- Data Accepted for Presentation at ESMO World
Congress on Gastrointestinal Cancer -
Seagen Inc. (Nasdaq:SGEN) today announced positive topline
results from the pivotal phase 2 MOUNTAINEER clinical trial
investigating TUKYSA® (tucatinib) in combination with trastuzumab
in patients with previously treated HER2-positive metastatic
colorectal cancer (mCRC). Data from this trial will form the basis
of a planned supplemental New Drug Application to the U.S. Food and
Drug Administration (FDA) under the FDA’s Accelerated Approval
Program. Merck, known as MSD outside the U.S. and Canada, is
commercializing TUKYSA in regions outside of the U.S., Canada and
Europe and plans to discuss these results with health authorities
as it continues to accelerate the filing of TUKYSA in its
territory.
Results showed a 38.1% confirmed objective response rate (cORR)
[95% Confidence Interval (CI): 27.7, 49.3] per blinded independent
central review (BICR). The median duration of response (DoR) per
BICR was 12.4 months [95% CI: 8.5, 20.5]. The combination of
tucatinib and trastuzumab was generally well-tolerated, and the
most common (greater than or equal to 20%) treatment-emergent
adverse events were diarrhea, fatigue, nausea and infusion-related
reaction, which were primarily low-grade.
Please see Important Safety Information at the end of this press
release for further safety information regarding tucatinib.
“People with HER2-positive previously treated metastatic
colorectal cancer have a significant unmet need for new therapies.
We are excited by the potential for this tucatinib combination to
help patients based on the excellent anti-tumor activity with
durable responses and a tolerable safety profile,” said Roger
Dansey, M.D., interim CEO and Chief Medical Officer, Seagen. “Based
on the strength of these data, we are planning to engage in
regulatory discussions with the FDA with the intent to submit a
supplemental New Drug Application for TUKYSA.”
Full data from the MOUNTAINEER trial will be presented by John
H. Strickler, M.D., Duke University Medical Center, at the European
Society for Medical Oncology (ESMO) World Congress on
Gastrointestinal Cancer in Barcelona, Spain from June 29 through
July 2, 2022.
About MOUNTAINEER
MOUNTAINEER is a U.S. and European multicenter, open-label,
phase 2 clinical trial of tucatinib in combination with trastuzumab
or as a single agent in 117 patients with HER2-positive metastatic
or unresectable colorectal cancer following previous
standard-of-care therapies. The primary endpoint of the trial is
confirmed objective response rate by RECIST (Response Evaluation
Criteria in Solid Tumors) version 1.1 criteria per blinded
independent central review in patients receiving the combination of
tucatinib and trastuzumab. Duration of response, progression-free
survival, overall survival and safety and tolerability of the
combination regimen are secondary objectives.
About Colorectal Cancer
Colorectal cancer is the third leading cause of cancer-related
deaths in the U.S. and is anticipated to lead to about 52,580
deaths in 2022.1 Approximately 22% of U.S. patients with colorectal
cancer are diagnosed at the advanced stage.2 Human epidermal growth
factor receptor 2 (HER2) is overexpressed in 3-5% of patients with
metastatic colorectal cancer.3,4 There are currently no
FDA-approved therapies that specifically target HER2 in colorectal
cancer.
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.
TUKYSA is approved in 36 countries. It was approved by the U.S.
FDA in April 2020 and by the European Medicines Agency and the UK
Medicines and Healthcare Products Regulatory Agency in February
2021. Merck, known as MSD outside the U.S. and Canada, has
exclusive rights to commercialize TUKYSA in Asia, the Middle East
and Latin America and other regions outside of the U.S., Canada and
Europe.
U.S. Indication and Important Safety
Information
TUKYSA is indicated 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.
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 of the statements made in this press release are forward
looking, such as those, among others, relating to the submission of
a supplemental New Drug Application to the FDA under the FDA’s
Accelerated Approval Program, the therapeutic potential of TUKYSA,
its possible efficacy, safety and therapeutic uses, and the TUKYSA
development program. 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
possibility that the data from the MOUNTAINEER trial may not be
sufficient to support accelerated approval or expansion of the
labeled indications of use for TUKYSA in the U.S; the possibility
of impediments or delays in the submission of a supplemental New
Drug Application to the FDA; the risk of adverse events, including
the potential for newly-emerging safety signals; delays, setbacks
or failures in clinical development activities for a variety of
reasons, including the difficulty and uncertainty of pharmaceutical
product development, adverse regulatory action, possible required
modifications to clinical trials, failure to properly conduct or
manage clinical trials and failure of clinical results to support
continued development or regulatory approvals. 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 March 31, 2022,
and subsequent periodic reports, 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.
- American Cancer Society: Key Statistics for Colorectal
Cancer-2022.
https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html.
Accessed March 2022.
- Wang J., et al. Metastatic patterns and survival outcomes in
patients with stage IV colon cancer: A population‐based analysis.
Cancer Med. 2020 Jan; 9(1): 361–373.
- Takegawa N and Yonesaka K (2017). HER2 as an emerging
oncotarget for colorectal cancer treatment after failure of
anti-epidermal growth factor receptor therapy. Clin Colorectal
Cancer 16: 247-51.
- Valtorta E., et al. Assessment of a HER2 scoring system for
colorectal cancer: results from a validation study. Mod Pathol 28:
1481-91 2015.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20220523005352/en/
For Media David Caouette Vice President, Corporate
Communications (310) 430-3476 dcaouette@seagen.com
For Investors Peggy Pinkston Senior Vice President,
Investor Relations (425) 527-4160 ppinkston@seagen.com
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