− Approval Based on Results from Positive, Global, Phase 3
FRESCO-2 Trial
− FRUZAQLA (fruquintinib) is the First Novel Targeted Therapy
in the EU for Metastatic Colorectal Cancer (mCRC) Regardless of
Biomarker Status in Over a Decade
Takeda (TSE:4502/NYSE:TAK) today announced that the European
Commission (EC) approved FRUZAQLA (fruquintinib) as a monotherapy
indicated for the treatment of adult patients with metastatic
colorectal cancer (mCRC) who have been previously treated with
available standard therapies, including fluoropyrimidine-,
oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF
agents, and anti-EGFR agents, and who have progressed on or are
intolerant to treatment with either trifluridine-tipiracil or
regorafenib. The decision follows a positive opinion from the
Committee for Medicinal Products for Human Use (CHMP) on April 25,
2024, and approval by the U.S. Food and Drug Administration (FDA)
for adults with mCRC who have been previously treated with
oxaliplatin- and irinotecan-based regimens on November 8,
2023.1,2
“People living with metastatic colorectal cancer face numerous
difficulties, stemming both from their illness and the adverse
effects of therapies. Given the complex nature of the disease,
introducing innovative treatments such as fruquintinib – an oral,
chemotherapy-free targeted agent – is essential. I am looking
forward to having a new choice for appropriate patients,” said
Josep Tabernero, MD, PhD, director of Vall d´Hebron Institute of
Oncology (VHIO).
The approval is based on results from the Phase 3 multi-regional
FRESCO-2 trial. The trial investigated FRUZAQLA 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 FRUZAQLA, regardless of the prior types of
therapies they received. FRUZAQLA demonstrated a manageable safety
profile in FRESCO-2. Adverse reactions leading to treatment
discontinuation occurred in 20% of patients treated with FRUZAQLA
plus BSC versus 21% of those treated with placebo plus BSC. Data
from FRESCO-2 were published in The Lancet in June 2023.3
“Today's approval marks an important moment for the colorectal
cancer community in the EU. For the first time in over a decade,
patients with previously treated metastatic colorectal cancer have
a new targeted treatment option that can be used irrespective of
whether their tumors harbor actionable mutations,” said Teresa
Bitetti, president of the Global Oncology Business Unit at Takeda.
“We look forward to offering patients a novel treatment option that
has a manageable safety profile and can be effective regardless of
the prior types of therapies they have received.”
About FRUZAQLA (fruquintinib)
FRUZAQLA is a selective oral inhibitor of all three VEGF
receptors (-1, -2 and -3). VEGFR inhibitors play a pivotal role in
blocking tumor angiogenesis. FRUZAQLA 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. FRUZAQLA was approved by the U.S. Food
and Drug Administration (FDA) in November 2023. 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®.
EUROPEAN UNION IMPORTANT SAFETY INFORMATION
Please consult the FRUZAQLA (fruquintinib) Summary of Product
Characteristics (SmPC) before prescribing.
Guidance for use: FRUZAQLA should be initiated by a
physician experienced in the administration of anticancer therapy.
Patients should be given the package leaflet.
CONTRAINDICATIONS: Hypersensitivity to the active
substance or to any of the excipients.
SPECIAL POPULATIONS: Renal impairment: No dose
adjustment is required for patients with mild, moderate, or severe
renal impairment; Hepatic impairment: No dose adjustment is
required for patients with mild or moderate hepatic impairment.
FRUZAQLA is not recommended for use in patients with severe hepatic
impairment as FRUZAQLA has not been studied in this population;
Elderly: No dose adjustment is required in patients aged 65
years or above; Paediatric population: There is no relevant
use of FRUZAQLA in the paediatric population for the indication of
metastatic colorectal cancer; Women of childbearing
potential/Contraception in females: Women of childbearing
potential should be advised to use highly effective contraception
during treatment and for at least 2 weeks following the last dose
of FRUZAQLA; Pregnancy: There are no clinical data available
on the use of FRUZAQLA in pregnant women. Based on its mechanism of
action, FRUZAQLA has the potential to cause foetal harm. Animal
studies have shown reproductive toxicity, including foetal
malformations. FRUZAQLA should not be used during pregnancy unless
the clinical condition of the woman requires treatment with
FRUZAQLA. If FRUZAQLA is used during pregnancy or if the patient
becomes pregnant while on treatment, the patient must be informed
of the potential hazard to the foetus; Breast-feeding: The
safe use of FRUZAQLA during breast-feeding has not been
established. It is not known whether FRUZAQLA or its metabolites
are excreted in human milk. There are no animal data on the
excretion of FRUZAQLA in animal milk. A risk to the breastfeeding
newborns/infants cannot be excluded. Breastfeeding should be
discontinued during treatment and for 2 weeks after the last dose;
Fertility: There are no data on the effects of FRUZAQLA on
human fertility. Results from animal studies indicate that FRUZAQLA
may impair male and female fertility.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
- Hypertension: Hypertension, including hypertensive
crisis, has been reported in patients treated with FRUZAQLA.
Pre-existing hypertension should be monitored and adequately
controlled in accordance with standard medical practices before
starting FRUZAQLA treatment. Hypertension should be medically
managed with antihypertensive medicinal products and adjustment of
the FRUZAQLA dose, if necessary. FRUZAQLA should be permanently
discontinued for hypertension that cannot be controlled with
antihypertensive therapy or in patients with hypertensive
crisis.
- Haemorrhagic events: Haemorrhagic events have been
reported in patients treated with FRUZAQLA, including
gastrointestinal (GI) tract events. Serious and sometimes fatal
bleeding events have been reported in patients after treatment with
FRUZAQLA. Haematologic and coagulation profiles should be monitored
in accordance with standard medical practices in patients at risk
for bleeding, including those treated with anticoagulants or other
concomitant medicinal products that increase the risk of bleeding.
In the event of severe bleeding requiring immediate medical
intervention, FRUZAQLA should be permanently discontinued.
- Gastrointestinal perforation: GI perforation events,
including fatal events, have been reported in patients treated with
FRUZAQLA. Symptoms of GI perforation should be periodically
monitored during treatment with FRUZAQLA. FRUZAQLA should be
permanently discontinued in patients developing GI
perforation.
- Proteinuria: Proteinuria events have occurred in
patients treated with FRUZAQLA. Proteinuria should be monitored
before initiation and during treatment with FRUZAQLA in accordance
with standard medical practices. If urine dipstick proteinuria ≥ 2
g / 24 hours is detected, dose interruptions, adjustments, or
discontinuation may be necessary. FRUZAQLA should be permanently
discontinued in patients developing nephrotic syndrome.
- Palmar-plantar erythrodysaesthesia syndrome (PPES): PPES
is the most frequently reported dermatological adverse reaction. If
Grade ≥ 2 skin reactions are detected, dose interruptions,
adjustments, or discontinuation may be necessary.
- Posterior reversible encephalopathy syndrome (PRES):
PRES has been reported in 1 patient (0.1%) treated with FRUZAQLA in
clinical studies. PRES is a rare neurologic disorder that can
present with headache, seizure, lethargy, confusion, altered mental
function, blindness, and other visual or neurological disturbances,
with or without associated hypertension. A diagnosis of PRES
requires confirmation by brain imaging, preferably magnetic
resonance imaging (MRI). In patients developing PRES,
discontinuation of FRUZAQLA, along with control of hypertension and
supportive medical management of other symptoms, are
recommended.
- Impaired wound healing: Impaired wound healing has been
reported in 1 patient (0.1%) treated with FRUZAQLA in clinical
studies. Patients are recommended to withhold FRUZAQLA for at least
2 weeks prior to surgery. FRUZAQLA should not be resumed for at
least 2 weeks after surgery, as clinically indicated when there is
evidence of adequate wound healing.
- Arterial and venous thromboembolic events: It is
recommended to avoid starting treatment with FRUZAQLA in patients
with a history of thromboembolic events (including deep vein
thrombosis and pulmonary embolism) within the past 6 months or if
they have a history of stroke and/or transient ischemic attack
within the last 12 months. If arterial thrombosis is suspected,
FRUZAQLA should be discontinued immediately.
INTERACTIONS
Effects of other medicinal products on the
pharmacokinetics of FRUZAQLA
CYP3A inducers
Co-administration of FRUZAQLA with rifampicin (a strong CYP3A
inducer) 600 mg once daily decreased FRUZAQLA AUCinf by 65% and
decreased Cmax by 12%. The concomitant use of FRUZAQLA with strong
and moderate CYP3A inducers should be avoided.
CYP3A inhibitors
Co-administration of FRUZAQLA with itraconazole (a strong CYP3A
inhibitor) 200 mg twice daily did not result in clinically
meaningful changes in the area under the concentration-time curve
(AUC) and Cmax of FRUZAQLA. No dose adjustment of FRUZAQLA is
needed during concomitant use with CYP3A inhibitors.
Gastric acid lowering agents
Co-administration of FRUZAQLA with rabeprazole (a proton pump
inhibitor) 40 mg once daily did not result in clinically meaningful
changes in the AUC of FRUZAQLA. No dose adjustment of FRUZAQLA is
needed during concomitant use with gastric acid lowering
agents.
Effect of FRUZAQLA on the pharmacokinetics
of other medicinal products
Medicinal products that are substrates of P-glycoprotein
(P-gp)
Co-administration of a single dose of dabigatran etexilate 150
mg (a P-gp substrate) with a single dose of FRUZAQLA 5 mg decreased
AUC of dabigatran by 9%. No dose adjustment is recommended for P-gp
substrates during concomitant use with FRUZAQLA.
Medicinal products that are substrates of breast cancer
resistance protein (BCRP)
Co-administration of a single 10 mg dose of rosuvastatin (a BCRP
substrate) with a single 5 mg dose of FRUZAQLA decreased AUC of
rosuvastatin by 19%. No dose adjustment is recommended for BCRP
substrates during concomitant use with FRUZAQLA.
UNDESIRABLE EFFECTS: The most commonly reported
adverse reactions with FRUZAQLA are:
Very common
(frequency ≥1/10)
Thrombocytopenia, hypothyroidism,
anorexia, hypertension, dysphonia, diarrhoea, stomatitis, aspartate
aminotransferase increased, total bilirubin increased, alanine
aminotransferase increased, palmar-plantar erythrodysaesthesia
syndrome, musculoskeletal discomfort, arthralgia, proteinuria,
asthenia, and fatigue
Common
(≥1/100 to <1/10)
Pneumonia, upper respiratory tract
infection, bacterial infections, leukopenia, neutropenia,
hypokalemia, epistaxis, throat pain, gastrointestinal haemorrhage,
gastrointestinal perforation, pancreatic enzymes increased, oral
pain, rash, and mucosal inflammation
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 and was associated
with more than 1.9 million new cases and 900,000 deaths in 2022. In
Europe, CRC was the second most common cancer in 2022, with
approximately 538,000 new cases and 248,000 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 in 2022, with more than 145,000 new
cases and 60,000 deaths.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 FRUZAQLA
plus BSC vs placebo plus BSC in patients with previously treated
mCRC (NCT04322539). The study met all of its primary and key
secondary endpoints, demonstrating that treatment with FRUZAQLA
resulted in statistically significant and clinically meaningful
improvement in OS and PFS. The safety profile of FRUZAQLA in
FRESCO-2 was consistent with previously reported fruquintinib
monotherapy studies. Results from the study were presented at ESMO
in September 2022 and subsequently published in The Lancet in June
2023.11,3
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.
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References:
- Takeda Pharmaceuticals. (2024 April 26). Takeda Receives
Positive CHMP Opinion for Fruquintinib in Previously Treated
Metastatic Colorectal Cancer [Press Release]. Available here.
- Takeda Pharmaceuticals. (2023 November 8). Takeda Receives U.S.
FDA Approval of FRUZAQLA™ (fruquintinib) for Previously Treated
Metastatic Colorectal Cancer [Press Release]. Available here.
- 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.
- Bray F, et al. Global cancer statistics 2022: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in
185 countries. CA Cancer J Clin. 2024 [online ahead of print]. doi:
10.3322/caac.21834
- 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
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Doi:10.1016/annonc/annonc1089.
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Media Contacts: Japanese Media Jun Saito
jun.saito@takeda.com U.S. and International Media Emma Nash
emma.nash@takeda.com
Takeda Pharmaceutical (NYSE:TAK)
過去 株価チャート
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Takeda Pharmaceutical (NYSE:TAK)
過去 株価チャート
から 6 2023 まで 6 2024