PARIS--(BUSINESS WIRE)--Regulatory News:
Ipsen (Euronext: IPN; ADR: IPSEY) today announced that data from the matching-adjusted indirect comparison (MAIC) of Cabometyx® (cabozantinib) versus Stivarga® (regorafenib) for the second-line (2L) treatment of patients with advanced hepatocellular carcinoma (aHCC) who received sorafenib as the only prior systemic therapy were published in Advances in Therapy. The MAIC represents the first published analysis of the comparative efficacy and safety of two key 2L treatments for aHCC.1
Preliminary data from the MAIC were presented by Dr. Katie Kelley, Associate Professor of Clinical Medicine, Department of Medicine (Hematology/Oncology) at the University of California, San Francisco, and lead investigator of this analysis, at the 13th Annual Conference of the International Liver Cancer Association (ILCA 2019) in September 2019.2
The MAIC examined data from the Phase III CELESTIAL and RESORCE trials and concluded that in the 2L CELESTIAL sub-population who had received sorafenib as the only prior systemic therapy, median progression-free survival (PFS) with Cabometyx® was significantly longer, with an additional 2.5 months provided vs. regorafenib (5.6 months [95% confidence interval (CI): 4.9-7.3] vs. 3.1 months [95% CI: 2.8-4.2], p=0.0005). Overall survival (OS) was numerically longer with cabozantinib, with a median OS of almost 1 year (11.4 months vs. 10.6 months), though statistical significance was not met.1
In the previously published randomized, double-blind, Phase III CELESTIAL trial evaluating Cabometyx® compared with placebo in previously treated patients with aHCC, in the overall CELESTIAL intent-to-treat population (n=707), Cabometyx® significantly improved median PFS, with an additional 3.3 months provided versus placebo (5.2 months vs. 1.9 months [hazard ratio (HR) 0.44, 95% CI: 0.36-0.52], p<0.0001), and median OS was numerically longer with cabozantinib, with an additional 2.2 months versus placebo (10.2 months vs. 8.0 months [HR 0.76, 95% CI: 0.63-0.92], p=0.0049).3
“Hepatocellular carcinoma is a devastating disease with only a few treatment options available to improve survival for patients with advanced disease, though we have seen significant progress with multiple new treatments demonstrating efficacy in the past few years,” said Dr. Kelley. “This MAIC analysis brings further insight into the comparative effectiveness of the key new second-line treatments for advanced hepatocellular carcinoma, particularly in relation to important endpoints like progression-free survival. The results published today may help clinicians in making informed treatment decisions for their patients.”
Grade 3/4 adverse events (AEs) affecting more than 5% of patients were similar for the two studies, except for diarrhea, which was significantly lower with regorafenib (p<0.001).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.4 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 have been used to inform clinical decision-making across a range of cancer types, including HCC, in the absence of direct comparative data.5-10 They use individual patient data (IPD), also referred to as individual-level data (ILD), from trials of one treatment to match baseline (BL) summary statistics reported from trials of another treatment and reduce observed cross-trial differences.4 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, 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 their patients,” said Amauri Soares, Vice-President, Medical Affairs Oncology at Ipsen. “The recent rapid development of new second-line treatments for patients with advanced hepatocellular carcinoma has led to the generation of information mainly based on placebo-controlled trials. While alternative methodological approaches such as MAIC are not substitutes for evidence-based prospective clinical trials, the publication of the MAIC for cabozantinib versus regorafenib provides healthcare professionals with timely new insights into the comparative effectiveness of current treatment approaches.”
About the MAIC of cabozantinib and regorafenib
The aim of this MAIC was to compare the efficacy and safety 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 CELESTIAL trial3 who had received cabozantinib as 2L therapy following sorafenib as the sole prior therapy (N=495) were adjusted to match the average BL characteristics of the 573 patients enrolled in the regorafenib study RESORCE,10 for which 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
- geographical region
- Eastern Cooperative Oncology Group (ECOG) performance status
- Child-Pugh class
- duration of prior sorafenib treatment
- extrahepatic disease
- macrovascular invasion
- etiology of HCC (hepatitis B, alcohol use and hepatitis C)
- alpha-fetoprotein tumor marker (AFP) 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 vs. regorafenib (5.6 months [95% CI: 4.9-7.3] vs. 3.1 months [95% CI: 2.8-4.2], p<0.0005)
- OS was numerically longer with cabozantinib, with a median OS of almost 1 year (11.4 months vs. 10.6 months), though statistical significance was not met
Grade 3/4 AEs affecting more than 5% of patients were comparable for the two studies, except for diarrhea which was significantly lower with regorafenib (p<0.001).1
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 controlled trial.1 While our MAIC procedures reduced the impact of potentially effect-modifying baseline characteristics, they could not adjust for between-trial differences in assessment schedules or for potential impact of sorafenib-intolerant patients in the CELESTIAL population.1
CELESTIAL is a randomized, double-blind, placebo-controlled global Phase III study of cabozantinib versus placebo in patients with aHCC 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 aHCC 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.3
The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and PFS. Exploratory endpoints included patient-reported outcomes, biomarkers and safety.3
Based on available clinical trial data from various published trials conducted in the 2L setting of aHCC, 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.3
The CELESTIAL trial met its primary endpoint of OS, with cabozantinib providing a statistically significant and clinically meaningful improvement in median OS compared with placebo in patients with aHCC. 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.3
HCC is an aggressive and lethal disease with the number of deaths per year close to its incidence worldwide.12 It accounts for about 90% of all liver cancers and there were over 840,000 new cases of liver cancer worldwide in 2018. It is the fifth most common cancer and the second most frequent cause of cancer-related death globally.13,14
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: CABOMETYX® is currently approved in 51 countries, including in the European Union, the U.K., Norway, Iceland, Australia, Switzerland, South Korea, Canada, Brazil, Taiwan, Hong-Kong, Singapore, Macau, Jordan, Lebanon, Russian Federation, Ukraine, Turkey, United Arab Emirates, Saudi Arabia, Serbia, Israel, Mexico, Chile and Panama for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy; in the European Union, the U.K., Norway, Iceland, Canada, Australia, Brazil, Taiwan, Hong Kong, Singapore, Jordan, Russian Federation, Turkey, United Arab Emirates, Saudi Arabia, Servia, Israel, Mexico, Chile and Panama for previously untreated intermediate- or poor-risk advanced RCC; and in the European Union, the U.K., Norway, Iceland, Canada, Australia, Switzerland, Saudi Arabia, Serbia, Israel , Taiwan, Hong Kong, South Korea, Singapore, Jordan, Russian Federation, Turkey, United Arab Emirates, and Panama for HCC in adults who have previously been treated with sorafenib.
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.
Hepatic encephalopathy: In the HCC study (CELESTIAL), hepatic encephalopathy was reported more frequently in the cabozantinib than the placebo arm.
Hepatic effects: Abnormalities of liver function tests have been frequently observed in patients treated with cabozantinib. Liver function tests should be performed before initiation and monitored closely during treatment. If there is worsening of liver function tests with no alternative cause evident, the dose should be modified as per SmPC.
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
The most common serious adverse reactions are hypertension, diarrhea, PPES, pulmonary embolism, fatigue and hypomagnesaemia. Very common (>1/10): anaemia, hypothyroidism, decreased appetite, hypomagnesaemia, hypokalaemia, dysgeusia, headache, dizziness, hypertension, haemorrhage, dysphonia, dyspnoea, cough, diarrhoea, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia, PPES, rash, pain in extremity, fatigue, mucosal inflammation, asthenia, peripheral oedema, weight decreased, serum ALT increased, AST increased. Common (>1/100 to <1/10): abscess, thrombocytopenia, neutropenia, dehydration, hypoalbuminaemia, hypophosphataemia, hyponatraemia, hypocalcaemia, hyperkalaemia, hyperbilirubinaemia, hyperglycaemia, hypoglycaemia, peripheral sensory neuropathy, tinnitus, venous thrombosis, arterial thrombosis, pulmonary embolism, gastrointestinal perforation, fistula, gastroesophageal reflux disease, haemorrhoids, oral pain, dry mouth, hepatic encephalopathy, pruritus, alopecia, dry skin, dermatitis acneiform, hair colour change, muscle spasms, arthralgia, proteinuria, blood ALP increased, GGT increased, blood creatinine increased, amylase increased, lipase increased, blood cholesterol increased, white blood cell count decreased. Uncommon (>1/1000 to <1/100): lymphopenia, convulsion, pancreatitis, glossodynia, hepatitis cholestatic, osteonecrosis of the jaw, blood triglycerides increased, wound complications. Frequency not known: cerebrovascular accident, myocardial infarction. Aneurysms and artery dissections. Selected adverse reactions: GI perforation, hepatic encephalopathy, diarrhoea, fistulas, haemorrhage, RPLS. Prescribers should consult the SmPC in relation to other adverse reactions.
Selected adverse event (AEs): GI perforation, hepatic encephalopathy, diarrhoea, 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.
U.S. Indications and Important Safety Information
CABOMETYX® (cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
CABOMETYX® (cabozantinib) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
IMPORTANT SAFETY INFORMATION
Warnings and precautions:
Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: GastrointestinaI (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic event requiring medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Proteinuria: Proteinuria occurred in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 28 days prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution.
Wound Complications: Wound complications were reported with CABOMETYX. Stop CABOMETYX at least 28 days prior to scheduled surgery. Resume CABOMETYX after surgery based on clinical judgment of adequate wound healing. Withhold CABOMETYX in patients with dehiscence or wound healing complications requiring medical intervention.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.
The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, and vomiting.
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.
Use in specific populations:
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.
Please see full Prescribing Information for more information.
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 €2.5 billion in 2019, 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 5,800 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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