–Phase 2 trial showed chemotherapy-free TUKYSA
combination resulted in clinically meaningful and durable tumor
responses–
–Results presented in late-breaking oral
session at the ESMO World Congress on Gastrointestinal Cancer–
Seagen Inc. (Nasdaq:SGEN) today announced full results from the
pivotal phase 2 MOUNTAINEER trial, which showed TUKYSA®
(tucatinib) in combination with trastuzumab was well-tolerated with
durable responses in patients with previously treated HER2-positive
metastatic colorectal cancer (mCRC). These late-breaking data were
presented in an oral session at the European Society for Medical
Oncology (ESMO) World Congress on Gastrointestinal Cancer on July 2
in Barcelona, Spain.
“Patients with chemotherapy-refractory HER2-positive metastatic
colorectal cancer receive limited clinical benefit with currently
available therapies,” said John H. Strickler, M.D., Associate
Professor of Medicine, Duke University School of Medicine and lead
trial investigator. “With sustained responses and favorable
tolerability in heavily pretreated patients, tucatinib in
combination with trastuzumab has the potential to be a new
treatment option for previously treated HER2-positive mCRC.”
“This study has shown the benefits of dual-HER2 inhibition with
tucatinib and trastuzumab in patients with HER2-positive metastatic
colorectal cancer, including many whose cancer had spread to the
liver or lungs before joining the trial,” said Roger Dansey, M.D.,
interim CEO and Chief Medical Officer, Seagen. “We believe this
chemotherapy-free combination may play an important role in
addressing the unmet needs of patients with this disease.”
At a median duration of follow-up of 20.7 months (interquartile
range: 11.7, 39.0), results of the MOUNTAINEER trial showed a 38.1%
confirmed objective response rate (cORR) (95% Confidence Interval
[CI]: 27.7, 49.3) per blinded independent central review (BICR) in
the HER2-positive patients who were assigned to receive tucatinib
in combination with trastuzumab (n=84 with a median age of 55.0
years [range 24 to 77]). In these patients, the median duration of
response (DoR) per BICR was 12.4 months (95% CI: 8.5, 20.5). Median
progression-free survival per BICR was 8.2 months (95% CI: 4.2,
10.3), and median overall survival was 24.1 months (95% CI: 20.3,
36.7). At study entry, 64.3% and 70.2% of these patients had liver
or lung metastases, respectively, and had received a median of 3.0
(1, 6) prior lines of systemic therapy.
In a cohort of patients who received tucatinib monotherapy
(n=30), the ORR per BICR by 12 weeks was 3.3% (95% CI: 0.1, 17.2)
and the disease control rate was 80.0%. Participants who did not
respond to tucatinib monotherapy by 12 weeks or progressed at any
time had the option to receive the combination of tucatinib and
trastuzumab.
The most common (greater than or equal to 20%)
treatment-emergent adverse events (AEs) in patients assigned to
receive tucatinib and trastuzumab (n=86) were diarrhea (Grade 1 or
2: 60.5%, Grade 3: 3.5%), fatigue (Grade 1 or 2: 41.9%, Grade 3:
2.3%), nausea (Grade 1 or 2: 34.9%) and infusion-related reaction
(Grade 1 or 2: 20.9%). The most common Grade ≥3 AE was hypertension
(Grade 3: 7.0%). AEs leading to discontinuation of any treatment
occurred in 5.8% of patients. No deaths due to AEs were reported.
Please see Important Safety Information at the end of this press
release for further safety information regarding tucatinib.
Data from this trial will form the basis of a planned
supplemental New Drug Application to the U.S. Food and Drug
Administration under the Accelerated Approval Program. 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 and plans to discuss these results with certain global
health authorities.
ABSTRACT TITLE
ABSTRACT #
PRESENTATION
LEAD AUTHOR
MOUNTAINEER: Open-label, phase 2 study of
tucatinib in combination with trastuzumab for HER2-positive
metastatic colorectal cancer (SGNTUC-017)
LBA-2
Saturday, July 2, 2022, 12:35-12:47 CEST
in Session XXII: Colorectal Cancer: Metastatic Disease
J. Strickler
About MOUNTAINEER
MOUNTAINEER is a U.S. and European multicenter, open-label,
randomized phase 2 clinical trial of tucatinib in combination with
trastuzumab or as a single agent that enrolled 117 patients with
HER2-positive metastatic or unresectable colorectal cancer
following previous standard-of-care therapies. MOUNTAINEER began as
a U.S. investigator-sponsored trial and initially consisted of a
single cohort (Cohort A) of patients who received tucatinib (300
mg) twice per day orally in combination with trastuzumab
intravenously (8 mg/kg loading dose, then 6 mg/kg every three weeks
thereafter). The trial was then expanded globally to include
patients who were randomized to receive tucatinib plus trastuzumab
(Cohort B) or tucatinib monotherapy (Cohort C).
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
(Cohorts A and B). Duration of response, progression-free survival,
overall survival and safety and tolerability of the combination
regimen are secondary objectives.
About Colorectal Cancer
Globally, more than 1.9 million new colorectal cancer cases and
935,000 deaths were estimated to occur in 2020, representing about
one in 10 cancer cases and deaths.1 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 2022.2 Approximately
22% of U.S. patients with colorectal cancer are diagnosed at the
advanced stage.3 Human epidermal growth factor receptor 2 (HER2) is
overexpressed in 3-5% of patients with metastatic colorectal
cancer.4,5 There are currently no FDA-approved therapies that
specifically target HER2 in colorectal cancer.
About TUKYSA
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 planned
submission of a supplemental New Drug Application to the FDA under
the FDA’s Accelerated Approval Program, discussions with global
health authorities, 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 and regulatory 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.
____________________________
1 American Cancer Society Journal: Global Cancer Statistics
2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for
36 Cancers in 185 Countries.
https://acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21660.
Accessed June 2022.
2 American Cancer Society: Key Statistics for Colorectal
Cancer-2022.
https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html.
Accessed March 2022.
3 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.
4 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.
5 Valtorta E., et al. Assessment of a HER2 scoring system for
colorectal cancer: results from a validation study. Mod Pathol 28:
1481-91 2015.
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version on businesswire.com: https://www.businesswire.com/news/home/20220702005001/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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