg taken orally twice daily. This step-up dosing regimen should be continued until disease progression or the development of unacceptable toxicity.
• Method of Administration: Patients should take Repotrectinib at approximately the same time each day. It can be administered with or without food. The capsules must be swallowed whole and should never be opened, crushed, chewed, or dissolved. Patients should not take any capsules that appear broken or damaged.
• Missed Dose: If a dose is missed or if the patient vomits after taking a dose, the patient should not take an extra dose but should take the next dose at the regularly scheduled time.

Dose Modifications for Toxicity

To manage adverse reactions, a structured approach to dose reduction is recommended. The dose of 160 mg twice daily can be reduced sequentially to 120 mg twice daily, and then to 80 mg twice daily. The table below outlines specific recommendations for managing key toxicities.

Adverse Reaction	Severity (Grade)	Recommended Action	Source(s)
Central Nervous System (CNS) Effects	Grade 2 (Intolerable) or Grade 3	Withhold until ≤ Grade 1 or baseline. Resume at the same or a reduced dose.
	Grade 4	Permanently discontinue.
Interstitial Lung Disease (ILD)/Pneumonitis	Any Grade (Suspected)	Immediately withhold.
	Any Grade (Confirmed)	Permanently discontinue.
Hepatotoxicity (ALT/AST Elevation)	Grade 3 (>5× to 20× ULN)	Withhold until ≤ Grade 1 or baseline. Resume at same or reduced dose.
	Grade 4 (>20× ULN)	Withhold until ≤ Grade 1 or baseline. Resume at a reduced dose or permanently discontinue.
	ALT/AST >3× ULN with Bilirubin >1.5× ULN	Permanently discontinue.
Myalgia with CPK Elevation	CPK >10× ULN	Withhold until resolved. Resume at same or reduced dose.
Hyperuricemia	Grade 3 or 4	Withhold until resolved. Resume at same or reduced dose.

Drug and Food Interactions

Repotrectinib's metabolism via the CYP3A4 pathway makes it susceptible to and a cause of significant drug-drug interactions.

• Effect of Other Drugs on Repotrectinib:
• Strong and Moderate CYP3A Inhibitors: Concomitant use with strong or moderate CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) should be avoided. These agents can significantly increase Repotrectinib plasma concentrations, raising the risk of toxicity. A washout period of 3 to 5 elimination half-lives of the inhibitor is recommended before starting Repotrectinib.
• Strong and Moderate CYP3A Inducers: Concomitant use with strong or moderate CYP3A inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) should be avoided. These agents can decrease Repotrectinib plasma concentrations, potentially compromising its efficacy.
• P-glycoprotein (P-gp) Inhibitors: Co-administration with P-gp inhibitors should also be avoided, as they may increase Repotrectinib exposure.
• Effect of Repotrectinib on Other Drugs:
• Sensitive CYP3A Substrates: Repotrectinib is a moderate CYP3A4 inducer and can decrease the plasma concentrations of other drugs metabolized by this enzyme. Concomitant use with sensitive CYP3A substrates, where even small changes in concentration can lead to loss of efficacy, should be avoided.
• Hormonal Contraceptives: This is a critical interaction. As a CYP3A4 inducer, Repotrectinib can significantly reduce the efficacy of estrogen- and progestin-based hormonal contraceptives. Female patients of reproductive potential must be advised to use an effective, non-hormonal method of contraception during treatment.

The complex, bidirectional nature of these interactions—where Repotrectinib is both a substrate and an inducer of the same major metabolic pathway, CYP3A4—presents a significant challenge in the polypharmacy setting common among cancer patients. Its clearance is dependent on CYP3A4, making it vulnerable to inhibitors and inducers. Simultaneously, it can reduce the effectiveness of other essential medications that are CYP3A4 substrates. This creates a high potential for clinically meaningful interactions that can lead to either increased toxicity or treatment failure (of Repotrectinib or the co-administered drug). Consequently, a thorough medication reconciliation by both the prescribing physician and the clinical pharmacist is not merely a recommendation but an essential safety measure before and during therapy with Repotrectinib.

• Food Interactions:
• Grapefruit: Patients must be strictly instructed to avoid consuming grapefruit and grapefruit juice during treatment. Grapefruit is a potent inhibitor of CYP3A4 and can significantly increase Repotrectinib plasma levels, leading to an increased risk of adverse reactions.

Regulatory History and Global Status

The development and approval of Repotrectinib were expedited by major regulatory agencies worldwide, reflecting a global consensus on its significant clinical benefit and its role in addressing a high unmet medical need for patients with ROS1- and NTRK-driven cancers.

United States (Food and Drug Administration - FDA)

The FDA recognized the potential of Repotrectinib early in its development, granting it multiple expedited program designations, including Priority Review, Breakthrough Therapy Designation, and Fast Track Designation.

• Initial Approval: On November 15, 2023, the FDA granted traditional approval to Repotrectinib for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC.
• Expanded Approval: On June 13, 2024, the FDA granted accelerated approval for the treatment of adult and pediatric patients aged 12 years and older with NTRK gene fusion-positive solid tumors that have progressed or have no satisfactory alternative treatments.

European Union (European Medicines Agency - EMA)

The EMA also facilitated an expedited review process for Repotrectinib.

• The Marketing Authorization Application was validated by the EMA in April 2024.
• On November 14, 2024, the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending approval.
• On January 13, 2025, the European Commission granted a conditional marketing authorization for Repotrectinib for both the ROS1-positive NSCLC and NTRK-positive solid tumor indications. The conditional pathway is used when the benefit of a medicine's immediate availability to patients outweighs the risk inherent in the fact that additional data are still required.

Australia (Therapeutic Goods Administration - TGA)

In Australia, Repotrectinib underwent a parallel process for regulatory review and reimbursement consideration.

• The application for Repotrectinib was accepted for evaluation by the TGA in May 2024.
• It was officially listed on the Australian Register of Therapeutic Goods (ARTG) on July 25, 2025, for the treatment of adult patients with ROS1-positive locally advanced or metastatic NSCLC.
• As of May 2025, it is under consideration by the Pharmaceutical Benefits Advisory Committee (PBAC) for listing on the Pharmaceutical Benefits Scheme (PBS) to ensure subsidized access for patients.

The rapid succession of these regulatory milestones and the consistent use of expedited pathways across different continents underscore the compelling nature of the clinical data. This concerted global regulatory push demonstrates a strong consensus among health authorities regarding the drug's substantial benefit-risk profile, particularly its ability to provide durable responses in patient populations with limited or no other effective treatment options.

Regulatory Agency	Date	Milestone/Action	Indication(s)	Source(s)
U.S. FDA	Nov 15, 2023	Traditional Approval	Adult patients with locally advanced or metastatic ROS1-positive NSCLC
U.S. FDA	Jun 13, 2024	Accelerated Approval	Adult and pediatric patients (≥12 years) with NTRK gene fusion-positive solid tumors
EMA	Nov 14, 2024	CHMP Positive Opinion	ROS1-positive advanced NSCLC and NTRK-positive advanced solid tumors
EMA	Jan 13, 2025	Conditional Marketing Authorisation	ROS1-positive advanced NSCLC and NTRK-positive advanced solid tumors
TGA (Australia)	May 2024	Application Accepted for Evaluation	Adult patients with ROS1-positive locally advanced or metastatic NSCLC
TGA (Australia)	Jul 25, 2025	ARTG Listing (Approval)	Adult patients with ROS1-positive locally advanced or metastatic NSCLC

Conclusion and Future Perspectives

Repotrectinib (AUGTYRO®) has firmly established itself as a cornerstone therapy for patients with tumors driven by ROS1 or NTRK genetic alterations. Its clinical profile is defined by a unique dual positioning: it serves as a best-in-class, highly durable first-line option for patients with ROS1-positive NSCLC, while also acting as a first-in-class salvage therapy for those with ROS1- or NTRK-positive cancers that have developed resistance to prior TKI treatments. The potent intracranial activity demonstrated in clinical trials addresses a critical unmet need, offering robust disease control in the central nervous system, a common and challenging site of metastasis.

Beyond its clinical efficacy, the development of Repotrectinib serves as a paradigm of modern, rational drug design. Its creation was not an iterative process but a direct, structure-based response to the known molecular mechanisms of failure of its predecessors. By engineering a compact, rigid macrocycle capable of overcoming steric hindrance from solvent-front mutations, its developers provided a blueprint for how to proactively design therapies against predictable resistance, a strategy that will undoubtedly influence the future of kinase inhibitor discovery.

The journey of Repotrectinib is not yet complete. Ongoing research is poised to further solidify and potentially expand its role in oncology. The TRIDENT-3 (NCT05118858) trial, a Phase 3 randomized study comparing Repotrectinib directly against the first-generation inhibitor crizotinib in TKI-naïve ROS1-positive NSCLC patients, is of particular strategic importance. While the current approval is based on compelling single-arm data, a positive result from this head-to-head trial would provide the highest level of clinical evidence (Level 1). Such an outcome would not only confirm its superiority but would also likely redefine the global standard of care, making it difficult to justify the first-line use of older agents and cementing Repotrectinib's market and clinical leadership.

Furthermore, exploratory studies are investigating its potential in new contexts. A Phase 1 trial (NCT04772235) is currently evaluating Repotrectinib in combination with osimertinib for patients with EGFR-mutant NSCLC, suggesting that its inhibitory profile, which includes kinases involved in bypass signaling pathways like SRC, may offer synergistic benefits beyond its primary targets.

In conclusion, Repotrectinib has fundamentally altered the treatment landscape for patients with ROS1 and NTRK fusion-driven malignancies. It offers the prospect of long-term, durable disease control, even in the brain and in the face of acquired resistance. Its successful development from a resistance-focused chemical design to a globally approved, practice-changing medicine provides both a powerful therapeutic tool for clinicians and an inspirational model for the future of precision oncology.

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