Tukysa tucatinib 150 mg Tablet, 120-count — NDC 51144-002-12 (Billing 51144-0002-12)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics 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.

12.3Pharmacokinetics 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 9.

The geometric mean (CV%) tucatinib AUC accumulation ratios ranged from 2.0 (26) fold to 2.5 (28) fold. Table 9: Tucatinib C max and AUC Tumor Type AUC ss (ng*h/mL) C max,ss (ng/mL) C trough,ss (ng/mL) mBC 5620 (43) 747 (45) 288 (59) mCRC 3370 (49) 405 (45) 197 (63) 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… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics 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 9.

The geometric mean (CV%) tucatinib AUC accumulation ratios ranged from 2.0 (26) fold to 2.5 (28) fold. Table 9: Tucatinib C max and AUC Tumor Type AUC ss (ng*h/mL) C max,ss (ng/mL) C trough,ss (ng/mL) mBC 5620 (43) 747 (45) 288 (59) mCRC 3370 (49) 405 (45) 197 (63) 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 Table 10: Effect of Other Drugs on TUKYSA Concomitant Drug (Dose) TUKYSA Dose Ratio (90% CI) of Tucatinib Exposure With and Without Concomitant Drug C max AUC Strong CYP3A Inhibitor Itraconazole (200 mg BID) 300 mg single dose 1.3 (1.2, 1.4) 1.3 (1.3, 1.4) Strong CYP3A/Moderate 2C8 Inducer Rifampin (600 mg once daily) 0.6 (0.5, 0.8) 0.5 (0.4, 0.6) Strong CYP2C8 Inhibitor Gemfibrozil (600 mg BID) 1.6 (1.5, 1.8) 3.0 (2.7, 3.5) Table 11: Effect of TUKYSA on Other Drugs Concomitant Drug (Dose) TUKYSA Dose Ratio (90% CI) of Exposure Measures of Concomitant Drug with/without Tucatinib C max AUC CYP2C8 Substrate Repaglinide (0.5 mg single… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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.

14 CLINICAL STUDIES

14.1HER2-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/m 2 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 (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 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. Table 12: Efficacy Results in HER2CLIMB BICR=blinded independent central review; CI=confidence interval; PFS=progression-free survival; OS=overall survival; ORR=objective response rate; CR=complete response; PR=partial response; DOR=duration of response.

TUKYSA + Trastuzumab + Capecitabine Placebo + Trastuzumab + Capecitabine PFS Primary PFS analysis conducted in first 480 randomized patients. N=320 N=160 Number of events (%) 178 (56) 97 (61) Median, months (95% CI) 7.8 (7.5, 9.6) 5.6 (4.2, 7.1) Hazard ratio… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility 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).