What are the benefits of this drug?

Table 1 shows efficacy results based on the progression-free survival 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, PFS among patients with a history or presence of brain metastases and confirmed objective response rate.

Table 1. Efficacy Results

BICR=blinded independent central review; CI=confidence interval; PFS=progression-free survival.

1. Primary PFS analysis conducted in first 480 randomized patients.
2. Hazard ratio and 95% confidence intervals are based on stratified Cox proportional hazards regression model controlling for stratification factors (presence or history of brain metastases, ECOG status, and region of world)
3. Two-sided p-value based on re-randomization procedure (Rosenberger and Lachin 2002) controlling for stratification factors, compared with the allocated alpha of 0.05

Adapted from TUKYSA Prescribing Information

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

Figure 5 shows the efficacy results by relevant demographic subgroups.

Figure 5. PFS per BIRC by Subgroups (ITT-PFS population)

Hazard ratio was calculated from cox regression model considering stratified factors from randomization. ITT=intent-to treat-population
'Race Non-White' included subjects with race other than white.
‘Hormone receptor status: ER and PR negative’ included subjects without positive estrogen or positive progesterone.
‘Baseline brain metastasis: Y’ included subjects with a history of brain metastases or presence of brain metastases or brain lesions of equivocal significance on screening MRI per EDC data.

FDA Review

What are the possible side effects?

Table 3 below summarizes common adverse reactions.

Table 3. Adverse Reactions (≥10%) in Patients Who Received TUKYSA and with a Difference Between Arms of ≥ 5% Compared to Placebo (All Grades)

1. Stomatitis includes stomatitis, oropharyngeal pain, oropharyngeal discomfort, mouth ulceration, oral pain, lip ulceration, glossodynia, tongue blistering, lip blister, oral dysesthesia, tongue ulceration, and aphthous ulcer
2. Rash includes rash maculo-papular, rash, dermatitis acneiform, erythema, rash macular, rash papular, rash pustular, rash pruritic, rash erythematous, skin exfoliation, urticaria, dermatitis allergic, palmar erythema, plantar erythema, skin toxicity, and dermatitis
3. Hepatotoxicity includes hyperbilirubinemia, blood bilirubin increased, bilirubin conjugated increased, alanine aminotransferase increased, transaminases increased, hepatotoxicity, aspartate aminotransferase increased, liver function test increased, liver injury, and hepatocellular injury
4. Anemia includes anemia, hemoglobin decreased, and normocytic anemia
5. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function
6. Peripheral neuropathy includes peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy

TUKYSA Prescribing Information

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

Analysis of side effects by age subgroups is presented below. Race and sex analyses were not conducted because of predominance of women and Whites.

Table 5. Summary of Treatment-Emergent Adverse Events (TEAEs) by Age

SAEs=serious adverse events

FDA Review and Clinical Trial Report

¹Serious adverse event was defined as any event that resulted in one of the following: death, life-threatening event, required hospitalization or extended a current hospital stay, persistent or significant disability/incapacity, or congenital anomaly or birth defect.

Who participated in the trials?

The demographic characteristics of the safety population are summarized in Table 6.

Table 6. Demographic Characteristics (safety population)

Adapted from FDA Review

How were the trials designed?

There was one trial that provided data for approval of TUKYSA.

Enrolled patients were required to have HER2-positive, unresectable locally advanced or metastatic breast cancer, with or without brain metastases, and had prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) separately or in combination, in the neoadjuvant, adjuvant or metastatic setting.

Patients received TUKYSA 300 mg or placebo, orally twice daily, in combination with a trastuzumab 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, 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, PFS among patients with a history or presence of brain metastases, and confirmed objective response rate (ORR).