On May 24, 2019 Ipsen (Euronext: IPN; ADR: IPSEY) reported that new data from clinical studies on investigational uses of cancer medicines cabozantinib (Cabometyx), liposomal irinotecan (Onivyde), and lanreotide autogel (Somatuline, marketed as Somatuline Depot in the United States) will be presented at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Ipsen, MAY 24, 2019, View Source [SID1234536560]). The meeting takes place in Chicago, Illinois, U.S., 31 May–4 June 2019; data featuring Ipsen medicines includes:
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New data from the Phase 3 CELESTIAL trial on the association of adverse events with efficacy outcomes for cabozantinib in patients with advanced hepatocellular carcinoma
Overview of the Phase 3 COSMIC-312 trial of cabozantinib in combination with atezolizumab vs sorafenib in patients with advanced hepatocellular carcinoma who have not received previous systemic anticancer therapy
First Phase 2 data from the CaboGIST study (trial 1317) from the European Organization for Research and Treatment of Cancer on the activity and safety of cabozantinib in patients with metastatic gastrointestinal stromal tumor after failure of imatinib and sunitinib
Preliminary results from the RESILIENT study of liposomal irinotecan injection in patients with small cell lung cancer
Results from a Phase 2 multicenter study of lanreotide autogel in the treatment of clinical symptoms associated with inoperable malignant intestinal obstruction
"At Ipsen, patients inspire and drive us to tackle some of the most difficult-to-treat cancers, particularly where few effective options exist. ASCO (Free ASCO Whitepaper) gives us the opportunity to share the progress we have made in our mission of developing and delivering therapeutic solutions that meet the real needs of patients and may help improve their lives," said Dr. Alexandre Lebeaut, Ipsen’s Executive Vice President, R&D, and Chief Scientific Officer. "With our continued clinical programs and collaborations, we are making strides in renal, liver and small cell lung cancers and other cancers with high unmet need, and we look forward to continuing to advance these programs."
Follow Ipsen on Twitter via @IpsenGroup and @IpsenUS and keep up to date with ASCO (Free ASCO Whitepaper) 2019 congress news and updates by using the hashtag #ASCO19.
Overview of key Ipsen presentations at ASCO (Free ASCO Whitepaper) 2019:
Medicine Abstract title
Abstract number/timing
(CDT)
Cabometyx
(cabozantinib)
Phase 3 (COSMIC-311) randomized, double-blind, placebo- controlled study of cabozantinib in patients with radioiodine (RAI)- refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy
Abstract TPS6097 Poster 82a – Category: Head and Neck Cancer; Saturday, 1 June, 1:15 PM – 4:15 PM; Hall A TIP
Association of adverse events (AEs) with efficacy outcomes for cabozantinib (C) in patients (pts) with advanced hepatocellular carcinoma (aHCC) in the Phase 3 CELESTIAL trial
Abstract 4088 Poster 193 – Category: Gastrointestinal (Noncolorectal) Cancer; Monday, 3 June, 8:00 AM – 11:00 AM; Hall A
Phase 3 (COSMIC-312) study of cabozantinib (C) in combination with atezolizumab (A) vs sorafenib (S) in patients (pts) with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy
Abstract TPS4157 Poster 254a – Category: Gastrointestinal (Noncolorectal) Cancer; Monday, 3 June, 8:00 AM – 11:00 AM; Hall A TIP
Onivyde (nal-
IRI/liposomal
irinotecan)
RESILIENT: Study of Irinotecan Liposome Injection (nal-IRI) in Patients with Small Cell Lung Cancer: Preliminary Findings from Part 1 Dose-defining Phase
Abstract 8562 Poster 318 – Category: Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers; Poster – Sunday, 2 June, 8:00 AM – 11:00 AM; Hall A
Somatuline Autogel
(lanreotide
autogel/depot)
Efficacy and Safety of Lanreotide Autogel (LAN) 120 mg in theTreatment of Clinical Symptoms Associated With Inoperable Malignant Intestinal Obstruction (IMIO): Results From A Phase II Multicenter Study
Abstract 4118 Poster 223 – Category: Gastrointestinal (Noncolorectal) Cancer; Poster – Monday, 3 June, 8:00 AM – 11:00 AM; Hall A
Overview of key investigator sponsored study presentations featuring Ipsen medicines at ASCO (Free ASCO Whitepaper) 2019:
Medicine Abstract title
Abstract number/timing
(CDT)
Cabometyx
(cabozantinib)
Activity and safety of cabozantinib in patients with metastatic gastrointestinal stromal tumor after failure of imatinib and sunitinib. European Organization for Research and Treatment of Cancer (EORTC) Phase 2 trial 1317 "CaboGIST" EORTC Sponsored Study
Abstract 11006 Oral: Category: Sarcoma; Monday, 3 June, 10:00 AM – 10:12 AM; E450
PDIGREE: An adaptive Phase 3 trial of PD-inhibitor nivolumab and Ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated Renal Cell Cancer (Alliance A031704) NCI Sponsored Study
Abstract TPS4596 Poster 417a – Category: Genitourinary (Nonprostate) Cancer; Poster – Monday, 3 June, 1:15 PM – 4:15 PM; Hall A
Prognostic value of sequential 18F- FDG + Na18F PET/CT (NaF+FDG PET) in metastatic genitourinary (GU) cancer patients (pts) treated with Cabozantinib/ Nivolumab +/- Ipilimumab (CaboNivoIpi) NCI Sponsored Study
Abstract 4544 Poster 370 – Category: Genitourinary (Nonprostate) Cancer; Poster – Monday, 3 June, 1:15 PM – 4:15 PM; Hall A
Circulating tumor cell (CTC) enumeration in patients (pts) with metastatic genitourinary (mGU) tumors treated in a phase I study of cabozantinib and nivolumab (CaboNivo) +/- ipilimumab (CaboNivoIpi)
Abstract 4555 Poster 381 – Category: Genitourinary (Nonprostate) Cancer; Poster – Monday, 3 June, 1:15 PM – 4:15 PM; Hall A
Correlates of overall survival (OS) in metastatic vs. primary uveal melanoma (UM) and results of a randomized trial of cabozantinib (cabo) vs. chemotherapy (chemo) Alliance A091201 NCI Sponsored Study
Abstract 9506 – Oral: Category: Melanoma/Skin Cancers; Poster – Tuesday, 4 June, 11:45 AM – 11:57 AM; S406
Onivyde (nal-
IRI/liposomal
irinotecan)
A multicenter phase Ib/II study of nalirinotecan, 5fluouracil and leucovorin in combination with nivolumab as second-line therapy for patients with advanced unresectable biliary tract cancer
Abstract TPS4154 Poster 252b – Category: Gastrointestinal (Noncolorectal) Cancer; Poster – Monday, 3 June, 8:00 AM – 11:00 AM; Hall A
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 ONIVYDE (irinotecan liposome injection)
ONIVYDE is an encapsulated formulation of irinotecan available as a 43 mg/10 mL single dose vial. This liposomal form is designed to increase length of tumor exposure to both irinotecan and its active metabolite, SN- 38.
On April 3, 2017, Ipsen completed the acquisition from Merrimack Pharmaceuticals of ONIVYDE and gained exclusive commercialization rights for the current and potential future indications for ONIVYDE in the US. Servier1 is responsible for the development and commercialization of ONIVYDE outside of the U.S. and Taiwan under an exclusive licensing agreement with Ipsen Biopharm Ltd.
ONIVYDE is approved by the U.S. FDA in combination with fluorouracil (5-FU) and leucovorin (LV) for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.
1 Servier is an international pharmaceutical company, governed by a non-profit foundation, with headquarters in the Paris metropolitan area.
IMPORTANT SAFETY INFORMATION – UNITED STATES
BOXED WARNINGS: SEVERE NEUTROPENIA and SEVERE DIARRHEA
Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with 5-FU and LV.
Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment
Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with 5-FU/LV. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2–4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity
CONTRAINDICATION
ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl
Warnings and Precautions
Severe Neutropenia: See Boxed WARNING. In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia was higher among Asian (18/33 [55%]) vs White patients (13/73 [18%]) Neutropenic fever/neutropenic sepsis was reported in 6% of Asian vs 1% of White patients
Severe Diarrhea: See Boxed WARNING. Severe and life-threatening late-onset (onset >24 hours after chemotherapy [9%]) and early-onset diarrhea (onset ≤24 hours after chemotherapy [3%], sometimes with other symptoms of cholinergic reaction) were observed
Interstitial Lung Disease (ILD): Irinotecan HCl can cause severe and fatal ILD. Withhold ONIVYDE I patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD
Severe Hypersensitivity Reactions: Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction
Embryo-Fetal Toxicity: ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during and for 1 month after ONIVYDE treatment
Adverse Reactions
The most common adverse reactions (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%)
The most common Grade 3/4 adverse reactions (≥10%) were diarrhea (13%), fatigue/asthenia (21%), and vomiting (11%)
Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/5- FU/LV; The most frequent adverse reactions resulting in discontinuation of ONIVYDE were diarrhea, vomiting, and sepsis
Dose reductions of ONIVYDE for adverse reactions occurred in 33% of patients receiving ONIVYDE/5 FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia
ONIVYDE was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia
The most common laboratory abnormalities (≥20%) were anemia (97%), lymphopenia (81%), neutropenia (52%), increased ALT (51%), hypoalbuminemia (43%), thrombocytopenia (41%), hypomagnesemia (35%), hypokalemia (32%), hypocalcemia (32%), hypophosphatemia (29%), and hyponatremia (27%)
Drug Interactions
Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme inducing therapies ≥2 weeks prior to initiation of ONIVYDE
Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to starting therapy
Special Populations
Pregnancy and Reproductive Potential: See WARNINGS & PRECAUTIONS. Advise males with female partners of reproductive potential to use condoms during and for 4 months after ONIVYDE treatment
Lactation: Advise nursing women not to breastfeed during and for 1 month after ONIVYDE treatment
Please see full U.S. Prescribing Information for ONIVYDE.
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
ONIVYDE is a registered trademark of Ipsen Biopharm Limited.
XERMELO is not marketed by Ipsen in the United States. The approved indications may vary by country. 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 SOMATULINE (lanreotide)
Indications
SOMATULINE DEPOT (lanreotide) is a somatostatin analog indicated for:
the treatment of adult patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival; and
the treatment of adults with carcinoid syndrome; when used, it reduces the frequency of short acting somatostatin analog rescue therapy.
IMPORTANT SAFETY INFORMATION
Contraindications
SOMATULINE DEPOT is contraindicated in patients with hypersensitivity to lanreotide. Allergic reactions (including angioedema and anaphylaxis) have been reported following administration of lanreotide.
Warnings and Precautions
Cholelithiasis and Gallbladder Sludge
SOMATULINE DEPOT may reduce gallbladder motility and lead to gallstone formation.
Periodic monitoring may be needed.
If complications of cholelithiasis are suspected, discontinue SOMATULINE DEPOT and treat appropriately
Hypoglycemia or Hyperglycemia
Patients treated with SOMATULINE DEPOT may experience hypoglycemia or hyperglycemia.
Blood glucose levels should be monitored when SOMATULINE DEPOT treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly.
Cardiovascular Abnormalities
SOMATULINE DEPOT may decrease heart rate.
In patients without underlying cardiac disease, SOMATULINE DEPOT may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia.
In patients suffering from cardiac disorders prior to treatment, sinus bradycardia may occur. Care should be taken when initiating treatment in patients with bradycardia.
Most Common Adverse Reactions
GEP-NETs: Adverse reactions in >10% of patients who received SOMATULINE DEPOT were abdominal pain (34%), musculoskeletal pain (19%), vomiting (19%), headache (16%), injection site reaction (15%), hyperglycemia (14%), hypertension (14%), and cholelithiasis (14%).
Carcinoid Syndrome: Adverse reactions occurring in the carcinoid syndrome trial were generally similar to those in the GEP-NET trial. Adverse reactions in ≥5% of patients who received SOMATULINE DEPOT and at least 5% greater than placebo were headache (12%), dizziness (7%) and muscle spasm (5%).
Drug Interactions: SOMATULINE DEPOT may decrease the absorption of cyclosporine (dosage adjustment may be needed); increase the absorption of bromocriptine; and require dosage adjustment for bradycardia-inducing drugs (e.g., beta-blockers).
Special Populations
Lactation: Advise women not to breastfeed during treatment and for 6 months after the last dose.
To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855- 463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please click here for the full Prescribing Information and Patient Information.