Repotrectinib

Repotrectinib inhibits the kinase ROS1, the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB and TRKC, and anaplastic lymphoma kinase (ALK), with IC50 values of 0.05 to 1.04 nM. Fusion proteins that contain ROS1 or TRK domains can drive tumour growth by over-activating downstream signalling pathways, which leads to uncontrolled cell proliferation.

Mechanism of Action

• Target inhibition: repotrectinib inhibits cell lines that express the ROS1, TRKA, TRKB and TRKC fusion oncogenes, in vitro and in vivo.
• Resistance mutations: it also inhibits cells carrying corresponding mutations (ROS1 G2032R and D2033N, TRKA G595R, TRKB G639R, TRKC G623R). It binds inside the ATP-binding pocket and avoids steric interference from both solvent-front and gatekeeper mutations.
• Cardiac electrophysiology: in 334 patients from the TRIDENT-1 study at the recommended dose, the upper limit of the 90% confidence interval of the mean QTcF change from baseline exceeded 10 ms at a few time points but stayed below 20 ms. Patients at increased risk of QTc prolongation were not enrolled.
• Clinical study: efficacy was evaluated in TRIDENT-1, a phase I/II multicentre, single-arm, open-label, multi-cohort study in adults with solid tumours carrying ROS1 or NTRK1-3 rearrangements.

Pharmacokinetics

• Absorption: rapid, with peak concentrations 2–3 hours after a dose when fasting. Absolute bioavailability is 45.7%. Exposure rises slightly less than in proportion to dose between 40 and 240 mg. A high-fat, high-calorie meal raised AUC by 42–56% and peak concentration by 110–149% (a low-fat meal by 36% and 124%), and delayed the peak to about 4–6 hours. The SmPC nevertheless allows the capsules to be taken with or without food. At steady state on 160 mg twice daily, peak concentration is about 572 ng/mL, trough about 158 ng/mL and average about 347 ng/mL.
• Distribution: 95.4% bound to plasma proteins in vitro; blood-to-plasma ratio 0.56; apparent volume of distribution 432 L.
• Metabolism: mainly by CYP3A4 to hydroxylated metabolites, then glucuronidation. No metabolite exceeded 10% of circulating drug-related radioactivity. Repotrectinib induces its own metabolism (CYP3A4 autoinduction), so its elimination is time-dependent.
• Elimination: apparent oral clearance is about 15.9 L/h after a single 160 mg dose. The terminal half-life is about 68.6 hours after a single dose and about 44.5 hours at steady state. After a radiolabelled dose, 88.8% was recovered in faeces (50.6% unchanged) and 4.84% in urine (0.56% unchanged).
• Special populations: mild or moderate renal impairment and mild hepatic impairment did not change clearance. It has not been studied in severe renal impairment or in moderate or severe hepatic impairment. Sex, age (18–93 years), body weight and race (Asian, White) had no clinically relevant effect. Adolescents aged 12 years and older have exposure similar to adults at the adult dose.
• In vitro: it induces CYP3A4, CYP2B6, CYP2C8, CYP2C9 and CYP2C19, and inhibits CYP3A4/5 (gut), CYP2C8, CYP2C9, UGT1A1, P-gp, BCRP, OATP1B1, MATE1 and MATE2-K. It is a substrate of P-gp.

Repotrectinib is used as monotherapy. It is authorised under a conditional marketing authorisation.

• ROS1-positive advanced NSCLC: adults with ROS1-positive advanced non-small cell lung cancer (NSCLC).
• NTRK gene fusion-positive advanced solid tumours: adults and paediatric patients 12 years of age and older with advanced solid tumours expressing an NTRK gene fusion, who either:
  • have received a prior NTRK inhibitor, or
  • have not received a prior NTRK inhibitor, and treatment options not targeting NTRK provide limited clinical benefit or have been exhausted.

• Hypersensitivity to repotrectinib or to any of the excipients.

In adults (TRIDENT-1, 565 patients), the most common adverse reactions were dizziness (65%), dysgeusia (57%), constipation (39%), paraesthesia (39%), anaemia (38%) and dyspnoea (31%). Grade 3 or higher reactions occurred in 43% of patients; the most frequent were anaemia (8.8%), dyspnoea (6.7%), pneumonia (5.7%), increased blood creatine phosphokinase (3.4%), weight increased (3.2%), increased aspartate aminotransferase (2.7%), pleural effusion (2.3%) and decreased neutrophil count (2.1%). Permanent discontinuation because of an adverse reaction occurred in 6.2% of patients.

Very common (≥1/10): pneumonia, anaemia, dizziness, ataxia, cognitive disorders, paraesthesia, peripheral sensory neuropathy, sleep disorders, headache, dysgeusia, vision disorders, dyspnoea, cough, nausea, vomiting, constipation, diarrhoea, muscular weakness, pain in extremity, arthralgia, myalgia, back pain, pyrexia, fatigue, decreased appetite, peripheral oedema, increased blood creatine phosphokinase, weight increased, increased alanine aminotransferase, increased aspartate aminotransferase.

Common (≥1/100 to <1/10): hyperuricaemia, pneumonitis (including interstitial lung disease), pleural effusion, abdominal pain, skeletal fractures, decreased lymphocyte count, decreased white blood cell count, decreased neutrophil count, increased gamma-glutamyltransferase, increased blood alkaline phosphatase, fall.

The most common serious reactions were pneumonia (6.2%), dyspnoea (3.5%), pleural effusion (3.0%), pyrexia (1.2%), muscular weakness (1.1%), anaemia (1.1%) and pneumonitis (1.1%).

Nervous system effects are frequent: ataxia occurred in 29.0% and cognitive disorders (mostly memory impairment and disturbance in attention) in 22.3% of adults, at similar rates with or without CNS metastases. Interstitial lung disease or pneumonitis occurred in 3.2% (grade 3 in 0.9%), and 0.9% stopped treatment because of it. Skeletal fractures occurred in 3.5% of adults. Raised ALT and AST occurred in 22.1% and 20.9%. Muscle weakness, with or without raised creatine phosphokinase, occurred in 21.6%.

In 38 patients in the paediatric CARE study (22 under 12 years, 14 aged 12–17 and 2 adults), reactions were comparable in frequency and intensity to those in adults, except skeletal fractures, which were more frequent (18.4% versus 3.5%). The most frequent reactions in children were constipation, fatigue and headache. In adults, serious reactions were more frequent in patients aged 65–75 years (48%) and 75 years or older (63%) than in those aged 18–65 years (37%), and discontinuations were also more frequent.

Repotrectinib is a substrate of CYP3A4 and P-gp and is a moderate CYP3A4 inducer. Interaction studies have been done only in adults.

• Strong or moderate CYP3A4 or P-gp inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, voriconazole, posaconazole, verapamil, nifedipine, felodipine, fluvoxamine, grapefruit, Seville oranges): raise repotrectinib levels and should be avoided. Itraconazole raised the AUC 5.9-fold with a single 80 mg dose.
• Strong or moderate CYP3A4 or P-gp inducers (carbamazepine, phenytoin, rifampicin, St John’s wort, apalutamide, ritonavir): lower repotrectinib levels and should be avoided. Rifampicin cut the AUC by 92%.
• CYP3A4 substrates: repotrectinib reduced the AUC of a single dose of a CYP3A4 substrate by 69%. Use caution with cisapride, ciclosporin, fentanyl, tacrolimus, alfentanil, sirolimus, everolimus, lovastatin and simvastatin, because of the risk of therapeutic failure.
• CYP2B6 substrates (for example bupropion, efavirenz): exposure may fall.
• CYP2C8, CYP2C9 and CYP2C19 substrates (for example repaglinide, warfarin, tolbutamide, omeprazole): exposure may change; the net effect in patients is not known.
• Transporter substrates: exposure may increase for P-gp substrates (dabigatran etexilate, digoxin, edoxaban, fexofenadine), BCRP substrates (methotrexate, rosuvastatin, sulfasalazine), OATP1B1 substrates (valsartan, statins) and MATE1 or MATE2-K substrates (metformin). The clinical relevance is unknown.
• Hormonal contraceptives: repotrectinib can lower progestin or oestrogen exposure enough to reduce the effectiveness of systemic hormonal contraceptives, including oral contraceptives. A barrier method should be added.
• Grapefruit and Seville oranges: do not take with repotrectinib.

Treatment must be started and supervised by physicians experienced in the use of anticancer medicinal products. ROS1-positive status in NSCLC, or NTRK-positive status in solid tumours, must be assessed with a CE-marked in vitro diagnostic test with the corresponding intended purpose or, if none is available, another validated test. The capsules are swallowed whole at the same time every day. They must not be opened, crushed or chewed, and their contents must not be dissolved. They may be taken with or without food, but not with grapefruit, grapefruit juice or Seville oranges.

Recommended Dose

• ROS1-positive NSCLC (adults): 160 mg once daily for 14 days, then 160 mg twice daily until disease progression or unacceptable toxicity.
• NTRK gene fusion-positive solid tumours (adults and paediatric patients 12 years and older): the same schedule, 160 mg once daily for 14 days, then 160 mg twice daily until disease progression or unacceptable toxicity.

Dose Reductions

• A prescribed 160 mg once daily is reduced to 120 mg once daily on the first occurrence and 80 mg once daily on the second.
• A prescribed 160 mg twice daily is reduced to 120 mg twice daily on the first occurrence and 80 mg twice daily on the second.

Dose Modifications for Specific Reactions

Severity is graded by NCI CTCAE version 4.0.

• Central nervous system effects: intolerable grade 2, withhold until grade 1 or baseline, then resume at the same or a reduced dose as clinically appropriate. Grade 3, withhold until grade 1 or baseline, then resume at a reduced dose. Grade 4, stop permanently.
• Interstitial lung disease or pneumonitis (any grade): withhold if suspected; stop permanently if confirmed.
• Other clinically relevant reactions: intolerable grade 2, withhold until grade 1 or baseline, then resume at the same or a reduced dose if resolution occurs within 4 weeks. Grade 3 or 4, withhold until the reaction resolves or improves to grade 1 or baseline, then resume at the same or a reduced dose if resolution occurs within 4 weeks. Stop permanently if the reaction does not resolve within 4 weeks, and for recurrent grade 4 events.

Special Populations

• Elderly (65 years and older): no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment; not studied in severe impairment.
• Hepatic impairment: no adjustment in mild impairment (total bilirubin above 1.0 to 1.5 times the upper limit of normal, or AST above the upper limit). Not studied in moderate (bilirubin above 1.5 to 3 times) or severe (above 3 times) impairment, and it should not be used in these patients.
• Children and adolescents: safety and efficacy below 18 years in ROS1-positive NSCLC, and below 12 years in NTRK-positive solid tumours, have not been established. Available data are described in the SmPC, but no dose recommendation can be made.

Missed or Vomited Dose

If a dose is missed, or the patient vomits at any time after taking a dose, continue with the next dose as prescribed. Two doses must not be taken at the same time.

Efficacy Across Tumour Types

In NTRK fusion-positive tumours, the benefit has been established in single-arm studies in adults (88 patients), based on overall response rate and response duration in a limited number of tumour types. The effect may differ depending on tumour type and on concomitant genomic alterations.

Central Nervous System Effects

A broad range of nervous system reactions has been reported, including dizziness, ataxia and cognitive disorders. Patients should be told of these risks and not drive or use machines while they have such reactions. Withhold the medicine, then resume at the same or a reduced dose after improvement, or stop permanently, according to severity.

Interstitial Lung Disease and Pneumonitis

Patients should report shortness of breath, cough, wheezing, chest pain or tightness, and coughing up blood, and should be monitored for new or worsening lung symptoms. Withhold repotrectinib if ILD or pneumonitis is suspected and stop it permanently if confirmed.

Skeletal Fractures

Fractures have been reported in adults and paediatric patients, some after a fall or other trauma to the area; some patients had radiological abnormalities possibly due to tumour involvement. Most were in the lower limbs (fibula, tibia or foot). Patients with pain, changed mobility or deformity should be assessed promptly.

Liver Function

Drug-induced hepatotoxicity has been reported. Monitor ALT, AST and bilirubin as clinically indicated. Repotrectinib should not be used in moderate or severe hepatic impairment, because of the risk of over-exposure and more adverse events.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy test and contraception: women of childbearing potential should have a medically supervised pregnancy test before starting and must use highly effective contraception during treatment and for at least 2 months after the last dose. Because repotrectinib may reduce the effectiveness of systemic hormonal contraceptives, a barrier method should be added if hormonal contraception is used. Male patients with female partners of childbearing potential must use condoms during treatment and for 4 months after the last dose.
• Pregnancy: there are no data in pregnant women. Animal studies and the mechanism of action indicate that repotrectinib may cause foetal harm; it should be used only if the woman’s clinical condition requires it.
• Breastfeeding: it is unknown whether repotrectinib or its metabolites pass into human milk. Breastfeeding should stop during treatment and for 10 days after the last dose.
• Fertility: no fertility studies have been done; the effect on male and female fertility is unknown.

Paediatric Use

Long-term safety data are not available for patients aged 12 years and older.

Effect on Driving

Repotrectinib has a moderate influence on the ability to drive and use machines because of possible nervous system effects and vision disorders. Patients should not drive or use machines while they have such reactions.

Augtyro capsules need no special storage conditions. The 40 mg capsules come in high-density polyethylene bottles with a child-resistant closure (60 or 120 capsules); the 160 mg capsules come in PVC/polychlorotrifluoroethylene blisters with aluminium foil (packs of 20 or 60). Not all pack sizes may be marketed.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), under restricted medical prescription (Annex II B). Treatment must be started and supervised by a physician experienced in anticancer medicines, after ROS1-positive NSCLC or an NTRK gene fusion has been confirmed with a CE-marked test. The capsules are taken at home, so they are supplied to the patient or to the treating clinic on prescription.