Zometa improves survival in Phase III trial in multiple myeloma
This article was originally published in Scrip
Novartis's bisphosphonate Zometa (zoledronic acid) has become the first drug of its class to improve overall survival in multiple myeloma (MM) in combination with standard treatment in a Phase III trial, lending further credence to the belief that it has an anticancer effect in addition to its beneficial effects on bone.
"These findings add to the growing body of clinical evidence suggesting the potential anticancer activity of Zometa," Novartis said. As it was an independent trial, no additional indication is expected from it, it told Scrip. However it added, "Novartis will coordinate with the study investigators to determine whether the data are appropriate for filing with health authorities."
"The study further supports the anticancer activity of zoledronic acid and provides evidence that it should be considered for early integration into treatment regimens in patients with newly diagnosed multiple myeloma," lead investigator Dr Gareth Morgan of London's Institute of Cancer Research (ICR), concluded in his presentation of the trial at the recent ASCO meeting in Chicago.
The 1,960-patient Myeloma IX study was predominantly funded by the UK's Medical Research Council (MRC). When used in conjunction with standard thalidomide-based combination induction therapy in MM, and compared with another bisphosphonate, clodronate (Sanofi-Aventis's Bonefos), Zometa demonstrated a 5.5-month median survival benefit. This benefit appeared to be independent of the drug's effect on bone complications, or skeletal-related events (SREs), based on an exploratory analysis. Zometa was also significantly superior to clodronate in the prevention of SREs associated with MM.
Zometa is already approved for the reduction or delay of SREs in MM and across a broad range of cancers (including breast, prostate and lung) which spread to the bone, and is the most widely used bisphosphonate in the oncology setting. SREs occur in at least half of MM patients. It is also the first once-yearly treatment for osteoporosis, marketed as Reclast/Aclasta. In MM, the demonstrated survival benefit could now spur further usage by doctors of the drug.
Zometa was Novartis's third best-selling drug of last year, with sales of about $1.5 billion. However, its US patent expires in 2012.
Preclinical studies have suggested that zoledronic acid may have anticancer effects as well as having beneficial effects on bone – including reducing cancer cells' ability to travel and adhere to each other and to the bone, breaking the feedback loop between osteoclasts and stromal cells, inhibiting angiogenesis, stimulating T-cells to fight cancer, inducing apoptosis, and increasing the effectiveness of other anticancer agents such as chemotherapy and radiotherapy.
Additionally, in a large Phase III trial in adjuvant breast cancer in premenopausal women which was presented at ASCO 2008 and updated at this meeting, the ABCSG-12study, it also demonstrated an anticancer effect, reducing the risk of breast cancer recurrence on top of hormone therapy by 32% in premenopausal women at low to intermediate risk of disease recurrence. It is also in several other Phase III trials in adjuvant postmenopausal breast, adjuvant prostate and adjuvant lung cancer to see if it can prevent cancer recurrence.
In MM, in additional to zoledronic acid, clodronate and pamidronate are used to treat bone metastases. The study investigators chose clodronate as a comparator to Zometa, an iv drug, as it was a more convenient oral option. Zometa, meanwhile, is one of the most potent bisphosphonates.
Amgen's new first-in-class RANK ligand inhibitor, denosumab, which was recently approved for postmenopausal osteoporosis, is awaiting US approval for treatment of bone metastases. In the Phase III "244" trial comparing it with Zometa, with the primary focus on skeletal outcomes, multiple myeloma patients represented about 10% of the total patient population. In an adhoc analysis, there was a difference in overall survival that favoured Zometa in these patients, but Amgen said that MM was a heterogeneous population at study entry with variability in significant confounding variables, including underlying disease and specific treatment. It is planning a myeloma-specific study.
Phase III results
In the Phase III zoledronic acid trial, newly diagnosed MM patients received standard therapy plus either zoledronic acid administered intravenously every 3-4 weeks or clodronate taken orally daily. Zoledronic acid-treated patients showed 5.5 months' prolonged overall compared with clodronate-treated patients (50 vs 44.5 months) and a 16% reduced risk of death over the course of the study at a median follow-up of 3.7 years (p= 0.0118). The survival benefit was maintained after adjustment for potential effects of SREs on survival, suggesting that it improved survival through anticancer activity. The survival advantage demonstrated by Zometa was observed in patients with Stage I, II or III MM.
The proportion of patients who experienced an SRE (including bone fractures, radiation to bone, surgery to bone, bone lesions and/or spinal cord compression), a secondary endpoint, was reduced by 24% in those receiving Zometa versus clodronate (27.0% versus 35.3%; p=0.0004).
Both drugs were generally welltolerated, and deterioration in renal function was similar between treatment groups. The incidence of confirmed osteonecrosis of the jaw was higher with zoledronic acid (3.5% vs 0.3%).