Adding Novartis Drug Zometa® to Chemotherapy Significantly Improved Overall Survival in Study of Newly Diagnosed Multiple Myeloma Patients

EAST HANOVER, N.J., June 5 /PRNewswire/ -- New data to be presented tomorrow at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, IL, show that the addition of Zometa® (zoledronic acid) to first-line chemotherapy significantly improved overall survival for newly diagnosed multiple myeloma patients by 16% (P=0.0118) and progression-free survival by 12% (P=0.0179) compared with oral clodronate plus first-line chemotherapy(1). The 5.5 month survival improvement demonstrated by Zometa in this study of nearly 2,000 patients was independent of the drug's effect on bone complications (also known as skeletal-related events or SREs)(1). Zometa was significantly superior to clodronate in the prevention of SREs associated with multiple myeloma, reducing the relative risk of SREs 24% more than clodronate (P=0.0004)(1).

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Zometa is approved in more than 100 countries for the reduction or delay of bone complications in multiple myeloma and across a broad range of metastatic cancers (breast, hormone-refractory prostate, lung and other solid tumors) involving bone, as well as for the treatment of hypercalcemia of malignancy (HCM)(2). It is the most widely used bisphosphonate in the oncology setting and has been used to treat more than 3.5 million patients worldwide(3).

"This is the first time we have seen in a large, Phase III independent trial that the addition of zoledronic acid to chemotherapy significantly improves survival in patients with multiple myeloma," said Dr. James R. Berenson, Medical & Scientific Director, Institute for Myeloma & Bone Cancer Research, Los Angeles, CA. "These data suggest that zoledronic acid has the potential to help multiple myeloma patients live longer."

Other Zometa data presented at ASCO include a five-year follow-up analysis from the Phase III Austrian Breast & Colorectal Cancer Study Group-12 (ABCSG-12) trial which showed that the addition of Zometa to hormonal therapy following surgery improved disease-free survival by 32% (HR=0.68 [95%CI 0.51,0.91], P=0.009) in premenopausal women with hormone receptor-positive (HR+) early breast cancer(4). These data confirm earlier results from ABCSG-12 presented at ASCO 2008(5). Data from the ABCSG-12 study are the basis of the Company's US and European Union regulatory filings for Zometa in the treatment of adjuvant breast cancer.

"These five-year data are exciting for oncologists and patients alike because they confirm that adding zoledronic acid to a post-surgical hormonal treatment regimen can reduce the risk of cancer returning," said Michael Gnant, MD, lead investigator and Professor of surgery at the Medical University of Vienna. "If approved for this indication, zoledronic acid may offer early breast cancer patients the opportunity to further reduce the risk of breast cancer returning, when added to post-surgery hormone therapy."

Myeloma IX study details(1)

Myeloma IX is a Phase III, prospective, multicenter, randomized, controlled study to compare intravenous (IV) Zometa (4mg every 3-4 weeks) with oral clodronate (1600 mg daily) based on the severity of bone disease and in improving survival. A total of 1,960 evaluable patients from the United Kingdom with newly diagnosed International Staging System (ISS) Stage I, II or III multiple myeloma entered either an intensive or non-intensive treatment pathway, determined on the basis of performance status, informed decision and consent. Patients were randomized for type of bisphosphonate therapy and first-line therapy (induction chemotherapy) on a 1:1 basis.

The primary study endpoints were overall survival (OS), progression free survival (PFS) and response. OS was defined as the length of time after randomization to death from any cause. PFS was defined as the length of time from randomization to disease progression or death. Secondary endpoints included SREs (including bone fractures, radiation to bone, surgery to bone, bone lesions and/or spinal cord compression) and safety.

At a median follow-up of 3.7 years, risk of death was reduced by 16% (P=0.0118) and the risk of progression-free survival events fell by 12% (P=0.0179) with Zometa versus oral clodronate. The proportion of patients who experienced an SRE was reduced by 24% in those receiving Zometa versus clodronate (27.0% versus 35.3%; P=0.0004). The survival advantage demonstrated by Zometa was observed in patients with Stage I, II or III newly diagnosed multiple myeloma. This survival advantage was also observed in addition to and independent of the drug's effect on SREs.

The tolerability profile of Zometa is well-established and results from this study were found to be consistent with the known profile. The incidence of osteonecrosis of the jaw (ONJ) in the Zometa and clodronate treatment arms was 3.6% and 0.3%, respectively. Renal deterioration was reported to be similar between treatment groups.

ABCSG-12 study details(4,6)

ABCSG-12 is an open-label, multicenter, Phase III study that enrolled 1,803 premenopausal women with estrogen receptor-positive Stage I or II breast cancer, with fewer than 10 axillary lymph nodes involved. Patients were recruited for the study after surgery and initiation of goserelin treatment for ovarian suppression, and randomly assigned into one of four study groups: (1) anastrozole plus Zometa; (2) anastrozole alone; (3) tamoxifen plus Zometa; (4) tamoxifen alone. The treatment period was three years and the median follow-up period was 62 months.

The primary endpoint for all four study arms was disease-free survival. Recurrence-free survival, overall survival and bone-mineral density were secondary endpoints. Disease-free survival was defined as the length of time after randomization during which patients had no local recurrence, contralateral breast cancer, distant metastasis, secondary carcinoma and/or death from any cause. Recurrence-free survival was defined as the length of time after randomization during which patients had no local recurrence, contralateral breast cancer, distant metastasis and/or secondary carcinoma. Bone-mineral density was a primary endpoint of the sub-study. Exploratory endpoints included bone metastasis-free survival.

At the median follow-up of 62 months, disease-free survival events were reduced by 32% (P=0.009) with Zometa added to hormone therapy versus hormone therapy alone. This updated analysis continues to show no difference between tamoxifen and anastrozole use, but that adding Zometa significantly improves disease-free survival (HR=0.68 for both arms). Overall, side effects were consistent with known drug profile. There were no cases of renal failure or confirmed cases of ONJ in the study.  

About ZOMETA(2)

ZOMETA is a treatment for hypercalcemia of malignancy (HCM; a condition resulting in high calcium blood levels due to cancer).  ZOMETA is also used to reduce and delay bone complications due to multiple myeloma and bone metastases from solid tumors; used with anti-cancer medicines.  ZOMETA is not an anti-cancer therapy. If you have prostate cancer, you should have failed treatment with at least one hormonal therapy prior to taking ZOMETA.

Important Safety Information

Do not use ZOMETA if you have had a severe allergic reaction to zoledronic acid or any components of ZOMETA. These reactions, including rare cases of hives and angioedema (swelling often near your eyes and lips), and very rare cases of life-threatening allergic reactions, have been reported.   ZOMETA is in a class of drugs called bisphosphonates, and contains the same active ingredient as that found in Reclast® (zoledronic acid).  If you are treated with ZOMETA, you should not be treated with Reclast.  

If you have HCM, you should drink plenty of clear fluids before using ZOMETA.  If you have kidney problems, tell your doctor.  The risk of adverse reactions (especially related to the kidney) may be greater for you.  ZOMETA treatment is not for patients with severe kidney problems.  Patients with kidney problems on multiple cycles of ZOMETA or other bisphosphonates are at greater risk for further kidney problems.  It is important to get your blood tests while you are receiving ZOMETA.  Your doctor will monitor your kidney function before each dose.  Tell your doctor if you are on other drugs, including aminoglycosides, loop diuretics, and drugs which may be harmful to the kidney.  

Osteonecrosis of the jaw (ONJ) has been reported mainly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving anti-cancer drugs and corticosteroids, which may make it more likely to get ONJ. If you have advanced breast cancer or a type of cancer called multiple myeloma, or if you have had dental extraction, periodontal disease, local trauma, including poorly fitting dentures, you may be at greater risk of getting ONJ.  Many reports of ONJ involved patients with signs of local infection, including bone/bone marrow inflammation. You should maintain good oral hygiene and have a dental examination with preventive dentistry prior to beginning ZOMETA. While on treatment, avoid invasive dental procedures, if possible, as recovery may take longer. If you develop ONJ while on bisphosphonate therapy, dental surgery may worsen the condition.  If you require dental procedures, there are no data available to suggest whether stopping ZOMETA treatment reduces the risk of ONJ.  A causal relationship between bisphosphonate use and ONJ has not been established. Based on your condition, your doctor will determine the treatment plan you will receive.

Do not use ZOMETA if you are pregnant or plan to become pregnant, or if you are breast-feeding.

Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates, including ZOMETA.  Do not continue using ZOMETA if severe symptoms develop, as some patients had the symptoms reappear after taking ZOMETA or another bisphosphonate again.  In aspirin sensitive patients, bronchoconstriction (tightening of the airways in the lungs) has been observed while taking bisphosphonates.

If you are an HCM patient with liver problems, talk to your doctor about whether ZOMETA is appropriate for you.

HCM patients may experience flu-like symptoms (fever, chills, flushing, bone pain and/or joint or muscle pain).  Common side effects in HCM patients include fever, nausea, constipation, anemia, shortness of breath, diarrhea, abdominal pain, worsening of cancer, insomnia, vomiting, anxiety, urinary tract infection, low phosphate levels, confusion, agitation, a fungal infection called moniliasis, low potassium levels, coughing, skeletal pain, low blood pressure, and low magnesium levels.  Redness and swelling may occur at the site that you are injected.

Common side effects for patients with multiple myeloma and bone metastases due to solid tumors include bone pain, nausea, fatigue, anemia, fever, vomiting, constipation, shortness of breath, diarrhea, weakness, muscle pain, anorexia, cough, joint pain, lower-limb swelling, worsening of your cancer, headache, dizziness (excluding vertigo), insomnia, decreased weight, back pain, numbness/tingling, and abdominal pain.  

Eye-related side effects may occur with bisphosphonates, including ZOMETA.  Cases of swelling related to fluid build-up in the eye, as well as inflammation of the uvea, sclera, episclera, conjunctiva, and iris of the eye have been reported.  

Patients with multiple myeloma and bone metastases from solid tumors should be taking an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.

Please see full Prescribing Information and talk to your doctor for more information.

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Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "potential," "can," "may," or similar expressions, or by express or implied discussions regarding potential new indications or labeling for Zometa or regarding potential future revenues from Zometa. You should not place undue reliance on these statements.  Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Zometa to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Zometa will be submitted or approved for any additional indications or labeling in any market. Nor can there be any guarantee that Zometa will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Zometa could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

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, the Novartis Group offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. The Novartis Group is the only company with leading positions in each of these areas. In 2009, the Group's continuing operations achieved net sales of USD 44.3 billion, while approximately USD 7.5 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.

References

1. Morgan, G. Evaluating the effects of zoledronic acid (ZOL) on overall survival (OS) in patients (Pts) with multiple myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX study. Abstract #8021. American Society of Clinical Oncology 2010 Annual Meeting.
2. Zometa® (zoledronic acid) US Prescribing Information. Novartis Pharmaceuticals Corporation. http://www.pharma.us.novartis.com/product/pi/pdf/Zometa.pdf.
3. Novartis data on file.
4. Gnant, M. Mature results from ABCSG-12: Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with endocrine-responsive early breast cancer. Abstract #533. American Society of Clinical Oncology 2010 Annual Meeting.
5. Gnant, M. Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with hormone-responsive, stage I and II breast cancer: First efficacy results from ABCSG-12. Abstract #LBA4. American Society of Clinical Oncology 2008 Annual Meeting.
6. Gnant, M, et al. Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer. New Engl J Med. 2009;360;679-91.

SOURCE Novartis Pharmaceuticals Corporation