OT3-01-09: Phase 3 Trial Comparing Capecitabine in Combination with SorafenIb or Placebo for Treatment of Locally Advanced or Metastatic HER2−Negative Breast Cancer (RESILIENCE).
Authors: Baselga J , Schwartzberg LS , Petrenciuc O , Shan M , Gradishar WJ 
Published: June 2012

Sorafenib (SOR) is an oral multikinase inhibitor with antiangiogenic and antiproliferative activity. SOR is currently indicated for renal cell and hepatocellular carcinoma, with indications in other tumor types being explored. In a double-blind, randomized phase 2b screening trial (SOLTI-0701) in patients with advanced HER2−negative breast cancer (BC), the addition of SOR to capecitabine (CAP) showed a statistically significant improvement in the primary endpoint of progression-free survival (PFS) compared with placebo (PL)+CAP (median 6.4 vs 4.1 mo; hazard ratio=0.58; 1-sided P=0.0006). The combination was tolerable. Grade 3/4 adverse events were comparable between treatment arms with the exception of grade 3 hand-foot skin reaction/syndrome (HFSR/HFS) (44% in SOR+CAP vs 14% in PL+CAP). The SOLTI-0701 results indicate a potential role for the oral combination of SOR+CAP in the treatment of BC and support a phase 3 trial.

Design: RESILIENCE is an ongoing multinational, double-blind, PL-controlled, randomized phase 3 trial designed to assess SOR+CAP as a first- or second-line therapy in advanced HER2−negative BC. Eligibility criteria include: ≥18 years of age; ≤1 prior chemotherapy regimen for advanced BC; and resistant to/failed taxane and anthracycline or no indication for further anthracycline treatment. Prior hormonal or radiation therapy is allowed, but prior use of VEGF inhibitors is not. Patients with significant cardiovascular disease or active brain metastases are not eligible. Patients are stratified by hormone receptor status, geographic region, and prior chemotherapy for advanced BC and randomized (1:1) to CAP (1000 mg/m2 po twice daily [BID], days 1–14 of a 21-day cycle) in combination with SOR (po BID, days 1–21, total dose 600 mg/day) or matching PL. CAP and SOR/PL doses can be escalated to 2500 mg/m2 per day and 800 mg/day, respectively, as tolerated. The protocol outlines strategies to manage toxicities with dose interruption and reduction. Dose re-escalation after reduction is allowed for SOR/PL (per protocol guidance) but not for capecitabine. Guidelines are provided for prophylactic and symptomatic treatment of HFSR/HFS. Radiographic assessment is every 6 wk for the first 36 wk, and every 9 wk thereafter. The primary endpoint is PFS. Assuming a 1-sided alpha of 0.005 and a power of 98.9%, the sample size is estimated at ∼519 patients, with primary analysis planned after 363 events. Secondary endpoints include overall survival, time to progression, overall response rate (RECIST 1.1 criteria), duration of response, and safety. In addition, patient reported outcomes will be assessed, and the trial will include an exploratory analysis of biomarkers. Enrollment began in Nov 2010. The trial is registered at ClinicalTrials.gov (NCT01234337).

Conclusions: RESILIENCE will provide definitive PFS data for SOR+CAP as a first- or second-line therapy in HER2−negative locally advanced or metastatic BC. The phase 3 design and improved dosing guidance since SOLTI-0701 will better characterize the benefit-to-risk profile of this regimen.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-09.