Targeted Therapies
FOLFOXIRI+ bevacizumab: Improved PFS and remission rates
Phase II clinical studies of FOLFOXIRI/bevacizumab have shown superior efficacy and manageable adverse effects. Tang Ligong, Department of General Surgery, Henan Cancer Hospital
The TRIBE phase III trial compared the efficacy of FOLFOXIRI/bevacizumab with that of FOLFIRI/bevacizumab in the first-line treatment of patients with inoperable resectable mCRC.
The results showed that FOLFOXIRI/bevacizumab significantly prolonged median PFS (9.7 months versus 12.2 months). Subgroup analysis based on stratification factors (PS, history of prior adjuvant chemotherapy) and patient characteristics (primary site, liver-only disease, surgical resection of primary disease) showed no significant interaction between treatment and analyzed factors. There was a trend toward better outcomes and significantly better remission rates (RECIST) in the group receiving no prior adjuvant chemotherapy (HR=0.68) than in the group receiving prior adjuvant chemotherapy (HR=1.18, P=0.071 for interaction) (65% versus 53%). fOLFOXIRI/bevacizumab did not increase the intention-to-treat (ITT) population (12% versus 15%) or the liver metastases only FOLFOXIRI/bevacizumab did not increase the rate of secondary surgical resection for R0 in the intention-to-treat (ITT) population (12% versus 15%) or the liver metastases only subgroup (28% versus 32%). Subgroup analysis suggested that there may be an interaction between prior adjuvant chemotherapy and PFS benefit, with no difference in secondary surgical resection rates between the two treatment groups.
FOLFOXIRI + bevacizumab: may improve R0 resection rates in CLM
OLIVIA is a randomized phase II clinical study comparing bevacizumab (BEV) in combination with mFOLFOX6 versus FOLFOXIRI for the treatment of initially unresectable mCRC with liver metastases only.
The results showed that FOLFOXIRI-BEV improved the R0 resection rate (48.8% versus 23.1%), overall remission rate (80.5% versus 61.5%), and median PFS (18.8 months versus 12 months) in patients with initially unresectable colorectal cancer with liver metastases compared with mFOLFOX6-BEV. Granulocytopenia (35% vs. 48%), fever (8% vs. 13%) and diarrhea (14% vs. 28%) occurred in 84% and 95% of patients in the mFOLX6-BEV and FOLFOXIRI-BEV groups, respectively. The incidence of chemotherapy and bevacizumab-related adverse events was as expected and manageable.
The study suggests that FOLFOXIRI-BEV should be further evaluated as an effective treatment option for the reduction of mCRC liver metastases.
No benefit of standard chemotherapy plus cetuximab
Surgical resection of colorectal cancer liver metastases with or without neoadjuvant chemotherapy is the standard of care, and the EPOC study demonstrated a 7.3% improvement in the 3-year PFS rate from 28.1% to 35.4% in the surgery-versus-chemotherapy group.
The new EPOC study evaluated the efficacy of adding cetuximab to standard chemotherapy in patients with operable KRAS wild-type colorectal cancer with liver metastases.
The results showed that 45.3% (96/212 cases) of expected events occurred and that PFS was significantly shorter in the cetuximab group (14.8 months versus 24.2 months). Preplanned analysis excluding 23 patients receiving irinotecan chemotherapy showed similar results (15.2 months versus 24.2 months).
The study suggests that there is no benefit of adding cetuximab to chemotherapy in patients with operable KRAS wild-type colorectal cancer with liver metastases.
FOLFIRI+ Bevacizumab has OS advantage over FOLFIRI+ Cetuximab
A German phase III clinical trial (FIRE-3) compared the efficacy of bevacizumab or cetuximab in combination with FOLFIRI in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer in a first “head-to-head” trial.
Of the 735 patients with ITT, 592 were wild-type patients with KRAS genes. The median duration of treatment was 4.7 and 5.3 months in the cetuximab + FOLFIRI group (group A, 400 mg/m2 , d1, followed by 250 mg/m2 , weekly) and the bevacizumab + FOLFIRI group (group B, 5 mg/kg, once every 2 weeks), respectively.
The ITT analysis showed comparable objective remission rates in both groups (62% versus 57%), with a superior ORR in Group A among evaluable patients; median PFS was similar in both groups (10.0 versus 10.3 months, P=0.69), however, OS was significantly better in Group A than in Group B (28.7 versus 25.0 months, P=0.0164). The 60-d mortality rate was lower in both groups (1.01% versus 2.71%).
Panitumumab + FOLFOX: OS benefit in wild-type RAS mCRC
The PRIME study is a phase III clinical study comparing panitumumab in combination with FOLFOX to FOLFOX as a first-line regimen for mCRC, analyzing KRAS/BRAF and NRAS mutations.
A previous phase III study of panitumumab monotherapy showed that KRAS and NRAS mutations were more predictive of panitumumab efficacy than KRAS exon (exon)2. The PRIME study evaluated the effect of panitumumab in combination with FOLFOX versus FOLFOX on the overall survival of patients with mCRC based on the mutational status of the RAS (KRAS or NRAS) or BRAF genes.
The results showed that the RAS mutation rate was 90%. The Tx HR for OS was 0.78 (median prolongation 5.8 months, P=0.04) and for PFS was 0.72 (P=0.01) in the panitumumab group for RAS wild-type patients, and 1.29 (P=0.31) and 1.28 (P=0.32) for OS and PFS, respectively, in patients with KRAS exon 2 wild-type/other RAS mutations.
This showed that panitumumab + FOLFOX had a significant difference in OS compared to FOLFOX in patients with wild-type RAS mCRC. There was a significant OS benefit for mCRC patients treated with this regimen. However, panitumumab was not beneficial for any patient with RAS mutations. In this analysis, BRAF gene mutations had no predictive value.
Abciximab + FOLFIRI: Consistent improvement in OS over time
A randomized controlled study, VELOUR, compared the efficacy and safety of FOLFIRI in combination with abciximab (ziv-aflibercept) or placebo in mCRC patients (1226 patients) previously treated with oxaliplatin.
The results showed a clinically meaningful improvement in median OS (13.5 months vs. 12.06 months), PFS and RR in the abciximab/FOLFIRI group. The study showed that the therapeutic effect of abciximab increased over time.
The incidence of grade 3 adverse reactions was higher in the abciximab/FOLFIRI group (45.1% versus 62.0%) and grade 4 adverse reactions were also higher than in the placebo group (17.4% versus 21.4%). The more common adverse reactions occurred in only a small proportion of the Abciximab/FOLFIRI cycles, such as grade 3 hypertension and diarrhea in 3.6% and 2.8% of the cycles in the two groups, respectively. The majority of Grade 3/4 adverse reactions occurred early in treatment (first 3-4 cycles). The majority of patients in the Abciximab/FOLFIRI group experienced only one episode of Grade 3 or higher adverse reactions. Notably, adverse reactions did not affect the ability of patients to receive chemotherapy in the VELOUR study.
In conclusion, there was a consistent and uniform improvement in OS over time with abciximab/FOLFIRI treatment. The overall incidence of grade 3/4 adverse reactions was higher in the abciximab/FOLFIRI group. Over the total treatment cycle, adverse reactions occurred in a small proportion of cycles early in treatment, with the vast majority being single episodes. Therefore, the efficacy and safety of FOLFIRI in combination with abciximab is reliable in patients with mCRC previously treated with oxaliplatin.