Tucatinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Overview
Tucatinib is a human epidermal growth factor receptor-2 (HER2) inhibitor that is FDA approved for the {{{indicationType}}} of Metastatic Breast Cancer TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.
Unresectable or Metastatic Colorectal Cancer TUKYSA is indicated in combination with trastuzumab for the treatment of adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.. Common adverse reactions include The following clinically significant adverse reactions are described elsewhere in the labeling:
- Diarrhea
- Hepatotoxicity.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Metastatic Breast Cancer TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.
Unresectable or Metastatic Colorectal Cancer TUKYSA is indicated in combination with trastuzumab for the treatment of adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
DOSAGE Tablets:
- 50 mg: round, yellow, film-coated, debossed with “TUC” on one side and “50” on the other side.
- 150 mg: oval-shaped, yellow, film-coated, debossed with “TUC” on one side and “150” on the other side.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tucatinib in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tucatinib in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tucatinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tucatinib in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tucatinib in pediatric patients.
Contraindications
None
Warnings
Diarrhea TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death.
If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
TUKYSA with trastuzumab and capecitabine
In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 0.5% with Grade 4 diarrhea and 12% with Grade 3 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB.
TUKYSA with trastuzumab
In MOUNTAINEER, diarrhea occurred in 64% of patients, including Grade 3 (3.5%), Grade 2 (10%), and Grade 1 (50%).
Hepatotoxicity TUKYSA can cause severe hepatotoxicity.
Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
TUKYSA with trastuzumab and capecitabine
In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase > 5 × ULN, 6% had an AST increase > 5 × ULN, and 1.5% had a bilirubin increase > 3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients.
TUKYSA with trastuzumab
In MOUNTAINEER, 6% of patients had a bilirubin increase > 3 × ULN (Grade ≥3), 6% had an AST increase > 5 × ULN, and 4.7% had an ALT increase > 5 × ULN. Hepatotoxicity led to dose reduction of TUKYSA in 3.5% of patients and discontinuation of TUKYSA in 2.3% of patients.
Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of tucatinib to pregnant rats and rabbits during organogenesis caused embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures ≥ 1.3 times the human exposure (AUC) at the recommended dose.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose.
TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
HER2-Positive Metastatic Breast Cancer
The safety of TUKYSA in combination with trastuzumab and capecitabine was evaluated in HER2CLIMB. Patients received either TUKYSA 300 mg twice daily plus trastuzumab or a non-US approved trastuzumab product, and capecitabine (n=404) or placebo plus trastuzumab or a non-US approved trastuzumab product and capecitabine (n=197). The median duration of treatment was 5.8 months (range: 3 days, 2.9 years) for the TUKYSA arm.
Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥ 2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.
Adverse reactions leading to treatment discontinuation occurred in 6% of patients who received TUKYSA. Adverse reactions leading to treatment discontinuation of TUKYSA in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%).
Adverse reactions leading to dose reduction occurred in 21% of patients who received TUKYSA. Adverse reactions leading to dose reduction of TUKYSA in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).
The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia, and rash.
Increased Creatinine
The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.
RAS Wild-Type, HER2-Positive Unresectable or Metastatic Colorectal Cancer
The safety of TUKYSA in combination with trastuzumab or a non-US approved trastuzumab product was evaluated in 86 patients enrolled in MOUNTAINEER with unresectable or metastatic colorectal cancer [see Clinical Studies (14.2)]. The median duration of exposure to TUKYSA was 6.9 months (range 0.7, 49.3).
Serious adverse reactions occurred in 22% of patients. Serious adverse reactions that occurred in ≥ 2% of patients were intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia (2.3%), abdominal pain (2.3%) and rectal perforation (2.3%).
Permanent discontinuation of TUKYSA due to an adverse reaction occurred in 6% of patients. The adverse reaction which resulted in permanent discontinuation of TUKYSA in ≥2% of patients was increased ALT (2.3%). Dosage interruptions of TUKYSA due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were increased ALT (3.5%) and diarrhea (3.5%). Dose reductions of TUKYSA due to an adverse reaction occurred in 9% of patients. Adverse reactions which required dose reductions in ≥2% of patients were increased ALT (2.3%) and diarrhea (2.3%).
The most common adverse reactions reported in ≥ 20% of patients treated with TUKYSA and trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia. The most common laboratory abnormalities reported in ≥ 20% of patients were increased creatinine, increased glucose, increased ALT, decreased hemoglobin, increased AST, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes, and decreased sodium.
Postmarketing Experience
There is limited information regarding Tucatinib Postmarketing Experience in the drug label.
Drug Interactions
Strong CYP3A Inducers or Moderate CYP2C8 Inducers Concomitant use of TUKYSA with a strong CYP3A or moderate CYP2C8 inducer decreased tucatinib plasma concentrations which may reduce TUKYSA activity.
Strong or Moderate CYP2C8 Inhibitors Concomitant use of TUKYSA with a strong CYP2C8 inhibitor increased tucatinib plasma concentrations which may increase the risk of TUKYSA toxicity.
CYP3A Substrates Concomitant use of TUKYSA with a CYP3A substrate increased the plasma concentrations of CYP3A substrate which may increase the toxicity associated with a CYP3A substrate.
P-glycoprotein (P-gp) Substrates Concomitant use of TUKYSA with a P-gp substrate increased the plasma concentrations of P-gp substrate which may increase the toxicity associated with a P-gp substrate.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Tucatinib in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tucatinib in women who are pregnant.
Labor and Delivery
TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy information.
Based on findings in animals and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on TUKYSA use in pregnant women to inform a drug-associated risk. In animal reproduction studies, administration of tucatinib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures ≥ 1.3 times the human exposure (AUC) at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Nursing Mothers
TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for lactation information.
There are no data on the presence of tucatinib or its metabolites in human or animal milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with TUKYSA and for 1 week after the last dose.
Pediatric Use
The safety and effectiveness of TUKYSA in pediatric patients have not been established.
Geriatic Use
In HER2CLIMB, 82 patients who received TUKYSA were ≥ 65 years, of whom 8 patients were ≥ 75 years. The incidence of serious adverse reactions in those receiving TUKYSA was 34% in patients ≥ 65 years compared to 24% in patients <65 years. The most frequent serious adverse reactions in patients ≥65 years who received TUKYSA were diarrhea (9%), vomiting (6%), and nausea (5%). There were no observed overall differences in the effectiveness of TUKYSA in patients ≥ 65 years compared to younger patients. There were too few patients ≥75 years to assess differences in effectiveness or safety.
In MOUNTAINEER, 12 patients were ≥65 years of age. There were too few patients ≥65 years to assess differences in effectiveness or safety.
Gender
TUKYSA can cause fetal harm when administered to a pregnant woman. TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for contraception and infertility information.
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating treatment with TUKYSA.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose.
Males
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose.
Infertility
Based on findings from animal studies, TUKYSA may impair male and female fertility
Race
There is no FDA guidance on the use of Tucatinib with respect to specific racial populations.
Renal Impairment
The use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (creatinine clearance [CLcr]: < 30 mL/min estimated by Cockcroft-Gault Equation), because capecitabine is contraindicated in patients with severe renal impairment. Refer to the Full Prescribing Information of capecitabine for additional information in severe renal impairment.
No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr: 30 to 89 mL/min).
Hepatic Impairment
Tucatinib exposure is increased in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.
No dose adjustment for TUKYSA is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tucatinib in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Tucatinib in patients who are immunocompromised.
Administration and Monitoring
Administration
Metastatic Breast Cancer
The recommended dosage of TUKYSA is 300 mg taken orally twice daily in combination with trastuzumab and capecitabine until disease progression or unacceptable toxicity.
Unresectable or Metastatic Colorectal Cancer
The recommended dosage of TUKYSA is 300 mg taken orally twice daily in combination with trastuzumab until disease progression or unacceptable toxicity.
Advise patients to swallow TUKYSA tablets whole and not to chew, crush, or split prior to swallowing. Advise patients not to ingest tablet if it is broken, cracked, or not otherwise intact.
Advise patients to take TUKYSA approximately 12 hours apart and at the same time each day with or without a meal.
If the patient vomits or misses a dose of TUKYSA, instruct the patient to take the next dose at its usual scheduled time.
When given in combination with TUKYSA, the recommended dosage of capecitabine is 1000 mg/m2 orally twice daily taken within 30 minutes after a meal. TUKYSA and capecitabine can be taken at the same time. Refer to the Full Prescribing Information for trastuzumab and capecitabine for additional information.
Monitoring
- Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA
IV Compatibility
There is limited information regarding the compatibility of Tucatinib and IV administrations.
Overdosage
There is limited information regarding Tucatinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Tucatinib Pharmacology in the drug label.
Mechanism of Action
Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed anti-tumor activity in HER2 expressing tumor cells. In vivo, tucatinib inhibited the growth of HER2 expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either drug alone.
Structure
There is limited information regarding Tucatinib Structure in the drug label.
Pharmacodynamics
Exposure Response Relationship
Tucatinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.
Cardiac Electrophysiology
No large mean increase in QTc (i.e., > 20 ms) was detected following treatment with TUKYSA at the recommended dose of 300 mg taken orally twice daily.
Pharmacokinetics
Tucatinib AUC0-INF and Cmax increased proportionally over a dosage range from 50 mg to 300 mg (0.17 to 1 times the approved recommended dosage). Time to steady state was approximately 4 days. Steady-state pharmacokinetic parameters following administration of TUKYSA 300 mg twice daily for 7 days in patients with mBC and mCRC are described in Table 9. The geometric mean (CV%) tucatinib AUC accumulation ratios ranged from 2.0 (26) fold to 2.5 (28) fold.
Absorption
The median time to peak plasma concentration of tucatinib was approximately 2 hours (range 1 to 4 hours).
Effects of Food
Following administration of a single oral dose of TUKYSA in 11 subjects after a high-fat meal (approximately 58% fat, 26% carbohydrate, and 16% protein), the mean AUC0-INF increased by 1.5-fold, the Tmax shifted from 1.5 hours to 4 hours, and Cmax was unaltered. The effect of food on the pharmacokinetics of tucatinib was not clinically meaningful.
Distribution
The geometric mean (CV%) apparent volume of distribution of tucatinib at steady-state were 903 (42) L and 829 (21) L in patients with mBC and mCRC, respectively. The plasma protein binding was 97.1% at clinically relevant concentrations.
At steady-state, concentrations of tucatinib and its metabolite ONT-993 in the cerebrospinal fluid were comparable to unbound plasma concentrations.
Elimination
At steady-state, tucatinib effective half-life was approximately 11.9 hours and geometric mean (CV%) apparent clearance was 53 (43) L/h in patients with mBC. Tucatinib effective half-life was approximately 16.4 hours and geometric mean (CV%) apparent clearance was 89 (49) L/h in patients with mCRC.
Metabolism
Tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A.
Excretion
Following a single oral dose of 300 mg radiolabeled tucatinib, approximately 86% of the total radiolabeled dose was recovered in feces (16% of the administered dose as unchanged tucatinib) and 4.1% in urine with an overall total recovery of 90% within 13 days post-dose. In plasma, approximately 76% of the plasma radioactivity was unchanged, 19% was attributed to identified metabolites, and approximately 5% was unassigned.
Specific Populations
Age (18-77 years), albumin (19 to 52 g/L), creatinine clearance (CLcr: 60 to 89 mL/min (n = 63); CLcr 30 to 59 mL/min (n = 6)), body weight (41 to 146 kg), sex (male (n = 170), female (n = 113)) and race (White (n = 205), Black (n = 37), or Asian (n = 25)) did not have a clinically meaningful effect on tucatinib exposure.
Renal Impairment
No clinically significant differences in the pharmacokinetics of tucatinib were observed in patients with mild to moderate renal impairment (CLcr: 30 to 89 mL/min by Cockcroft-Gault). The effect of severe renal impairment (CLcr: < 30 mL/min) on the pharmacokinetics of tucatinib is unknown.
Hepatic Impairment
Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment had no clinically relevant effect on tucatinib exposure. Tucatinib AUC0-INF was increased by 1.6 fold in subjects with severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function.
Nonclinical Toxicology
Carcinogenicity studies have not been conducted with tucatinib.
Tucatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Tucatinib was not clastogenic in either an in vitro chromosome aberration assay or an in vivo mouse bone marrow micronucleus assay.
Fertility studies in animals have not been conducted. In repeat-dose toxicity studies up to 13 weeks duration, decreased corpora lutea/corpus luteum cyst, increased interstitial cells of the ovary, atrophy of the uterus, and mucification of the vagina were observed in female rats at doses ≥ 6 mg/kg/day (approximately 0.1 times the human exposure at the recommended dose based on AUC). Atrophy and edema of the testes and oligospermia/germ cell debris in the epididymides were observed in male rats at ≥ 120 mg/kg/day (approximately 13 times the human exposure at the recommended dose based on AUC).
Clinical Studies
HER2-Positive Metastatic Breast Cancer The efficacy of TUKYSA in combination with trastuzumab and capecitabine was evaluated in 612 patients in HER2CLIMB (NCT02614794), a randomized (2:1), double-blind, placebo-controlled trial. Patients were required to have HER2-positive, unresectable locally advanced or metastatic breast cancer, with or without brain metastases, and prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) separately or in combination, in the neoadjuvant, adjuvant or metastatic setting. HER2 positivity was based on archival or fresh tissue tested with an FDA-approved test at a central laboratory prior to enrollment with HER2 positivity defined as HER2 IHC 3+ or ISH positive.
Patients with brain metastases, including those with progressing or untreated lesions, were eligible provided they were neurologically stable and did not require immediate radiation or surgery. The trial excluded patients with leptomeningeal disease. Randomization was stratified by the presence or history of brain metastases (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1), and region (U.S., Canada, or rest of world).
Patients received TUKYSA 300 mg or placebo orally twice daily with a trastuzumab or a non-US approved trastuzumab product loading dose of 8 mg/kg on Day 1 of Cycle 1 if needed and then a maintenance dose of 6 mg/kg on Day 1 of every 21-day cycle thereafter and capecitabine 1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle. An alternate trastuzumab dosing regimen was 600 mg administered subcutaneously on Day 1 of every 21-day cycle. Patients were treated until disease progression or unacceptable toxicity. Tumor assessments, including brain-MRI in patients with presence or history of brain metastases at baseline, occurred every 6 weeks for the first 24 weeks and every 9 weeks thereafter.
The major efficacy outcome measure was progression-free survival (PFS) in the first 480 randomized patients assessed by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional efficacy outcome measures were evaluated in all randomized patients and included overall survival (OS), PFS among patients with a history or presence of brain metastases (PFSBrainMets), and confirmed objective response rate (ORR).
The median age was 54 years (range: 22 - 82); 116 (19%) patients were age 65 or older. The majority were White (73%) and female (99%) and 51% had an ECOG performance status of 1. Sixty percent had estrogen and/or progesterone receptor-positive disease. Forty-eight percent had a presence or history of brain metastases; of these patients, 23% had untreated brain metastases, 40% had treated but stable brain metastases, and 37% had treated but radiographically progressing brain metastases. Seventy-four percent of patients had visceral metastases. Patients had received a median of 4 (range, 2 to 17) prior lines of systemic therapy and a median of 3 (range, 1 to 14) prior lines of systemic therapy in the metastatic setting. All patients received prior trastuzumab and T-DM1 and all but two patients had prior pertuzumab.
Efficacy results are summarized in Table 12 and Figure 1 and 2. Efficacy results were consistent across patient subgroups defined by stratification factors (presence or history of brain metastases, ECOG status, region of world) and hormone receptor status.
HER2-Positive Metastatic Colorectal Cancer The efficacy of TUKYSA in combination with trastuzumab was evaluated in 84 patients in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. Patients were required to have HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer and prior treatment with fluoropyrimidines, oxaliplatin, irinotecan, and anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb). Patients whose disease had deficient mismatch repair (dMMR) proteins or microsatellite instability-high (MSI-H) must have also received an anti-programmed cell death protein-1 (PD-1) mAb. Patients who received prior anti-HER2 targeting therapy were excluded. HER2 positivity as defined by HER2 overexpression or gene amplification was prospectively determined in local laboratories using immunohistochemistry (IHC), in situ hybridization (ISH), and/or next generation sequencing (NGS) on tumor tissue. RAS status was performed as standard of care prior to study entry based on expanded RAS testing including KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4.
The median age was 55 years (range: 24 to 77); 12 (14%) patients were age 65 or older. Seventy-seven percent of patients were White, 4% were Black, 4% were Asian, and 4% were Hispanic or Latino. Sixty-one percent of patients were male. Seventy percent of patients had lung metastases, 64% had liver metastases, 60% had an ECOG performance status of 0, 37% had an ECOG performance status of 1, and 4% had an ECOG performance status of 2. Ninety-nine percent of patients received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan and 83% and 52% received anti-VEGF antibodies and anti-EGFR antibodies respectively; 23%, 38%, and 39% received 1, 2, or ≥3 prior lines of therapy, respectively.
Patients received TUKYSA 300 mg orally twice per day with a loading dose of trastuzumab or a non-US approved trastuzumab product 8 mg/kg intravenously on Day 1 of Cycle 1, followed by a maintenance dose of trastuzumab 6 mg/kg on Day 1 of each subsequent 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.
The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review (BICR) according to RECIST version 1.1.
How Supplied
TUKYSA 50 mg tablets are supplied as yellow, film-coated, round tablets containing 50 mg of tucatinib. Each tablet is debossed with “TUC” on one side and “50” on the other side, and is packaged as follows:
- 50 mg tablets: 60 count in 75 cc bottle: NDC 51144-001-60
- TUKYSA 150 mg tablets are supplied as yellow, film-coated, oval-shaped tablets containing 150 mg of tucatinib. Each tablet is debossed with “TUC” on one side and “150” on the other side, and is packaged as follows:
- 150 mg tablets: 60 count in 75 cc bottle: NDC 51144-002-60
- 150 mg tablets: 120 count in 150 cc bottle: NDC 51144-002-12
Storage
Store at controlled room temperature, 20ºC to 25ºC (68ºF to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF)
Dispense to patient in original container only. Store in original container to protect from moisture. Replace cap securely each time after opening. Do not discard desiccant.
Once opened, use within 3 months. Discard any unused tablets 3 months after opening the bottle.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Diarrhea
- Inform patients that TUKYSA has been associated with severe diarrhea. Instruct patients on how to manage diarrhea and to inform their provider immediately if there is any change in bowel patterns.
Hepatotoxicity
- Inform patients that TUKYSA has been associated with severe hepatotoxicity and that they should report signs and symptoms of liver dysfunction to their healthcare provider immediately.
Embryo-Fetal Toxicity
- Inform pregnant women and females of reproductive potential of the risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.
- Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose.
- Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose.
- Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.
Lactation
- Advise women not to breastfeed during treatment with TUKYSA and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Refer to the Full Prescribing Information of trastuzumab and capecitabine for lactation information.
Infertility
- Advise males and females of reproductive potential that TUKYSA may impair fertility [see Use in Specific Populations (8.3)]. Refer to the Full Prescribing Information of trastuzumab and capecitabine for infertility information.
Precautions with Alcohol
Alcohol-Tucatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
TUKYSA
Look-Alike Drug Names
There is limited information regarding Tucatinib Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.