Novartis International AG /Novartis drug Afinitor® extends progression-free survival in patients with advanced pancreatic NET, study published in NEJM shows Processed and transmitted by Thomson Reuters.the issuer is solely responsible for the content of this announcement.
* RADIANT-3 trial shows everolimus more than doubled median progression-free survival from 4.6 to 11.0 months versus placebo[1]
* No tumor growth after 18 months in 34% of the patients treated with everolimus versus in 9% of those treated with placebo[1]
* These data, previously reported at oncology congresses, support worldwide regulatory submissions for treatment of advanced neuroendocrine tumors (NET), which has received priority review designation by US FDA
Basel, February 9, 2011 – the New England Journal of Medicine (NEJM) published astudy today that shows Afinitor® (everolimus) tablets plus best supportive care(BSC) more than doubled progression-free survival (PFS), or time without tumorgrowth, versus placebo plus BSC in patients with advanced pancreaticneuroendocrine tumors (NET)[1].
Data from the study, RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors), werefirst presented last year at the 12th World Congress on Gastrointestinal Cancerin Barcelona[2]. Regulatory submissions for everolimus to treat this patientpopulation are underway worldwide.
Results from the trial showed that everolimus more than doubled median PFS from4.6 to 11.0 months when compared with placebo and reduced the risk of cancerprogression by 65% (hazard ratio=0.35 [95% confidence interval (CI), 0.27 to0.45]; p=20%) were stomatitis/oral mucositis/ulcers(64% everolimus vs. 17% placebo; includes stomatitis, aphthous stomatitis, mouthulceration and tongue ulceration), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), infections (23% vs. 6%), nausea (20% vs. 18%), peripheraledema (20% vs. 3%) and decreased appetite (20% vs. 7%); most were grade one ortwo. Grade three and four adverse events (>=5%) include stomatitis/oralmucositis/ulcers (7% vs. 0%; includes stomatitis, aphthous stomatitis, mouthulceration and tongue ulceration), anemia (6% vs. 0%) and hyperglycemia (5% vs.2%). Median exposure to everolimus was 2.3-fold longer than exposure to placebo(38 vs. 16 weeks)[1].
About RADIANT-2RADIANT-2 is a Phase III randomized, double-blind, placebo-controlled, multicenter study. the trial examined the efficacy and safety of everolimus plusSandostatin® LAR® (octreotide acetate for injectable suspension) versus placeboplus octreotide LAR in 429 patients with advanced carcinoid tumors. Patients whomet the study´s entry criteria were randomized 1:1 to receive either oraleverolimus (10 mg daily) plus octreotide LAR (30 mg intramuscularly every 28days) or placebo daily plus octreotide LAR. Patients had radiologicaldocumentation of disease progression within 12 months prior to randomization[9].
The study did not meet its primary endpoint of PFS as assessed by independentradiological review (p=0.026 vs. p=0.0246 predefined) (hazard ratio=0.77 [95%CI, 0.59 to 1.00]). Secondary endpoints from the trial include safety, overallresponse rate and overall survival[9].
In the initial review of the data an imbalance in baseline characteristics wasobserved between the two treatment arms, including prior treatment withchemotherapy, primary tumors located in the lung and a poorer World HealthOrganization (WHO) performance status (an assessment of each patient´sfunctional/physical performance). Further, inconsistencies were found betweenanalyses of radiology scans, which resulted in censoring of patients from thetrial. These imbalances and the censoring of data seem to favor the control armand may have impacted the outcome of the study. Additional analyses to adjustfor imbalances in the treatment arms show everolimus plus octreotide LARsignificantly reduced risk of disease progression (hazard ratio=0.60 [95% CI, 0.44 to 0.84])[9].
In the study, the most frequent all grade drug-related adverse events witheverolimus plus octreotide LAR were stomatitis, rash, fatigue, diarrhea, nauseaand infections; most were grade one or two. Grade three and four adverse events(>=5%) with everolimus plus octreotide LAR were stomatitis (7%; includesstomatitis, aphthous stomatitis, mouth ulceration and tongue ulceration), fatigue (7%), diarrhea (6%), infections/infestations (5%) and hyperglycemia(5%)[9].
About neuroendocrine tumors (NET)Neuroendocrine tumors arise from cells that can produce and secrete a variety ofhormones that regulate bodily functions[10]. There are many types of NET thatcan occur throughout the body; however, most are found in the GI tract, pancreasand lungs[6,11]. Many patients with NET have no symptoms or nonspecificsymptoms, such as flushing and diarrhea, which often lead to delays in diagnosisof five to seven years[12,13]. As a result, many patients with NET often haveadvanced disease when diagnosed, meaning the cancer has spread to other parts ofthe body and has become more difficult to treat[3,5]. Approximately 64% ofpatients with pancreatic NET are diagnosed in advanced stages[6].
About Afinitor (everolimus)Afinitor® (everolimus) tablets is approved in the European Union (EU) for thetreatment of patients with advanced renal cell carcinoma (RCC) whose disease hasprogressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy and also in the US for the treatment of patients with advancedRCC after failure of treatment with sunitinib or sorafenib.
Afinitor is also approved in the US to treat patients with subependymal giantcell astrocytoma (SEGA) associated with tuberous sclerosis who requiretherapeutic intervention but are not candidates for curative surgical resection.the effectiveness of Afinitor is based on an analysis of change in SEGA volume.Clinical benefit such as improvement in disease-related symptoms or increase inoverall survival has not been shown. Novartis has submitted marketingapplications for everolimus to the European Medicines Agency (EMA) and the SwissAgency for Therapeutic Products (Swissmedic), and additional regulatorysubmissions are underway worldwide.
In the EU, everolimus is available in different dosage strengths under the tradename Certican® for the prevention of organ rejection in heart and kidneytransplant recipients. In the US, everolimus is available in different dosagestrengths under the trade name Zortress® for the prophylaxis of organ rejectionin adult patients at low-moderate immunologic risk receiving a kidneytransplant.
Everolimus is exclusively licensed to Abbott and sublicensed to BostonScientific for use in drug-eluting stents.
Not all indications are available in every country. As an investigationalcompound the safety and efficacy profile of everolimus has not yet beenestablished in NET. Access to everolimus outside of the approved indications hasbeen carefully controlled and monitored in clinical trials designed to betterunderstand the potential benefits and risks of the compound. Because of theuncertainty of clinical trials, there is no guarantee that everolimus willbecome commercially available for NET or any additional indications anywhere inthe world.
Important Safety Information about Afinitor (everolimus) tabletsAfinitor is contraindicated in patients with hypersensitivity to everolimus, toother rapamycin derivatives or to any of the excipients.
Cases of non-infectious pneumonitis have been described; some of these have beensevere and occasionally fatal. Management of pneumonitis may require doseadjustment and/or interruption, or discontinuation of treatment and/or additionof corticosteroid therapy.
Afinitor is immunosuppressive. Localized and systemic bacterial, fungal, viralor protozoal infections (e.g., pneumonia, aspergillosis, candidiasis, hepatitisB reactivation) have been described; some of these have been severe andoccasionally fatal. Pre-existing infections should be treated prior to startingtreatment. Patients and physicians should be vigilant for symptoms and signs ofinfection; in case of emergent infections, appropriate treatment should bepromptly instituted and interruption or discontinuation of Afinitor should beconsidered. Patients with systemic invasive fungal infections should not receiveAfinitor.
Hypersensitivity reactions have been observed.
Mouth ulcers, stomatitis and oral mucositis have been seen. Topical treatmentsare recommended; alcohol- or peroxide-containing mouthwashes should be avoided.
Monitoring of renal function, blood glucose and complete blood counts isrecommended prior to initiation and periodically during treatment. Cases ofrenal failure, some fatal, have been observed.
Afinitor is not recommended in patients with severe hepatic impairment.
Use of live vaccines should be avoided.
Afinitor is not recommended during pregnancy or for women of childbearingpotential not using contraception. Afinitor may cause fetal harm in pregnantwomen. Women taking Afinitor should not breast feed. Male fertility may becompromised by Afinitor.
Avoid concurrent treatment with strong CYP3A4 and PgP inhibitors and use cautionwith moderate inhibitors. Avoid concurrent treatment with strong CYP3A4 or PgPinducers.
In advanced RCC, the most common adverse reactions (>=10%) include stomatitis, rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation, vomiting, cough, infections, peripheral edema, dry skin, epistaxis, pneumonitis, pruritus and dyspnea. Common adverse reactions (>=1 to =1 to =1/10) adverse drug reactions in clinical studies with SandostatinLAR were diarrhea, abdominal pain, nausea, constipation, flatulence, headache, cholelithiasis, hyperglycemia and injection-site localized pain. Common(>=1/100, bloating, steatorrhea, loose stools, discoloration of feces, dizziness, hypothyroidism, thyroid dysfunction (e.g., decreased thyroid stimulatinghormone, decreased Total T4 and decreased Free T4), cholecystitis, biliarysludge, hyperbilirubinemia, hypoglycemia, impairment of glucose tolerance, anorexia, elevated transaminase levels, pruritus, rash, alopecia, dyspnea andbradycardia.
The uncommon (>=1/1000, tachycardia. the following adverse reactions have been reported postmarketing:anaphylaxis, allergy/hypersensitivity reactions, urticaria, acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice, arrhythmia, increased alkaline phosphataselevels and increased gamma glutamyl transferase levels.
DisclaimerThe foregoing release contains forward-looking statements that can be identifiedby terminology such as “encouraging, ” “potential, ” “priority review, ” “likely, “could, ” “will, ” or similar or similar expressions, or by express or implieddiscussions regarding potential submissions or approvals for new indications orlabeling for Afinitor, or regarding the potential timing of any such approvals, or regarding potential future revenues from Afinitor. You should not place unduereliance on these statements. Such forward-looking statements reflect thecurrent views of management regarding future events, and involve known andunknown risks, uncertainties and other factors that may cause actual resultswith Afinitor to be materially different from any future results, performance orachievements expressed or implied by such statements. There can be no guaranteethat Afinitor will be submitted or approved for any additional indications orlabeling in any market. Nor can there be any guarantee that Afinitor willachieve any particular levels of revenue in the future. In particular, management´s expectations regarding Afinitor could be affected by, among otherthings, unexpected regulatory actions or delays or government regulationgenerally; unexpected clinical trial results, including unexpected new clinicaldata and unexpected additional analysis of existing clinical data; the company´sability to obtain or maintain patent or other proprietary intellectual propertyprotection; competition in general; government, industry and general publicpricing pressures; the impact that the foregoing factors could have on thevalues attributed to the Novartis Group´s assets and liabilities as recorded inthe Group´s consolidated balance sheet, and other risks and factors referred toin Novartis AG´s current Form 20-F on file with the US Securities and ExchangeCommission. Should one or more of these risks or uncertainties materialize, orshould underlying assumptions prove incorrect, actual results may varymaterially from those anticipated, believed, estimated or expected. Novartis isproviding the information in this press release as of this date and does notundertake any obligation to update any forward-looking statements contained inthis press release as a result of new information, future events or otherwise.
About NovartisNovartis provides healthcare solutions that address the evolving needs ofpatients and societies. Focused solely on healthcare, Novartis offers adiversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools andconsumer health products. Novartis is the only company with leading positions inthese areas. In 2010, the Group´s continuing operations achieved net sales ofUSD 50.6 billion, while approximately USD 9.1 billion (USD 8.1 billion excludingimpairment and amortization charges) was invested in R&D throughout the Group.Headquartered in Basel, Switzerland, Novartis Group companies employapproximately 119,000 full-time-equivalent associates (including 16,700 Alconassociates) and operate in more than 140 countries around the world. for moreinformation, please visitnovartis.com.
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References[1] Yao, et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. NewEng J Med 2011;364:514-23.[2] Yao, et al. Everolimus versus placebo in patients with advanced pancreaticneuroendocrine tumors (pNET) (RADIANT-3). 12th World Congress onGastrointestinal Cancer, Barcelona. July 1, 2010.[3] National Library of Medicine and the National Institutes of Health.Pancreatic islet cell tumor. Availableatnlm.nih.gov/medlineplus/ency/article/000393.htm. Accessed February2011.[4] American Cancer Society Detailed Guides. Pancreatic Cancer. Availableatcancer.org/Cancer/PancreaticCancer/DetailedGuide/pancreatic-cancer-what-is-pancreatic-cancer. Accessed February 2011.[5] Halfdanarson, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Annals of Onc19: 1727-1733, 2008.[6] Yao, et al. one Hundred Years after “Carcinoid:” Epidemiology of andPrognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the UnitedStates. Journal of Clinical Oncology. June 20 2009; vol. 26, number 18.[7] Motzer, et. al. Phase 3 Trial of Everolimus for Metastatic Renal CellCarcinoma. Cancer 2010 Sep; 116(18):4256-4265.[8] US Food and Drug Administration. Fast Track, Accelerated Approval andPriority Review. Availableatfda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm. Accessed February 2011.[9] Pavel et al. A randomized, double-blind, placebo-controlled, multicenterphase III trial of everolimus + octreotide LAR vs placebo + octreotide LAR inpatients with advanced neuroendocrine tumors (NET) (RADIANT-2). 35th EuropeanSociety for Medical Oncology Congress. October 9, 2010.[10] National Library of Medicine and the National Institutes of Health.Neuroendocrine Tumor. available atcancer.gov/dictionary/?CdrID=44904.Accessed February 2011.[11] American Cancer Society Detailed Guides. Gastrointestinal Carcinoid Tumors.Availableatcancer.org/Cancer/GastrointestinalCarcinoidTumor/DetailedGuide/gastrointestinal-carcinoid-tumors-key-statistics. Accessed February 2011.[12] Modlin, et al. Priorities for Improving the Management ofGastroenteropancreatic Neuroendocrine Tumors. J Natl Cancer Inst2008;100:1282-1289.[13] National Library of Medicine and the National Institutes of Health.Carcinoid syndrome. Availableatnlm.nih.gov/medlineplus/ency/article/000347.htm. Accessed February2011.
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