The FDA has approved tucatinib 300 mg orally twice daily with trastuzumab and pertuzumab as maintenance treatment for adults with unresectable locally advanced or metastatic HER2-positive breast cancer following induction therapy.

The indication requires no investigator-assessed progression after four to eight cycles of
trastuzumab, pertuzumab, and a taxane. Maintenance trastuzumab and pertuzumab may be
administered intravenously or as the subcutaneous fixed-dose trastuzumab-pertuzumab-
hyaluronidase formulation. Patients with hormone receptor-positive disease may continue
endocrine therapy.

This differs from tucatinib’s earlier breast cancer indication with trastuzumab and capecitabine
after at least one prior anti-HER2 regimen in the metastatic setting. The new approval moves
tucatinib into front-line maintenance while removing capecitabine from the regimen.

HER2CLIMB-05 Establishes a Progression-Free Survival Benefit

HER2CLIMB-05 enrolled 654 patients in a randomized, double-blind, placebo-controlled phase
3 trial. Participants had HER2-positive unresectable locally advanced or metastatic disease,
with no or asymptomatic brain metastases, and no progression following induction.
Patients received tucatinib plus trastuzumab and pertuzumab (n=326) or placebo plus
trastuzumab and pertuzumab (n=328) until progression or unacceptable toxicity.

Investigator-assessed median progression-free survival was 24.9 months with tucatinib and
16.3 months with placebo (hazard ratio, 0.64; 95% confidence interval, 0.51-0.80; P<.0001).
Blinded central review was consistent, with median progression-free survival of 28.9 versus 16.0
months and a hazard ratio of 0.65.

Benefit was observed across prespecified subgroups, including hormone receptor status and
the presence or absence of brain metastases. Among the relatively small subgroup with
baseline brain metastases, median central nervous system progression-free survival was 8.5
versus 4.3 months. That analysis was preliminary and should not be treated as definitive
evidence of intracranial superiority.

Overall-survival data were immature at the primary analysis.

“Tucatinib combined with trastuzumab and pertuzumab represents a new treatment option for
patients with metastatic HER2-positive breast cancer after completing their initial chemotherapy
plus HP,” Dr. Sarah Poland, a breast medical oncologist and assistant professor of hematology
and oncology at the University of Chicago, told SurvivorNet.

The benefit must be interpreted from the point of maintenance randomization, not from initiation
of first-line treatment. The study excluded patients whose disease progressed during induction. This
limits direct comparisons with trials that measured progression-free survival from the start of
first-line therapy.

Boxed Warning Changes the Risk Discussion

The updated label contains a boxed warning for severe and fatal hepatotoxicity, particularly
following rechallenge.

In HER2CLIMB-05, alanine aminotransferase increased to more than five times the upper limit
of normal in 18% of tucatinib-treated patients, aspartate aminotransferase exceeded that
threshold in 10%, and bilirubin exceeded three times the upper limit in 1.2%. Five confirmed
Hy’s Law cases occurred, including one fatal drug-induced liver injury. All five followed tucatinib
rechallenge.

Hepatotoxicity led to tucatinib dose interruption in 19%, dose reduction in approximately 16%,
and permanent discontinuation in 8%.

The label calls for alanine aminotransferase, aspartate aminotransferase, and bilirubin testing at
baseline, every two weeks for the first two months, every three weeks thereafter, and as
clinically indicated. Selected elevations require repeat testing within 48 to 72 hours.
Rechallenge, when permitted by the label, requires weekly monitoring after recovery.

Diarrhea occurred in 73%, including grade 3 events in 6%. Median onset was 11 days, and
median resolution was two days. Tucatinib interruption, reduction, or discontinuation may be
required alongside antidiarrheal treatment and evaluation for alternative causes.

Serious adverse reactions occurred in 17% of tucatinib-treated patients. Overall, 49% required
an interruption, 29% a dose reduction, and 14% permanent discontinuation because of adverse
reactions.

Tucatinib may also raise serum creatinine by inhibiting tubular creatinine transport without
reducing glomerular function. Cystatin C or another non-creatinine-based assessment may be
useful when renal function is clinically uncertain.

Where the Regimen May Fit

As Dr. Poland put it, the regimen offers “a more intensive maintenance option, with the potential
for longer cancer control without continued chemotherapy,” but its added benefit must be
weighed against diarrhea and liver dysfunction.

Selection will likely depend on the durability of induction response, baseline liver function, drug
interactions, tolerance for three-drug HER2 blockade, hormone receptor status, and central
nervous system disease history.

Unanswered questions include mature overall survival, longer-term central nervous system
outcomes, quality of life, optimal selection relative to other evolving first-line strategies, and the
efficacy of subsequent HER2-directed therapies after progression on tucatinib maintenance.