A comparison of FOLFIRI (Folinic Acid, Fluorouracil and Irinotecan) Plus Bevacizumab and FLOLFIRI Plus Aibercept as Second-Line Treatment for Metastatic Colorectal Cancer

Background: To date, there are few clinical studies comparing the ecacy and safety of FOLFIRI (folinic acid, uorouracil and irinotecan) plus bevacizumab or aibercept in metastatic colorectal cancer patients (mCRC) pretreated with oxaliplatin-based chemotherapy. Methods: We analyzed the treatment outcomes of patients receiving FOLFIRI in combination with bevacizumab or aibercept as second-line treatment for mCRC between October 2017 and March 2020. This analysis included 67 patients receiving FOLFIRI plus aibercept and 83 receiving FOLFIRI plus bevacizumab. Results: The overall response rate (ORR) was 13.6% (95% CI: 4.85-22.34) in the FOLFIRI-aibercept group and 14.7% (95% CI: 6.68-22.71) in the FOLFIRI-bevacizumab group. This difference in ORR was not statistically signicant. The median progression free survival (PFS) was 8.6 months in the FOLFIRI-bevacizumab group and 8.5 months in the FOLFIRI-aibercept group (P = 0.752) (Fig. 1). Patients in the FOLFIRI-bevacizumab group showed a median overall survival (OS) of 12.4 months, while patients in the FOLFIRI-aibercept group had a median OS of 13.7 months (P = 0.276). There were no signicant differences in survival between the two treatment groups. The adverse events were also largely similar between the two groups. However, hypertension of grade 3 or more was more frequent in the FOLFIRI-aibercept group. Conclusion: FOLFIRI plus bevacizumab and FOLFIRI plus aibercept had similar anti-tumor activities and toxicity proles when used as second-line therapy in mCRC patients. Based on these data, both aibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI for mCRC.

FOLFIRI-a ibercept group had a median OS of 13.7 months (P = 0.276). There were no signi cant differences in survival between the two treatment groups. The adverse events were also largely similar between the two groups. However, hypertension of grade 3 or more was more frequent in the FOLFIRIa ibercept group.
Conclusion: FOLFIRI plus bevacizumab and FOLFIRI plus a ibercept had similar anti-tumor activities and toxicity pro les when used as second-line therapy in mCRC patients. Based on these data, both a ibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI for mCRC.

Background
Colorectal cancer is the second most commonly diagnosed cancer in Korea, with an estimated 25,881 new cases of colorectal cancer being diagnosed in 2017 [1]. It is also the third leading cause of cancerrelated death among both men and women, with an estimated 8,758 people dying of colorectal cancer in 2018 [1]. Treatment for metastatic colorectal cancer (mCRC) commonly involves 5-uoruracil, leucovorin, and oxaliplatin (FOLFOX) or 5-uorouracil, leucovorin, and irinotecan (FOLFIRI) as standard rst-line treatment [2,3]. More recently, biological therapies targeted against epidermal growth factor (cetuximab and panitumumab), angiogenesis inhibitors (bevacizumab, a ibercept, and ramucirumab), and other therapies (regorafenib, tri uridine/tipiracil) have been added to these combinations [4][5][6][7]. The use of targeted agents in rst-and second-line treatment can improve both the overall survival and progressionfree survival of mCRC patients [8].
Hurwitz and colleagues reported a signi cant increase in survival in metastatic colorectal cancer patients when 5-uoruracil based chemotherapy was combined with bevacizumab [9]. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF), thereby preventing its angiogenic effects. Bevacizumab is indicated in combination with both rst-and second-lines chemotherapies for mCRC patients [5].
Herein, we analyzed the e cacy and safety of targeted therapies (a ibercept or bevacizumab) used in combination with FOLFIRI as second-line treatment in patients with mCRC.

Patients
From October 2017 to March 2020 at Samsung Medical Center in Seoul, Korea, mCRC patients treated with FOLFIRI-a ibercept (N = 67) or FOLFIRI-bevacizumab (N = 83) after progression on an oxaliplatinbased therapy were analyzed in this study. Patients had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [12]. The following clinicopathological characteristics were collected for all 150 patients: age, gender, primary site, number of metastatic sites, RAS mutational status, and information on chemotherapy. All patients had pathologically or cytologically proven metastatic or recurrent CRC. The left side of the colon was de ned as the descending colon, sigmoid colon, and rectum, while the right side of the colon was de ned as the cecum and ascending colon. This retrospective study was approved by the Institutional Review Board of Samsung Medical Center and was conducted in accordance with the ethical principles of the Declaration of Helsinki. And written informed consent was waived because of its retrospective study design.

Chemotherapy
The choice between of using bevacizumab or a ibercept in combination with FOLFIRI was determined by each patient's physician. In the FOLFIRI-a ibercept group, patients received 4 mg/kg of a ibercept (intravenously [IV]) over 1 hour on day 1 of cycle 1, followed immediately by the FOLFIRI regimen (irinotecan 180 mg/m 2 IV over 90 minutes with leucovorin 200 mg/m 2 IV over 2 hours, followed by a FU 400 mg/m 2 bolus and FU 2400 mg/m 2 continuous infusion over 46 hours) on days 1 and 3 of cycle 1.
This treatment regimen was repeated every two weeks until disease progression or death. In the FOLFIRIbevacizumab group, patients received 5 mg/kg of bevacizumab (intravenously [IV]) over 1 hour on day 1 of cycle 1, followed immediately by the FOLFIRI regimen, as outlined above. This treatment regimen was repeated every two weeks until disease progression or death.

Statistical analyses
The statistical analysis of baseline demographics and clinical outcomes was based on all data available up to the cutoff date of March 15, 2020. Descriptive statistics were used to compare the patient characteristics. Survival analyses were performed using the Kaplan-Meier method and log-rank tests. Progression-free survival (PFS) was de ned as the time from the start of FOLRIFI-a ibercept or FOLRIFIbevacizumab treatment until the date of disease progression or death resulting from any cause. Overall survival (OS) was measured from the start of FOLRIFI-a ibercept or FOLRIFI-bevacizumab treatment to the date of death from any cause. All P-values were two-sided, and statistical signi cance was set at P < 0.05. Statistical analysis was performed using the IBM SPSS software package, version 25.

Patient characteristics
Baseline patient characteristics are provided in Table 1. The FOLFIRI plus a ibercept treatment was used in 67 patients, while the FOLFIRI plus bevacizumab treatment was applied in 83 patients. Of all 150 patients, 75 (50.0%) were men and 75 (50.0%) were female. The right side of the colon was the most common location of the primary tumor (62.6%), and RAS mutations were found in 76 patients (50.6%). At the beginning of the second treatment, all patients had ECOG PS 0-1. The median age was 55.96 years in the FOLFIRI-a ibercept group, and 57.40 years in the FOLFIRI-bevacizumab group. There were no signi cant differences in the clinical characteristics of patients between the two groups (Table 1).  Survival analyses were done for 134 patients. Among the 150 patients included in this study, 16 patients were excluded from the survival analyses due to loss to follow-up. The median progression-free survival (PFS) was 8.6 months in the FOLFIRI-bevacizumab group and 8.5 months in the FOLFIRI-a ibercept group (P = 0.752) (Fig. 1). Patients in the FOLFIRI-bevacizumab group showed a median overall survival (OS) of 12.4 months, while patients in the FOLFIRI-a ibercept group had a median OS of 13.7 months (P = 0.276) (Fig. 2). There was no signi cant difference in survival between the two groups.

Adverse events
The safety pro les of the treatment regimens are provided in Table 3. Treatment-related adverse events of any grade were reported in 86.5% of patients treated with FOLFIRI plus a ibercept and in 83.1% of patients treated with FOLFIRI plus bevacizumab. Adverse events of grade 3 or 4 were reported in 11.9% of patients in the FOLFIRI-a ibercept group and 2.4% of patients in the FOLFIRI-bevacizumab group. The most common adverse event was anorexia, followed by nausea, hypertension, neutropenia, and mucositis. There were no signi cant differences in the incidences adverse events between two regimens. In the FOLFIRI-a ibercept group, eight patients discontinued treatment due to the adverse event of hypertension. One patient experienced reversible cerebral vasoconstriction syndrome, and fully recovered from it after discontinuation of a ibercept. Another patient experienced a hypertensive crisis after a ibercept infusion, and recovered from it after discontinuation of the a ibercept. In the FOLFIRIbevacizumab group, two patients discontinued treatment: one due to the patient's worsening condition and one due to persistent neutropenia.

Discussion
In the present study, we compared FOLFIRI plus a ibercept with FOLFIRI plus bevacizumab as secondline therapy in mCRC patients who had experienced disease progression following oxaliplatin-based palliative chemotherapy. Based on this study, we con rmed that FOLFIRI plus bevacizumab and FOLFIRI plus a ibercept had similar anti-tumor activities and toxicity pro les when used as second-line therapy in mCRC patients. Our data support that both a ibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI for second-line treatment of mCRC.
As described earlier, VELOUR trial reported that adding a ibercept to FOLFIRI for treatment of mCRC patients who experienced disease progression following rst-line oxaliplatin-based chemotherapy improved their median OS and PFS when compared to patients treated with FOLFIRI plus placebo group [11]. In other previous study, Alessandro Ottaiano and colleagues conducted a study comparing FOLFIRI plus a ibercept with FOLFIRI plus bevacizumab as second-line therapy in RAS-mutated mCRC patients.
Although not statistically signi cant, the OS showed favorable trend in the FOLFIRI plus a ibercept group (FOLFIRI plus a ibercept: 12.1 months vs. FOLFIRI plus bevacizumab: 8.9 months; P = 0.9331) [13]. In the present study, the median PFS was not signi cantly different between the FOLFIRI-bevacizumab and FOLFIRI-a ibercept groups (8.61 months vs. 8.55 months, respectively; P = 0.752). Furthermore, the OS was also not statistically different between the two treatment groups (FOLFIRI-bevacizumab: 12.4 months vs. FOLFIRI-a ibercept: 13.7 months; P = 0.276). Therefore, our data were consistent with those of previous studies.
Bevacizumab binds human VEGF-A, but with a markedly lower a nity than a ibercept [14]. The association rate for a ibercept binding to VEGF-A is orders of magnitude faster than that measured for bevacizumab. Similarly, in cell-based bioassays, a ibercept inhibited the activation of VEGFR1 and VEGFR2, as well as VEGF-A-induced calcium mobilization and cell migration, in human endothelial cells more potently than bevacizumab [10,14,15]. Binding kinetics and a nity are key determinants of the biological activity of antibody-like drugs. Anti-VEGF therapy has also demonstrated improved results in mCRC when given in combination with chemotherapy [9,11,16]. However, not all patients bene t from this type of treatment. Thus, the identi cation of biomarkers that are able to pinpoint patients who are likely to bene t from anti-angiogenic agents is very important. In previous studies, researchers have tried to nd a variety of markers of response to antiangiogenic therapies in patients with colorectal cancer. Osterlund et al. showed that hypertension within the rst three months of antiangiogenic treatment was predictive for an improved OS [17]. Circulating levels of PIGF have been shown to increase in response to anti-VEGF treatment. Plasma PlGF levels were highest at the point before progression and patients with high plasma P1GF levels were resistant to treatment with bevacizumab [18,19]. Plasma VEGF-A levels were signi cantly positively associated with worse PFS and OS in mCRC patients who received either FOLFOX with bevacizumab or FOLFIRI with bevacizumab [20]. In other studies of patients treated with regorafenib, a better OS and PFS were observed in patients with lower VEGF-A levels [21]. As described earlier, a ibercept has the propensity to block VEGF-A and -B, as well as placental growth factor (PlGF)-1 and-2, thus preventing their interactions with growth factor receptors [10,22]. Switching therapeutic approaches based on the patient's PIGF and VEGF levels to target these alternative mechanisms, through the use of such drugs as a ibercept, may be bene cial. In our study, the e cacy of a ibercept is comparable to that of bevacizumab. Future studies are needed to con rm the importance of serum VEGF-A and PlGF levels in terms of using anti-angiogenic agents.
There are limitations to this study. First, it was a retrospective study, and clinically heterogeneous populations are subject to potential biases. Second, the study included a relatively small number of patients with anti-angiogenetic agents making it di cult to draw de nite conclusions regarding biomarkers. Third, only Asian patients were analyzed in the study, and differences in genomic pro les and clinical features exist between Western and Eastern patients with solid tumors. Therefore, our ndings must be interpreted with a level of caution.
In conclusion, we con rmed that FOLFIRI plus bevacizumab and FOLFIRI plus a ibercept had similar antitumor activities and toxicity pro les when used as second-line therapies in mCRC patients. Our data support that both a ibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI.  Figure 1