Trial suggests optimal approach for unresectable CRC liver metastases

For patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI plus bevacizumab (Avastin) was the “preferred” systemic induction regimen for those with a right or RAS- Or BRAF Primary tumor mutated to V600E, according to a phase III randomized trial.

Among these patients, the median progression-free survival (PFS) was 9.0 months in those receiving FOLFOX or FOLFIRI plus bevacizumab versus 10.6 months in those receiving FOLFOXIRI plus bevacizumab (stratified RR 0.76, 95% CI 0, 60-0.98, P= 0.032), reported Cornelis Punt, MD, PhD, of the University Medical Center Utrecht at Utrecht University in the Netherlands, and colleagues from the Dutch Colorectal Cancer Study Group.

FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus bevacizumab also significantly increased objective response rates (54% versus 33%, P=0.0004) and disease control rate (93% versus 81%, P=0.0028) compared to FOLFOX or FOLFIRI plus bevacizumab, they noted in Lancet Oncology.

Complete local treatment was performed in 51% and 37% of patients, respectively (P=0.013).

“Although the benefit in terms of median progression-free survival is small, the increase in the proportion of patients who received complete local treatment could be considered of greater clinical significance,” Punt and colleagues wrote.

Punt and colleagues also evaluated patients with left-sided and RAS Or BRAF Wild-type V600E tumors treated with FOLFOX or FOLFIRI in combination with bevacizumab or the anti-EGFR antibody panitumumab (Vectibix).

Median PFS was similar in bevacizumab-treated and panitumumab-treated patients (10.8 months and 10.4 months, respectively; stratified RR 1.11, 95% CI 0.84-1.48, P=0.46).

The addition of panitumumab significantly increased the objective response rate (80% versus 53%, P<0.0001), but complete local treatment rate was achieved in 58% of both groups.

“Since local treatment remains the only form of treatment that offers the possibility of prolonged survival, it should be noted that a better objective response did not translate into a better conversion rate,” Katsunori Imai wrote. , MD, PhD, and Hideo Baba. , MD, PhD, both from Kumamoto University in Japan, in a commentary accompanying the study. “In general, the objective response rate is significantly associated with the resection rate.”

Punt and colleagues said this association between objective response rate and resection rate will be analyzed in the future, and that overall survival data “should be awaited before drawing any firm conclusions.”

Regarding safety, serious adverse events occurred in 31% of patients who received FOLFOX or FOLFIRI plus bevacizumab and 52% of those who received FOLFOXIRI plus bevacizumab.

“The significantly higher incidence of grade 3 or worse adverse events with the use of FOLFOXIRI compared to FOLFOX or FOLFIRI plus bevacizumab is consistent with previous studies and was primarily caused by a higher incidence of diarrhea and non-febrile neutropenia,” the authors noted.

Panitumumab was also associated with increased toxicity, which Punt and colleagues said was consistent with previous studies. Serious adverse events occurred in 36% of patients who received bevacizumab and 42% of those who received panitumumab, the difference being mainly due to higher rates of skin toxicity and diarrhea with panitumumab, whereas bevacizumab was associated with a higher incidence of hypertension.

In explaining the rationale for CAIRO5, the researchers pointed out that patients with initially unresectable colorectal cancer liver metastases may subsequently benefit from curative local treatment (such as surgery or local ablative therapy) if they obtain a sufficient response to systemic induction therapy.

However, “there is no consensus on the optimal systemic induction regimen for patients with initially unresectable colorectal cancer liver metastases,” they wrote. “Furthermore, published data in this patient population are difficult to interpret due to absent or variable resectability or non-resectability criteria, the paucity of long-term follow-up of patients who received local treatment, and the heterogeneity study populations, trial design and use. RAS/BRAF Mutation status V600E.”

Thus, they wanted to compare the currently most active systemic induction patterns in this setting. They also noted that this was the first study to prospectively compare bevacizumab to an anti-EGFR antibody – both with a chemotherapy backbone – and which took into account both RAS And BRAF V600E mutation status and side of primary tumor.

The open-label CAIRO5 study included 530 patients (median age 62 years, 62% men) enrolled in 46 Dutch centers and one Belgian center. All patients had histologically confirmed colorectal cancer, known RAS/BRAF V600E mutation status, a WHO performance status of 0-1 and initially unresectable colorectal cancer liver metastases.

Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists at baseline and every 2 months thereafter according to predefined criteria.

Most patients had synchronous disease and liver metastases from colorectal cancer considered potentially resectable by the panel of experts.

From November 2014 to January 2022, patients with a primary tumor site on the right side or RAS- Or BRAF V600E mutated tumors were randomized 1:1 to receive FOLFOX or FOLFIRI plus bevacizumab (n=148) or FOLFOXIRI plus bevacizumab (n=146). Patients with the left side and RAS- And BRAF V600E wild-type tumors were randomized 1:1 to receive FOLFOX or FOLFIRI plus bevacizumab (n=118) or FOLFOX or FOLFIRI plus panitumumab (n=118).

The median follow-up at the time of this analysis was 51.1 months in the first two groups and 49.9 months in the second two groups.

A limitation of this study was that the use of FOLFOXIRI has not been studied in patients with RAS– And BRAF Wild-type tumors V600E.