Adding Sorafenib to Topotecan in Platinum-Resistant Ovarian Cancer
In a German phase II trial reported in The Lancet Oncology, Chekerov et al found that the addition of sorafenib (Nexavar) to topotecan improved progression-free survival in women with platinum-resistant ovarian cancer.
Study Details
In the multicenter investigator-initiated double-blind trial, 172 patients who started study treatment and who had previously received two or fewer chemotherapy lines for recurrent disease were randomized between January 2010 and September 2013 to receive topotecan 1.25 mg/m2 on days 1 to 5 plus oral sorafenib 400 mg (n = 83) or placebo (n = 89) twice daily on days 6 to 15 every 21 days for six cycles; patients without progression received daily maintenance sorafenib or placebo for up to 1 year.
The primary endpoint was investigator-assessed progression-free survival among all patients who received at least one dose of study drug.
Progression-Free Survival
After completing chemotherapy, 42% of patients in the sorafenib group and 38% in the placebo group received maintenance therapy. Median progression-free survival was 6.7 months in the sorafenib group vs 4.4 months in the placebo group (hazard ratio = 0.60, P = .0018). Median overall survival was 17.1 months vs 10.1 months (HR = 0.65, P = .017). After discontinuing study therapy, 97% of 56 sorafenib patients and 91% of 46 placebo patients with available post-progression data on additional treatment received further chemotherapy. HRs for progression-free and overall survival for sorafenib vs placebo were 0.47 (P = .005) and 0.70 (P = .19) among patients receiving study treatment as second-line therapy and 0.70 (P = .11) and 0.61 (P = .043) among those receiving third- or fourth-line therapy.
Adverse Events
The most common grade 3 or 4 adverse events were leukopenia (69% vs 53%), neutropenia (55% vs 54%), and thrombocytopenia (28% vs 22%). Serious adverse events occurred in 59% vs 51% of patients. Sorafenib was associated with increased frequency of grade 3 hand-foot skin reaction (13% vs 0%) and grade 2 alopecia (29% vs 13%). Adverse events led to death in four sorafenib patients (dyspnea and poor general condition, septic shock, ascites and dyspnea, and sigma perforation) and five placebo patients (pulmonary embolism in two, sepsis with fever, pleural effusion, and tumor cachexia).
The investigators concluded, “Sorafenib—when given orally in combination with topotecan and continued as maintenance therapy—showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies.”
The study was funded by Bayer, Amgen, and GlaxoSmithKline.
Radoslav Chekerov, MD, of Charité—Universitätsmedizin Berlin, is the corresponding author for The Lancet Oncology article.
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