AVANT

Background

Phase III, open-label, 3-arm RCT. 3451 patients with stage III colon cancer after curative resection. Tested bevacizumab added to two different oxaliplatin-based adjuvant regimens versus FOLFOX4 alone. The largest adjuvant anti-VEGF trial in colon cancer at the time.

Interventions and follow up

Arm A: FOLFOX4 × 12 cycles (reference)
Arm B: FOLFOX4 × 12 cycles + bevacizumab 5mg/kg q2wk × 36 doses (18 mo)
Arm C: XELOX (oxaliplatin 130mg/m² D1 + capecitabine 1000mg/m² BID D1–14 q3wk) × 8 cycles + bevacizumab 7.5mg/kg q3wk × 24 doses
Primary endpoint: Disease-free survival (DFS)
mFollow up: 48 mo

Results

DFS (Arm B vs A): HR 1.17, 95% CI 1.00–1.36 — no benefit, trend toward harm
DFS (Arm C vs A): HR 1.07, 95% CI 0.93–1.24 — not significant
OS (Arm B vs A): HR 1.27 — not significant
OS (Arm C vs A): HR 1.15 — not significant

Adverse events

Vascular/anti-VEGF: Grade ≥3 AEs increased with bevacizumab — hypertension (Arm B 18.4%, Arm C 20.6% vs Arm A 5.9%), proteinuria (5.2%, 4.7% vs 0.9%), arterial thromboembolism (1.5%, 2.2% vs 0.8%)
Surgical/other: Wound healing complications (1.9%, 0.9% vs 0.5%); neuropathy and GI toxicities similar across arms

Conclusions

Adding bevacizumab to FOLFOX4 or XELOX in stage III adjuvant colon cancer did not improve DFS and showed a non-significant trend toward worse DFS and OS in the FOLFOX4+bevacizumab arm. AVANT definitively confirmed that bevacizumab has no role in adjuvant colon cancer.

Key Limitations

Key Limitations: The HR of 1.17 for FOLFOX4+bev vs FOLFOX4 suggests potential harm, though confidence intervals cross 1.0. The biological explanation for the lack of benefit and possible harm may relate to rebound angiogenesis after bev discontinuation, anti-angiogenic effects on wound healing and tissue repair, or pro-tumorigenic hypoxia induction. The open-label design may have influenced reporting. The 3-arm design provides important comparative data between FOLFOX4 and XELOX backbones as well as with bev.

Clinical Context

AVANT, alongside NSABP C-08, firmly established that bevacizumab adds no benefit in adjuvant colon cancer. This finding is not explained by bevacizumab dose or schedule. Current ESMO guidelines do not recommend anti-VEGF therapy in adjuvant colon cancer regardless of stage. The AVANT trial also provides data confirming similar DFS outcomes with XELOX vs FOLFOX4 adjuvant chemotherapy (both without bev), supporting CAPOX as an alternative adjuvant regimen.

References

References: de Gramont A et al, Lancet Oncol 2012