− If Approved in the European Union, Fruquintinib Will Be the
First Novel Targeted Therapy for Metastatic Colorectal Cancer
Regardless of Biomarker Status in Over a Decade
− Positive Opinion Based on Results from a Phase 3 Clinical
Trial Which Demonstrated Significant Improvements in Overall
Survival and Progression Free Survival versus Placebo Plus Best
Supportive Care, with Benefit Seen Regardless of Prior Types of
Therapy Received
Takeda (TSE:4502/NYSE:TAK) today announced that the European
Medicines Agency’s (EMA) Committee for Medicinal Products for Human
Use (CHMP) has recommended the approval of fruquintinib, a
selective inhibitor of vascular endothelial growth factor receptors
(VEGFR) -1, -2 and -3 for the treatment of adult patients with
previously treated metastatic colorectal cancer (mCRC). The
European Commission (EC) will consider the CHMP positive opinion
when determining the potential marketing authorization for
fruquintinib for mCRC throughout the European Union (EU), Norway,
Liechtenstein and Iceland. If approved, fruquintinib will be the
first and only selective inhibitor of all three VEGF receptors
approved in the EU for previously treated mCRC.1,2
“People living with metastatic colorectal cancer in the European
Union currently have limited treatment options, which can lead to
poor outcomes. With this positive opinion for fruquintinib, we are
one step closer to potentially offering patients a new, oral,
chemotherapy-free option that may provide a survival benefit,” said
Awny Farajallah, M.D., chief medical officer, oncology at Takeda.
“We look forward to the European Commission’s official decision in
the near future as we work to redefine the treatment landscape and
help address a significant unmet need for those affected by
mCRC.”
The Committee’s positive opinion was primarily based on results
from the Phase 3 multi-regional FRESCO-2 trial. The trial
investigated fruquintinib plus best supportive care (BSC) versus
placebo plus BSC in patients with previously treated mCRC. FRESCO-2
met all its primary and key secondary efficacy endpoints and showed
consistent benefit among patients treated with fruquintinib,
regardless of the prior types of therapies they received.
Fruquintinib demonstrated a manageable safety profile in FRESCO-2.
Adverse reactions leading to treatment discontinuation occurred in
20% of patients treated with fruquintinib plus BSC versus 21% of
those treated with placebo plus BSC. Data from FRESCO-2 were
published in The Lancet in June 2023.3
About Fruquintinib
Fruquintinib is a selective oral inhibitor of VEGFR -1, -2 and
-3. VEGFR inhibitors play a pivotal role in blocking tumor
angiogenesis. Fruquintinib was designed to have enhanced
selectivity that limits off-target kinase activity, allowing for
high drug exposure, sustained target inhibition, and flexibility
for potential use as part of combination therapy.
Takeda has the exclusive worldwide license to further develop,
commercialize, and manufacture fruquintinib outside of mainland
China, Hong Kong and Macau. Fruquintinib was approved by the U.S.
Food and Drug Administration (FDA) in November 2023 and is marketed
under the brand name FRUZAQLA®. A submission to the Japan
Pharmaceuticals and Medical Devices Agency (PMDA) took place in
September 2023. Fruquintinib is developed and marketed in China by
HUTCHMED. Fruquintinib was approved for marketing by the China
National Medical Products Administration (NMPA) in September 2018
and commercially launched in China in November 2018 under the brand
name ELUNATE®.
U.S. IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
- Hypertension occurred in 49% of 911 patients with mCRC
treated with FRUZAQLA, including Grade 3-4 events in 19%, and
hypertensive crisis in three patients (0.3%). Do not initiate
FRUZAQLA unless blood pressure is adequately controlled. Monitor
blood pressure weekly for the first month and at least monthly
thereafter as clinically indicated. Initiate or adjust
anti-hypertensive therapy as appropriate. Withhold, reduce dose, or
permanently discontinue FRUZAQLA based on severity of
hypertension.
- Hemorrhagic Events including serious, fatal events can
occur with FRUZAQLA. In 911 patients with mCRC treated with
FRUZAQLA, 6% of patients experienced gastrointestinal hemorrhage,
including 1% with a Grade ≥3 event and 2 patients with fatal
hemorrhages. Permanently discontinue FRUZAQLA in patients with
severe or life-threatening hemorrhage. Monitor the International
Normalized Ratio (INR) levels in patients receiving
anticoagulants.
- Infections. FRUZAQLA can increase the risk of
infections, including fatal infections. In 911 patients with mCRC
treated with FRUZAQLA, the most common infections were urinary
tract infections (6.8%), upper respiratory tract infections (3.2%)
and pneumonia (2.5%); fatal infections included pneumonia (0.4%),
sepsis (0.2%), bacterial infection (0.1%), lower respiratory tract
infection (0.1%), and septic shock (0.1%). Withhold FRUZAQLA for
Grade 3 or 4 infections, or worsening infection of any grade.
Resume FRUZAQLA at the same dose when the infection has
resolved.
- Gastrointestinal Perforation occurred in patients
treated with FRUZAQLA. In 911 patients with mCRC treated with
FRUZAQLA, 1.3% experienced a Grade ≥3 gastrointestinal perforation,
including one fatal event. Permanently discontinue FRUZAQLA in
patients who develop gastrointestinal perforation or fistula.
- Hepatotoxicity. FRUZAQLA can cause liver injury. In 911
patients with mCRC treated with FRUZAQLA, 48% experienced increased
ALT or AST, including Grade ≥3 events in 5%, and fatal events in
0.2% of patients. Monitor liver function tests (ALT, AST, and
bilirubin) before initiation and periodically throughout treatment
with FRUZAQLA. Temporarily hold and then reduce or permanently
discontinue FRUZAQLA depending on the severity and persistence of
hepatotoxicity as manifested by elevated liver function tests.
- Proteinuria. FRUZAQLA can cause proteinuria. In 911
patients with mCRC treated with FRUZAQLA, 36% experienced
proteinuria and 2.5% of patients experienced Grade ≥3 events.
Monitor for proteinuria before initiation and periodically
throughout treatment with FRUZAQLA. For proteinuria ≥2g/24 hours,
withhold FRUZAQLA until improvement to ≤Grade 1 proteinuria and
resume FRUZAQLA at a reduced dose. Discontinue FRUZAQLA in patients
who develop nephrotic syndrome.
- Palmar-Plantar Erythrodysesthesia (PPE) occurred in 35%
of 911 patients treated with FRUZAQLA, including 8% with Grade 3
events. Based on severity of PPE, withhold FRUZAQLA and then resume
at the same or reduced dose.
- Posterior Reversible Encephalopathy Syndrome (PRES), a
syndrome of subcortical vasogenic edema diagnosed by characteristic
finding on MRI, occurred in one of 911 patients treated with
FRUZAQLA. Perform an evaluation for PRES in any patient presenting
with seizures, headache, visual disturbances, confusion, or altered
mental function. Discontinue FRUZAQLA in patients who develop
PRES.
- Impaired Wound Healing. In 911 patients with mCRC
treated with FRUZAQLA, 1 patient experienced a Grade 2 event of
wound dehiscence. Do not administer FRUZAQLA for at least 2 weeks
prior to major surgery. Do not administer FRUZAQLA for at least 2
weeks after major surgery and until adequate wound healing. The
safety of resumption of FRUZAQLA after resolution of wound healing
complications has not been established.
- Arterial Thromboembolic Events. In 911 patients with
mCRC treated with FRUZAQLA, 0.8% of patients experienced an
arterial thromboembolic event. Initiation of FRUZAQLA in patients
with a recent history of thromboembolic events should be carefully
considered. In patients who develop arterial thromboembolism,
discontinue FRUZAQLA.
- Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and
No. 6 (Sunset Yellow FCF). FRUZAQLA 1 mg capsules contain
FD&C Yellow No. 5 (tartrazine), which may cause allergic-type
reactions (including bronchial asthma) in certain susceptible
persons. FRUZAQLA 1 mg contains FD&C Yellow No. 6 (sunset
yellow FCF), which may cause allergic reactions.
- Embryo-Fetal Toxicity. Based on findings in animal
studies and its mechanism of action, FRUZAQLA can cause fetal harm
when administered to pregnant women. Advise pregnant women of the
potential risk to a fetus. Advise females of childbearing potential
and males with female partners of childbearing potential to use
effective contraception during treatment with FRUZAQLA and for 2
weeks after the last dose.
ADVERSE REACTIONS
The most common adverse reactions (incidence ≥20%) following
treatment with FRUZAQLA included hypertension, palmar-plantar
erythrodysesthesia (hand-foot skin reactions), proteinuria,
dysphonia, abdominal pain, diarrhea, and asthenia.
DRUG INTERACTIONS: Avoid concomitant administration of
FRUZAQLA with strong or moderate CYP3A inducers.
USE IN SPECIFIC POPULATIONS
- Lactation: Advise women not to breastfeed during
treatment with FRUZAQLA and for 2 weeks after the last dose.
To report SUSPECTED ADVERSE REACTIONS, contact Takeda
Pharmaceuticals at 1-844-662-8532 or the FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
Please see FRUZAQLA (fruquintinib) full Prescribing
Information
About CRC
CRC is a cancer that starts in either the colon or rectum.
According to the International Agency for Research on Cancer, CRC
is the third most prevalent cancer worldwide, associated with more
than 935,000 deaths in 2020. In Europe, CRC was the second most
common cancer in 2020, with approximately 520,000 new cases and
245,000 deaths.4 In the U.S., it is estimated that 153,000 patients
will be diagnosed with CRC and 53,000 deaths from the disease will
occur in 2024.5 In Japan, CRC was the most common cancer, with an
estimated 148,000 new cases and 60,000 deaths, in 2020.4 Although
early-stage CRC can be surgically resected, metastatic CRC remains
an area of high unmet need with poor outcomes and limited treatment
options. Some patients with metastatic CRC may benefit from
personalized therapeutic strategies based on molecular
characteristics; however, most patients have tumors that do not
harbor actionable mutations.6,7,8,9,10
About the Phase 3 FRESCO-2 Trial
The FRESCO-2 study is a multi-regional clinical trial conducted
in the U.S., Europe, Japan and Australia investigating fruquintinib
plus BSC vs placebo plus BSC in patients with previously treated
mCRC (NCT04322539). The study met all its primary and key secondary
endpoints, demonstrating that treatment with fruquintinib resulted
in statistically significant and clinically meaningful improvement
in OS and PFS. The safety profile of fruquintinib in FRESCO-2 was
consistent with previously reported fruquintinib studies. Results
from the study were presented at ESMO in September 2022 and
subsequently published in The Lancet in June 2023.11,3
The Phase 3 FRESCO-2 trial supported the marketing authorization
application (MAA) from the EMA for fruquintinib, which was
validated and accepted for review in June 2023.
About Takeda
Takeda is focused on creating better health for people and a
brighter future for the world. We aim to discover and deliver
life-transforming treatments in our core therapeutic and business
areas, including gastrointestinal and inflammation, rare diseases,
plasma-derived therapies, oncology, neuroscience and vaccines.
Together with our partners, we aim to improve the patient
experience and advance a new frontier of treatment options through
our dynamic and diverse pipeline. As a leading values-based,
R&D-driven biopharmaceutical company headquartered in Japan, we
are guided by our commitment to patients, our people and the
planet. Our employees in approximately 80 countries and regions are
driven by our purpose and are grounded in the values that have
defined us for more than two centuries. For more information, visit
www.takeda.com.
Important Notice
For the purposes of this notice, “press release” means this
document, any oral presentation, any question and answer session
and any written or oral material discussed or distributed by Takeda
Pharmaceutical Company Limited (“Takeda”) regarding this release.
This press release (including any oral briefing and any
question-and-answer in connection with it) is not intended to, and
does not constitute, represent or form part of any offer,
invitation or solicitation of any offer to purchase, otherwise
acquire, subscribe for, exchange, sell or otherwise dispose of, any
securities or the solicitation of any vote or approval in any
jurisdiction. No shares or other securities are being offered to
the public by means of this press release. No offering of
securities shall be made in the United States except pursuant to
registration under the U.S. Securities Act of 1933, as amended, or
an exemption therefrom. This press release is being given (together
with any further information which may be provided to the
recipient) on the condition that it is for use by the recipient for
information purposes only (and not for the evaluation of any
investment, acquisition, disposal or any other transaction). Any
failure to comply with these restrictions may constitute a
violation of applicable securities laws.
The companies in which Takeda directly and indirectly owns
investments are separate entities. In this press release, “Takeda”
is sometimes used for convenience where references are made to
Takeda and its subsidiaries in general. Likewise, the words “we”,
“us” and “our” are also used to refer to subsidiaries in general or
to those who work for them. These expressions are also used where
no useful purpose is served by identifying the particular company
or companies.
Forward-Looking Statements
This press release and any materials distributed in connection
with this press release may contain forward-looking statements,
beliefs or opinions regarding Takeda’s future business, future
position and results of operations, including estimates, forecasts,
targets and plans for Takeda. Without limitation, forward-looking
statements often include words such as “targets”, “plans”,
“believes”, “hopes”, “continues”, “expects”, “aims”, “intends”,
“ensures”, “will”, “may”, “should”, “would”, “could”,
“anticipates”, “estimates”, “projects” or similar expressions or
the negative thereof. These forward-looking statements are based on
assumptions about many important factors, including the following,
which could cause actual results to differ materially from those
expressed or implied by the forward-looking statements: the
economic circumstances surrounding Takeda’s global business,
including general economic conditions in Japan and the United
States; competitive pressures and developments; changes to
applicable laws and regulations, including global health care
reforms; challenges inherent in new product development, including
uncertainty of clinical success and decisions of regulatory
authorities and the timing thereof; uncertainty of commercial
success for new and existing products; manufacturing difficulties
or delays; fluctuations in interest and currency exchange rates;
claims or concerns regarding the safety or efficacy of marketed
products or product candidates; the impact of health crises, like
the novel coronavirus pandemic, on Takeda and its customers and
suppliers, including foreign governments in countries in which
Takeda operates, or on other facets of its business; the timing and
impact of post-merger integration efforts with acquired companies;
the ability to divest assets that are not core to Takeda’s
operations and the timing of any such divestment(s); and other
factors identified in Takeda’s most recent Annual Report on Form
20-F and Takeda’s other reports filed with the U.S. Securities and
Exchange Commission, available on Takeda’s website at:
https://www.takeda.com/investors/sec-filings-and-security-reports/
or at www.sec.gov. Takeda does not undertake to update any of the
forward-looking statements contained in this press release or any
other forward-looking statements it may make, except as required by
law or stock exchange rule. Past performance is not an indicator of
future results and the results or statements of Takeda in this
press release may not be indicative of, and are not an estimate,
forecast, guarantee or projection of Takeda’s future results.
Medical Information
This press release contains information about products that may
not be available in all countries, or may be available under
different trademarks, for different indications, in different
dosages, or in different strengths. Nothing contained herein should
be considered a solicitation, promotion or advertisement for any
prescription drugs including the ones under development.
References:
- Xu X, et al. Efficacy and safety of regorafenib and
fruquintinib as third-line treatment for colorectal cancer: a
narrative review. Transl Cancer Res 2022;11(1):276-287. doi:
10.21037/tcr-20-3539.
- Sun Q, et al. (2014) Discovery of fruquintinib, a potent and
highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine
kinases for cancer therapy, Cancer Biol Ther. 2014 15:12,
1635-1645. Doi: 10.4161/15384047.2014.964087.
- Dasari NA, et al. Fruquintinib versus placebo in patients with
refractory metastatic colorectal cancer (FRESCO-2): an
international, multicentre, randomised, double-blind, phase 3
study. Lancet. 2023;402(10395):41-53.
doi:10.1016/S0140-6736(23)00772-9.
- Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN
Estimates of Incidence and Mortality Worldwide for 36 Cancers in
185 Countries. CA Cancer J Clin. 2021;71(3):209-249.
doi:10.3322/caac.21660.
- American Cancer Society. Cancer Facts & Figures 2024.
Atlanta, American Cancer Society; 2024.
- Bando H, et al. Therapeutic landscape and future direction of
metastatic colorectal cancer. Nat Rev Gastroenterol Hepatol 2023;
20(5)306-322. doi:10.1038/s41575-022-00736-1.
- D'Haene N, et al. Clinical application of targeted
next-generation sequencing for colorectal cancer patients: a
multicentric Belgian experience. Oncotarget.
2018;9(29):20761-20768. Published 2018 Apr 17.
doi:10.18632/oncotarget.25099.
- Venderbosch, et al. Mismatch repair status and braf mutation
status in metastatic colorectal cancer patients: A pooled analysis
of the Cairo, Cairo2, coin, and Focus Studies. Clinical Cancer
Res.,2014; 20(20):5322–5330.
doi:10.1158/1078-0432.ccr-14-0332.
- Koopman, M., et al. Deficient mismatch repair system in
patients with sporadic advanced colorectal cancer. Br J Cancer.
209;100(2), 266–273. doi:10.1038/sj.bjc.6604867.
- Ahcene Djaballah S, et al. HER2 in Colorectal Cancer: The Long
and Winding Road From Negative Predictive Factor to Positive
Actionable Target. Am Soc Clin Oncol Educ Book. 2022;42:1-14.
doi:10.1200/EDBK_351354.
- Dasari NA, et al. LBA25 – FRESCO-2: A global phase 3
multiregional clinical trial (MRCT) evaluating the efficacy and
safety of fruquintinib in patients with refractory metastatic
colorectal cancer. Ann Oncol. 2022 Sep;33(suppl_7): S808-S869.
Doi:10.1016/annonc/annonc1089.
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Media:
Japanese Media Jun Saito jun.saito@takeda.com
U.S. and International Media Emma Nash
emma.nash@takeda.com
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