SILVER SPRING, MD. – A new molecular weight heparin for preventing deep vein thromboses and pulmonary emboli in select cancer patients on chemotherapy failed to pass muster with a Food and Drug Administration panel on June 20.
The FDA’s Oncologic Drugs Advisory Committee voted 14 to 1, with 1 abstention, that semuloparin sodium lacked a favorable risk-benefit profile when used to prevent venous thromboembolic events (VTEs) in patients receiving chemotherapy for locally advanced or metastatic lung or pancreatic cancer, or for patients receiving chemotherapy for locally advanced or metastatic solid tumors who are determined to be at a high risk of VTEs – the indication proposed for approval by the drug’s manufacturer, Sanofi-Aventis U.S.
Semuloparin sodium, administered subcutaneously once a day, has not been approved anywhere, and if approved for this indication, it would be the first low-molecular-weight heparin (LMWH) – and the first anticoagulant – approved for preventing VTEs in cancer patients. One of the FDA reviewers pointed out that approval of the drug would "set a new standard of care" that would affect a large proportion of patients with cancer in the United States.
Current guidelines from the American Society of Clinical Oncology recommend anticoagulants for the treatment and prevention of recurrent VTE. The routine use of VTE prophylaxis is not advised for patients with cancer, except for those who are hospitalized, scheduled for major oncologic surgery, or receiving thalidomide or lenalidomide-based treatment.
In the SAVE-ONCO study, an international phase III trial of 3,212 patients undergoing chemotherapy for locally advanced cancers (most had lung or colorectal cancer; the rest had stomach, ovarian, pancreatic, or bladder cancer), participants were randomized to 20 mg of semuloparin daily or placebo for at least 3 months during chemotherapy.
The primary end point – a composite of symptomatic DVT, nonfatal pulmonary embolism, or VTE-related deaths from the time the patients were randomized until 3 days after the last study drug injection – was 1.2% in those on semuloparin, compared with 3.4% of those on placebo, a highly significant difference that represented a 64% reduced risk (N. Engl. J. Med. 2012;366:601-9).
But the absolute risk reduction was a modest 2.2%, and overall survival at 1 year, a secondary end point, was similar between the two groups. At 1 year, about 40% of patients in each group had died. The rate of VTE-related deaths was also similar between the two groups.
While the rates of major bleeding events were similar in the two groups (1.2% in the semuloparin arm and 1.1% in the placebo arm), seven patients who received semuloparin had a major bleeding event into a critical area or organ, which included one fatal intracranial bleed, compared with none of those on placebo. Compared with the placebo group, patients on semuloparin had more bleeding events overall (20% vs. 16%), more clinically relevant bleeding events (2.8% vs. 2.0%), and more cases of bleeding that led to discontinuation of treatment (2.3% vs. 1.6%).
Members of the panel pointed out that there were many unresolved issues, including the need for more information about the types of patients who would benefit from preventive treatment, uncertainty over how long patients should be treated with the drug for prophylaxis, problems with the single clinical trial that did not have robust results, uncertainty about how the drug would be used, and the lack of a clear benefit and toxic effects of the treatment.
Several panelists noted that there was a need for such a treatment, and encouraged the company to continue studying the drug and determine the types of patients with cancer who could benefit from the agent.
The FDA usually follows advisory panel recommendations, which are not binding. The panelists had been cleared of potential conflicts of interest related to the topic of the meeting.