The Clinical Efficacy of FOLFIRI and Bevacizumab in Combination as First-Line Therapy of Metastatic Colorectal Cancer

Research inBrief

The Clinical Efficacy of FOLFIRI and Bevacizumab in Combination as First-Line Therapy of Metastatic Colorectal Cancer Introduction Standard care for first-line therapy of metastatic colorectal carcinoma (mCRC) includes administration of the antiangiogenic, vascular endothelial growth factor–targeted agent bevacizumab in combination with chemotherapy.1-4 Bevacizumab was established as first-line therapy after results of the landmark phase III trial AVF2107 demonstrated superiority of IFL (irinotecan/5-fluorouracil [5-FU]/leucovorin [LV]) plus bevacizumab compared with IFL alone in terms of median overall survival (OS), progression-free survival (PFS), response rate (RR), and response duration.2 Based on the robust efficacy of bevacizumab in this trial, the FDA approved its use in intravenous 5-FU–based regimens for firstline treatment of mCRC in February 2004.5 However, the final results from the Intergroup N9741 trial, presented in June 2004, demonstrated that FOLFOX (5-FU/LV/oxaliplatin) was significantly superior to IFL in terms of RR, time to progression (P < .001), and survival (P = .026), thereby challenging the role of IFL as first-line therapy.6 Subsequent to N9741 and the second-line phase III trial E3200, which showed that the addition of bevacizumab to FOLFOX was efficacious and tolerable, FOLFOX in combination with bevacizumab emerged as standard first-line therapy option for patients with mCRC.7 At the same time, 2 randomized studies showed that FOLFOX and FOLFIRI, another irinotecan-containing regimen in which 5-FU Prepared by: Erin Grothey, MS Reviewed by: Edward Chu, MD

was administered by infusion rather than bolus, had similar efficacy and no substantial difference in safety profiles.8,9 Several trials have since been conducted to investigate the efficacy and safety of FOLFIRI in combination with bevacizumab in the first-line setting.

FOLFIRI Versus IFL The landmark randomized phase III BICC-C (Bevacizumab plus Irinotecan in Colorectal Cancer) trial was the first study to make a head-to-head comparison of the efficacy and safety of FOLFIRI and IFL. As originally designed, patients were randomized between 3 different irinotecan-containing regimens: FOLFIRI (irinotecan 180 mg/m2, LV 400 mg/m2, and bolus 5-FU 400 mg/m2 plus infusional 5-FU 2400 mg/m2 over 46 hours, every 2 weeks), modified IFL (irinotecan 125 mg/m2, LV 20 mg/m2, and bolus 5-FU 500 mg/m2 weekly for 2 weeks, every 3 weeks), and CAPIRI (irinotecan 250 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily for 14 days, every 3 weeks).10 A second randomization was incorporated in which patients were subsequently randomized to receive the cyclooxygenase-2 inhibitor celecoxib or placebo. Patients (n = 430) were randomized to 1 of these 3 treatment arms during period 1 of the study. However, this study was subsequently redesigned to be a randomized phase II study, and a second accrual period (n = 117) was initiated in order to add bevacizumab to the FOLFIRI (5 mg/kg) and modified IFL (7.5 mg/kg) arms after bevacizumab was approved by the FDA. For period 2, the CAPIRI arm was eliminated because bevacizumab had only been approved for use in combination with intravenous

5-FU–based regimens, which would not include the oral fluoropyrimidine capecitabine. Eligible patients were required to have no previous systemic therapy, measurable disease, adjuvant therapy ≥ 1 year before study enrollment, and an Eastern Cooperative Oncology Group (ECOG) performance status of < 1. The primary endpoint of the study was PFS, and secondary endpoints were OS, response, and safety. The results from period 1 revealed that combining irinotecan with infusional 5-FU was superior to bolus 5-FU in terms of response and PFS (Table 1).10 Patients treated with FOLFIRI experienced a higher objective RR (47.3%) compared with patiens who received modified IFL (43.3%) and a statistically significant improvement in median PFS (7.8 months vs. 5.9 months; P = .003). A trend toward improved survival was noted for patients treated with FOLFIRI (23.1 months vs. 17.6 months). Therapy with FOLFIRI was also better tolerated than modified IFL, especially with regard to the rates of grade 3/4 diarrhea (13.9% vs. 19%), dehydration (5.8% vs. 7.3%), febrile neutropenia (3.6% vs. 12.4%), and myocardial infarction/stroke (0.7% vs. 3.6%). In terms of myelosuppression, the incidence of grade 3/4 neutropenia was slightly increased in the FOLFIRI arm (43.1% vs. 40.9%).

FOLFIRI in Older Patients (Aged > 65 Years) To further evaluate the utility of FOLFIRI and FOLFIRI/bevacizumab as first-line therapy for patients with mCRC, a secondary analysis of the

Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

Clinical Colorectal Cancer September 2007 • 621

Table 1: Phase III BICC-C Trial: Final Efficacy Analysis Period 1 Efficacy Measure

FOLFIRI (n = 144)

CR (%)*

5.6

PR (%)* SD (%)* Median PFS

(Months)*†

Median OS (Months)‡ *Intent-to-treat †P

Period 2 + Bevacizumab

Modified IFL CAPIRI (n = 141) (n = 145)

FOLFIRI (n = 57)

Modified IFL (n = 60)

4.3

2.8

NA

NA

41.7

39

35.9

NA

NA

27.8

36.9

30.3

NA

NA

7.8†

5.9†

5.8

11.2

8.3

23.1

17.6

18.9

NR§

19.2§

population.

= .003. statistically significant. = .01. Abbreviations: NA = not assessed; NR = not reached

‡Not §P

Table 2: Comparison of Younger Versus Older Patients Treated with FOLFIRI in Period 1 of BICC-C: Efficacy Efficacy Measure

P Value

a65 Years > 65 Years

a70 Years > 70 Years

P Value

Median PFS (Months) Irinotecan

6.8

6.6

.9

6.6

7.6

.9

FOLFIRI

7.8

7.5

.8

7.8

7.6

.7

Irinotecan

19.2

21.9

.5

18.4

21

.5

FOLFIRI

24.3

20.1

.3

24.1

20.1

.4

Median OS (Months)

Table 3: Comparison of Younger Versus Older Patients Treated with FOLFIRI in BICC-C: Adverse Events Grade 3/4 Adverse Event (%)

a65 Years

> 65 Years

Nausea

11.7

10.8

11.7

10.8

Vomiting

11.4

7.2

11.4

7.2

Diarrhea

a 70 Years > 70 Years

26.2

30.1

26.2

30.1

Dehydration

9

18.1

9

18.1

Neutropenia

36.7

45.8

36.7

45.8

Febrile Neutropenia

8.1

6

8.1

6

Hypertension

<5

<5

<5

<5

Thrombosis/Deep Vein Thrombosis

8.4

7.2

8.4

7.2

Pulmonary Embolism

5.4

3.6

5.4

3.6

BICC-C trial was initiated to assess whether FOLFIRI was tolerable and efficacious in an older patient population.11 No significant differences in efficacy or safety were observed between the younger and older patient groups, for either FOLFIRI or modified IFL. Patients were subgrouped at cutoff ages of 65 years (> 65 years and ≤ 65 years) and 70 years (> 70 years and ≤ 70 years). For both the 65- and 70-year subgroup analyses, no significant differences were noted in median PFS (P = .8 and P = .7)

or median OS (P = .3 and P = .4) in patients treated with FOLFIRI during period 1 (Table 2).11 The safety profile of FOLFIRI was similarly not agedependent. No appreciable difference between patient groups was observed in the incidence of grade 3/4 nausea, vomiting, diarrhea, dehydration, neutropenia, febrile neutropenia, hypertension, thrombosis/deep vein thrombosis, or pulmonary embolism (Table 3).11 These results mirror those found in a similar analysis of FOLFOX4 in elderly

622 • Clinical Colorectal Cancer September 2007

patients, which demonstrated no difference in efficacy benefit derived from FOLFOX4 for younger or older patients and that the efficacy/safety ratio was maintained despite age.12 The findings of this secondary analysis of BICCC now support the first-line use of FOLFIRI in patients with mCRC irrespective of age.

FOLFIRI/Bevacizumab as First-Line Treatment? A comparison of period 1 and period 2 of BICC-C found that the addition of bevacizumab to FOLFIRI improved patient outcome compared with FOLFIRI alone.10 Median PFS was increased from 7.8 months to 11.2 months when bevacizumab was added to FOLFIRI. In addition, median PFS was longer for patients treated with FOLFIRI/bevacizumab than with modified IFL/bevacizumab (11.2 months vs. 8.3 months), although this result was not statistically significant (P = .28). Although median OS had yet to be reached in the FOLFIRI/bevacizumab arm when the results were reported, there was a statistically significant improvement in 1-year survival (87% vs. 61%; P = .01), suggesting that first-line treatment with FOLFIRI/bevacizumab was associated with longer survival than with modified IFL/bevacizumab. Bevacizumab-associated adverse events reported for patients in the FOLFIRI/bevacizumab and the modified IFL/bevacizumab arms were diarrhea (10.7% vs. 11.9%), palmarplantar erythrodysesthesia (3.6% vs. 0), and hypertension (12.5% vs. 1.7%), and 60-day mortality was substantially higher in patients who received modified IFL/bevacizumab (6.8% vs. 1.8%). In addition to the BICC-C study, there are 2 single-arm trials investigating the FOLFIRI/bevacizumab regimen, and the results from these studies provide further support that FOLFIRI/bevacizumab can induce high RRs and delay disease progression.13,14 A single-arm phase II trial at the University of Texas M. D. Anderson Cancer Center investigated FOLFIRI/bevacizumab (irinotecan 180 mg/m2, bolus 5-FU 400 mg/m2,

Figure 1: Phase II Study of FOLFIRI/Bevacizumab in First-Line mCRC: Trial Schema Bevacizumab 5 mg/kg

Infusional 5-FU 2400 mg/m2

Bolus 5-FU 400 mg/m2 Leucovorin 400 mg/m2 Irinotecan 180 mg/m2

–30 to –60 Minutes

0

10 Minutes

90 Minutes

120 Minutes

48 Hours

Table 4: Phase II and Phase IV Trial of FOLFIRI/Bevacizumab in Patients with mCRC Compared with AVF2107 Historical Controls: Efficacy FOLFIRI/ Bevacizumab (n = 43)13

FOLFIRI/ Bevacizumab (n = 209)14

Modified IFL/ Bevacizumab (AVF2107; n = 402)10

CR (%)

0

3.3

3.7

PR (%)

60

49.8

41

Overall RR (%)

60

53.1

44.7

Efficacy Measure

Median PFS (Months)

12.5

11.1

10.6

Median OS (Months)

Not reached

Not reached

20.3

LV 400 mg/m2, with 46-hour infusion of 5-FU 2400 mg/m2 and bevacizumab 5 mg/kg biweekly) in patients with chemotherapy-naive mCRC (Figure 1).13 Patients with uncontrolled hypertension, myocardial infarction, or stroke within the previous 6 months were excluded from enrollment. The primary endpoint of the trial was PFS, and secondary endpoints included RR, OS, and tolerability. The trial was powered (80%) to detect a median PFS > 8 months. A total of 43 patients were enrolled onto the study, with a median age of 57 years. Approximately 86% of patients had moderately differentiated adenocarcinoma, and 88% had liver metastases. After a median follow-up of 15 months, median PFS for patients was 12.5 months, and median OS had not yet been reached (Table 4).10,13,14 The 1-year survival rate was 95%, and 75% of patients survived 20 months. The median PFS and 1-year survival rate are comparable with outcome measures for the BICC-C trial (11.2 months and 87%, respectively). The overall RR of 60% compared favorably with that found for

BICC-C (47.3%), but interestingly, time to response was long, with a median reached at 4 months of treatment, and some responses still noted at 6 months. Approximately 16% of patients became surgical candidates after a minimum of 9 cycles of FOLFIRI/bevacizumab, and 1 of these resections (liver) was classified as a complete pathologic response. Treatment was tolerable, although 53% of patients required dose reduction to control grade 3/4 toxicities, and 26% of patients had to discontinue treatment because of toxicity. The main grade 3/4 adverse events observed in this study were fatigue (14%), hypertension (19%), venous thrombosis (7%), pulmonary embolism (9%), pain (7%), infection (9%), palmar-plantar erythrodysesthesia (7%), and transaminitis (9%). The incidence of grade 3/4 neutropenia (40%) was high but was related to time on treatment. A larger multicenter, single-arm, phase IV trial (AVIRI [Avastin plus FOLFIRI]) was initiated in Italy to evaluate the efficacy and safety of FOLFIRI/ bevacizumab as first-line therapy for

mCRC in an attempt to produce clinical data with phase III levels of significance.14 Eligible patients were required to have mCRC, an ECOG PS of 0/1, and no central nervous system metastases. The primary objective for the trial was PFS compared with historical controls, and secondary objectives included safety, RR, time to response, duration of response, and OS. Using the same dose/schedule as in the phase II study by Kopetz and colleagues,13 patients were treated biweekly, and follow-up included assessing tumor size/progression every 3 months for the first year.14 A total of 209 patients were enrolled and were subsequently followed for a median of 13.3 months. Median age for the cohort was 62 years, and disease characteristics include a colon-rectum ratio for primary disease site of 68%:21.5%; 72 percent of metastases were to the liver. In terms of clinical efficacy, treatment with FOLFIRI/bevacizumab yielded a median PFS of 11.1 months and an overall RR of 53.1%, which are both superior to those found for modified IFL/bevacizumab regimen in the AVF2107 trial. Response was maintained for a medium of 8.5 months. At the time of presentation, the data relating to OS was not yet mature enough for analysis. In terms of safety profile, FOLFIRI/bevacizumab was tolerable, and all-grade bevacizumab-related events included bleeding (52%), hypertension (27%), venous thromboembolic events (4%), wound-healing complications (7%), gastrointestinal perforation (2%), and proteinurea (2%). The notable grade 3-5 adverse events included neutropenia (29%), febrile neutropenia (6%), diarrhea (12%), nausea (6%), vomiting (7%), and constipation (4%). The 60-day mortality rate was 2%.

Conclusion Recently presented data of the randomized BICC-C trial and 2 singlearm studies confirm that FOLFIRI plus bevacizumab can be regarded as one of the standard treatment options in the first-line palliative therapy for mCRC. In addition, FOLFIRI/bevacizumab has shown to be efficacious, tolerable, and

Clinical Colorectal Cancer September 2007 • 623

suitable for an elderly patient cohort. Therefore, FOLFIRI/bevacizumab should be the preferred regimen in mCRC whenever a combination of irinotecan plus bevacizumab is considered. In contrast, the weekly bolus IFL regimen should no longer be regarded as an appropriate treatment option because of its inferior efficacy and safety profile compared with FOLFIRI.

References

1. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9:669-676. 2. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362:841-844. 3. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335-2342. 4. Saltz L, Clarke S, Diaz-Rubio E, et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: efficacy results from XELOX-1/NO16966, a ran-

5.

6.

7.

8.

9.

domized phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC). Presented at: the American Society of Clinical Oncology 2007 Gastrointestinal Cancers Symposium; January 1921, 2007; Orlando, FL. Abstract #238. Listing of approved oncology drugs with approved indications. 2007. Food and Drug Administration Web site. Available at: http://www.fda.gov/cder/ cancer/druglistframe.htm. Accessed August 27, 2007. Goldberg RM, Sargent D, Morton RF, et al. N9741: FOLFOX (oxaliplatin(Oxal)/5-fluorouracil (5-FU)/leucovorin (LV)) or reduced dose R-IFL (CPT-11 + 5-FU/LV) in advanced colorectal cancer (CRC): final efficacy data from an Intergroup study. Proc Am Soc Clin Oncol 2004; 23:275 (Abstract #3621). Giantonio BJ, Catalano PJ, Meropol NJ, et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol 2005; 23(16 suppl):1s (Abstract #2). Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 2005; 23:4866-4875. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence

624 • Clinical Colorectal Cancer September 2007

10.

11.

12.

13.

14.

in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22:229237. Fuchs C, Marshall J, Mitchell E, et al. A randomized, multi-center phase III trial of irinotecan in combination with three different methods of administration of fluoropyrimidine with celecoxib versus placebo as first-line treatment for patients with metastatic colorectal cancer. J Clin Oncol 2007; 25(18 suppl):170s (Abstract #4027). Barrueco J, Marshall J, Mitchell E, et al. Safety and efficacy of first-line irinotecan/fluoropyrimidine combinations in mCRC patients > 65 years compared with those < 65 years: the BICC-C study. J Clin Oncol 2007; 25(18 suppl):182s (Abstract #4076). Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006; 24:4085-4091. Kopetz S, Glover KY, Eng C, et al. Phase II study of infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for metastatic colorectal cancer. J Clin Oncol 2007; 25(18 suppl):185s (Abstract #4089). Sobrero AF, Young S, Balcewicz S, et al. Phase IV study of first-line bevacizumab plus irinotecan and infusional 5-FU/LV in patients with metastatic colorectal cancer: AVIRI. J Clin Oncol 2007; 25(18 suppl):180s (Abstract #4068).