In a population of patients with metastatic colorectal cancer deemed to be at high risk by the presence of circulating tumor cells (CTCs), first-line treatment with FOLFOXIRI plus bevacizumab improved progression-free survival by about 3 months, compared with modified FOLFOX plus bevacizumab, although patients experienced more side effects.¹

Javier Sastre, MD, PhD

“This study suggests that FOLFOXIRI plus bevacizumab could be considered an adequate treatment option for patients with metastatic colorectal cancer and three or more CTCs,” said Javier Sastre, MD, PhD, of Hospital Clínico San Carlos, Spain, reporting the results of the phase III VISNU-1 trial at the 2019 ASCO Annual Meeting.

VISNU-1 is the first study in metastatic colorectal cancer performed in a population selected by baseline CTC count. Although FOLFOXIRI (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) plus bevacizumab has been shown to produce better outcomes than FOLFOX (5-FU, leucovorin, oxaliplatin) plus bevacizumab, the regimen is not routinely recommended because of toxicity. The investigators hoped to optimize the patient population who might benefit most from the more intensive regimen.

“We considered that it would be of interest to explore the role of this combination in a subgroup of patients with poor prognostic factors,” Dr. Sastre said. Higher CTC levels have been shown to be a poor prognostic factor for survival. VISNU-1 considered CTC counts ≥ 3 as the cutoff for high risk.

VISNU-1 Details and Results

VISNU-1 is an open, multicenter, randomized phase III trial that enrolled 349 patients up to 70 years of age with a good performance status. Patients with at least 3 CTCs were randomly assigned to modified FOLFOX or FOLFOXIRI, both with bevacizumab, until disease progression. After accrual of 63 patients, the protocol was changed to recommend the use of granulocyte colony-stimulating factor in the FOLFOXIRI arm due to a high rate of neutropenia.

The median progression-free survival was significantly longer with FOLFOXIRI/bevacizumab: 12.4 months vs 9.3 months with FOLFOX/bevacizumab (hazard ratio [HR] = 0.64; P = .0006). Its superiority was shown in virtually all subgroups except for patients with P13K mutations. The benefit appeared to be greatest for patients with left-sided primary tumors and wild-type RAS/BRAF tumors, Dr. Sastre reported.

In the multivariate analysis, treatment with FOLFOXIRI/bevacizumab, BRAF and RAS mutant status, CTC counts > 20, and an Eastern Cooperative Oncology Group performance status of 1 were independent predictors for progression-free survival. At a median follow-up of 50.7 months, the overall survival analysis is not mature, but survival was also numerically prolonged with FOLFOXIRI/bevacizumab (22.3 months) vs FOLFOX/bevacizumab (17.6 months; HR = 0.84; P = .1407).

There was no statistically significant difference between the two arms in objective response rate or duration of response in the intent-to-treat analysis. However, in patients evaluated for response, 69% responded to FOLFOXIRI/bevacizumab, compared with 57% who responded to FOLFOX/bevacizumab (HR = 0.61; P = .0381), with this arm showing a longer duration of response (9.9 vs 8.1 months; HR = 1.786; P = .0010).

FOLFOXIRI/bevacizumab was associated with more grade ≥ 3 toxicities, 78% vs 67% (P = .022), especially asthenia, diarrhea, and febrile neutropenia. ■

DISCLOSURE: Dr. Sastre is speaker and received honoraria and/or held advisory roles for Roche, Sanofi, Amgen, Bayer, MSD, BMS, Celgene, Merck, Servier, Pfizer and Ipsen. Traveling support: Merck and Celgene.

REFERENCE

1. Sastre J, et al: Randomized phase III study comparing FOLFOX + bevacizumab vs FOLFOXIRI + bevacizumab as first line treatment in patients with metastatic colorectal cancer with ≥ 3 baseline circulating tumor cells. 2019 ASCO Annual Meeting. Abstract 3507. Presented June 1, 2019.