Results from a matching-adjusted indirect
comparison (MAIC) suggest that cabozantinib provides two additional
months of progression-free survival versus regorafenib in the
second-line treatment of advanced hepatocellular carcinoma1
Regulatory News:
Ipsen (Euronext: IPN; ADR: IPSEY)
today presents results from the matching-adjusted indirect
comparison (MAIC) of cabozantinib (Cabometyx®) versus regorafenib
(Stivarga®) for the second-line treatment (2L) of patients with
advanced hepatocellular carcinoma (aHCC) who received sorafenib as
the only prior systemic therapy. Using data from the Phase III
CELESTIAL and RESORCE trials, the MAIC showed that cabozantinib
offers greater efficacy versus regorafenib.
Using data from the Phase III CELESTIAL and RESORCE trials, the
MAIC showed that in the 2L CELESTIAL sub-population who had
received sorafenib as the only prior systemic therapy, cabozantinib
significantly improved progression-free survival (PFS), with an
additional 2.4 months provided vs. regorafenib (5.6 months vs. 3.2
months [95% confidence interval (CI): 4.90-7.26], p<0.05).
Median overall survival (OS) was also favorable with cabozantinib
(11.4 months vs. 10.8 months), though statistical significance was
not met.1
Results from MAIC will be presented by Dr. Katie Kelley,
oncologist at the University of California, San Francisco and lead
investigator, at the 13th Annual Conference of the International
Liver Cancer Association (ILCA 2019) taking place on 20-22
September 2019 in Chicago, USA (poster/abstract #P-021).
In the previously presented randomized, double-blind, Phase III
CELESTIAL trial evaluating cabozantinib compared with placebo in
previously treated patients with aHCC, in the overall CELESTIAL
intent-to-treat population, cabozantinib significantly improved
median PFS, with an additional 3.3 months provided vs placebo (5.2
months vs. 1.9 months [95% CI, 4.0 to 5.5], p<0.001) and median
OS, with an additional 2.2 months vs placebo (10.2 months vs. 8.0
months [95% confidence interval (CI): 9.1 to 12.0), p=0.005).1
“Hepatocellular carcinoma is a devastating disease with only a
few treatment options demonstrating survival benefits and many
investigational drugs have failed to meet overall survival
endpoints in clinical trials,” said Dr. Kelley. “The MAIC analysis
brings further insight into the comparative effectiveness of the
key second-line treatments for advanced hepatocellular carcinoma,
particularly in relation to important endpoints like
progression-free survival. These results may support clinicians in
making informed treatment decisions in order to deliver optimal
care for their patients.”
Grade 3/4 adverse events affecting more than 5% of patients were
comparable for the two studies, except for diarrhea which was lower
with regorafenib.1
MAICs are a way of providing a timely comparison of the
effectiveness of different medical interventions in the absence of
head-to-head randomized trials.2 While indirect comparisons of
treatments across separate studies can be performed, these analyses
may be biased by cross-trial differences in patient populations,
sensitivity to modeling assumptions, and differences in the
definitions of outcome measures. MAICs use individual patient data
(IPD), also referred to as individual-level data, from trials of
one treatment to match baseline summary statistics reported from
trials of another treatment and reduce observed cross-trial
differences.2 After matching, treatment outcomes are compared
across balanced trial populations. It should be noted that, even
after matching, bias may still occur in MAIC due to imbalance in
unobserved factors, and it cannot completely replace a head-to-head
randomized and controlled trial.1
“At Ipsen, our mission is to prolong and improve patients’ lives
and health outcomes, and we acknowledge the importance of providing
healthcare professionals with the best available evidence to
achieve these goals for patients,” said Dr. Yan Moore, Ipsen’s
Senior Vice President, Head of Oncology Therapeutic Area. “The
recent rapid development of new second-line treatments for patients
with advanced HCC has led to the generation of information mainly
based on placebo-controlled trials. While alternative
methodological approaches such as MAIC are not substitutes to
evidence-based prospective clinical trials, it is important to
recognize the need for further insights into the comparative
effectiveness of current treatment approaches.”
About the matching-adjusted indirect comparison of
cabozantinib and regorafenib The aim of this MAIC was to
compare the safety and efficacy of cabozantinib and regorafenib for
patients with aHCC who have received sorafenib as the only prior
systemic therapy. Through the MAIC, IPD from patients enrolled in
the CELESTIAL3 who had received cabozantinib as second-line therapy
following sorafenib as the sole prior therapy (N=495) were adjusted
to match the average baseline (BL) characteristics of the 573
patients enrolled in the regorafenib study RESORCE,4 for which
individual-level data (ILD) are not available.
After matching, the selected BL characteristics were balanced
across trials. The BL characteristics available for matching for
both trials and deemed potential effect modifiers by key opinion
leaders were:1
- age group
- race
- geographical region
- ECOG (Eastern Cooperative Oncology Group) performance
status
- Child-Pugh class
- duration of prior sorafenib treatment
- extrahepatic disease
- macrovascular invasion
- etiology of HCC (hepatitis B, alcohol use and hepatitis C)
- AFP (alpha-fetoprotein tumor marker) level
In the first indirect comparison of cabozantinib and regorafenib
in 2L HCC (post-sorafenib):1
- Cabozantinib significantly improved median PFS, with an
additional 2.4 months provided versus regorafenib (5.59 months vs.
3.19 months [95% CI: 4.90-7.26], p<0.05)
- OS also favored cabozantinib, with a median OS of almost 1 year
(11.37 months vs. 10.79 months), though statistical significance
was not met
Grade 3/4 adverse events (AEs) affecting more than 5% of
patients were comparable for the two studies, except for diarrhea
which was significantly lower with regorafenib.
It should be noted that, even after matching, bias may still
occur in MAIC due to imbalance in unobserved factors, and it cannot
replace a head-to-head randomized control trial.
About CELESTIAL CELESTIAL is a randomized, double-blind,
placebo-controlled global Phase III study of cabozantinib versus
placebo in patients with advanced hepatocellular carcinoma (HCC)
who have been previously treated with sorafenib. The study was
conducted at more than 100 sites globally in 19 countries. The
trial was designed to enroll 760 patients with advanced
hepatocellular carcinoma (HCC) who previously received sorafenib
and may have received up to two prior systemic cancer therapies for
hepatocellular carcinoma (HCC) and had adequate liver function.
Enrollment of the trial was completed in September 2017, and 773
patients were ultimately randomized. Patients were randomized 2:1
to receive 60 mg of cabozantinib once daily or placebo and were
stratified based on etiology of the disease (hepatitis C, hepatitis
B or other), geographic region (Asia versus other regions) and
presence of extrahepatic spread and/or macrovascular invasion (yes
or no). No cross-over was allowed between the study arms.
The primary endpoint for the trial is OS, and secondary
endpoints include objective response rate and progression-free
survival. Exploratory endpoints included patient-reported outcomes,
biomarkers and safety.
Based on available clinical trial data from various published
trials conducted in the second-line setting of advanced
hepatocellular carcinoma (HCC), the CELESTIAL trial statistics for
the primary endpoint of OS assumed a median OS of 8.2 months for
the placebo arm. A total of 621 events provide the study with 90
percent power to detect a 32 percent increase in median OS (HR =
0.76) at the final analysis. Two interim analyses were planned and
conducted at 50 percent and 75 percent of the planned 621
events.
CELESTIAL trial met its primary endpoint of overall survival
(OS), with cabozantinib providing a statistically significant and
clinically meaningful improvement in median OS compared to placebo
in patients with advanced HCC. The independent data monitoring
committee for the study recommended that the trial should be
stopped for efficacy following review of the second planned interim
analysis. The safety data in the study were consistent with the
established profile of cabozantinib.
About hepatocellular carcinoma (HCC) HCC is an aggressive
and lethal disease with the number of deaths per year close to its
incidence worldwide.5 It accounts for about 90% of all liver
cancers and there were over 840,000 new cases of liver cancer in
worldwide in 2018.5,6 It is the fifth most common cancer and the
second most frequent cause of cancer-related death globally.7
About Ipsen products This press release mentions
investigational uses of Ipsen products. Product indications and
approvals for use vary by jurisdiction; please see SmPC/PI for full
indications and safety information.
About CABOMETYX® (cabozantinib) CABOMETYX® is not
marketed by Ipsen in the U.S.
CABOMETYX® 20mg, 40mg and 60mg film-coated unscored tablets
Active ingredient: Cabozantinib (S)-malate 20mg, 40mg and
60mg
Other components: Lactose
Indications: In the U.S., CABOMETYX® tablets are approved
for the treatment of patients with advanced RCC and for the
treatment of patients with hepatocellular carcinoma (HCC) who have
been previously treated with sorafenib.
CABOMETYX® tablets are also approved in: the European Union,
Norway, Iceland, Australia, Switzerland, South Korea, Canada,
Brazil and Taiwan for the treatment of advanced RCC in adults who
have received prior VEGF-targeted therapy; in the European Union
for previously untreated intermediate- or poor-risk advanced RCC;
in Canada for adult patients with advanced RCC who have received
prior VEGF targeted therapy; and in the European Union, Norway and
Iceland for HCC in adults who have previously been treated with
sorafenib.
CABOMETYX® is not indicated for previously untreated advanced
HCC.
Dosage and administration: The recommended dose of
CABOMETYX® is 60 mg once daily. Treatment should continue until the
patient is no longer clinically benefiting from therapy or until
unacceptable toxicity occurs. Management of suspected adverse drug
reactions may require temporary interruption and/or dose reduction
of CABOMETYX therapy. For dose modification, please refer to full
SmPC. CABOMETYX® is for oral use. The tablets should be swallowed
whole and not crushed. Patients should be instructed to not eat
anything for at least 2 hours before through 1 hour after taking
CABOMETYX®.
Contraindications: Hypersensitivity to the active
substance or to any of the excipients listed in the SmPC.
Special warnings and precautions for use: Monitor closely
for toxicity during first 8 weeks of therapy. Events that generally
have early onset include hypocalcemia, hypokalemia,
thrombocytopenia, hypertension, palmar-plantar erythrodysaesthesia
syndrome (PPES), proteinuria, and gastrointestinal (GI) events.
Perforations and fistulas: serious gastrointestinal
perforations and fistulas, sometimes fatal, have been observed with
cabozantinib. Patients with inflammatory bowel disease, GI tumor
infiltration or complications from prior GI surgery should be
evaluated prior to therapy and monitored; if perforation and
unmanageable fistula occur, discontinue cabozantinib.
Thromboembolic events: use with caution in patients with
a history of or risk factors for thromboembolism; discontinue if
acute myocardial infarction (MI) or other significant arterial
thromboembolic complication occurs.
Hemorrhage: not recommended for patients that have or are
at risk of severe hemorrhage.
Wound complications: treatment should be stopped at least
28 days prior to scheduled surgery (including dental).
Hypertension: monitor blood pressure (BP); reduce with
persistent hypertension and discontinue should uncontrolled
hypertension or hypertensive crisis occur.
Palmar-plantar erythrodysesthesia (PPES): interrupt
treatment if severe PPES occurs.
Proteinuria: discontinue in patients with nephrotic
syndrome.
Reversible posterior leukoencephalopathy syndrome (RPLS):
discontinue in patients with RPLS.
QT interval prolongation: use with caution in patients
with a history of QT prolongation, those on antiarrhythmics or with
pre-existing cardiac disease.
Excipients: do not use in patients with hereditary
problems of galactose intolerance, Lapp lactase deficiency or
glucose-galactose malabsorption.
Drug interactions: Cabozantinib is a CYP3A4 substrate.
Potent CYP3A4 inhibitors may result in an increase in cabozantinib
plasma exposure (e.g. ritonavir, itraconazole, erythromycin,
clarithromycin, grapefruit juice). Coadministration with CYP3A4
inducers may result in decreased cabozantinib plasma exposure (e.g.
rifampicin, phenytoin, carbamazepine, phenobarbital, St John's
Wort). Cabozantinib may increase the plasma concentration of
P-glycoprotein substrates (e.g. fexofenadine, aliskiren,
ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc,
posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol,
tolvaptan). MRP2 inhibitors may increase cabozantinib plasma
concentrations (e.g. cyclosporine, efavirenz, emtricitabine). Bile
salt sequestering agents may impact absorption or reabsorption
resulting in potentially decreased cabozantinib exposure. No dose
adjustment when co-administered with gastric pH modifying agents. A
plasma protein displacement interaction may be possible with
warfarin. INR values should be monitored in such a combination.
Women of childbearing potential/contraception in males and
females: Ensure effective measures of contraception (oral
contraceptive plus a barrier method) in male and female patients
and their partners during therapy and for at least 4 months after
treatment.
Pregnancy and lactation: CABOMETYX® should not be used during
pregnancy unless the clinical condition of the woman requires
treatment. Lactation – discontinue breast-feeding during and for at
least 4 months after completing treatment. Drive and use machines:
Caution is recommended
Adverse reactions: The most common serious adverse
reactions are hypertension, diarrhea, PPES, pulmonary embolism,
fatigue and hypomagnesaemia. Very common (>1/10): anemia,
lymphopenia neutropenia, thrombocytopenia, hypothyroidism,
dehydration, decreased appetite, hyperglycemia, hypoglycemia,
hypophosphatasemia, hypoalbuminemia, hypomagnesaemia, hyponatremia,
hypokalemia, hyperkalemia, hypocalcemia, hyperbilirubinemia,
peripheral sensory neuropathy, dysgeusia, headache, dizziness,
hypertension, dysphonia, dyspnea, cough, diarrhea, nausea,
vomiting, stomatitis, constipation, abdominal pain, dyspepsia, oral
pain, dry mouth, PPES, dermatitis acneiform, rash, rash
maculopapular, dry skin, alopecia, hair color change, pain in
extremity, muscle spasms, arthralgia, proteinuria, fatigue, mucosal
inflammation, asthenia, weight decreased, serum ALT, AST, and ALP
increased, blood bilirubin increased, creatinine increased,
triglycerides increased, white blood cell decreased, GGT increased,
amylase increased, blood cholesterol increased, lipase increased.
Common (>1/100 to <1/10): abscess, tinnitus, pulmonary
embolism, pancreatitis, abdominal pain upper, gastro-esophageal
reflux disease, hemorrhoids, pruritus, peripheral edema, wound
complications. Uncommon (>1/1000 to <1/100): convulsion, anal
fistula, hepatitis cholestatic, osteonecrosis of the jaw. Selected
adverse events: GI perforation, fistulas, hemorrhage, RPLS.
Prescribers should consult the SPC in relation to other adverse
reactions.
For more information, see the regularly updated registered
product information on the European Medicine Agency
www.ema.europa.eu
CABOMETYX® is marketed by Exelixis, Inc. in the United States.
Ipsen has exclusive rights for the commercialization and further
clinical development of CABOMETYX® outside of the United States and
Japan.
About Ipsen Ipsen is a global specialty-driven
biopharmaceutical group focused on innovation and specialty care.
The group develops and commercializes innovative medicines in three
key therapeutic areas – Oncology, Neuroscience and Rare Diseases.
Its commitment to Oncology is exemplified through its growing
portfolio of key therapies for prostate cancer, neuroendocrine
tumors, renal cell carcinoma and pancreatic cancer. Ipsen also has
a well-established Consumer Healthcare business. With total sales
over €2.2 billion in 2018, Ipsen sells more than 20 drugs in over
115 countries, with a direct commercial presence in more than 30
countries. Ipsen’s R&D is focused on its innovative and
differentiated technological platforms located in the heart of the
leading biotechnological and life sciences hubs (Paris-Saclay,
France; Oxford, UK; Cambridge, US). The Group has about 5,700
employees worldwide. Ipsen is listed in Paris (Euronext: IPN) and
in the United States through a Sponsored Level I American
Depositary Receipt program (ADR: IPSEY). For more information on
Ipsen, visit www.ipsen.com.
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1 Abou-Alfa, G.K., et al. Cabozantinib in patients with advanced
and progressing hepatocellular carcinoma. NEJM. 2018;379:54-63.
Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa1717002.
Accessed August 2019. 2 Signorovitch, J.E., et al.
Matching-adjusted indirect comparisons: a new tool for timely
comparative effectiveness research. Value Health. 2012;15(6):940-7.
Available at https://www.ncbi.nlm.nih.gov/pubmed/22999145. Accessed
August 2019 3 Bruix, J., et al. Regorafenib for patients with
hepatocellular carcinoma who progressed on sorafenib treatment
(RESORCE): a randomized, double-blind, placebo-controlled, phase 3
trial. Lancet. 2017;389(10064):56-66. Available at:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32453-9/fulltext.
Accessed August 2019 4Aggarwal, M., et al. Systemic treatment for
hepatocellular carcinoma. Chronic Dis Transl Med.
2018;4(3):148–155. Available at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160617/. Accessed
August 2019. 5 American Institute of Cancer Research. Liver cancer
statistics. Available at:
https://www.wcrf.org/dietandcancer/cancer-trends/liver-cancer-statistics.
Accessed August 2019. 6 European Association for the Study of the
Liver. EASL Clinical Practice Guidelines: Management of
hepatocellular carcinoma. J. Hepatol. 2018;69(1):182–236. Available
at:
https://www.journal-of-hepatology.eu/article/S0168-8278(18)30215-0/pdf.
Accessed August 2019.
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Christian Marcoux Corporate Communications +33 (0) 1 58 33 67 94
christian.marcoux@ipsen.com
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kelly.blaney@ipsen.com
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Relations +44 (0) 1753 627721 eugenia.litz@ipsen.com
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04 myriam.koutchinsky@ipsen.com
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