On April 17, 2020, tucatinib was approved for use in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer. These patients included those with brain metastases and those who have received one or more prior anti-HER2–based regimens in the metastatic setting.^1,2

Supporting Efficacy Data

Approval was based on findings in the phase III HER2CLIMB trial (ClinicalTrials.gov identifier NCT02614794).^2,3 In the trial, 612 patients with HER2-positive metastatic breast cancer who had prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) were randomly assigned 2:1 to receive oral tucatinib at 300 mg twice daily plus trastuzumab and capecitabine (n = 410) or placebo plus trastuzumab and capecitabine (n = 202). Trastuzumab was given at a loading dose of 8 mg/kg on day 1 of cycle 1 if needed and then at a maintenance dose of 6 mg/kg on day 1 of 21-day cycles thereafter. Capecitabine was administered orally at 1,000 mg/m² twice daily on days 1 through 14 of every 21-day cycle. An alternate trastuzumab dosing regimen consisted of 600 mg subcutaneously on day 1 of every 21-day cycle.

Patients were treated until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival on blinded independent central review in the initial study of 480 randomly assigned patients, consisting of 320 in the tucatinib group and 160 in the control group.

The median patient age was 54 years (19% ≥ 65 years); 73% were white, 99% were female, 51% had an Eastern Cooperative Oncology Group performance status of 1, and 60% had estrogen and/or progesterone receptor–positive disease. In addition, 48% had a presence or history of brain metastases, 23% of whom had untreated metastases, 40% had treated but stable brain metastases, 37% had treated but radiographically progressing metastases, and 74% had visceral metastases. All patients had received prior trastuzumab and T-DM1, and all but two patients had received prior pertuzumab.

Among the first 480 randomly assigned patients, median progression-free survival was 7.8 months (95% confidence interval [CI] = 7.5–9.6 months) in the tucatinib group vs 5.6 months (95% CI = 4.2–7.1 months) in the control group (hazard ratio [HR] = 0.54, 95% CI = 0.42–0.71, P < .00001).

Other outcomes were analyzed in the entire randomized population. Median overall survival was 21.9 months in the tucatinib group vs 17.4 months in the control group (HR = 0.66, P = .00480). Median progression-free survival among patients with brain metastases was 7.6 months vs 5.4 months (HR = 0.48, P < .00001). Objective response rates among patients with measurable disease were 40.6% vs 22.8% (P = .00008).

How It Works

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 shows antitumor activity in HER2-expressing tumor cells. In vivo, tucatinib inhibited the growth of HER2-expressing tumors. The combination of tucatinib and trastuzumab showed increased antitumor activity in vitro and in vivo compared with either drug alone.

How It Is Used

The recommended dosage of tucatinib is 300 mg orally twice daily in combination with trastuzumab and capecitabine until disease progression or unacceptable toxicity. The recommended starting dosage in patients with severe hepatic impairment is 200 mg twice daily. Prescribing information for trastuzumab and capecitabine should be consulted for recommended dosing and dosage modifications.

Recommended dose reductions of tucatinib for adverse reactions are sequentially to 250, 200, and 150 twice daily. Treatment should be discontinued in patients unable to tolerate 150 mg twice daily.Product labeling provides instructions on dosing modifications for adverse reactions including grade 3 or 4 diarrhea, grade 2 to 4 hepatotoxicity, and other grade 3 or 4 adverse reactions.

Concomitant use of tucatinib with strong CYP2C8 inhibitors should be avoided. If such use cannot be avoided, the tucatinib dosage should be reduced to 100 mg orally twice daily. Concomitant use with strong CYP3A inducers or moderate CYP2C8 inducers should be avoided. Product labeling provides information on concomitant use with CYP3A substrates and P-glycoprotein substrates.

Safety Profile

In the HER2CLIMB trial, the most common adverse events of any grade (≥ 20%) in patients who received tucatinib were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

The most common adverse events of any grade occurring in at least 20% of the tucatinib-plus-trastuzumab/capecitabine group and at a ≥ 5% higher frequency vs the placebo-plus-trastuzumab/capecitabine group were diarrhea (81% vs 53%), palmar-plantar erythrodysesthesia (63% vs 53%), nausea (58% vs 44%), hepatotoxicity (42% vs 24%), vomiting (36% vs 25%), stomatitis (32% vs 21%), decreased appetite (25% vs 20%), anemia (21% vs 13%), and rash (20% vs 15%). The most common grade 3 or 4 adverse events included diarrhea (13% vs 9%), palmar-plantar erythrodysesthesia syndrome (13% vs 9%), and hepatotoxicity (9% vs 4%). The most common grade 3 or 4 laboratory abnormalities included decreased phosphate (8% vs 7%), increased levels of alanine transaminase (ALT; 8% vs 0.5%), and increased levels of aspartate transaminase (AST; 6% vs 5%).

Serious adverse events occurred in 26% of patients in the tucatinib group, with the most common being diarrhea, vomiting, nausea, abdominal pain, and seizure. Adverse events led to tucatinib dose reduction in 21% of patients, with the most common causes being hepatotoxicity and diarrhea. Treatment was discontinued in 6% of patients, with the most common causes being hepatotoxicity and diarrhea. Adverse events led to death in 2% of patients, with causes including sudden death, sepsis, dehydration, and cardiogenic shock.

Tucatinib has warnings/precautions for diarrhea, hepatotoxicity, and embryofetal toxicity. Severe diarrhea has been reported, as well as severe hepatotoxicity. ALT, AST, and bilirubin levels should be monitored prior to starting tucatinib, every 3 weeks during treatment, and as clinically indicated. Patients should be advised not to breastfeed while receiving tucatinib. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer. Accessed May 11, 2020.

2. Tukysa (tucatinib) tablets prescribing information, Seattle Genetics, Inc, April 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213411s000lbl.pdf. Accessed May 11, 2020.

3. Murthy RK, Loi S, Okines A, et al: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 382:597-609, 2020.