QUASAR2 Trial: Adjuvant Capecitabine ± Bevacizumab in Patients with Stage II/III Colorectal Cancer

Conference Correspondent - ESMO 2014 - Gastrointestinal and Head & Neck Cancer

Bevacizumab has an established role in the treatment of patients with metastatic colorectal cancer (CRC) in combination with chemotherapy. However, its efficacy as adjuvant therapy is not defined; data from previous studies were unable to demonstrate any benefit for the addition of bevacizumab to chemotherapy in this setting. To address this question, the phase 3, randomized controlled QUASAR 2 clinical trial evaluated the overall survival benefit of adding bevacizumab to capecitabine in patients with resected CRC; another goal was to validate and/or identify new biomarkers for bevacizumab efficacy and toxicity (Kerr et al. ESMO 2014: Abstract LBA12). Based on the hypothesis that patients with mismatch repair deficient (MMRd) or microsatellite instability (MSI) tumors, or those with a high tumor stroma ratio could be subgroups that may potentially benefit from bevacizumab therapy, these 2 biomarkers were analyzed for their prognostic and predictive significance.

The 1941 eligible patients in this trial (840 with MMRd/MSI tumors) were randomized to receive bevacizumab 7.5 mg/kg every 3 weeks plus capecitabine 1250 mg/m2 or capecitabine alone. Efficacy analysis in the total population showed that the addition of bevacizumab did not improve overall survival (OS) outcomes for the 3-year disease-free survival (DSF) compared with capecitabine alone in the adjuvant setting (75.2% vs 78.2%, respectively; hazard ratio [HR], 1.06; P = .54) and 3-year OS (85.5% vs 87.2%; HR, 1.12; P = .38).

The hypothesis-driven biomarker analyses showed that MSI positivity was associated with reduced DFS in patients receiving bevacizumab plus capecitabine compared with those receiving capecitabine alone (HR, 1.43; P = .005), suggesting a negative predictive value for bevacizumab; by contrast, there was no significant DFS difference in MSI-positive patients (HR, 0.74; P = .42). Although high tumor stromal content conferred a worse 3-year DFS outcome (HR, 1.58; P = .001), it did not predict response to bevacizumab.

In terms of safety, patients who received bevacizumab plus capecitabine combination therapy experienced a significantly higher incidence of adverse events (all grades), including hypertension, proteinuria, poor wound healing, hand-foot syndrome, and epistaxis, many of which were previously defined toxicities of bevacizumab. The investigators also reported a significantly higher incidence of potential treatment-related deaths in patients receiving bevacizumab (1.9% vs 0.9%; HR, 2.3; P = .05).

Kerr and colleagues concluded that there was no role for bevacizumab in combination with capecitabine in the adjuvant treatment of patient with CRC in any of the subgroups tested..