Denosumab Superior to Zoledronic Acid in Reducing Incidence of Skeletal-Related Events in Breast Cancer Patients with Bone Metastases

Data Presented at earlier this month at the San Antonio Breast Cancer Symposium demonstrates that treatment with denosumab, a new drug in late stage clinical development, is superior to the standard of care in advanced breast cancer patients. Among patients with bone metastasis from breast cancer, denosumab was superior to zoledronic acid in reducing the incidence of complications from bone metastases.

"Denosumab prevented more events, was better tolerated and is more convenient for patients," said Alison Stopeck, M.D., associate professor of medicine at the University of Arizona Cancer Center who presented the results of this phase III, double blind study at the 2009 CTRC-AACR San Antonio Breast Cancer Symposium.

Stopeck and colleagues enrolled 2,048 patients with bone metastasis who had never received treatment with intravenous bisphosphonates. They randomly assigned patients to treatment with 120 mg subcutaneous denosumab (Amgen) or 4 mg intravenous zoledronic acid (Zometa, Novartis) every four weeks.

Denosumab, is an investigational first fully human monoclonal antibody developed by Amgen. It works differently from existing bone treatments by specifically targeting a protein called RANK Ligand (RANKL), which plays an important role in regulating osteoclast activity and function and has been linked with increased bone loss and complications from bone metastases.

Stopeck presented data confirming that denosumab significantly delayed time to first on-study skeletal-related event compared with zoledronic acid (HR=0.82; 95% CI, 0.71-0.95), as well as time to first, and subsequent, on-study skeletal-related event (rate ratio=0.77; 95% CI, 0.66-0.89). In this study, patients assigned to denosumab had 491 skeletal-related events compared with 623 for patients assigned to zoledronic acid.

"In clinical trials testing new medications for bone metastases, treatment success is measured by whether the bone complications, or skeletal related events, caused by the tumor are reduced or delayed," Stopeck explained. "Skeletal complications from bone metastases are a critical and painful health concern for patients with advanced breast cancer, and can increase the risk of mortality. Patients who have a first skeletal related event are twice as likely to experience a subsequent SRE, so it is imperative to treat these advanced breast cancer patients."

“Denosumab resulted in a considerable delay in the development of moderate-to-severe pain compared to zoledronic acid,” Stopeck said.

Additional data from this study showed that denosumab significantly reduced the mean annual skeletal morbidity rate (SMR) (the ratio of the number of skeletal complications to the time on trial) compared with Zometa (0.45 vs. 0.58, respectively; p=0.004).

Overall, the incidence of adverse events (96% denosumab, 97% zoledronic acid) and serious adverse events (44% denosumab, 46% zoledronic acid) was consistent with what has previously been reported for these two agents. Adverse events potentially associated with acute phase reactions during the first three days of the study were reported in 10.4 percent of the denosumab arm and 27.3% of the zoledronic acid arm. Adverse events potentially associated with renal toxicity occurred in 4.9% of patients treated with denosumab compared to 8.5% in patients treated with zoledronic acid.

Osteonecrosis of the jaw (ONJ) was seen infrequently in both treatment groups (20 patients receiving denosumab [2.0%] as compared with 14 patients [1.4%t] receiving Zometa). Rates of new primary malignancies were similar between treatment arms (5 patients receiving denosumab [0.5%] and 5 receiving zoledronic acid [0.5%]). Time to disease progression or overall survival was balanced between the study arms.

At 34 months, 30.7% of patients treated with denosumab arm experienced at least one skeletal-related event (95% CI, 33.5%-39.4%) compared with 36.5% of those treated with zoledronic acid. Denosumab also reduced mean skeletal morbidity rate (0.45 vs. 0.58; P=.004).

Clinical relevance
Bone metastases, cancer cells that separate from tumors and migrate to bone tissue where they settle and grow, occur in more than 1.5 million people worldwide. With improvements in cancer care, including earlier diagnosis and new treatment options, leading to increases in survival rates, the number of patients developing metastatic disease secondary to a primary cancer is increasing. Bone metastases are a significant problem for patients with certain types of advanced cancer, with incidence rates of nearly 100 percent in myeloma patients and as high as 75 percent in breast and prostate cancer patients.

With bone metastases the growing cancer cells weaken and destroy the bone around the tumor. The damage the tumor has caused to the bone can result in a number of serious complications, collectively called SREs. These include fracture of a bone, the need for radiation to bone, the need for bone surgery, or spinal cord compression. All are serious complications for advanced cancer patients.

The economic burden of United States (U.S.) patients with bone metastases is significant and was estimated to be $12.6 billion last year. Patients with bone metastases who experience an SRE incur significantly higher medical costs compared with those who do not experience an SRE.

The results of this study are therefore clinically relevant. Before the availability of bisphosphonates 64% patients with breast cancer with bone metastases generally developed a skeletal-related event, including fracture or pain. With the introduction of Bisphosphonates, this was reduced this to 43%. Today, with more potent agents such as zoledronic acid, the development of skeletal-related event are less than 34%. The results of this trial comparing denosumab vs zoledronic acid shows further improvement with a 27% reduction of incidence rate.

This oral presentation of the denosumab 136 data by Dr. Alison Stopeck was presented at the 2009 CTRC-AACR San Antonio Breast Cancer Symposium. on Thursday, December 10 at 3:15 PM (CT) in Exhibit Hall D of the Henry B. Gonzalez Convention Center, San Antonio, Texas.

For more information

• Downey L, Livingstone R, Stopeck A. Diagnosing and treating breast cancer in elderly women: a call for improved understanding. J Am Geriatr Soc 2007 Oct;55(10):1636-44. Epub 2007 Aug 28.
• Coleman R. Potential use of bisphosphonates in the prevention of metastases in early-stage breast cancer. Clin Breast Cancer 2007 Jul;7 Suppl 1:S29-35
• Coleman R. On the horizon: can bisphosphonates prevent bone metastases? Breast. 2007 Dec;16 Suppl 3:S21-7. Epub 2007 Nov 7. Review.
• Coleman RE. The benefits and costs of bisphosphonates. J Support Oncol 2007 Nov-Dec;5(10):483-4.
• Brown JE, Coleman RE. The present and future role of bisphosphonates in the management of patients with breast cancer. Breast Cancer Res. 2002;4(1):24-9. Epub 2001 Nov 26. Review.
• Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001 Sep-Oct;7(5):377-87.
• Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001 Jun;27(3):165-76. Review.
• Capanna R, Coia LR, Coleman R. et al. eds. Textbook of Bone Metastases Hoboken, NJ: Edition: John Wiley and Sons; 2005:105.
• Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002 Aug;2(8):584-93. Review
• Schulman KL, Kohles J. Economic burden of metastatic bone disease in the U.S. Cancer. 2007 Jun 1;109(11):2334-42.
• Mortimer JE, Schulman K, Kohles JD. Patterns of bisphosphonate use in the United States in the treatment of metastatic bone disease. Clin Breast Cancer. 2007 Aug;7(9):682-9.

Also follow

• Onco'Zine - The International Cancer Network

Everolimus (Afinitor®) Licensed in UK for Advanced Kidney Cancer Patients After Failure of First Line Vascular Targeted Therapy

Everolimus (Afinitor®, Novartis AG, Basel, Switzerland) has recently been licensed in the United Kingdom for the treatment of advanced kidney cancer after failure of treatments which prevent the growth of the tumor’s blood vessels, which is essential for the cancer to survive. The European Commission (EC) approved everolimus for this use on 3rd August 2009 for patients with advanced kidney cancer whose disease progressed on or after treatment with VEGF-targeted therapy.

Everolimus belongs to a class of drugs called kinase inhibitors, which interfere with cell communication, preventing tumor growth. The drug is intended for those patients with advanced renal cell cancer who have already tried another kinase inhibitor, sunitinib (Sutent, Pfizer Inc., New York, USA) or sorafenib (Nexavar, Bayer HealthCare AG, Leverkusen, Germany).

Mechanism of Action
While sunitinib and sorafenib are multiple kinase inhibitors (acting on a number of cellular targets), everolimus works by blocking a specific protein known as the mammalian target of rapamycin or mTOR, a protein that acts as a central regulator of tumor cell division, blood vessel growth and cell metabolism.

A clinical trial studying the safety and effectiveness of everolimus was discontinued after an interim analysis showed that, in patients receiving the drug, the growth or spread of the tumor was delayed when compared to patients who did not receive the drug. In addition, disease progression was delayed approximately five months in half of the patients who received everolimus. In contrast, disease progression was delayed two months in patients who did not receive the drug.

The most frequent adverse reactions in the trial (occurring in at least 20 percent of patients) included inflammation in the mouth, loss of strength, diarrhea, poor appetite, fluid buildup in the extremities, shortness of breath, coughing, nausea, vomiting, rash, and fever. Laboratory tests of blood samples determined that at least half of all patients experienced anemia, low white blood counts, high cholesterol and high triglycerides and high blood sugar.

Patients with advanced renal cell cancer have limited options once tumors progress after first line standard therapy. Now, phase III trials show that everolimus more than doubles the median time without tumor growth and reduces the risk of disease worsening or death by 67% compared with placebo.

Prior to this date, there were no licensed treatment options in the United Kingdom for advanced renal cell carcinoma patients whose cancer progressed while on or after treatment with these targeted therapies.

Incidence
Advanced renal cell carcinoma, the most common type of kidney cancer, accounts for approximately 2% of all new cancers. In the UK, the incidence of kidney cancer is increasing, due in part to obesity and smoking.

Renal cell cancer originates in the lining of the small tubules in the kidney that filter waste products from the blood. The cancer is resistant to such standard treatments as radiation therapy and chemotherapy, and the initial treatment for most patients is surgical removal of the kidney. If the cancer is confined to the kidney, the five-year survival rate is 60 to 70 percent. However, if left untreated, the tumor can spread to neighboring lymph nodes and eventually to other organs, considerably reducing the survival rate.

"I am delighted that there is now a proven treatment option available to people living with advanced kidney cancer in the UK, who have progressed after treatment with a targeted therapy. The availability of Afinitor is an important step in ensuring this population of poor prognosis patients have the potential to control their disease even further," said Tim Eisen, Professor of Medical Oncology at the University of Cambridge.

Expert consensus opinion, recently published in a review article in the British Journal of Hospital Medicine, has been updated to recommend everolimus as a Second-Line Therapy treatment option for advanced kidney cancer therapy after progression on targeted therapies.

Data that led to the European approval show that everolimus, when compared with placebo, more than doubled the median time without tumor growth or death in patients with advanced kidney cancer whose disease progressed following prior vascular targeted therapy (4.9 vs. 1.9 months). The data showed the reduction of the risk of disease progression or death by 67% based on the primary endpoint of progression-free survival (PFS) (hazard ratio=0.33 with 95% confidence interval 0.25 to 0.43; P<0.001.>

Every year there are 7,000 newly diagnosed cases of kidney cancer which also causes around 3,700 deaths a year," said Pat Hanlon, Kidney Cancer UK. "While many of these cancer patients will be diagnosed early and undergo surgery to cure them, 40% of patients will be diagnosed in the advanced stages when prognosis is extremely poor and the cancer is notoriously difficult to treat."

James Whale, Founder of The James Whale Fund for Kidney Cancer, adds: "We at the Fund are pleased everolimus has been granted a license in the UK as, given the poor prognosis of kidney cancer, it is critical for people living with the disease to have access to life-extending treatments. This has been proven to provide benefit to kidney cancer patients, enabling them to spend precious time with family and friends."

The U.S. Food and Drug Administration (FDA) approved everolimus oral tablets for the treatment of patients with advanced kidney cancer whose disease has progressed after treatment with other cancer therapies in March 2009. Following the approval in the US National Comprehensive Cancer Network (NCCN) updated the NCCN Clinical Practice Guidelines in Oncology™ for Kidney Cancer to reflect th eFDA approval of everolimus.

For more information:

• Afinitor® website (for non-US healthcare professionals)
• Afinitor® website (for US healthcare professionals)
• EPARs for Authorised Medicinal Products for Human Use
• Escudier, B et al. 72O - Phase III Randomised Trial of Everolimus (RAD001) vs Placebo in Metastatic Renal Cell Carcinoma. Presented at the European Society for Medical Oncology (ESMO) 33rd Congress, Stockholm, Sweden on 16 September 2008
• Escudier B, Kataja V; ESMO Guidelines Working Group. Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009 May;20 Suppl 4:81-2.
• Motzer RJ, Escudier B, Oudard S, Hutson TE, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22.
• Nathan P, Wagstaff J, Porfiri E, Powles T, Eisen T. UK Guidelines for the Systemic Treatment of Renal Cell Carcinoma. Br J Hosp Med (Lond). 2009 May;70(5):284-6. Review.
• Eisen T, Oudard S, Szczylik C, Gravis G, et al; TARGET Study Group. Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J Natl Cancer Inst. 2008 Oct 15;100(20):1454-63. Epub 2008 Oct 7.
• McLaughlin JK, Lipworth L, Tarone RE. Epidemiologic aspects of renal cell carcinoma.
  Semin Oncol. 2006 Oct;33(5):527-33. Review.
• Motzer RJ, Agarwal N, Beard C, Bolger GB, et al. NCCN clinical practice guidelines in oncology: kidney cancer. J Natl Compr Canc Netw. 2009 Jun;7(6):618-30.
• Highlights of the NCCN 13th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care™, published as a supplement to The Oncology Report: The mTOR pathway as a new target.

Zoledronic Acid May Have Anti-Tumor Properties

Early evaluations of the bisphosphonate zoledronic acid (Zometa® , Novartis Oncology) suggest a possible direct anti-tumor effect when combined with neoadjuvant chemotherapy in breast cancer treatment, according to data presented to scientists and other medical professionals gathered at the Henry B. Gonzales Convention Center in San Antonio to hear and present the latest scientific findings in breast cancer research during the CTRC-AACR San Antonio Breast Cancer Symposium (December 10-14, 2008 ).

There is substantial in vitro evidence that zoledronic acid has direct antitumour effects and synergy with chemotherapy agents. Bisphosphonates may therefore be an adjuvant therapeutic strategy of potential importance.

‘Zoledronic acid is primarily targeted to bone and metastasis within the bone marrow microenvironment, but it may also be enhancing the response in the primary breast tumor,’ explained Robert Coleman, M.D., FRCP, professor of medical oncology at the University of Sheffield in the United Kingdom.

Coleman is the lead researcher on the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, a prospective, randomised, open label, parallel group trial designed to to evaluate the effect of zoledronic acid on breast cancer. ‘Although the larger AZURE trial is still being evaluated, if the findings in this smaller study are confirmed, the effect could be practice changing,' Coleman said.

The AZURE trial opened to recruitment in September 2003. Patients were recruited from 176 centres worldwide, completing accrual in January 2006, 8 months ahead of schedule, and enrolled 3,360 women with stage II/III breast cancer. The trial was set up to determine whether adjuvant treatment with 4 mg zoledronic acid in addition to adjuvant or neoadjuvant chemotherapy would improve the disease-free and bone metastasis-free survival of women with breast cancer at high risk of relapse.

Analysis of the characteristics of the study population shows that both groups are well
matched across all criteria. 51% of patients have T2 tumour at presentation, with 76.6% being ER positive. 60.6% and 33.2% had 1-3 and ≥4 axillary nodes involved respectively and 6.4% were treated in the neoadjuvant setting. Anthracyclines were administered to 92.6% and 22.7% received taxanes, in large part due to accrual into the TANGO trial concurrent with AZURE. Only 4.6% received endocrine therapy alone. Almost half of the patients (44.6%) were premenopausal at randomisation.

Coleman and colleagues performed a retrospective pathology analysis on 205 patients who received neoadjuvant chemotherapy to determine zoledronic acid’s impact on the primary tumor. Zoledronic acid appeared to reduce tumor size from 30 mm in the chemotherapy alone group to 20.5 mm in the combination group.

After adjusting for variables like estrogen receptor status and treatment duration, the difference remained at 42.4 mm in the chemotherapy group and 28.2 mm in the combination group. The pathological complete response rate was 5.8 percent in the chemotherapy arm and 10.9 percent in the zoledronic acid group.

The number of patients requiring mastectomy was 77.9 percent in the chemotherapy group and 65.3 percent in the combination group. ‘Zoledronic acid is currently approved for the treatment of bone metastasis and osteoporosis. If the AZURE trial remains positive, then we’ll file for an additional indication,’ Coleman said.

For more information, read:

• Winter MC, Thorpe HC, Burkinshaw R, Beevers SJ, Coleman RE. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response exploratory evidence for direct anti-tumor activity in breast cancer. Abstract 5101. Poster Session V: Treatment: Neoadjuvant Therapy. San Antonio Breast Cancer Symposium.

Also read:

• Click here for full prescribing information.
• The Institute of Cancer Research

Also read PubMed Abstracts:

• Lyseng-Williamson KA. Zoledronic Acid: a review of its use in breast cancer. Drugs. 2008;68(18):2661-82
• Brufsky A. Management of cancer-treatment-induced bone loss in postmenopausal women undergoing adjuvant breast cancer therapy: a Z-FAST update. Semin Oncol. 2006 Apr;33(2 Suppl 7):S13-7.