FOLFOXIRI Plus Bevacizumab Shows Positive Efficacy But Increased Toxicity in CRC Liver Metastases

Phase 3 CAIRO5 showed improvements in progression-free survival and overall response with FOLFOXIRI plus bevacizumab in colorectal cancer liver metastases, but the combination demonstrated a toxic safety profile.

In the phase 3 CAIRO5 clinical trial (NCT02162563), treatment with FOLFOXIRI plus bevacizumab (Avastin; FOLFOXIRI-B) led to a significant improvement in progression-free survival (PFS), objective response rate (ORR), and R0/1 resections vs FOLFOX/FOLFIRI plus bevacizumab (FOLFOX/FOLFIRI-B) but lead to increased toxicity in patients with initially unresectable colorectal cancer (CRC) liver metastases and right-sided and/or RAS- or BRAF V600E–mutated primary tumors, according to findings presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

At a median follow-up of 41 months, the median PFS was 9.0 months with FOLFOX/FOLFIRI-B (arm A) vs 10.6 months with FOLFOXIRI-B (arm B; HR, 0.77; 95% CI, 0.60-0.99; P = .038).

“CAIRO5 is the first randomized study that prospectively evaluates systemic induction regimens in patients with initially unresectable CRC liver metastases according to predefined criteria by a central liver expert panel,” lead study author Cornelis J. A. Punt, MD, PhD, full professor of oncology at the University Medical Center Utrecht in Utrecht, Netherlands, said in a presentation on the findings. “Triplet versus doublet chemotherapy plus bevacizumab significantly increases PFS, response rates, and successful local treatments as defined by R0/R1 resection plus or minus ablation rates at the cost of increased but manageable toxicity.”

The management of patients with unresectable CRC liver metastases varies, as do the criteria for unresectability and the optimal systemic induction regimen for potentially resectable disease.

As such, the CAIRO5 study was designed to determine the optimal induction regimen for patients with initially unresectable CRC liver metastases.

To be eligible for enrollment, patients had to be at least 18 years of age and have previously untreated liver-only metastases; metastases that were not resectable with surgery in one stage as defined by an expert panel; extrahepatic lesions less than or equal to 1 cm; a right-sided primary tumor and/or RAS- or BRAF V600E–mutated tumor; WHO performance status of 0 or 1; be candidates for systemic and local therapy; and have a resectable primary tumor.

Patients who presented with initially unresectable CRC liver metastases underwent a panel evaluation to confirm unresectability and were then stratified into 2 groups: those with a right-sided and/or RAS- and BRAF V600E–mutated primary tumor, or a left-sided and/or RAS- and BRAF V600E–wild-type primary tumor. The latter study arm closed in March 2022, so data are not yet available. Patients in the former arm were then randomized to a choice of FOLFOX or FOLFIRI-B, or FOLFOXIRI-B at which point the panel evaluated patients every 2 months for resectability.

The panel consisted of 15 liver surgeons and 3 abdominal radiologists. In the absence of consensus among 3 liver surgeons, evaluation by 2 additional liver surgeons and decision by majority vote would be made.

Bevacizumab was given intravenously at a dose of 5 mg/kg. Within the FOLFOX/FOLFIRI regimen, patients received either oxaliplatin at a dose of 85 mg/m2 or irinotecan at a dose of 180 mg/m2 with 400 mg/m2 of leucovorin in a 120-minute bolus plus 400 mg/m2 of 5-flourouracil (5-FU), or 2400 mg/m2 of infusional 5-FU over 46 hours.

The FOLFOXIRI regimen comprised 85 mg/m2 of oxaliplatin, 165 mg/m2 of irinotecan plus 400 mg/m2 of leucovorin in a 120-minute infusion plus 3200 mg/m2 of 5-FU over 46 hours.

Treatment was administered every 2 weeks for a maximum of 12 cycles and was followed by maintenance with 5-FU plus leucovorin and bevacizumab until disease progression.

The primary end point was PFS, with secondary end points of overall survival (OS), ORR, toxicity, R0/1 resection rates, and postoperative morbidity.

Between December 2014 and March 2021, 294 patients were randomized: 148 in arm A and 146 in arm B in 43 Dutch and 1 Belgian sites. Three ineligible patients were excluded from analysis.

Regarding patient characteristics, most patients were male, had a WHO performance status of 0, RAS-mutant disease, synchronous metastases, preference for oxaliplatin, and potentially resectable disease. Notably, patients in both arms had a median of 12 CRC liver metastases.

A total of 676 CT scan evaluations were performed, the median turnaround time for which was 6 days (range, 4-9). Most of the panel agreed on unresectability status at baseline (66%). However, consensus decreased to 41% at follow-up evaluation.

Patients received a median of 7 cycles (range, 4-12) of induction therapy in arm A vs 6 induction cycles (range, 2-12) in arm B.

Regarding baseline characteristics in arm A, the median age was 61 years, and most patients were male (63.9%). Less than half of patients had a right-sided primary tumor (39.5%). In terms of mutational status, most patients had RAS mutations (85.7%), and few patients had BRAF V600E mutations (6.8%). Additionally, synchronous disease was present in 86.4% of patients, 4.8% received prior adjuvant chemotherapy, and the median number of CRC liver metastases was 12.

In arm B, the median age was 65 years, and most patients were male (60.4%). Less than half of patients had a right-sided primary tumor (41.7%). In terms of mutational status, most patients had RAS mutations (86.1%); few patients had BRAF V600E mutations (8.3%). Additionally, synchronous disease was present in 89.6% of patients, 4.9% received prior adjuvant chemotherapy, and the median number of CRC liver metastases was 12.

Additional findings indicated that the objective response rate was 32.0% in arm A vs 52.1% in arm B (P < .001).

OS data were not mature at the time of data cutoff.

The rate of R0/1 resection with or without resection was 37% in arm A vs 51% in arm B (P = .02). Postoperative complications were reported in 40% of patients and 51% of patients, respectively (P = .19).

Notably, median PFS was prolonged in both arms with successful local treatment vs without and was improved with FOLFOXIRI-B.

Grade 3 or greater adverse effects (AEs) occurred in 58.5% of patients in arm A vs 75.0% of patients in arm B (P = .003). The most common AEs in arms A and B, respectively, were neutropenia (12.9% vs 38.2%; P < .001), hypertension (14.3% vs 13.9%; P = 1), and diarrhea (3.4% vs 19.4%; P < .001).

The rates of R0/1 resection with or without ablation were 37.4% of patients in arm A vs 51.4% of patients in arm B (P = .02) with 2-stage procedures in 16.4% and 32.4% of patients, respectively (P = .04). Postoperative complications occurred in 38.2% of patients in arm A vs 51.2% of patients in arm B (P = .14); grade 3 or greater Clavien Dindo occurred in 14.7% and 26.8% of patients, respectively (P = .08).

“In patients with initially unresectable CRC liver metastasis and right-sided and/or RAS- or BRAF-mutated primary tumor, the use of a liver expert panel is feasible and allows the selection of an increased number of patients who are eligible for local treatment with curative intent,” Punt concluded.

Reference

Punt CJA, Bond MJG, Bolhuis K, et al. FOLFOXIRI + bevacizumab versus FOLFOX/FOLFIRI + bevacizumab in patients with initially unresectable colorectal liver metastases (CRLM) and right-sided and/or RAS/BRAFV600E-mutated primary tumor: Phase III CAIRO5 study of the Dutch Colorectal Cancer Group. J Clin Oncol. 2022;40(suppl 17):LBA3506. doi:10.1200/JCO.2022.40.17_suppl.LBA3506