Patients with metastatic colorectal cancer with poor prognosis had longer progression-free survival while taking FOLFOXIRI plus bevacizumab in comparison with those taking FOLFOX plus bevacizumab, according to the results of the VISNU-1 trial (abstract 3507) presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 31–June 4 in Chicago.
“The triple combination FOLFOXIRI [fluorouracil, leucovorin, oxaliplatin, and irinotecan] plus bevacizumab has been shown to improve progression-free survival and overall survival when compared with FOLFIRI [fluorouracil, leucovorin, and irinotecan] plus bevacizumab in first-line metastatic colorectal cancer patients. However, this schedule has not been adopted as the gold standard for all patients with metastatic colorectal cancer mainly due to a higher rate of toxicity compared with the biologic drugs,” said Javier Sastre, MD, PhD, on behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors, who presented the results.
Therefore, the researchers sought to define which patient population would benefit most from the triple combination treatment. VISNU-1—an open-label, multicenter, randomized phase III trial—compared the triple combination treatment of FOLFOXIRI plus bevacizumab with FOLFOX [fluorouracil, leucovorin, and oxaliplatin] plus bevacizumab in patients with metastatic colorectal cancer and ≥ 3 circulating tumor cells (CTCs) at baseline.
“We see that patients with 3 or more CTCs in blood prior to chemotherapy have significantly shorter progression-free survival and overall survival than patients with low CTCs,” said Hanna Kelly Sanoff, MD, MPH, of the Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, who was the discussant for the study.
A total of 349 intention-to-treat patients, who were required to be ≤ 70 years in age and have an ECOG score of 0 to 1, were randomized to receive either FOLFOXIRI (n = 172; median age, 59 years [range, 27–70]) or FOLFOX (n = 177; median age, 61 years [range, 37–70]) in addition to bevacizumab every 2 weeks until death, unacceptable toxicity, or withdrawal. The primary endpoint was PFS. The secondary endpoints were objective response rate (ORR) and overall survival (OS).
Both patient groups were predominantly male (FOLFOXIRI, 68.6% male and 31.4% female; FOLFOX, 67.2% male and 32.8% female). Patients were stratified according to KRAS exon 2 and 3 mutation status and the number of organs affected. Approximately 50% of patients in both treatment groups had mutated RAS (FOLFOXIRI, 49.4% and FOLFOX, 47.5%); some patients also had PIK3CA (15.1% and 9.6%) and BRAF (9.3% and 9.6%) mutations and a variety of microsatellite instabilities.
Patients in the FOLFOXIRI arm had longer PFS (median, 12.4 months) compared with patients in the FOLFOX arm (median, 9.3 months; hazard ratio [HR], 0.64; 95% CI, 0.49–0.82; P = .0006). In a multivariate analysis, BRAF mutation (HR, 2.49; 95% CI, 1.52–4.06; P < .001), RAS mutation (HR, 1.89; 95% CI, 1.42–2.51; P < .001), CTC count ≥ 20 (HR, 1.77; 95% CI, 1.21–2.57; P = .003), and ECOG score of 1 (HR, 1.40; 95% CI, 1.06–1.84; P = .017) were independent prognostic factors for PFS. However, no difference was observed in either of the secondary endpoints: ORR (median, 59.0% vs 52.0%; odds ratio [OR], 0.74; 95% CI, 0.49–1.14; P = .1685) and OS (median, 22.3 months vs 17.6 months; HR, 0.84; 95% CI, 0.66–1.06; P = .1407, respectively) at a median follow-up of 50.7 months.
Grade 3/4 treatment-related adverse events were more frequent in the FOLFOXIRI arm compared with the FOLFOX arm (78% vs 67%; P = .022), particularly, asthenia (16% vs 7%; P = .007), diarrhea (21% vs 6%; P < .001), and febrile neutropenia (9% vs 2%; P = .004). Deaths associated with treatment were similar between the two arms (5% vs 3%; P = .553).
“The incremental benefit of FOLFOXIRI was actually really quite similar to what we have seen in other FOLFOXIRI trials. So, CTCs to me appear to be prognostic but not particularly predictive for FOLFOXIRI benefit,” said Sanoff.