- Oral presentation on Sandostatin(R) LAR Depot Phase III data shows significant antitumor benefit in patients with advanced neuroendocrine tumors of the midgut
- Early data show that at eight weeks of treatment, Afinitor(R) stabilized or reduced tumor size in 61% of patients with advanced liver cancer
- New data reveal postmenopausal women with breast cancer taking Femara(R) experience better cognitive function than those taking tamoxifen
- Phase II data show potential of Glivec(R) in treating patients with advanced KIT-mutated melanoma; other Novartis data on advanced melanoma also presented
EAST HANOVER, N.J., May 28 /PRNewswire/ -- Novartis announced today that data on more than 15 compounds in its robust oncology portfolio will be included at the 2009 American Society of Clinical Oncology (ASCO) annual meeting. These studies provide new research on multiple tumor types and rare cancers.
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"Our strong presence at ASCO showcases our continued progress in developing innovative therapies for patients with cancer through our comprehensive discovery and development program," said David Epstein, President and CEO, Novartis Oncology, Novartis Molecular Diagnostics. "We look forward to continuing to explore novel ways to help patients in need of new treatments."
Sandostatin LAR in metastatic neuroendocrine midgut tumors
Data from the PROMID study (abstract #4508)* show Sandostatin(R) LAR Depot (octreotide acetate for injectable suspension) demonstrated a significant antitumor effect in patients with metastatic neuroendocrine tumors (NET) of the midgut(1).
Sandostatin LAR, when compared to placebo, more than doubled time without tumor growth (15.6 months vs. 5.9 months) and reduced the risk of disease progression by 67% (hazard ratio=0.33 with 95% confidence interval 0.19 to 0.55; P=0.000017)(1).
This important benefit was seen in patients with functioning tumors (i.e., tumors that are associated with carcinoid syndrome due to the secretion of various hormones that cause symptoms, such as diarrhea or flushing) and non-functioning (non-secreting) tumors. In an analysis of patients with non-functioning tumors, which affect the majority of people with NET, time to tumor progression for patients receiving Sandostatin LAR was 27.14 months versus 7.21 months for those on placebo (P=0.0008)(1).
Further, a statistically significant benefit was observed in patients with tumor load less than or equal to 10%, which suggests a potentially important role for treatment in the early stages of the disease. The median time to tumor progression was 27.1 months in the patients receiving Sandostatin LAR versus 7.2 months in the placebo group (P<0.0001)(1).
The trial, called PROMID (Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors), is a Phase IIIb study conducted at 18 sites in Germany to evaluate the antitumor effect of Sandostatin LAR in patients with midgut NET. The study included 85 patients who were treated with either Sandostatin LAR (30 mg/month) or placebo for 18 months, or until tumor progression or death. All patients in the study were treatment-naive, had locally inoperable or metastatic NET with the primary tumor located in the midgut, were without curative therapeutic options and had tumors that were either functioning or non-functioning. Interim results from PROMID were presented at the 2009 ASCO Gastrointestinal Cancer Symposium(1).
Neuroendocrine tumors originate from cells that have roles both in the endocrine and nervous systems. While these NET are often slow-growing, when the tumor is inoperable patients with advanced NET have limited treatment options(2).
The safety findings observed in the PROMID study were consistent with those seen in previous studies of Sandostatin LAR in patients with NET. The most frequently observed serious adverse events affected the gastrointestinal tract, hematopoietic system and other general symptoms such as fatigue and fever(1).
Afinitor in patients with advanced liver cancer
Phase I data (abstract #4587) demonstrated that 61% of patients with advanced hepatocellular carcinoma (HCC) who received daily treatment with Afinitor(R) (everolimus) tablets had tumors that stabilized or reduced in size(3).
There are currently a limited number of treatment options for patients with advanced HCC, the stage when most are diagnosed(4)(5). Everolimus shows potential to help address this unmet medical need(3).
The trial, conducted in Taiwan by Dr Li-Tzong Chen from the National Health Research Institute, included 36 advanced HCC patients who progressed after various systemic therapies or who were no longer candidates for local therapies, including surgery, percutaneous ablation or transcatheter arterial chemoembolization. Of the 31 patients evaluable in the trial, 16 received everolimus (known as RAD001 in this study) daily. The study objective was to define the maximum tolerated dose and pharmacokinetics of everolimus(3).
The Grade 3 and 4 adverse events reported in the study included elevated bilirubin, drop in platelets count, diarrhea, bleeding, cardiac ischemia, elevated liver function tests and infection. Reactivation of Hepatitis B virus was observed in four patients as well as reactivation of Hepatitis C virus in one patient(3).
Based on these data, a global Phase III clinical trial to study the daily everolimus regimen in patients with advanced HCC is in development by Novartis.
Femara BIG 1-98 data on cognitive function
Impaired cognition is a concern among breast cancer patients taking hormonal therapies. Estrogen is believed to have a direct influence on cognitive function. Aromatase inhibitors reduce the level of circulating estrogen in the body. It has been suggested that reduced estrogen in the body is linked to a decline in cognitive function(6).
A new substudy (abstract #510) conducted within a subgroup of patients enrolled in the independent Breast International Group (BIG) 1-98 study (Femara(R) [letrozole tablets] vs. tamoxifen) found that postmenopausal women with hormone receptor-positive early breast cancer taking adjuvant Femara had better overall cognitive function than those taking tamoxifen, based on validated scales of cognitive function collected at the fifth year of endocrine treatment(6).
Results from this study revealed that the group of patients receiving Femara had clinically and significantly better overall cognitive function than the patients in the tamoxifen group (difference in mean composite scores =0.23, P=0.04, 95% confidence interval: 0.02-0.54). Overall, both groups performed below age norms on most domains(6).
Highlights in melanoma
New data highlight the potential of two Novartis products as treatments for advanced melanoma, the most serious form of skin cancer. Melanoma accounts for 41,000 deaths worldwide each year(7)(8). While melanoma is curable when diagnosed and treated in early stages, advanced melanoma is often resistant to currently available treatments(9).
New data from a Phase II study (abstract #9001) show the potential of Gleevec(R)(#) (imatinib mesylate) in treating patients with advanced melanoma harboring KIT mutations. A mutation in the protein called KIT, located on the surface of normal cells, signals cells to continually grow and divide. Similar KIT mutations in GIST were shown to be treated effectively by Gleevec. The preliminary data from the investigator-driven study show that five out of five patients evaluable for responses showed either partial responses to Gleevec (3 out of 5) or stable disease (2 out of 5). Responses in two of the three patients are ongoing past 18 weeks. These favorable results have allowed the study to continue to a second expanded stage of enrollment(10).
Other data on advanced melanoma include preliminary results from a Phase II trial (abstract #9027) that show 72% of patients (20 out of 28) with advanced melanoma treated with everolimus in combination with bevacizumab experienced a clinical benefit (4% had a partial response and 68% had stable disease). The combination of everolimus and bevacizumab was generally well tolerated. According to the abstract, one patient withdrew from the trial due to interstitial pneumonitis, which was reversible, and one patient had a fatal heart attack, possibly bevacizumab-related. Grade 3 mucositis occurred in 13% of patients and all other grade 3 toxicities occurred in <10% of patients(11).
Early stage development data
About the Novartis Oncology pipeline
The Novartis Oncology pipeline features 18 new molecular entities. These compounds are being studied in more than 40 different cancer types in approximately 15,000 patients. The pipeline portfolio encompasses a broad array of therapeutic strategies for fighting cancer, including novel targeted agents, monoclonal antibodies, deacetylase (DAC) inhibitors, multiligand somatostatin analogs and novel cytotoxics.
Sandostatin LAR important safety information
Sandostatin LAR is a long-acting, injectable depot formulation of octreotide acetate, that is approved for the treatment of acromegaly, diarrhea/flushing episodes associated with advanced carcinoid tumors and profuse watery diarrhea associated with VIP-secreting tumors. Based on these attributes, octreotide has been used to treat symptoms associated with metastatic carcinoid tumors (flushing and diarrhea) and vasoactive intestinal peptide (VIP) secreting adenomas (watery diarrhea). In addition, octreotide substantially reduces and in many cases can control growth hormone and/or normalize IGF-1 levels in patients with acromegaly, a disease caused by a GH-secreting pituitary adenoma. Sandostatin LAR is not indicated as a treatment for tumor control. The clinical trials that supported approval of Sandostatin LAR did not study effect on tumor size or rate of growth.
The most frequently reported drug-related adverse events were biliary disorders (62%), gastrointestinal disorders (14% to 38%), and injection-site pain (20% to 50%). Hypoglycemia (4%), hyperglycemia (27%), sinus bradycardia (19%), conduction abnormalities (9%), and arrhythmias (3%) have been reported. Additional adverse reactions identified in clinical studies include nausea, abdominal pain, gas, constipation, vomiting, pain on injection, high or low blood sugar levels and slow or irregular heart rate. Many patients developed gallstones, although few patients required treatment.
For full prescribing information, please visit www.us.sandostatin.com.
Afinitor important safety information
Afinitor is approved in the US as the first oral, daily therapy (5 mg and 10 mg tablets) to treat patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Afinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives or to any of the excipients. Potentially serious adverse reactions include non-infectious pneumonitis and infections for which patients should be monitored carefully and treated as needed. In addition, non-infectious pneumonitis may require temporary dose reduction and/or interruption or discontinuation. Patients with systemic invasive fungal infections should not receive Afinitor. Oral ulceration is a common side effect with Afinitor. Renal function, blood glucose, lipids and hematological parameters should be evaluated prior to the start of therapy with Afinitor and periodically thereafter. Strong or moderate CYP3A4 or P-glycoprotein inhibitors should be avoided. An increase in the dose of Afinitor is recommended when co-administered with a strong CYP3A4 inducer. Live vaccinations and close contact with those who have received live vaccines should be avoided by patients taking Afinitor. Afinitor should not be used in patients with severe hepatic impairment. Afinitor may cause fetal harm in pregnant women.
The most common adverse reactions irrespective of causality (incidence greater than or equal to 30%) were stomatitis, infections, asthenia, fatigue, cough and diarrhea. The most common grade 3/4 adverse reactions irrespective of causality (incidence greater than or equal to 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain and asthenia. The most common laboratory abnormalities (incidence greater than or equal to 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia and increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence greater than or equal to 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed in patients receiving Afinitor.
Femara important safety information
You should not take Femara if you are premenopausal. Your doctor should discuss the need for adequate birth control if you have the potential to become pregnant, if you are not sure of your postmenopausal status, or if you recently became postmenopausal. Femara is only indicated in postmenopausal women. Talk to your doctor if you're allergic to Femara or any of its ingredients. You should not take Femara if you are pregnant as it may cause fetal harm. Some women reported fatigue and dizziness with Femara. Until you know how it affects you, use caution before driving or operating machinery. Some patients taking Femara had an increase in cholesterol. Additional follow-up is needed to determine the risk of bone fracture associated with long-term use of Femara.
In the adjuvant setting, commonly reported side effects are generally mild to moderate. The most common side effects seen with Femara include hot flashes, joint pain, night sweats, weight gain, nausea, tiredness, other heart-related events and bone fractures. Other less commonly reported side effects include vaginal bleeding, blood clots, other cancers, osteoporosis, stroke, heart attack and endometrial cancer.
In the extended adjuvant setting, commonly reported side effects are generally mild to moderate. Commonly reported side effects for Femara include hot flashes, fatigue, joint pain, headache, increase in sweating, swelling due to fluid retention, increase in cholesterol, dizziness, constipation, nausea, cardiovascular ischemic events, muscle pain, osteoporosis, arthritis and bone fracture.
In the metastatic cancer setting, commonly reported side effects are generally mild to moderate and may include bone pain, hot flashes, back pain, nausea, joint pain, shortness of breath, tiredness, coughing, constipation, limb pain, chest pain and headache.
Gleevec important safety information
Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking Gleevec tablets and to avoid breast-feeding while taking Gleevec tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking Gleevec should use adequate contraception. If the patient does become pregnant while taking Gleevec, the patient should be advised of the potential hazard to the fetus.
In adult Ph+ CML patients, severe (NCI Grades 3/4) lab abnormalities-including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (approx 5%)--and severe adverse experiences (NCI Grades 3/4), including severe fluid retention (e.g., pleural effusion, pulmonary edema, and ascites) and superficial edema (1.3%-11%), hemorrhage (1.8%-19%), and musculoskeletal pain (2%-9%) were reported among patients receiving Gleevec*. Severe fluid retention appears to be dose-related, was more common in the advanced-phase studies (where the dosage was 600 mg/day), and is more common in the elderly.
In HES/CEL patients, instances of Grade 3 leukopenia, neutropenia, lymphopenia, and anemia were reported.
For DFSP, severe (NCI Grades 3/4) lab abnormalities included anemia (17%), thrombocytopenia (17%), neutropenia (8%), and increased creatinine (8%).
In GIST, severe (NCI Grades 3/4) lab abnormalities (400 mg/day; 600 mg/day)--including neutropenia (10%; 11%), anemia (3%; 9%), thrombocytopenia (0%; 1%), and hepatotoxicity (6%; 8%)--and severe adverse experiences (NCI Grades 3/4), including severe fluid retention (eg, pleural effusion or ascites; 3%; 8%) and superficial edema (6%; 5%), hemorrhage (6%; 11%), abdominal pain (11%; 4%), nausea (6%; 4%), diarrhea (3%; 7%), and musculoskeletal pain (6%; 1%) were reported among patients receiving Gleevec.
Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.
Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse reactions, or hematologic adverse reactions. Therapy with Gleevec was discontinued for drug-related adverse reactions in 2.4% to 5% of adult patients with Ph+ CML and for adverse reactions in 5% of KIT+ GIST patients. None of the 5 patients in the ASM study discontinued Gleevec due to drug-related events or abnormal laboratory values. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months).
A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.
Some GIST patients (5%) were reported to have severe gastrointestinal (GI) bleeds and/or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds.
Patients should be weighed and monitored regularly for signs and symptoms of edema, which can be serious or life-threatening. There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, increased intracranial pressure, papilledema, and GI perforation.
In patients with HES and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporarily withholding imatinib. MDS/MPD disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for 1-2 weeks concomitantly with imatinib should be considered at the initiation of therapy.
Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of Gleevec at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.
Consider potential toxicities-specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.
Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of Gleevec should increase by at least 50%, and clinical response should be carefully monitored, in patients receiving Gleevec with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with Gleevec include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions).
For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablets to reduce exposure to iron.
Common side effects of Gleevec tablets
The majority of adult Ph+ CML patients who received Gleevec in clinical studies experienced adverse reactions at some time, but most were mild to moderate in severity. The most frequently reported adverse reactions (all Grades) were superficial edema (60%-74%), nausea (50%-73%), muscle cramps (28%-62%), vomiting (23%-58%), diarrhea (43%-57%), musculoskeletal pain (38%-49%), and rash and related terms (36%-47%).*(+)
The adverse reactions and safety profile for Ph+ ALL, MDS/MPD, ASM, and HES/CEL were generally similar to the safety profile for Ph+ CML.
The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea, vomiting, diarrhea, myalgia, muscle cramps, and rash, which were easily manageable. Superficial edemas were also a common finding in all studies and were described primarily as periorbital or lower-limb edemas. However, these edemas were rarely severe and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Gleevec.
Frequently reported adverse reactions (all Grades) in the seven MDS/MPD patients assessed were nausea (57%); diarrhea and muscle cramps (43% each); anemia, fatigue, arthralgia, and periorbital edema (29% each).
All ASM patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash, and lower respiratory tract infection.
All HES/CEL patients experienced at least one adverse reaction, the most common being gastrointestinal, cutaneous, and musculoskeletal disorders. Hematologic abnormalities were also frequent, with instances of Grade 3 leukopenia, neutropenia, lymphopenia, and anemia.
Frequently reported adverse reactions (all Grades) in the 12 DFSP patients assessed included nausea and fatigue (42% each); periorbital, peripheral and eye edema (33% each); diarrhea, vomiting, rash, lacrimation increased, and anemia (25% each); face edema, pyrexia, exertional dyspnea, rhinitis, and anorexia (17% each).
The majority of patients who received Gleevec in the GIST study experienced adverse reactions at some time. Most adverse reactions were mild to moderate in severity. The most frequently reported adverse reactions (400 mg/day; 600 mg/day) (all Grades) were superficial edema (81%; 77%), nausea (63%; 74%), muscle cramps (47%; 58%), diarrhea (59%; 70%), fatigue (48%; 53%), abdominal pain (40%; 37%), rash and related terms (38%; 53%), vomiting (38%; 35%), musculoskeletal pain (37%; 30%), and hemorrhage (26%; 34%).(+)
Supportive care may help management of some mild-to-moderate adverse reactions so that the prescribed dose can be maintained whenever possible. However, in some cases, either a dose reduction or interruption of treatment with Gleevec may be necessary.
Gleevec tablets should be taken with food and a large glass of water to minimize GI irritation. Gleevec tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.
Patients should be informed to take Gleevec exactly as prescribed, not to change their dose or stop taking Gleevec unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose.
* Numbers indicate the range of percentages in 4 studies among adult patients with Ph+ CML in blast crisis, accelerated phase, and chronic phase.
(+) For more detailed study information, please see full Prescribing Information.
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Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG which provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. Novartis is the only company with leading positions in these areas. In 2008, the Group's continuing operations achieved net sales of USD 41.5 billion and net income of USD 8.2 billion. Approximately USD 7.2 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 98,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.
Novartis Oncology Media only: Megan Humphrey Novartis Oncology P: +1 862 778 6724 Dana Kahn Cooper P: +1 732 817 1800 F: +1 732 817 1834 e-mail: firstname.lastname@example.org Investors only: Richard Jarvis Novartis Corporation P: +1 212 830 2433 e-mail: email@example.com
(#) Known as Glivec (imatinib) outside the US, Canada and Israel.
(*) Updated data from all abstracts may be presented at the ASCO annual meeting
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