Repotrectinib Oral

Non-small Cell Lung Cancer

Repotrectinib is used for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose cancer is c-ros oncogene-1 (ROS-1)-positive.^[1] The drug has been designated an orphan drug by FDA for use in this condition.^[2]

Clinical Experience

The indication for repotrectinib in the treatment of ROS-1-positive locally advanced or metastatic NSCLC is based principally on the results of a multicenter, open-label, phase 1/2 trial (TRIDENT-1).^[1][3] The trial included patients with ROS-1-positive locally advanced or metastatic NSCLC who were naive to ROS-1 TKI therapy or previously treated with a prior ROS-1-targeted TKI with no prior platinum-based chemotherapy or immunotherapy.^[1] ROS-1 fusion was determined using fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), or polymerase chain reaction (PCR); ROS-1 positivity via FISH testing was confirmed by a central laboratory using a validated NGS test.^[1] Patients received repotrectinib 160 mg orally once daily for 14 days, followed by an increase in frequency to 160 mg twice daily until disease progression or unacceptable toxicity occurred.^[1] The primary efficacy endpoint was objective response rate as evaluated by a blinded independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).^[1] Duration of response and intracranial response were evaluated as secondary endpoints.^[1][3]

Among 71 ROS-1-positive patients who were TKI-naive at baseline, the median age was 57 years; 97.2% had adenocarcinoma histology, 66.2% had an Eastern Cooperative Oncology Group (ECOG) performance status of 1, 25.4% were white, 67.6% were Asian, 60.6% were female, and 28.2% had received prior platinum-containing therapy or immunotherapy for locally advanced or metastatic disease.^[1] Most patients (94.4%) had metastatic disease; CNS metastases were present in 25.4% of patients.^[1] Among 56 ROS-1-positive patients who previously received treatment with a TKI targeting ROS-1 (crizotinib, 82%; entrectinib, 16%) and had not received prior platinum-based chemotherapy or immunotherapy, the median age was 57 years; 94.6% had adenocarcinoma histology, 67.9% had an ECOG performance status of 1, 44.6% were white, 48.2% were Asian, and 67.9% were female.^[1] Most patients (98.2%) had metastatic disease and 42.9% had CNS metastases.^[1]

At the time of data analysis, the objective response rate for patients receiving repotrectinib was 79% among patients who were ROS-1 inhibitor-naive and 38% among patients who were previously treated with a ROS-1 inhibitor;^[1][3] complete response was achieved in 10 or 5% of patients who were ROS-1 inhibitor-naive or had previously been treated with a ROS-1 inhibitor, respectively.^[3] Partial response was achieved in 69 or 32% of patients, respectively.^[3] The median duration of response was 34.1 months among ROS-1 inhibitor-naive patients and 14.8 months among patients previously treated with a ROS-1 inhibitor.^[1][3] Intracranial response (as assessed by a blinded independent review committee) was achieved in 8 of 9 ROS-1 inhibitor naive patients with measurable CNS metastases at baseline and 5 of 13 patients previously treated with a ROS-1 inhibitor who had measurable CNS metastases at baseline.^[3] All intracranial responses, with the exception of 1 patient who was ROS-1 inhibitor-naive at baseline, were partial responses.^[3]

Clinical Perspective

A relatively small subset of patients with NSCLC have ROS-1-positive disease (approximately 1-2%), which indicates potential responsiveness to ROS-1 inhibitor therapy.^[4] Patients with ROS-1-positive disease are typically younger (median age approximately 50 years at diagnosis), of Asian descent, and nonsmokers.^[4] Trials of initially approved TKI therapies targeting ROS-1 (i.e., crizotinib and entrectinib) did not include patients who received prior treatment with ROS-1 targeted therapy in their pivotal trials.^[4] However, mechanisms of resistance have now been identified among patients with ROS-1-positive NSCLC previously treated with such agents.^[4]

The American Society of Clinical Oncology (ASCO) guidelines on management of stage IV NSCLC with driver alterations addresses treatment of patients harboring ROS-1 mutations.^[5] According to ASCO, first-line treatment recommendations for patients with stage IV NSCLC and ROS-1 mutations include repotrectinib, entrectinib, and crizotinib.^[5] Ceritinib or lorlatinib may be given when these therapies are not available or not tolerated.^[5] Repotrectinib is also recommended as a second-line therapy in patients who were previously treated with entrectinib, crizotinib, ceritinib, or lorlatinib.^[5]

Solid Tumors with Neurotrophic Receptor Tyrosine Kinase Gene Fusion

Repotrectinib is used in adults and pediatric patients >=12 years of age for the treatment of solid tumors harboring a neurotrophic receptor tyrosine kinase (NTRK) gene fusion (without a known acquired mutation for resistance), in patients who have locally advanced or metastatic disease or may experience severe morbidity following surgical resection, and whose disease progressed following prior therapy or have no satisfactory alternative treatment option.^[1] Repotrectinib has been designated an orphan drug by FDA for the treatment of these cancers.^[2] The accelerated approval of repotrectinib for this indication is based on objective response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit of repotrectinib in confirmatory studies.^[1]

Clinical Experience

The indication for repotrectinib in the treatment of solid tumors with _NTRK_fusion is based principally on the results of a multicenter, open-label, phase 1/2 trial (TRIDENT-1), which included 88 adult patients with locally advanced or metastatic NTRK (1-3) gene fusion-positive solid tumors.^[1] The trial included both patients who were naive to TKI therapy and those previously treated with a TKI.^[1] NTRK fusion was determined using FISH, NGS, or PCR; NTRK positivity via FISH testing was confirmed by a central laboratory using a validated NGS test.^[1] Patients received repotrectinib 160 mg orally once daily for 14 days, followed by an increase in frequency to 160 mg twice daily, given until disease progression or unacceptable toxicity occurred.^[1] The main efficacy endpoints assessed were overall response rate (as evaluated by a blinded independent review committee according to RECIST 1.1) and duration of response.^[1]

Among 40 NTRK-positive patients who were TKI-naive at baseline, the median age was 61 years; 55% had an ECOG performance status of 1, 25% were white, 53% were Asian, and 60% were female.^[1] Most patients (98%) had metastatic disease; CNS metastases were present in 23% of patients and 70% of patients were previously treated with systemic therapy.^[1] Among 48 NTRK-positive patients who previously received treatment with a TKI, the median age was 58 years; 60% had an ECOG performance status of 1, 65% were white, 25% were Asian, and 48% were female.^[1] Most patients (96%) had metastatic disease, 25% had CNS metastases, and 77% of patients were previously treated with >=2 systemic therapies.^[1]

At the time of data analysis, the objective response rate for patients receiving repotrectinib for the treatment of locally advanced or metastatic NTRK-positive solid tumors was 58% among TKI-naive patients and 50% among patients who were previously treated with a TKI; complete response was achieved in 15 and 0% of patients who were TKI-naive and TKI-experienced, respectively.^[1] Partial response was achieved in 43 and 50% of patients, respectively.^[1] The estimated median duration of response was not evaluable among patients who were TKI-naive and was 9.9 months among patients previously treated with a TKI.^[1] Overall response rates varied substantially based on solid tumor type.^[1] The most common NTRK fusion was _ETV6-NTRK3,_which was present in 12 TKI-naive patients and 24 TKI-experienced patients.^[1]

Clinical Perspective

The incidence of solid tumors harboring activating NTRK fusions is low (present in approximately 0.28% of cancers).^[6] Testing for NTRK fusions is recommended in patients with metastatic or advanced solid tumors who may be candidates for tropomyosin receptor kinase (TRK) inhibitor therapy; ASCO states that clinicians should consider the prevalence of NTRK fusions in individual tumor types when deciding whether to perform _NTRK_fusion testing.^[6] International experts have published consensus statements on the treatment of TRK fusion cancers in adults and pediatric patients.^[7][8]

Adults

Treatment with a selective TRK inhibitor (e.g., entrectinib, larotrectinib) should be considered in adult patients with TRK fusion-positive cancers including radioactive iodine-refractory thyroid carcinoma, colorectal cancer (if alternative treatments are not suitable, but also may be considered in the first-line setting), NSCLC, soft tissue sarcoma, salivary gland carcinoma, and other TRK fusion-positive cancers where no other effective or suitable treatment options are available.^[7]

Pediatric Patients

Because NTRK gene fusions are pathognomonic in infantile fibrosarcoma, international experts recommend considering a selective TRK inhibitor as first-line systemic therapy in patients with unresectable or metastatic infantile fibrosarcoma.^[8] TRK inhibitors have demonstrated high response rates in infantile fibrosarcoma with the potential to prevent disfiguring surgery, such as limb amputations, and to avoid cytotoxic chemotherapy in very young patients.^[8] Selective TRK inhibitors should also be considered in pediatric patients with other TRK fusion-positive cancers, including unresectable/metastatic non-rhabdomyosarcoma soft tissue sarcoma, differentiated thyroid carcinoma (if standard therapy is not effective or suitable), unresectable/metastatic glioma, and other TRK fusion-positive cancers without other effective or suitable treatment options.^[8]

General

Pretreatment Screening

Confirm the presence of ROS-1 rearrangement(s) in tumor specimens prior to initiating repotrectinib therapy for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC).^[1]Confirm the presence of neurotrophic tyrosine receptor kinase (NTRK) 1/2/3 rearrangements in tumor specimens prior to initiating repotrectinib therapy for the treatment of solid tumors.^[1]Assess serum uric acid levels prior to initiating repotrectinib.^[1]Perform liver function tests (including AST, ALT, and bilirubin) prior to initiating repotrectinib.^[1]Verify pregnancy status in females of reproductive potential.^[1]

Patient Monitoring

Monitor patients for new or worsening pulmonary symptoms indicative of interstitial lung disease/pneumonitis.^[1]Monitor liver function tests (including ALT, AST, and bilirubin) every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated.^[1]Monitor serum creatine phosphokinase (CPK) levels every 2 weeks during the first month of treatment, during therapy, and as needed in patients reporting unexplained muscle pain, tenderness, or weakness.^[1]Monitor serum uric acid levels periodically during treatment.^[1]

Other General Considerations

Discontinue strong and moderate cytochrome P-450 (CYP) 3A inhibitors for 3-5 elimination half-lives of the CYP3A inhibitor prior to initiating repotrectinib.^[1]

Administration

Repotrectinib is available as capsules containing 40 mg or 160 mg of the drug.^[1]

Administer repotrectinib orally at approximately the same time each day, with or without food.^[1]

Swallow repotrectinib capsules whole; do not open, chew, crush, or dissolve the capsules prior to swallowing.^[1] Do not take any repotrectinib capsules that are broken, cracked, or damaged.^[1]

If a dose of repotrectinib is missed or if vomiting occurs at any time after taking a dose, skip the dose and resume repotrectinib at its regularly scheduled time.^[1]

Store repotrectinib capsules at 20-25°C (excursions permitted between 15-30°C).^[1]

Dosage

Select patients for the treatment of locally advanced or metastatic NSCLC with repotrectinib based on the presence of ROS-1 rearrangement(s) in tumor specimens; an FDA-approved test to detect ROS-1 rearrangements is not currently available.^[1]

Select patients for the treatment of solid tumors with repotrectinib based on the presence of _NTRK_1/2/3 rearrangements in tumor specimens; an FDA-approved test to detect _NTRK_1/2/3 rearrangements is not currently available.^[1] In patients with secretory breast cancer or mammary analogue secretory cancer, consider treatment with repotrectinib without confirmation of NTRK rearrangements in tumor specimens.^[1]

Pediatric Dosage

Solid Tumors

The recommended dosage of repotrectinib for the treatment of NTRK gene fusion-positive solid tumors in pediatric patients >=12 years of age is 160 mg orally once daily for 14 days, then increased to 160 mg twice daily.^[1] Continue therapy until disease progression or unacceptable toxicity occurs.^[1]

Adult Dosage

Non-small Cell Lung Cancer

The recommended adult dosage of repotrectinib for the treatment of ROS-1-positive locally advanced or metastatic NSCLC is 160 mg orally once daily for 14 days, then increased to 160 mg twice daily.^[1] Continue therapy until disease progression or unacceptable toxicity occurs.^[1]

Solid Tumors

The recommended adult dosage of repotrectinib for the treatment of NTRK gene fusion-positive solid tumors is 160 mg orally once daily for 14 days, then increased to 160 mg twice daily.^[1] Continue therapy until disease progression or unacceptable toxicity occurs.^[1]

Dosage Modification for Toxicity

If adverse effects occur during repotrectinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.^[1]

Consult Table 1 for recommended repotrectinib dosage reductions for adverse reactions.^[1]

Consult Table 2 for recommended dosage adjustments for adverse reactions based on severity.^[1]

Special Populations

Hepatic Impairment

No dosage modification of repotrectinib is required for patients with mild (total bilirubin >1-1.5 times ULN or AST greater than ULN) hepatic impairment.^[1]

The recommended dosage of repotrectinib has not been established in patients with moderate (total bilirubin >1.5-3 times ULN with any AST) or severe (total bilirubin >3 times ULN with any AST) hepatic impairment.^[1]

Renal Impairment

No dosage modification of repotrectinib is required for patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-90 mL/minute).^[1]

The recommended dosage of repotrectinib has not been established in patients with severe renal impairment or kidney failure (eGFR <30 mL/minute) and patients on dialysis.^[1]

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.^[1]

Contraindications

None.^[1]

Warnings/Precautions

CNS Adverse Reactions

Repotrectinib can cause CNS adverse reactions.^[1] In the TRIDENT-1 trial, a broad spectrum of CNS adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 77% of patients treated with repotrectinib, with grade 3 or 4 events occurring in 4.5% of patients.^[1] The incidences of CNS adverse reactions observed were similar in patients with and without CNS metastases.^[1]

Dizziness, including vertigo, occurred in 65% of patients, with grade 3 dizziness occurring in 2.8% of patients.^[1] The median time to onset of dizziness was 7 days (range, 1 day to 1.4 years).^[1] Dosage interruption and reduction of repotrectinib was required in 9 and 11% of patients, respectively.^[1]

Ataxia, including gait disturbance and balance disorder, occurred in 28% of patients, with grade 3 ataxia occurring in 0.5% of patients.^[1] The median time to onset of ataxia was 15 days (range, 1 day to 1.4 years).^[1] Dosage interruption and reduction was required in 5 and 8% of patients, respectively; 1 patient permanently discontinued repotrectinib due to ataxia.^[1]

Cognitive impairment reported in patients receiving repotrectinib included memory impairment (15%), disturbance in attention (12%), and confusional state (2%); grade 3 cognitive impairment occurred in 0.9% of patients.^[1] The median time to onset of cognitive disorders was 37 days (range, 1 day to 1.4 years).^[1] Dosage interruption and reduction was required in 2 and 2.1% of patients, respectively; 0.5% of patients permanently discontinued repotrectinib due to cognitive adverse reactions.^[1]

Mood disorders (e.g., anxiety) occurred in 6% of patients, with grade 4 mood disorders (mania) occurring in 0.2% of patients.^[1] Dosage interruption was required in 0.2% of patients, and dosage reduction was required in 0.2% of patients.^[1]

Sleep disorders including insomnia and hypersomnia occurred in 18% of patients.^[1] Somnolence was also reported.^[1] Dosage interruption and reduction was required in 0.7 and 0.2% of patients, respectively.^[1]

Advise patients and caregivers of the risk of CNS adverse reactions with repotrectinib.^[1] Advise patients not to drive or operate machinery if they are experiencing CNS adverse reactions.^[1] If CNS adverse reactions occur, withhold repotrectinib and then resume at same or reduced dosage upon improvement, or permanently discontinue repotrectinib based on severity.^[1]

Interstitial Lung Disease/Pneumonitis

Repotrectinib can cause interstitial lung disease (ILD)/pneumonitis.^[1]

In the TRIDENT-1 trial, ILD/pneumonitis occurred in 3.1% of patients treated with repotrectinib, with grade 3 ILD/pneumonitis occurring in 1.2% of patients.^[1] The median time to onset of ILD/pneumonitis was 45 days (range, 19 days to 0.9 years).^[1] Dosage interruption, dosage reduction, and permanent discontinuance of repotrectinib were required in 1.4, 0.5, and 1.1% of patients, respectively.^[1]

Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis.^[1] In patients with suspected ILD/pneumonitis, immediately withhold repotrectinib.^[1] If ILD/pneumonitis is confirmed, permanently discontinue repotrectinib.^[1]

Hepatotoxicity

Repotrectinib can cause hepatotoxicity.^[1]

In the TRIDENT-1 trial, increased ALT and AST occurred in 38 and 41% of patients treated with repotrectinib, respectively, including grade 3 or 4 increased ALT (3.3%) and increased AST (2.9%).^[1] The median time to onset of increased ALT or AST was 15 days (range, 1 day to 1.9 years).^[1] Increased ALT or AST leading to dosage interruption and reduction occurred in 2.8 and 1.2% of patients, respectively.^[1] Hyperbilirubinemia leading to dosage interruption occurred in 0.5% of patients.^[1]

Monitor liver function tests, including ALT, AST, and bilirubin, prior to initiating repotrectinib, every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated.^[1] If hepatotoxicity occurs, withhold and then resume repotrectinib at the same or reduced dosage upon improvement, or permanently discontinue repotrectinib based on severity.^[1]

Myalgia with Elevation in CPK

Repotrectinib can cause myalgia with or without CPK elevation.^[1]

In the TRIDENT-1 trial, myalgia occurred in 13% of patients treated with repotrectinib, with grade 3 myalgia occurring in 0.7% of patients.^[1] The median time to onset of myalgia was 19 days (range, 1 day to 2 years).^[1] Concurrent increased CPK within a 7-day window was observed in 3.7% of patients.^[1] One patient with myalgia and concurrent CPK elevation required dosage interruption.^[1]

Advise patients to report any unexplained muscle pain, tenderness, or weakness.^[1] Monitor serum CPK levels during repotrectinib therapy.^[1] Monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness.^[1] Initiate supportive care as clinically indicated.^[1] If myalgia occurs, withhold and then resume repotrectinib at the same or reduced dosage upon improvement, based on severity.^[1]

Hyperuricemia

Repotrectinib can cause hyperuricemia.^[1]

In the TRIDENT-1 trial, hyperuricemia was reported in 5% of patients treated with repotrectinib, with 0.7% of patients experiencing grade 3 or 4 hyperuricemia.^[1] One patient without pre-existing gout required urate-lowering therapy.^[1]

Monitor serum uric acid levels prior to initiating repotrectinib and periodically during treatment.^[1] Initiate urate-lowering therapy as clinically indicated.^[1] If hyperuricemia occurs, withhold and then resume repotrectinib at the same or reduced dosage upon improvement, or permanently discontinue repotrectinib based on severity.^[1]

Skeletal Fractures

Repotrectinib can cause skeletal fractures.^[1] No data are available on the effects of repotrectinib on healing of known fractures and risk of future fractures.^[1]

In the TRIDENT-1 trial, fractures occurred in 2.3% of patients treated with repotrectinib.^[1] Fractures involved the ribs, feet, spine, acetabulum, sternum, and ankles; some fractures occurred at sites of disease and prior radiation therapy.^[1] The median time to fracture was 71 days (range, 31 days to 1.4 years).^[1] Dosage interruption was required in 0.3% of patients.^[1]

Fractures requiring dosage interruption have also been reported in pediatric patients.^[1]

Promptly evaluate patients with signs or symptoms of fractures (e.g., pain, changes in mobility, deformity).^[1]

Fetal/Neonatal Morbidity and Mortality

Repotrectinib use during pregnancy can cause fetal harm based on data in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal reproduction studies, and the mechanism of action of repotrectinib.^[1]

Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended 160 mg twice daily dose based on body surface area (BSA).^[1]

Verify pregnancy status in females of reproductive potential prior to initiating repotrectinib.^[1] Apprise pregnant women and females of reproductive potential of the potential hazard to a fetus.^[1] Advise females of reproductive potential to use effective non-hormonal contraception during treatment with repotrectinib and for 2 months after the last dose.^[1] Advise males with female partners of reproductive potential to use effective contraception during treatment with repotrectinib and for 4 months after the last dose.^[1]

Specific Populations

Pregnancy

Repotrectinib use during pregnancy can cause fetal harm based on data in humans with congenital mutations leading to changes in TRK signaling, findings from animal reproduction studies, and the mechanism of action of repotrectinib.^[1] There are no available human data on the use of repotrectinib during pregnancy.^[1]

Oral administration of repotrectinib to pregnant rats during organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended 160 mg twice daily dose based on BSA.^[1] Apprise pregnant women of the potential hazard to a fetus.^[1]

Lactation

It is unknown whether repotrectinib is distributed into human milk or if the drug has any effect on milk production or the breast-feeding infant.^[1]

Because of the potential for serious adverse reactions in nursing children, advise lactating women to discontinue breast-feeding during treatment with repotrectinib and for 10 days after the last dose.^[1]

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to initiating repotrectinib.^[1]

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with repotrectinib and for 2 months after the last dose, since repotrectinib can render some hormonal contraceptives ineffective.^[1]

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with repotrectinib and for 4 months after the last dose.^[1]

Pediatric Use

The safety and effectiveness of repotrectinib for the treatment of locally advanced or metastatic neurotrophic tyrosine receptor kinase_(NTRK)_-positive solid tumors have been established in pediatric patients >=12 years of age.^[1] The safety and effectiveness of repotrectinib have not been established in pediatric patients <12 years of age with _NTRK_gene fusion-positive solid tumors.^[1]

The safety and effectiveness of repotrectinib in pediatric patients with ROS-1-positive non-small cell lung cancer (NSCLC) have not been established.^[1]

Geriatric Use

In the TRIDENT-1 trial evaluating repotrectinib in patients with ROS-1-positive NSCLC or with _NTRK_gene fusion-positive solid tumors, 19% of patients who received repotrectinib were 65-75 years of age, and 6% were >=75 years of age.^[1] There were no clinically important differences in repotrectinib efficacy or safety between geriatric (>=65 years of age) and younger patients.^[1]

Hepatic Impairment

No clinically important differences in the pharmacokinetics of repotrectinib have been observed based on mild hepatic impairment (total bilirubin >1-1.5 times the upper limit of normal [ULN] or AST greater than ULN).^[1] The effect of moderate (total bilirubin >1.5-3 times ULN with any AST) or severe (total bilirubin >3 times ULN with any AST) hepatic impairment on repotrectinib pharmacokinetics is unknown or not fully characterized.^[1]

Renal Impairment

No clinically important differences in the pharmacokinetics of repotrectinib have been observed based on mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to <90 mL/minute).^[1] The effect of severe renal impairment, kidney failure (eGFR <30 mL/minute), or dialysis on repotrectinib pharmacokinetics is unknown or not fully characterized.^[1]

Common Adverse Effects

Adverse effects reported in >=20% of patients receiving repotrectinib were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.^[1]

Repotrectinib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.^[1]

In vitro, repotrectinib induces CYP isoenzymes 3A4, 2B6, 2C8, 2C19, and 2C9 but does not induce CYP isoenzyme 1A2.^[1] Repotrectinib inhibits CYP3A4/5 (GI tract) and uridine diphosphate-glucuronosyl transferase (UGT) 1A1.^[1] Repotrectinib inhibits P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and multidrug and toxin extrusion 2 (MATE2)-K.^[1] Repotrectinib is a substrate of P-gp.^[1]

Drugs Affecting Hepatic Microsomal Enzymes

Strong and Moderate CYP3A Inhibitors

Concomitant use of repotrectinib with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may consequently increase the incidence and severity of adverse reactions related to repotrectinib.^[1]

Repotrectinib AUC and peak plasma concentration increased by 5.9- and 1.7-fold, respectively, following concomitant use with itraconazole, a strong CYP3A and P-gp inhibitor.^[1]

Avoid concomitant use of repotrectinib with strong or moderate CYP3A inhibitors.^[1] Discontinue CYP3A inhibitors for 3-5 elimination half-lives of the CYP3A inhibitor prior to initiating repotrectinib.^[1]

Strong and Moderate CYP3A Inducers

Concomitant use of repotrectinib with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may consequently decrease repotrectinib efficacy.^[1]

Repotrectinib AUC and peak plasma concentration decreased by 92 and 79%, respectively, following concomitant use with rifampin, a strong CYP3A and P-gp inducer.^[1]

Avoid concomitant use of repotrectinib with strong or moderate CYP3A inducers.^[1]

Drugs Metabolized by Hepatic Microsomal Enzymes

Certain CYP3A4 Substrates

Concomitant use of repotrectinib decreases the plasma concentration of CYP3A4 substrates, which can consequently reduce the efficacy of these substrates.^[1]

In patients who were previously administered repotrectinib 160 mg once daily for 14 days followed by 160 mg twice daily for 7 days, concomitant use with midazolam (CYP3A substrate) decreased midazolam AUC and peak plasma concentration by 69 and 48%, respectively.^[1]

Avoid concomitant use with CYP3A substrates where minimal concentration changes can cause reduced efficacy, unless otherwise recommended in the prescribing information for the CYP3A substrate.^[1] If concomitant use cannot be avoided, increase the dosage of the CYP3A4 substrate in accordance with approved product labeling.^[1]

Drugs Affecting the P-glycoprotein Transport System

Concomitant use of repotrectinib with a P-gp inhibitor may increase repotrectinib exposure, which may consequently increase the incidence and severity of adverse reactions related to repotrectinib.^[1]

Repotrectinib AUC and peak plasma concentration increased by 5.9- and 1.7-fold, respectively, following concomitant use with itraconazole, a strong P-gp and CYP3A inhibitor.^[1]

Avoid concomitant use of repotrectinib with P-gp inhibitors.^[1]

Hormonal Contraceptives

Repotrectinib can decrease the exposure of progestin or estrogen to an extent that could reduce the effectiveness of hormonal contraceptives.^[1]

Avoid concomitant use of repotrectinib with hormonal contraceptives.^[1] Advise females of reproductive potential to use an effective nonhormonal contraceptive.^[1]

Repotrectinib is an inhibitor of multiple receptor tyrosine kinases including tropomyosin receptor kinase (TRK) A, TRKB, TRKC, and proto-oncogene tyrosine-protein kinase ROS-1.^[1] ROS-1 and TRK fusion proteins can produce hyperactivation of downstream signaling pathways, leading to unconstrained cell proliferation and tumorigenic potential.^[1] Repotrectinib exhibited anti-tumor activity in cultured cells expressing ROS-1 fusions and any of several mutations; repotrectinib also inhibited cell proliferation in cultured cells expressing NTRK fusions and any of several mutations.^[1]

The exposure-response relationships of repotrectinib and the time course of pharmacodynamic responses are not fully characterized.^[1] Repotrectinib AUC and peak plasma concentration increase approximately dose-proportional (but less than linear with estimated slopes of 0.70 and 0.78, respectively) over the single dosage range of 40-240 mg (0.25-1.5 times the approved recommended dosage).^[1] Steady-state is achieved within 14 days of daily administration of repotrectinib 160 mg.^[1] Steady-state pharmacokinetics are time-dependent with an autoinduction of cytochrome P-450 (CYP) isoenzyme 3A4.^[1] The geometric mean absolute bioavailability of repotrectinib is 45.7%.^[1] Peak plasma concentrations of repotrectinib occurred at approximately 2-3 hours after a single oral dose of 40-240 mg (0.25-1.5 times the usual dosage) under fasted conditions.^[1] Following administration of a high-fat meal (approximately 800-1000 calories, 50% fat), no clinically important differences in repotrectinib pharmacokinetics were observed in patients with cancer.^[1]

In vitro, plasma protein binding of repotrectinib was 95.4% and the blood-to-plasma ratio was 0.56.^[1] Repotrectinib elimination is time-dependent due to autoinduction of CYP3A4.^[1] The mean terminal half-life of repotrectinib is approximately 60.7 hours for patients with cancer following a single dose, and the steady-state terminal half-life is approximately 40.3 hours.^[1] Repotrectinib is principally metabolized by CYP3A4 followed by secondary glucuronidation.^[1] Following a single, radiolabeled, oral dose of repotrectinib 160 mg, 4.84% (0.56% unchanged) of the dose was recovered in urine and 88.8% (50.6% unchanged) in feces.^[1] No clinically important differences in repotrectinib pharmacokinetics were observed based on age (12--93 years), sex, or race (white, Asian, Black).^[1]

Advise patients to read the FDA-approved patient labeling (Patient Information).^[1]Advise patients to swallow repotrectinib capsules whole with or without food.^[1]Instruct patients that if they miss a dose of repotrectinib, or vomit at any time after taking a dose, to skip that dose and take the next dose of repotrectinib at the next scheduled time.^[1]Advise patients to inform their clinician if they experience new or worsening CNS symptoms (e.g., dizziness, vertigo, ataxia, changes in mood, cognitive disorders).^[1] Instruct patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions.^[1]Advise patients to inform their clinician if they experience new or worsening pulmonary symptoms indicative of interstitial lung disease or pneumonitis.^[1]Advise patients to immediately report symptoms of hepatotoxicity to their clinician.^[1] Inform patients of the need for laboratory tests to monitor liver function.^[1]Advise patients to inform their clinician if they experience muscle pain.^[1]Advise patients to inform their clinician if they experience signs or symptoms associated with hyperuricemia.^[1]Advise patients of the risk of bone fractures with repotrectinib and to report symptoms to their clinician.^[1]Advise women to inform their clinician of a known or suspected pregnancy.^[1] Advise pregnant women and females of reproductive potential of the potential risk to a fetus.^[1]Advise patients that hormonal contraceptives can be ineffective while taking repotrectinib.^[1] Advise females of reproductive potential to use effective non-hormonal contraception during treatment with repotrectinib and for 2 months after the final dose.^[1] Advise males with female partners of reproductive potential to use effective contraception during treatment with repotrectinib and for 4 months after the final dose.^[1]Advise females not to breast-feed during treatment with repotrectinib and for 10 days after the final dose.^[1]Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^[1] Advise patients to avoid grapefruit or grapefruit juice while taking repotrectinib.^[1]Inform patients of other important precautionary information.^[1]

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Repotrectinib is only available through specialty pharmacies; visit the Augtyro^® website (https://www.augtyro.com/ros1/cost-and-access) for more information on access to repotrectinib.^[9]

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