FOLFOXIRI plus bevacizumab an option for patients with mCRC and poor prognosis

Medical writer: Debra Gordon

FOLFOXIRI plus bevacizumab improves progression-free survival (PFS) by about 3 months compared to FOLFOX plus bevacizumab in patients with first-line metastatic colorectal cancer (mCRC) and a poor prognosis, albeit with a higher rate of serious side effects, according to the results of the phase III VISNU-1 trial (Abstract 3507) reported during the Gastrointestinal (Colorectal) Cancer Oral Abstract Session on June 1.

VISNU-1 is the first mCRC study performed in a population selected by baseline circulating tumour cell (CTC) count.

Although FOLFOXIRI plus bevacizumab has a demonstrated PFS and overall survival (OS) benefit compared with FOLFOX plus bevacizumab, this schedule is not routinely recommended in all patient groups because of toxicity, lead author Javier Sastre, MD, PhD, of Hospital Clínico San Carlos, Spain, said.

“We considered that it would be of interest to explore the role of this combination in a subgroup of patients with poor prognostic factors,” he said, specifically patients with CTCs greater than or equal to three. Higher CTC levels have been shown to be a poor prognostic factor for survival.¹

VISNU-1 is an open, multicentre, randomized phase III trial. Investigators screened 1,252 patients, enrolling 349 patients younger than age 70 with an ECOG score of 0 to 1.

After accrual of 63 patients, the protocol was changed to recommend the use of prophylactic GCSF in the FOLFOXIRI arm due to a high rate of neutropenia, Dr. Sastre said.

There was a significant difference in PFS between the two arms, with a PFS of 12.4 months in the FOLFOXIRI arm compared with 9.3 months in the FOLFOX arm (HR 0.64, 95% CI [0.49, 0.82]; P = 0.0006). A subgroup analysis showed that most subgroups would benefit from the FOLFOXIRI combination, except patients with a P13K mutation. These data also suggested a greater benefit for those with a primary tumour located on the left side and with a wild-type RAS/BRAF tumour, Dr. Sastre said.

The multivariate analysis demonstrated that BRAF and RAS status, CTCs greater than 20, and an ECOG score of 1 were independent predictors for PFS, he said.

Although the OS was not statistically significant at a median follow-up of 50.7 months, “these are not final results,” Dr. Sastre said. Additional data should be available by the end of the year.

There was no statistically significant difference between the two arms in objective response rate (ORR) or duration of response in the intent-to-treat analysis. However, there were statistically significant differences in ORR in the overall population (57% for FOLFOX compared with 69% for FOLFOXIRI; HR 0.61, 95% CI [0.38, 0.97]; P = 0.0381).

Overall, there were 133 grade 3 or higher toxicities in the FOLFOXIRI arm vs. 119 in the FOLFOX arm (P = 0.022).

“This study suggests that FOLFOXIRI plus bevacizumab could be considered an adequate treatment option for patients with mCRC and three or more CTCs,” Dr. Sastre said, although further studies evaluating the role of CTCs as a predictive factor are needed.

“To what extent can we generalize these trials to the patient sitting in front of us?” asked Discussant Hanna K. Sanoff, MD, MPH, of the University of North Carolina Lineberger Comprehensive Centre. Although the subgroup analyses are based on small numbers of patients, “to me, the lack of a consistent pattern is reassuring that there isn’t any particular subgroup for which FOLFOXIRI won’t work,” she said.

Nonetheless, she said, “I don’t feel comfortable generalizing the results to patients older than 70 or those with a poor performance status,” because neither were represented in the study.

She also questioned the effect of FOLFOXIRI on the patient experience and whether the additional toxicity was worth the survival benefit. “The bottom line is that we have no systematically collected patient-related outcomes data to know how the [toxicities] relate to the patient experience vs. chemotherapy,” she said.

1. Sastre J, et al. Oncologist. 2012;17:947-55.

Posted on 15 July 201921 May 2024