OSAKA, Japan & CAMBRIDGE, Mass. - Saturday, 22. June 2024 AETOSWire
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
(BUSINESS WIRE) -- 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
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Sep;33(suppl_7): S808-S869. Doi:10.1016/annonc/annonc1089.
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Contacts
Media Contacts:
Japanese Media
Jun Saito
jun.saito@takeda.com
U.S. and International Media
Emma Nash
emma.nash@takeda.com
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