What Is Repotrectinib (Augtyro)? FDA Approval, Authorization and Reimbursement Status in Turkey

• FDA Approval: Yes (Initial approval date: November 15, 2023)
• Brand Name: Augtyro
• Active Ingredient: Repotrectinib
• Route of Administration: Oral capsule
• Class: Tyrosine kinase inhibitor (TKI)
• Category: Targeted antineoplastic agent
• Manufacturer: Bristol-Myers Squibb
• Distribution in Turkey: Not yet authorized in Turkey; access may be possible through special imports or clinical trials.
• Cancers for Which It Is Approved: ROS1-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC); NTRK fusion-positive, locally advanced or metastatic solid tumors in adults and children aged 12 and older

What Is Repotrectinib? How Does It Work?

Repotrectinib is a targeted tyrosine kinase inhibitor used to treat certain advanced cancers. It is particularly effective in solid tumors positive for ROS1 or NTRK gene fusions. This molecularly developed agent suppresses specific signaling pathways that regulate tumor cell growth and proliferation.

How Does It Work?

Repotrectinib targets specific tyrosine kinases involved in intracellular signaling. Its main targets are:

• ROS1 (c-ros oncogene 1)
• NTRK1, NTRK2, NTRK3 (neurotrophic receptor tyrosine kinase genes)
• ALK (anaplastic lymphoma kinase, to a lesser extent)

Fusions or rearrangements in these genes produce abnormal proteins that drive uncontrolled cancer cell growth.

Repotrectinib binds with high affinity to the active sites of these abnormal kinase receptors and prevents phosphorylation, with the following effects:

• Interruption of signaling, particularly MAPK/ERK and PI3K/AKT: proliferation and survival signals are blocked.
• Induction of apoptosis (programmed cell death): tumor cells are driven to self-destruction.
• Its structure was developed to overcome resistance and remains active against mutated targets, offering an alternative for tumors resistant to other TKIs.

Repotrectinib's small-molecule structure facilitates central nervous system penetration and strong binding to mutated kinase targets.

FDA (US Food and Drug Administration) Approval History

• June 13, 2024: The FDA approved Augtyro (repotrectinib) for NTRK-positive, locally advanced or metastatic solid tumors.
• November 16, 2023: The FDA approved Augtyro (repotrectinib) for locally advanced or metastatic ROS1-positive NSCLC.
• August 16, 2023: Updated Data — TRIDENT-1 results showed durable efficacy with repotrectinib in locally advanced or metastatic ROS1-positive NSCLC.
• May 30, 2023: Announcement — The FDA granted Priority Review to Bristol Myers Squibb's repotrectinib application for locally advanced or metastatic ROS1-positive NSCLC.
• July 27, 2022: Regulatory Update — Turning Point Therapeutics shared a regulatory development for repotrectinib in ROS1-positive advanced NSCLC.

Authorization in Turkey

Not yet authorized in Turkey; special imports, clinical trials or early access programs may provide access.

Therapeutic Indications

• Indicated for adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).
• NTRK Fusion-Positive Solid Tumors: Used for locally advanced or metastatic tumors with NTRK1, NTRK2 or NTRK3 fusions when surgery is unsuitable, in adults and pediatric patients aged 12 and older.
• For both indications, repotrectinib is used in genetic subtypes identified through molecular diagnosis.
• NTRK fusions occur in diverse solid tumors, including thyroid, pancreatic, breast and colon cancers, sarcomas and brain tumors. The indication is therefore tumor-agnostic.
• Genetic testing must identify a ROS1 or NTRK fusion before treatment.

Resistance Mechanisms

• Repotrectinib is active in ROS1- and NTRK-fusion-positive tumors. However, some patients may experience declining effectiveness over time because cancer cells develop resistance.
• Secondary Target-Gene Mutations: The drug binds kinase domains produced by ROS1 and NTRK genes. New mutations may alter the binding site's structure and prevent effective repotrectinib binding. Mutations in the kinase ATP-binding region are a particularly common cause.
• Alternative Signaling: Cancer cells may continue growing by activating pathways outside those inhibited by repotrectinib, including backup PI3K/AKT and MAPK/ERK signaling. Tumor cells can then continue receiving survival signals even when the target gene is suppressed.
• Drug Efflux: Some tumor cells produce proteins, such as P-glycoprotein, that actively expel repotrectinib. Intracellular drug levels fall, making treatment ineffective.
• Tumor Heterogeneity and Clonal Selection: Tumors contain different cell populations, some resistant from the outset. Treatment kills sensitive cells while resistant subclones become dominant, causing the initial response to fade.

Absorption

• Rapidly absorbed after oral administration.
• Absorption (bioavailability): 45.7%
• Peak blood levels reached within 2–3 hours.
• Food does not significantly alter the drug's effect.

Distribution

• High volume of distribution: ~432 L
• Plasma protein binding: 95.4%
• Blood/plasma ratio: 0.56

Metabolism

• Metabolized in the liver through CYP3A4.
• Also undergoes glucuronidation.
• May also induce or inhibit CYP enzymes and certain transport systems.

Elimination

• Mean half-life: 60.7 hours after a single dose and approximately 40.3 hours at steady state
• Urinary excretion: 4.84% (only 0.56% unchanged)
• Fecal excretion: 88.8% (approximately 50.6% unchanged)

Dose Range

• ROS1-Positive NSCLC: Adults with locally advanced or metastatic ROS1-fusion-positive non-small cell lung cancer.
• Starting dose: 160 mg in 1 daily dose (QD) for 14 days; maintenance after day 14: 160 mg 2 times daily (BID)
• Treatment continues until progression or intolerable toxicity. Taken orally as capsules, with or without food.
• NTRK Fusion-Positive Solid Tumors: Adults and pediatric patients aged 12 and older with locally advanced/metastatic NTRK-fusion-positive solid tumors unsuitable for surgery
• For adults and children weighing ≥50 kg: 160 mg 1x1 (QD, once daily) for 14 days, followed by maintenance 160 mg 2x1 (BID, twice daily).
• For children weighing <50 kg, weight-based dosing data remain limited and are being established in clinical trials. Adjustment should follow specialist pediatric protocols. Continue while the tumor responds or until serious toxicity develops.

Drug Interactions

• CYP3A4 Inhibitors (Increased Effect and Toxicity Risk): Itraconazole, ketoconazole, clarithromycin, voriconazole and grapefruit juice may increase repotrectinib blood levels approximately 6-fold. Toxicities such as QT prolongation, fatigue or elevated liver enzymes may increase. Avoid strong inhibitors or consider dose reduction.
• CYP3A4 Inducers (Reduced Effect and Risk of Treatment Failure): Rifampin, carbamazepine, phenytoin and St. John's wort may reduce repotrectinib levels by up to 90%, reducing treatment response. These drugs must not be used concomitantly.
• CYP3A4 Substrates (May Reduce Other Drugs' Effects): Repotrectinib induces CYP3A4 and may lower levels of drugs metabolized by it, such as midazolam, simvastatin, erythromycin and tacrolimus. Monitor dosing or use alternatives because effectiveness may fall.
• Transporter Interactions: Repotrectinib inhibits P-gp, BCRP, OATP1B1 and MATE2-K. This may increase levels and adverse effects of drugs eliminated through these transporters, such as digoxin and statins.

Situations Requiring Attention

• Genetic Testing: Confirm a ROS1 or NTRK fusion molecularly before starting treatment. Treatment without testing is not recommended because the drug is effective only in patients carrying these alterations.
• Liver and Kidney Function: No adjustment is required in mild–moderate hepatic impairment. Data in severe hepatic impairment are inadequate, requiring caution. Pharmacokinetic data are also inadequate in severe renal impairment or dialysis.
• CYP3A4 Interactions: Repotrectinib is metabolized by and induces CYP3A4. Strong CYP3A4 inhibitors, such as itraconazole, or inducers, such as rifampin, may cause serious interactions. If necessary, consider dose adjustments or alternative drugs.
• QT Prolongation and Cardiac Monitoring: Trials found no QT increase >20 ms with repotrectinib. Nevertheless, caution is needed with heart disease or electrolyte abnormalities such as low potassium or magnesium. Monitor ECG if needed.
• Central Nervous System (Brain) Metastases: The drug crosses the blood-brain barrier and may be effective against brain metastases, an important advantage.
• Pregnancy and Breastfeeding: Repotrectinib may harm the fetus and should not be used during pregnancy. Use effective contraception during treatment and for at least 3 weeks afterward. Breastfeeding is not recommended because passage into breast milk is unknown.
• Children and Older Adults: May be used from age 12 for NTRK-positive tumors. In patients older than 65, effectiveness and safety resemble those in adults overall, but assessment should consider general health.

Side Effects

The following summarizes adverse events and frequencies reported in clinical trials of repotrectinib (Augtyro).

• Dizziness: 63%
• Taste changes (dysgeusia): 48%
• Peripheral neuropathy: 47%
• Constipation: 36%
• Shortness of breath (dyspnea): 30%
• Ataxia (impaired balance): 28%
• Fatigue: 24%
• Cognitive impairment: 23%
• Muscle weakness: 21%
• Headache: 19%
• Nausea: 19%
• Cough: 14%
• Diarrhea: 13%
• Muscle pain (myalgia): 12%
• Visual disturbances: 11%
• Vomiting: 10%
• Interstitial lung disease / Pneumonitis: 3.1%
• Elevated liver enzymes: <3%
• Elevated muscle enzymes (CPK): <3%
• Hyperuricemia: <3%
• Bone fractures, particularly in children: <3%
• Visual effects (blurred vision, night blindness): <3%
• Embryo-fetal toxicity (fetal harm during pregnancy): Unknown (precautionary warning)

Recommendations

• Liver function tests: Monitor at treatment initiation and regularly during therapy.
• Muscle enzymes (CPK) and uric acid: Check periodically before and during treatment.
• Visual and neurological assessment: Monitor for visual disturbances and cognitive changes.
• Respiratory symptoms: Evaluate new or worsening symptoms for ILD/pneumonitis.