FDA Panel Rejects VTE Prophylaxis During Chemotherapy

Nick Mulcahy

June 20, 2012

June 20, 2012 — The Oncologic Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted overwhelmingly to reject the use of semuloparin sodium injection (sanofi-aventis) for the prophylaxis of venous thromboembolism (VTE) in some cancer patients receiving chemotherapy.

Specifically, the vote was related to the use of semuloparin for VTE prophylaxis in patients with locally advanced or metastatic pancreatic or lung cancer and in patients with locally advanced or metastatic solid tumors and a VTE risk score of at least 3.

Semuloparin is a hemisynthetic ultra-low-molecular-weight heparin. There are no low-molecular-weight heparins or other anticoagulants approved for use in cancer patients undergoing chemotherapy, according to the FDA.

The committee was asked to vote on a single question: Is there sufficient demonstration of a positive benefit-to-risk assessment to recommend approval of semuloparin for thromboprophylaxis in any population or subpopulation of patients with cancer?

Fourteen members of the committee voted no, 1 voted yes, and 1 abstained.

The indication for semuloparin originally proposed was for "prophylaxis of venous thromboembolism in patients receiving chemotherapy for locally advanced or metastatic solid tumors." That was revised to a more specific patient population at the request of the FDA.

The data on semuloparin do not support the use of anticoagulation therapy in a new setting, especially in the "absence of a survival benefit," opined committee member Deborah K. Armstrong, MD, during the hearing. She is associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland.


The basis for the approval application was data from the SAVE-ONCO trial, previously reported by Medscape Medical News. SAVE-ONCO was a multinational, phase 3, randomized, double-blind, placebo-controlled trial of 3212 patients who underwent chemotherapy for locally advanced or metastatic cancer of the lung, pancreas, stomach, colon/rectum, bladder, or ovary. Patients were randomized to either subcutaneous semuloparin 20 mg daily or placebo for a minimum of 3 months while receiving chemotherapy.

In the primary efficacy analysis of SAVE-ONCO, symptomatic VTE events were observed in 1.2% of patients in the semuloparin group and in 3.4% of patients in the placebo group (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.21 to 0.60; P < .0001). The relative risk reduction was statistically significant, but the difference in absolute risk was only 2.2%. There was no difference between groups in the secondary end point of overall survival at 1 year, with 40.0% observed deaths in the semuloparin group and 41.5% in the placebo group (HR, 0.95; 95% CI, 0.85 to 1.05; P = 0.31).

Notably, 36% of study patients did not complete at least 3 months of treatment. Early discontinuation from study treatment resulted in "early censoring of a large percentage (32.5% within the first 3 months) of patient's times in the primary efficacy analysis," according to FDA documents.

Various adverse events occurred more frequently with semuloparin than with placebo. These included treatment-emergent bleeding events (20.0% vs 16.0%), serious bleeding events (1.9% vs 1.5%), and bleeding events leading to treatment discontinuation (2.3% vs 1.6%).

The indication for semuloparin was sought partly on the basis of a subanalysis of lung and pancreas cancer patients in the study; patients with the other cancers (stomach, colon/rectum, bladder, or ovary) showed no significant benefit from the anticoagulant. A drug approval on the basis of a secondary analysis "always makes me uncomfortable," said committee chair Wyndham Wilson, MD, PhD, from the National Cancer Institute in Rockville, Maryland.

Multiple committee members said that they hope the company will pursue their investigation of this agent. Better identification of patients at high risk for VTEs is needed, a number suggested.


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