Novartis has submitted applications in the United States and Europe for Glivec (imatinib) as treatment for four rare types of cancer. These filings underscore how cancers of different origin and location can share common pathways that respond to the same targeted treatment, a company release said.
"Thanks to the success of targeted therapies like Glivec, these filings speak to the fundamental shift that we are seeing in the approach to cancer treatment," said Diane Young, vice president and global head of clinical development at Novartis Oncology. "One day, cancer may no longer be classified by site, or even by single genes or proteins, but instead by the way in which the cancer is expressed. This could potentially give rise to more targeted treatment options such as Glivec."
Glivec targets the activity of proteins called tyrosine kinases that play important roles within some cancer cells. Glivec has been shown to inhibit the function of the tyrosine kinase Bcr-Abl in Philadelphia-chromosome positive (Ph+) chronic myeloid leukaemia (CML), and the receptor tyrosine kinase Kit in Kit (CD117)-positive gastrointestinal stromal tumours (GIST). Researchers have found that Glivec also inhibits other receptor tyrosine kinases, including platelet-derived growth factor (PDGFR), that have been shown to be activated in disease pathways that underlie a number of rare heamatologic diseases as well as some solid tumours.
The diseases found to have Glivec-sensitive pathways include the solid tumour dermatofibrosarcoma protuberans (DFSP), a type of tumour that begins as a hard lump found in the skin of the chest, abdomen or leg. Three heamatologic diseases were also found: certain forms of myeloproliferative disorders (MPD), diseases in which too many types of certain blood cells are made in the bone marrow; hypereosinophilic syndrome (HES), which is characterized by the persistent overproduction of the white blood cells eosinophils; and systemic mastocytosis (SM), which is marked by the presence of too many mast cells, a certain type of white blood cell. These diseases are rare but may be life threatening. For many of the patients who suffer from them, no approved treatment is available. Novartis submitted the marketing applications in Europe and the United States for DFSP and MPD in 2005 and for SM and HES in 2006.
The submissions are based on a Novartis-sponsored clinical study and clinical data from trials done by independent medical researchers and cooperative trial groups demonstrating efficacy and safety of Glivec in the treatment of these different rare diseases.
Glivec is indicated in the EU for the treatment of patients with newly diagnosed Ph+ CML for whom bone marrow transplantation is not considered as the first line of treatment. Glivec/Gleevec is approved in the U.S. for newly diagnosed adult patients with Ph+ chronic phase CML and paediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell (an unspecialized cell that gives rise to differentiated cells) transplant or who are resistant to interferon-alpha treatment. In Japan, Glivec is approved for adult patients in all phases of Ph+ CML. In addition, Glivec is already approved for the treatment of adult patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha treatment in more than 90 countries worldwide.
Glivec is also approved in the EU, US and other countries for the treatment of patients with Kit (CD117)-positive gastrointestinal tumours (GISTs), which cannot be surgically removed and/or have already spread to other parts of the body (metastasized). In Japan, Glivec is approved for the treatment of patients with Kit (CD117)-positive GISTs. Not all indications are available in every country.
The effectiveness of Glivec is measured by overall heamatologic and cytogenetic response rates and progression-free survival in CML and objective response rates in GIST. There are no controlled trials demonstrating increased survival.
The most common undesirable effects experienced during Glivec treatment in GIST are: headache, nausea, vomiting, diarrhoea, dyspepsia, myalgia, muscle spasm and cramps, joint swelling, dermatitis, eczema, rash, edema, fluid retention, neutropenia, thrombocytopenia or anaemia.
In the first-line study (IRIS), the safety profile with Glivec was similar to that of previous Phase II studies in other CML patients. The majority of patients treated with Glivec experienced adverse events at some time. Most events were of mild to moderate grade and treatment was discontinued for adverse events only in 2 per cent of patients in chronic phase, 3 per cent in accelerated phase and 5 per cent in blast crisis. The most common side effects included nausea, superficial edema, muscle cramps, skin rash, vomiting, diarrhoea, haemorrhage, fatigue, headache, joint pain, cough, dizziness, dyspepsia and dyspnoea, as well as neutropenia and thrombocytopenia.
Glivec is contraindicated in patients with known hypersensitivity to imatinib or any of its excipients. Women of childbearing potential should be advised to avoid becoming pregnant while taking Glivec.