- Approved for Adult Patients with
HER2-Positive Metastatic Breast Cancer Who Have Received at Least
Two Prior Anti-HER2 Treatment Regimens -
- First HER-2 Tyrosine Kinase Inhibitor
Combination Regimen to Improve Overall and Progression-Free
Survival in Previously Treated Patients with Metastatic
HER2-Positive Breast Cancer With or Without Brain Metastases -
Seagen Inc. (Nasdaq:SGEN) today announced that the European
Commission (EC) has granted marketing authorization for
TUKYSA® (tucatinib) in combination with trastuzumab and
capecitabine for the treatment of adult patients with HER2-positive
locally advanced or metastatic breast cancer who have received at
least two prior anti-HER2 treatment regimens. TUKYSA is an oral,
small molecule tyrosine kinase inhibitor (TKI) of HER2, a protein
that contributes to cancer cell growth.1,2
“This approval is a significant advancement for patients in
Europe, who will for the first time have an approved medicine
demonstrating a survival benefit for HER2-positive metastatic
breast cancer after disease progression following two standard
anti-HER2 treatment regimens,” said Prof. Dr. Med Volkmar Mueller,
Deputy Director at the University Medical Center Hamburg-Eppendorf,
Hamburg, Germany and investigator for the pivotal trial. “In the
HER2CLIMB pivotal trial, the tucatinib combination regimen improved
overall and progression-free survival compared to trastuzumab and
capecitabine alone, including in patients with active, untreated or
progressing brain metastases, a population with significant unmet
“The TUKYSA combination is a landmark therapy for patients with
HER2-positive metastatic breast cancer with or without brain
metastases, extending overall survival in these patients after two
prior anti-HER2 treatment regimens,” said Clay Siegall, Ph.D.,
Chief Executive Officer at Seagen. “We are pleased TUKYSA is now
approved in Europe, and we look forward to further collaborating
with individual countries to ensure it is available to
The Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Agency adopted a positive opinion for TUKYSA in
December 2020. The approval of TUKYSA is valid in all countries of
the European Union, as well as Norway, Liechtenstein, Iceland and
HER2CLIMB Efficacy and Safety
Patients who received TUKYSA in combination with trastuzumab and
capecitabine in the pivotal trial had a 46 percent reduction in the
risk of cancer progression or death (PFS), the primary endpoint,
compared to patients who received trastuzumab and capecitabine
alone (hazard ratio (HR)=0.54 [95% Confidence Interval (CI): 0.42,
0.71]; p<0.00001) and improved overall survival with a reduction
in the risk of death by 34 percent (HR=0.66 [95% CI: 0.50, 0.87];
p=0.0048). The most common adverse reactions occurring in 20
percent or more of patients who received TUKYSA were diarrhea,
nausea, vomiting, stomatitis, AST increase, ALT increase, and
The pivotal trial, HER2CLIMB, is a randomized (2:1),
double-blind, placebo-controlled, active comparator, global trial
that enrolled 612 patients with HER2-positive unresectable locally
advanced or metastatic breast cancer who had previously received,
either separately or in combination, trastuzumab, pertuzumab, and
trastuzumab emtansine (T-DM1 SmPC).
About HER2-Positive Breast Cancer
Patients with HER2-positive breast cancer have tumors with high
levels of a protein called human epidermal growth factor receptor 2
(HER2), which promotes the growth of cancer cells. In 2020, more
than two million new cases of breast cancer were diagnosed
worldwide, including 531,086 in Europe.3 Between 15 and 20 percent
of breast cancer cases are HER2-positive.4 HER2-positive breast
cancer tends to be more aggressive and more likely to recur than
HER2-negative breast cancer.4,5,6 Up to 50 percent of metastatic
HER2-positive breast cancer patients develop brain metastases over
About TUKYSA (tucatinib)
TUKYSA is an oral medicine that is a tyrosine kinase inhibitor
of the HER2 protein. In vitro (in lab studies), TUKYSA inhibited
phosphorylation of HER2 and HER3, resulting in inhibition of
downstream MAPK and AKT signaling and cell growth (proliferation),
and showed anti-tumor activity in HER2-expressing tumor cells. In
vivo (in living organisms), TUKYSA inhibited the growth of
HER2-expressing tumors. The combination of TUKYSA and the anti-HER2
antibody trastuzumab showed increased anti-tumor activity in vitro
and in vivo compared to either medicine alone.
U.S. Important Safety Information
Warnings and Precautions
- Diarrhea – TUKYSA can cause severe diarrhea including
dehydration, hypotension, acute kidney injury, and death. In
HER2CLIMB, 81% of patients who received TUKYSA experienced
diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4
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 on HER2CLIMB. If diarrhea occurs, administer antidiarrheal
treatment as clinically indicated. Perform diagnostic tests as
clinically indicated to exclude other causes of diarrhea. Based on
the severity of the diarrhea, interrupt dose, then dose reduce or
permanently discontinue TUKYSA.
- Hepatotoxicity – TUKYSA can cause severe hepatotoxicity.
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. Monitor ALT, AST, and bilirubin
prior to starting TUKYSA, every 3 weeks during treatment, and as
clinically indicated. Based on the severity of hepatotoxicity,
interrupt dose, then dose reduce or permanently discontinue
- Embryo-Fetal Toxicity – TUKYSA can cause fetal harm.
Advise pregnant women and females of reproductive potential risk to
a fetus. Advise females of reproductive potential, and male
patients with female partners of reproductive potential, to use
effective contraception during TUKYSA treatment and for at least 1
week after the last dose.
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 led to treatment discontinuation in 6% of
patients who received TUKYSA; those occurring in ≥1% of patients
were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led
to dose reduction in 21% of patients who received TUKYSA; those
occurring in ≥2% of patients were hepatotoxicity (8%) and diarrhea
The most common adverse reactions in patients who received
TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia,
nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased
appetite, abdominal pain, headache, anemia, and rash.
In HER2CLIMB, Grade ≥3 laboratory abnormalities reported in ≥5%
of patients who received TUKYSA were: decreased phosphate,
increased ALT, decreased potassium, and increased AST. The mean
increase in serum creatinine was 32% within the first 21 days of
treatment with TUKYSA. The serum creatinine increases persisted
throughout treatment and were reversible upon treatment completion.
Consider alternative markers of renal function if persistent
elevations in serum creatinine are observed.
- Strong CYP3A or Moderate CYP2C8 Inducers: Concomitant
use may decrease TUKYSA activity. Avoid concomitant use of
- Strong or Moderate CYP2C8 Inhibitors: Concomitant use of
TUKYSA with a strong CYP2C8 inhibitor may increase the risk of
TUKYSA toxicity; avoid concomitant use. Increase monitoring for
TUKYSA toxicity with moderate CYP2C8 inhibitors.
- CYP3A Substrates: Concomitant use may increase the
toxicity associated with a CYP3A substrate. Avoid concomitant use
of TUKYSA where minimal concentration changes may lead to serious
or life-threatening toxicities. If concomitant use is unavoidable,
decrease the CYP3A substrate dosage.
- P-gp Substrates: Concomitant use may increase the
toxicity associated with a P-gp substrate. Consider reducing the
dosage of P-gp substrates where minimal concentration changes may
lead to serious or life-threatening toxicity.
Use in Specific Populations
- Lactation: Advise women not to breastfeed while taking
TUKYSA and for at least 1 week after the last dose.
- Renal Impairment: Use of TUKYSA in combination with
capecitabine and trastuzumab is not recommended in patients with
severe renal impairment (CLcr < 30 mL/min), because capecitabine
is contraindicated in patients with severe renal impairment.
- Hepatic Impairment: Reduce the dose of TUKYSA for
patients with severe (Child-Pugh C) hepatic impairment.
For more information, please see the full Prescribing
Information for TUKYSA here.
Seagen is a global biotechnology company that discovers,
develops, and commercializes transformative cancer medicines to
make a meaningful difference in people’s lives. Seagen is
headquartered in the Seattle, Washington area, and has locations in
California, Canada, Switzerland, and the European Union. For more
information on the company’s marketed products and robust pipeline,
visit www.seagen.com and follow @SeagenGlobal on Twitter.
Certain statements made in this press release are forward
looking, such as those, among others, relating to the therapeutic
potential of TUKYSA including its efficacy, safety and therapeutic
uses, and the potential to make TUKYSA available to patients in
Europe. Actual results or developments may differ materially from
those projected or implied in these forward-looking statements.
Factors that may cause such a difference include the possibilities
that we may experience delays or setbacks in seeking pricing and
reimbursement approvals or otherwise in commercializing TUKYSA in
Europe; that adverse events or safety signals may occur; and that
adverse regulatory actions may occur. More information about the
risks and uncertainties faced by Seagen is contained under the
caption “Risk Factors” included in the company’s Quarterly Report
on Form 10-Q for the quarter ended September 30, 2020 and the
company’s Current Report on Form 8-K dated December 30, 2020 filed
with the U.S. Securities and Exchange Commission. Seagen disclaims
any intention or obligation to update or revise any forward-looking
statements, whether as a result of new information, future events
or otherwise, except as required by law.
TUKYSA [package insert]. Bothell,
WA: Seagen Inc.
Anita Kulukian, Patrice Lee,
Janelle Taylor, et al. Preclinical Activity of HER2-Selective
Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in
Combination with Trastuzumab or Docetaxel in Solid Tumor ModelsMol
Breast. Globocan 2020. World
Health Organization. 2020.
Loibl S, Gianni L. HER2-positive
breast cancer. Lancet. 2017; 389(10087): 2415-29.
Slamon D, Clark G, Wong S, et al.
Human breast cancer: correlation of relapse and survival with
amplification of the HER-2/neu oncogene. Science. 1987; 235(4785):
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American Cancer Society website.
Accessed March 9, 2020.
Freedman RA, Gelman RS, Anders
CK, et al. TBCRC 022: a phase II trial of neratinib and
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Olson EM, Najita JS, Sohl J, et
al. Clinical outcomes and treatment practice patterns of patients
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