In the Dutch Colorectal Cancer Group phase III CAIRO5 study reported in The Lancet Oncology, Bond et al investigated first-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases. The researchers found that FOLFOXIRI (leucovorin, fluorouracil, oxaliplatin, and irinotecan) plus bevacizumab was the best option for patients with right-sided or RAS- or BRAF V600E–mutated primary tumors.

Study Details

In the multicenter open-label trial, between November 2014 and January 2022, 291 patients in the modified intent-to-treat population with a right-sided primary tumor site or RAS- or BRAF V600E–mutated tumors were randomly assigned to receive either FOLFOX (leucovorin, fluorouracil, oxaliplatin) or FOLFIRI (leucovorin, fluorouracil, irinotecan) plus bevacizumab (group A, n = 147) or FOLFOXIRI plus bevacizumab (group B, n = 144). A total of 230 patients in the modified intent-to-treat population of patients with left-sided and RAS- and BRAF V600E wild-type tumors were randomly assigned to receive FOLFOX or FOLFIRI plus bevacizumab (group C, n = 114) or FOLFOX or FOLFIRI plus panitumumab (group D, n = 116). 

The primary outcome measure was progression-free survival in the modified intention-to-treat population.

Progression-Free Survival

Median follow-up was 51.1 months in groups A and B and 49.9 months in groups C and D. Groups C (FOLFOX or FOLFIRI plus bevacizumab) and D (FOLFOX or FOLFIRI plus panitumumab) including patients with left-sided and RAS and BRAF V600E wild-type tumors were prematurely closed for futility.

Among patients with right-sided primary tumor sites or RAS- or BRAF V600E–mutated tumors, median progression-free survival was 10.6 months (95% confidence interval [CI] = 9.9–12.1 months) in group B (FOLFOXIRI plus bevacizumab) vs 9.0 months (95% CI = 7.7–10.5 moths) in group A (FOLFOX or FOLFIRI plus bevacizumab); the stratified hazard ratio favoring group B was 0.76 (95% CI = 0.60–0.98, P =.032).

Among patients with left-sided and RAS and BRAF V600E wild-type tumors, median progression-free survival was 10.4 months (95% CI = 9.8–13.0 months) in group D (FOLFOX or FOLFIRI plus panitumumab) vs 10.8 months (95% CI = 9.9–12.6 months) in group C (FOLFOX or FOLFIRI plus bevacizumab) with a stratified hazard ratio of 1.11 (95% CI = 0.84–1.48, P = .46).

Adverse Events

The most frequent grade 3 or 4 adverse events in groups A vs B were neutropenia (13% vs 40%, P < .0001), hypertension (14% vs 14%, P = 1.00), and diarrhea (3% vs 19%, P < .0001). The most frequent grade 3 or 4 adverse events in groups C vs D were neutropenia (25% vs 21%, P = .44), skin toxicity (1% vs 25%, P < .0001), hypertension (18% vs 7%, P = .016), and diarrhea (4% vs 16%, P = .0072).

Serious adverse events occurred in 31% of patients in group A, 52% of group B, 36% of group C, and 42% of group D. Treatment-related deaths were reported in seven patients in group B (two due to multiorgan failure and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death); one patient in group C (multiorgan failure); and three patients in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis in one each).

The investigators concluded: “In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI/bevacizumab was the preferred treatment in patients with a right-sided or RAS- or BRAF V600E–mutated primary tumor. In patients with a left-sided and RAS and BRAF V600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab but was associated with more toxicity. “

Cornelis J.A. Punt, MD, of the Department of Epidemiology, University Medical Centre Utrecht, Utrecht University, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Roche and Amgen. For full disclosures of the study authors, visit thelancet.com.