- Recommendation for Approval in the European
Union Based on Results of Pivotal HER2CLIMB Trial -
Seagen Inc. (Nasdaq:SGEN) today announced that the Committee for
Medicinal Products for Human Use (CHMP) of the European Medicines
Agency adopted a positive opinion recommending the approval of
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 2 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
The CHMP positive opinion will now be considered by the European
Commission (EC), which has the authority to approve medicines in
the European Union (EU). TUKYSA is approved in the United States,
Canada, Switzerland, Singapore and Australia.
“We are pleased the CHMP has recognized TUKYSA as a meaningful
clinical advance for people with advanced HER2-positive metastatic
breast cancer, including those with cancer that has spread to the
brain,” said Roger Dansey, M.D., Chief Medical Officer at Seagen.
“This opinion brings us one step closer to making TUKYSA available
to patients in the EU and aligns with our commitment to bring
innovative therapies to patients around the world.”
The positive CHMP opinion is based on results of the pivotal
trial HER2CLIMB and were published in The New England Journal of
Medicine in December 2019.
About HER2CLIMB
HER2CLIMB is a randomized, 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 ado-trastuzumab emtansine
(T-DM1). The results for the primary endpoint showed patients who
received TUKYSA in combination with trastuzumab and capecitabine
had a 46 percent reduction in the risk of cancer progression or
death (PFS) 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). A secondary endpoint showed that
the addition of TUKYSA reduced the risk of death (OS) by 34 percent
compared to trastuzumab and capecitabine alone (HR=0.66 [95% CI:
0.50, 0.87]; p=0.0048). Based on the results, TUKYSA was approved
in the U.S. in combination with trastuzumab and capecitabine for
treatment of adult patients with advanced unresectable or
metastatic HER2-positive breast cancer, including patients with
brain metastases, who have received one or more prior
anti-HER2-based regimens in the metastatic setting.
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 2018, more
than two million new cases of breast cancer were diagnosed
worldwide, including 522,513 in Europe.3 Between 15 and 20 percent
of breast cancer cases are HER2-positive.4 Historically,
HER2-positive breast cancer tends to be more aggressive and more
likely to recur than HER2-negative breast cancer.5,4,6 Up to 50
percent of metastatic HER2-positive breast cancer patients develop
brain metastases over time.7,8,9
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.1
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
TUKYSA.
- 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.
Adverse Reactions
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
(6%).
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.
Lab Abnormalities
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.
Drug Interactions
- Strong CYP3A or Moderate CYP2C8 Inducers: Concomitant
use may decrease TUKYSA activity. Avoid concomitant use of
TUKYSA.
- 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.
About Seagen
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.
Forward-Looking Statements
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. 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 difficulty and
uncertainty of pharmaceutical product development, the risk of
adverse events or safety signals, the inability to show sufficient
activity in clinical trials and the possibility of adverse
regulatory actions. 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 filed with the 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.
_________________________
1
https://www.ema.europa.eu/en/documents/smop-initial/chmp-summary-positive-opinion-tukysa_en.pdf
2 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 Cancer Ther 2020;19:976-987. 3 Breast.
Globocan 2018. World Health Organization. 2019.
https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf
4 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): 177-82. 5 Loibli S,
Gianni L. HER2-positive breast cancer. Lancet. 2017; 389(10087):
2415-29. 6 Breast Cancer HER2 Status. American Cancer Society
website.
https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html.
Accessed March 9, 2020. 7 Freedman RA, Gelman RS, Anders CK, et al.
TBCRC 022: a phase II trial of neratinib and capecitabine for
patients with human epidermal growth factor receptor 2-positive
breast cancer and brain metastases. J Clin Oncol.
2019;37:1081-1089. 8 Olson EM, Najita JS, Sohl J, et al. Clinical
outcomes and treatment practice patterns of patients with
HER2-positive metastatic breast cancer in the post-trastuzumab era.
Breast. 2013;22:525-531. 9 Bendell JC, Domchek SM, Burstein HJ, et
al. Central nervous system metastases in women who receive
trastuzumab-based therapy for metastatic breast carcinoma. Cancer.
2003;97:2972-2977.
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version on businesswire.com: https://www.businesswire.com/news/home/20201211005284/en/
Peggy Pinkston (425) 527-4160 ppinkston@seagen.com
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