TUKYSA - SEAGEN INC. | Sharp Packaging Services, LLC

Maintenance Treatment of HER2-Positive Breast Cancer

TUKYSA is indicated in combination with trastuzumab and pertuzumab for the maintenance treatment of adult patients with unresectable locally advanced or metastatic HER2-positive breast cancer following induction treatment.

HER2-Positive 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.

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.

Select patients for treatment of unresectable or metastatic colorectal cancer with TUKYSA based on the presence of:

• HER2 overexpression or gene amplification [see Clinical Studies (14.2)]. FDA-authorized tests for the detection of HER2 overexpression and gene amplification in patients with unresectable or metastatic colorectal cancer are not currently available, and
• RAS wild-type [see Clinical Studies (14.2)]. Information on FDA-authorized tests for the detection of RAS mutations in patients with unresectable or metastatic colorectal cancer is available at www.fda.gov/CompanionDiagnostics.

The recommended dosages for TUKYSA are listed in Table 1.

Administration Instructions

Advise patients to swallow TUKYSA tablets whole and not to chew, crush, or split prior to swallowing. Advise patients not to ingest a 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 [see Clinical Pharmacology (12.3)].

If the patient vomits or misses a dose of TUKYSA, instruct the patient to take the next dose at its usual scheduled time.

The recommended TUKYSA dose reductions and dosage modifications for adverse reactions are provided in Tables 2 and 3. Refer to the Prescribing Information of combination agents for information about dosage modifications for these drugs.

Permanently discontinue TUKYSA in patients unable to tolerate 150 mg orally twice daily.

For patients with severe hepatic impairment (Child-Pugh C), reduce the recommended dosage to 200 mg orally twice daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

Avoid concomitant use of strong CYP2C8 inhibitors with TUKYSA. If concomitant use with a strong CYP2C8 inhibitor cannot be avoided, reduce the recommended dosage to 100 mg orally twice daily. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, resume the TUKYSA dose that was taken prior to initiating the inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

TUKYSA can cause severe and fatal hepatotoxicity, particularly after rechallenge [see Adverse Reactions (6.1)].

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 2 weeks for the first 2 months, then every 3 weeks during treatment, and as clinically indicated. For patients who experience AST/ALT >3 × ULN and bilirubin > ULN to ≤2 × ULN, repeat testing within 48-72 hours. For patients who experience AST/ALT >5 × ULN, withhold TUKYSA and repeat testing within 48-72 hours to determine if worsening. Based on the severity of hepatotoxicity, reduce dose or permanently discontinue TUKYSA [see Dosage and Administration (2.3)]. Institute weekly liver function monitoring if TUKYSA is resumed after resolution to Grade ≤1.

TUKYSA with trastuzumab and pertuzumab

In HER2CLIMB-05, 18% of patients who received TUKYSA had an ALT increase >5 × ULN, 10% had an AST increase >5 × ULN, and 1.2% had a bilirubin increase >3 × ULN (Grade ≥3). There were five confirmed Hy’s Law cases, including a fatal case. All occurred following rechallenge with TUKYSA. Hepatotoxicity led to dose reduction of TUKYSA in 16% of patients and discontinuation of TUKYSA in 8% of patients.

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.

TUKYSA can cause severe diarrhea, including dehydration, hypotension, acute kidney injury, and death [see Adverse Reactions (6.1)].

If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the diarrhea severity, interrupt dose, reduce dose, or permanently discontinue TUKYSA [see Dosage and Administration (2.3)].

TUKYSA with trastuzumab and pertuzumab

In HER2CLIMB-05, 73% of patients who received TUKYSA experienced diarrhea, including 6% with Grade 3 events. The median time to onset of the first episode of diarrhea was 11 days and the median time to resolution was 2 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1.5% of patients. Prophylactic use of antidiarrheal treatment was not required in HER2CLIMB-05.

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 in HER2CLIMB.

TUKYSA with trastuzumab

In MOUNTAINEER, diarrhea occurred in 64% of patients, including Grade 3 (3.5%), Grade 2 (10%), and Grade 1 (50%).

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 [see Use in Specific Populations (8.1, 8.3)].

TUKYSA is used in combination with other agents. Refer to the Prescribing Information of combination agents for pregnancy and contraception information.

TUKYSA can increase serum creatinine. Across three clinical trials in 816 patients (HER2CLIMB-05, HER2CLIMB, and MOUNTAINEER), the mean increase in serum creatinine was 29%-32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. These increases were not associated with changes in glomerular function [see Adverse Reactions (6.1)]. These increases in serum creatinine may be due to inhibition of renal tubular transport of creatinine. During TUKYSA treatment, use alternative measures that are not based on serum creatinine to assess renal function [see Clinical Pharmacology (12.3)].

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.

Unresectable or Metastatic Breast Cancer

Maintenance Treatment of HER2-Positive Metastatic Breast Cancer (HER2CLIMB-05)

The safety of TUKYSA in combination with trastuzumab and pertuzumab was evaluated in HER2CLIMB-05 [see Clinical Studies (14.1)]. Patients received TUKYSA 300 mg twice daily plus trastuzumab and pertuzumab (n = 326) or placebo plus trastuzumab and pertuzumab (n = 324). The median duration of treatment was 17 months (range: 0.4 to 37) for the TUKYSA arm.

Serious adverse reactions occurred in 17% of patients who received TUKYSA. Serious adverse reactions in ≥1% of patients included hepatotoxicity (3.9%). One patient experienced a fatal adverse reaction of drug-induced liver injury.

Permanent discontinuation of TUKYSA due to an adverse reaction occurred in 14% of patients. Adverse reactions leading to permanent discontinuation in ≥1% of patients were hepatotoxicity (8%) and diarrhea (1.5%).

Dosage interruptions of TUKYSA due to an adverse reaction occurred in 49% of patients. Adverse reactions which required dosage interruption in >5% of patients included hepatotoxicity (19%) and diarrhea (9%).

Dose reduction of TUKYSA due to an adverse reaction occurred in 29% of patients. Adverse reactions leading to dose reduction in ≥2% of patients were hepatotoxicity (16%) and diarrhea (6%).

The most common (≥20%) adverse reactions were diarrhea, musculoskeletal pain, hepatotoxicity, nausea, fatigue, rash, and vomiting.

Table 4 summarizes the adverse reactions in HER2CLIMB-05.

Other clinically relevant adverse reactions in <10% of patients who received TUKYSA in combination with trastuzumab and pertuzumab included epistaxis (3.7%).

Treatment of HER2-Positive Breast Cancer (HER2CLIMB)

The safety of TUKYSA in combination with trastuzumab and capecitabine was evaluated in HER2CLIMB [see Clinical Studies (14.1)]. 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.

Table 6 summarizes the adverse reactions in HER2CLIMB.

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.

Table 8 summarizes the adverse reactions in MOUNTAINEER.

Other clinically relevant adverse reactions in <10% of patients who received TUKYSA in combination with trastuzumab include epistaxis (7%), weight decreased (7%), oropharyngeal pain (5%), oral dysesthesia (1%), and stomatitis (1%).

Table 10 summarizes the effect of other drugs on TUKYSA.

Table 11 summarizes the effect of TUKYSA on other drugs.

Risk Summary

TUKYSA is used in combination with other agents. Refer to the Prescribing Information of combination agents 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 (see Data). 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.

Data

Animal Data

In pilot embryo-fetal development studies, pregnant rats and rabbits received oral doses of tucatinib up to 150 mg/kg/day during the period of organogenesis.

In rats, oral administration of tucatinib resulted in maternal toxicity (body weight loss, reduced body weight gain, low food consumption) at doses ≥90 mg/kg/day. Fetal effects included reduced number of live fetuses, decreased fetal weight, and fetal abnormalities (increase in skeletal variations, incomplete ossification) at ≥90 mg/kg/day (approximately 3.5 times the human exposure at the recommended dose based on AUC).

In rabbits, oral administration of tucatinib resulted in increased resorptions, decreased percentages of live fetuses, and skeletal, visceral, and external malformations in fetuses at doses ≥90 mg/kg/day (1.3 times the human exposure at the recommended dose based on AUC). Fetal abnormalities included domed head, brain dilation, incomplete ossification of frontal and parietal bones, and a hole in the parietal bone.

Risk Summary

TUKYSA is used in combination with other agents. Refer to the Prescribing Information of combination agents for lactation information. When TUKYSA is used in combination, advise patients not to breastfeed during treatment and for the longest post-treatment duration recommended in the Prescribing Information of any of the individual products.

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.

TUKYSA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. TUKYSA is used in combination with other agents. Refer to the Prescribing Information of combination agents for contraception and infertility information. When TUKYSA is used in combination, advise patients to use effective contraception during treatment and for the longest post-treatment duration recommended in the Prescribing Information of any of the individual products.

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 [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of TUKYSA in pediatric patients have not been established.

In HER2CLIMB-05, 51 patients who received TUKYSA were ≥65 years of age of whom 12 patients were ≥75 years of age. The incidence of ≥ Grade 3 adverse reactions was 57% in patients ≥65 years of age compared to 40% in patients <65 years of age. There were no overall differences in the effectiveness of TUKYSA in patients ≥65 years of age compared to younger patients. There were too few patients ≥75 years of age to assess differences in effectiveness or safety.

In HER2CLIMB, 82 patients who received TUKYSA were ≥65 years of age, of whom 8 patients were ≥75 years of age. The incidence of serious adverse reactions in those receiving TUKYSA was 34% in patients ≥65 years of age compared to 24% in patients <65 years of age. The most frequent serious adverse reactions in patients ≥65 years of age 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 of age compared to younger patients. There were too few patients ≥75 years of age to assess differences in effectiveness or safety.

In MOUNTAINEER, 12 patients were ≥65 years of age. There were too few patients ≥65 years of age to assess differences in effectiveness or safety.

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 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).

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 [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

No dose adjustment for TUKYSA is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

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.

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.

Tucatinib AUC_0-INF and C_max 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 12. 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 AUC_0-INF increased by 1.5-fold, the T_max shifted from 1.5 hours to 4 hours, and C_max 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 AUC_0-INF was increased by 1.6 fold in subjects with severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function.

Drug Interaction Studies

Clinical Studies

No clinically significant difference in the pharmacokinetics of tucatinib were observed when used concomitantly with omeprazole (proton pump inhibitor) or tolbutamide (sensitive CYP2C9 substrate).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Tucatinib is a reversible inhibitor of CYP2C8 and CYP3A and a time-dependent inhibitor of CYP3A, but is not an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6.

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Tucatinib is not an inhibitor of UGT1A1.

Transporter Systems: Tucatinib is a substrate of P-gp and BCRP, but is not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, or BSEP.

Tucatinib inhibits MATE1/MATE2-K-mediated transport of metformin and OCT2/MATE1-mediated transport of creatinine. The observed serum creatinine increase in clinical studies with tucatinib is due to inhibition of tubular secretion of creatinine via OCT2 and MATE1.

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).

Maintenance Treatment of HER2-Positive Breast Cancer

HER2CLIMB-05

The efficacy of TUKYSA in combination with trastuzumab and pertuzumab was evaluated in 654 adult patients in HER2CLIMB-05 (NCT05132582), a randomized (1:1), double-blind, placebo-controlled trial. Eligible patients were required to have HER2-positive, unresectable locally advanced or metastatic breast cancer, with or without brain metastases, and no evidence of disease progression by investigator assessment (i.e., experiencing a complete response, partial response, or stable disease) after induction treatment with 4-8 cycles of trastuzumab, pertuzumab, and a taxane. Tumor HER2 positivity was determined at a central laboratory by immunohistochemistry (IHC) and in situ hybridization (ISH) prior to randomization (defined as a 3+ score on IHC and/or 2+ IHC and concurrent positive by ISH).

Patients with a presence or history of brain metastases were eligible provided they were asymptomatic and stable and did not require immediate local treatment. Randomization was stratified by the presence or history of brain metastases (yes vs. no), hormone receptor status (positive vs. negative), and diagnosis (de novo vs. recurrent).

Patients received TUKYSA 300 mg or placebo orally twice daily with trastuzumab 6 mg/kg intravenously or subcutaneously at a fixed dose of 600 mg and pertuzumab 420 mg intravenously once every 21 days, or with a fixed-dose combination of 600 mg trastuzumab, 600 mg pertuzumab, and 20,000 units hyaluronidase given subcutaneously every 21 days. Patients with hormone receptor positive disease were permitted to continue endocrine therapy (with ovarian suppression, if applicable). Patients were treated until disease progression or unacceptable toxicity.

The primary efficacy outcome measure was progression-free survival (PFS) by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional efficacy outcome measures included overall survival (OS).

The median age was 54 years (range: 24 - 83); 108 (17%) patients were 65 years of age and older. Forty-five percent were White, 35% were Asian, and 3% were Black; 19% were Hispanic or Latino and 66% were not Hispanic or Latino, and 14% were missing/unknown; all were female; and patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (64%), 1 (36%), or 2 (0.3%). Fifty-three percent had estrogen and/or progesterone receptor-positive disease. Twelve percent had a presence or history of brain metastases and 56% of patients had visceral metastases.

Efficacy results are summarized in Table 15 and Figure 1. Overall survival data were not mature at the time of PFS analysis, with 51 deaths (8%) across both arms in the overall population.

Figure 1: Kaplan-Meier Plot of PFS per Investigator in HER2CLIMB-05

Treatment of HER2-Positive Breast Cancer

HER2CLIMB

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), 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-U.S. 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 PFS in the first 480 randomized patients assessed by Blinded Independent Central Review (BICR) using RECIST v1.1. Additional efficacy outcome measures were evaluated in all randomized patients and included OS, PFS among patients with a history or presence of brain metastases (PFS_BrainMets) 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 2 patients had prior pertuzumab.

Efficacy results are summarized in Table 16 and Figures 2 and 3. 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.

Figure 2: Kaplan-Meier Plot of PFS per BICR in HER2CLIMB

Figure 3: Kaplan-Meier Plot of Overall Survival in HER2CLIMB

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-U.S. 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 BICR according to RECIST version 1.1.

Efficacy results are summarized in Table 17.

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: bottle of 60 tablets (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: bottle of 60 tablets (NDC 51144-002-60)

     150 mg tablets: bottle of 120 tablets (NDC 51144-002-12)

Store at controlled room temperature at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature].

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.