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