The VISNU-1 randomized phase III trial compared FOLFOX + bevacizumab with FOLFOXIRI + bevacizumab as first line treatment in patients with metastatic colorectal cancer with poor prognosis. Poor prognosis was defined as ≥3 baseline circulating tumour cells. Patients who received FOLFOXIRI + BEV had a statistically significant benefit for progression-free survival compared with patients who received FOLFOX + BEV, with a magnitude of 3 months, while overall survival showed a trend of benefit in the experimental arm.
The combination of FOLFOXIRI and bevacizumab (BEV) has shown a benefit in progression-free survival (PFS) and overall survival (OS) compared with FOLFIRI + BEV as first line treatment of patients with metastatic colorectal cancer (mCRC).1,2 However, this schedule is not routinely recommended for these patients, mainly due to its high toxicity. Additionally, a baseline circulating tumour cell count (bCTC) of ≥3 has been defined as a poor prognostic factor for survival.3 At ASCO 2019, Javier Sastre presented the results of the VISNU-1 trial, which compared FOLFOX + BEV with FOLFOXIRI + BEV in mCRC patients with poor prognosis as defined by ≥3 bCTCs.4
VISNU-1 is an open, multicentre, randomized phase III trial. Patients with mCRC and ≥3 bCTCs younger than 70 years were randomized to receive FOLFOX+BEV (arm A) or FOLFOXIRI+BEV (arm B). The treatment was administered every 2 weeks until disease progression, unacceptable toxicity, or withdrawal of informed consent. Randomization was stratified according to KRAS-mutation (mutated versus wildtype) and number of involved organs (1 versus >1). PFS was the primary endpoint. Secondary endpoints included objective response rate (ORR) and OS.
In the intention-to-treat population 349 patients were included (arm A: 177 patients; arm B: 172 patients). Median PFS was 9.3 months in arm A and 12.3 months in arm B (HR 0.64 [95% CI 0.49-0.82]; p=0.0006). Subgroup analysis suggested that almost all subgroups of patients might benefit from the combination FOLFOXIRI+BEV, except for patients with PI3K mutations. Additionally, patients with the primary tumour located on the left side, patients with RAS-wildtype, and patients with BRAF-wildtype might show greater benefits. With a median follow-up of 50 months, OS was 17.6 months in arm A and 22.3 months in arm B (HR 0.84 [95% CI 0.66-1.06]; p=0.1407). ORR was 57% in arm A and 69% in arm B, when looking at the patients evaluated for response (OR 0.61 [95% CI 0.38-0.97]; p=0.0381). Furthermore, the median response duration was significantly longer in arm B (9.9 months) compared to arm A (8.1 months, p=0.0010). Safety analysis has been previously presented at ASCO 2018 and showed an acceptable toxicity profile for both treatment regimens.
In this population with very bad prognosis, the VISNU-1 study met its primary endpoint. Patients who received FOLFOXIRI + BEV had a statistically significant benefit for PFS compared with patients who received FOLFOX + BEV, with a magnitude of 3 months. Additionally, subgroup analysis suggested a greater PFS benefit for patients with left-sided primary tumours and patients with wildtype RAS/BRAF. OS showed a trend of benefit in the experimental arm. According to these results, FOLFOXIRI + BEV could be considered an adequate treatment option for patients with mCRC and ≥3 bCTCs. Further studies evaluating the role of CTCs as a predictive factor are warranted.