Chekerov R, et al. - In this randomised phase 2 TRIAS trial, researchers investigated the efficacy of the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. Women with platinum-resistant ovarian cancer showed a statistically and clinically significant improvement in progression-free survival, when received sorafenib in combination with topotecan orally and continued it as maintenance therapy. Outcomes thereby support the vital role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies.

Methods

• At 20 sites in Germany, a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial was performed.
• Researchers stratified patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease (first vs later relapse) in block sizes of four.
• Using a web-generated response system, they performed random assignment of the patients (1:1) to topotecan (1·25 mg/m ² on days 1–5) plus either oral sorafenib 400 mg or placebo twice daily on days 6–15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression.
• Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label.
• All patients who received at least one dose of study drug were analyzed for the primary endpoint including investigator-assessed progression-free survival.

Results

• Enrollment of 185 patients was performed between Jan 18, 2010, and Sept 19, 2013; 174/185 were randomly assigned: 85 to sorafenib and 89 to placebo.
• Serious adverse events were recorded in 2 patients in the sorafenib group before treatment and thus these patients were excluded from analyses.
• Treatment was initiated in 83 patients in the sorafenib group and 89 in the placebo group.
• Sorafenib vs placebo resulted in significantly improved progression-free survival (hazard ratio 0·60, 95% CI 0·43–0·83; p=0·0018).
• Median progression-free survival was 6·7 months (95% CI 5·8–7·6) vs 4·4 months (3·7–5·0) with sorafenib vs placebo.
• Leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]) were recorded as the most common grade 3–4 adverse events.
• In this trial, 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients experienced serious adverse events.
• In the sorafenib group, these events were fatal in four patients (5%) (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) vs seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia).
• Increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%]) were observed in association with sorafenib.