Seagen Inc. (Nasdaq: SGEN) today announced that the Phase 3
HER2CLIMB-02 clinical trial of TUKYSA® (tucatinib) in
combination with the antibody-drug conjugate ado-trastuzumab
emtansine (Kadcyla®) met its primary endpoint of progression-free
survival (PFS). Patients in the trial had unresectable locally
advanced or metastatic human epidermal growth factor receptor
2-positive (HER2-positive) breast cancer and had received previous
treatment with a taxane and trastuzumab. Overall survival (OS)
data, a secondary endpoint, are not yet mature. Discontinuations
due to adverse events were more common in the combination arm of
the trial, but no new safety signals emerged for the
combination.
“We are encouraged by these results for TUKYSA in combination
with Kadcyla® in metastatic HER2-positive breast cancer, including
in patients with brain metastases,” said Roger Dansey, President of
Research and Development and Chief Medical Officer at Seagen. “We
plan to present the HER2CLIMB-02 data at an upcoming medical
meeting and discuss the results with the FDA.”
About HER2CLIMB-02
HER2CLIMB-02 is a global, multicenter, randomized, double-blind,
placebo-controlled, Phase 3 clinical trial of tucatinib in
combination with ado-trastuzumab emtansine (T-DM1) in patients with
HER2-positive metastatic or unresectable breast cancer (MBC) who
have had prior treatment with a taxane and trastuzumab in any
setting. Trial enrollment began in 2019. The primary endpoint of
the trial is PFS per Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1 by investigator assessment. OS, PFS by blinded
independent committee review (BICR), objective response rate,
duration of response, PFS and OS in patients with brain metastases
at baseline, and safety and tolerability of the combination regimen
are secondary objectives.
About the TUKYSA Breast Cancer Development Program
TUKYSA is currently approved in the U.S. in combination with
trastuzumab and capecitabine for 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. Seagen has a
robust development program for TUKYSA, including a study with
registrational intent in first-line maintenance with trastuzumab
and pertuzumab (HER2CLIMB-05). Seagen is also supporting a
cooperative group study in adjuvant high-risk HER2-positive breast
cancer in combination with T-DM1.
About HER2-positive Breast Cancer
An estimated 300,590 people will be diagnosed with breast cancer
in the United States this year.1 Between 15 and 20 percent of
breast cancer cases are HER2-positive, which means tumors have high
levels of a protein called HER2 that promotes the growth of cancer
cells.2 Up to 50 percent of patients with HER2-positive MBC develop
brain metastases over time.3
About TUKYSA (tucatinib)
TUKYSA (tucatinib) is an oral medicine that is a tyrosine kinase
inhibitor of the HER2 protein. It is approved in more than 40
countries. Merck, known as MSD outside the U.S. and Canada, has
exclusive rights to commercialize TUKYSA in regions outside of the
U.S., Canada and Europe.
TUKYSA is approved in the U.S.:
- in combination with trastuzumab and capecitabine for 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.
- in combination with trastuzumab for adult patients with RAS
wild-type, HER2-positive unresectable or metastatic colorectal
cancer that has progressed following treatment with
fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy.
This indication is approved under accelerated approval based on
tumor response rate and durability of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in confirmatory trials.
Important U.S. Safety
Information
Warnings and Precautions
- Diarrhea: TUKYSA can cause severe diarrhea including
dehydration, hypotension, acute kidney injury, and death. 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. In HER2CLIMB, when TUKYSA was given in
combination with trastuzumab and capecitabine, 81% of patients who
received TUKYSA experienced diarrhea, including 0.5% with Grade 4
and 12% with Grade 3. Both patients who developed Grade 4 diarrhea
subsequently died, with diarrhea as a contributor to death. 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 TUKYSA dose
reductions in 6% of patients and TUKYSA discontinuation in 1% of
patients. Prophylactic use of antidiarrheal treatment was not
required on HER2CLIMB. In MOUNTAINEER, when TUKYSA was given in
combination with trastuzumab, diarrhea occurred in 64% of patients,
including Grade 3 (3.5%), Grade 2 (10%) and Grade 1 (50%).
- Hepatotoxicity: TUKYSA can cause severe hepatotoxicity.
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. 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 TUKYSA dose reductions in 8% of
patients and TUKYSA discontinuation in 1.5% of patients. In
MOUNTAINEER, 6% of patients had a bilirubin increase > 3 × ULN
(Grade ≥3), 6% had an AST increase > 5 × ULN, and 4.7% had an
ALT increase > 5 × ULN. Hepatotoxicity led to dose reduction of
TUKYSA in 3.5% of patients and discontinuation of TUKYSA in 2.3% of
patients.
- Embryo-Fetal Toxicity: TUKYSA can cause fetal harm.
Advise pregnant women and females of reproductive potential of the
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 1 week after the last dose.
Adverse Reactions
In HER2CLIMB, serious adverse reactions occurred in 26% of
patients; the most common (in ≥2% of patients) 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; the most
common (in ≥1% of patients) were hepatotoxicity (1.5%) and diarrhea
(1%). Adverse reactions led to dose reduction in 21% of patients
who received TUKYSA; the most common (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, hepatotoxicity,
vomiting, stomatitis, decreased appetite, anemia and rash.
In MOUNTAINEER, serious adverse reactions occurred in 22% of
patients; the most common (in ≥2% of patients) were intestinal
obstruction (7%), urinary tract infection (3.5%), pneumonia,
abdominal pain and rectal perforation (2.3% each). Adverse
reactions leading to permanent discontinuation of TUKYSA occurred
in 6% of patients; the most common (in ≥2% of patients) was
increased ALT (2.3%). Adverse reactions leading to dosage
interruption occurred in 23% of patients; the most common (in ≥3%
of patients) were increased ALT and diarrhea (3.5% each). Adverse
reactions leading to dose reduction occurred in 9% of patients; the
most common (in ≥2% of patients) were increased ALT and diarrhea
(2.3% each). The most common adverse reactions (≥20%) in patients
treated with TUKYSA and trastuzumab were diarrhea, fatigue, rash,
nausea, abdominal pain, infusion-related reactions and pyrexia.
Other adverse reactions (<10%) include epistaxis (7%), weight
decreased (7%), oropharyngeal pain (5%), oral dysesthesia (1%) and
stomatitis (1%).
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.
In MOUNTAINEER, Grade ≥3 laboratory abnormalities reported in
≥5% of patients who received TUKYSA were decreased lymphocytes,
decreased sodium, increased AST, and increased bilirubin. 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 in 87% of patients with
values outside normal lab limits upon treatment completion.
Consider alternative markers of renal function if persistent
elevations in serum creatinine are observed.
Drug Interactions
- Strong CYP3A/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 with a CYP3A substrate, 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 toxicities.
Use in Specific Populations
- Lactation: Advise women not to breastfeed while taking
TUKYSA and for 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
Founded 25 years ago, Seagen Inc. is a global biotechnology
company that discovers, develops, manufactures and commercializes
targeted cancer therapeutics, with antibody-drug conjugates (ADCs)
at our core. Our colleagues work together with urgency to improve
and extend the lives of people living with cancer. An ADC
technology trailblazer, approximately one-third of FDA-approved and
marketed ADCs use Seagen technology. Seagen is headquartered in
Bothell, Washington and has locations in California, Canada,
Switzerland and across Europe. For additional information, visit
seagen.com and follow us on Twitter and LinkedIn.
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, its safety, efficacy and therapeutic uses and
plans to discuss the data from the HER2CLIMB-02 trial with the FDA.
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 without limitation the
possibility that data from the HER2CLIMB-02 trial may not be
sufficient to support any regulatory approvals; adverse events,
including the potential for newly-emerging safety signals; adverse
regulatory actions; delays, setbacks or failures in product
development activities, the submission of regulatory applications
and the regulatory review process for a variety of reasons,
including without limitation the inherent difficulty and
uncertainty of pharmaceutical product development; possible
required modifications to clinical trials; the inability to provide
information and institute safety mitigation measures as may be
required by the FDA or other regulatory authorities from time to
time; 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 Seagen’s Quarterly Report on Form 10-Q for the
quarter ended June 30, 2023, and Seagen’s subsequent 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 applicable law.
Kadcyla® (ado-trastuzumab-emtansine) is a registered trademark
of Genentech, a member of the Roche Group.
1 American Cancer Society. Cancer Statistics Center. 2023
Statistics.
https://cancerstatisticscenter.cancer.org/?_gl=1*fpr3v6*_ga*NjMxOTA1ODkzLjE2ODg4NTQ0MTI.*_ga_12CJLLFFQT*MTY4ODg1NDQxMS4xLjEuMTY4ODg1NDU0My4wLjAuMA..&_ga=2.246019588.1877360464.1688854412-631905893.1688854412#!/.
Accessed July 2023.
2 American Cancer Society. Breast Cancer HER2 Status.
https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html.
Accessed July 2023.
3 Garcia-Alvarez, Oliveira. NCBI. Brain Metastases in
HER2-Positive Breast Cancer: Current and Novel Treatment
Strategies. doi: 10.3390/cancers13122927. Accessed July 2023.
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version on businesswire.com: https://www.businesswire.com/news/home/20230816497169/en/
For Media David Caouette (310) 430-3476 dcaouette@seagen.com For
Investors Doug Maffei (425) 527-4160 dmaffei@seagen.com
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