Maintenance with 5-FU/LV-aflibercept after induction with FOLFIRI-aflibercept versus FOLFIRI-aflibercept until progression as second-line treatment in older adults with metastatic colorectal cancer: the AFEMA phase II randomized trial

Abstract

Background: The combination chemotherapy i.v. 5-fluorouracil (5-FU), irinotecan, and aflibercept (FOLFIRI-A) is a standard second-line treatment of metastatic colorectal cancer (mCRC). The aim was to assess maintenance treatment in second-line setting in older patients (aged ≥70 years) with mCRC.

Patients and methods: We evaluated FOLFIRI-A given for six cycles followed by maintenance with 5-FU/leucovorin (LV)-A (arm A) or FOLFIRI-A (arm B) until progression in older adults with mCRC in the AFEMA randomized, open-label, non-inferiority phase II trial (EudraCT2016-004076-21/NCT03279289). Patients aged ≥70 years who previously failed oxaliplatin-fluoropyrimidine were randomly allocated (1 : 1) to either arm A (experimental) or arm B (control). After enrolling 35 patients, the FOLFIRI dose was reduced to level 1 in both arms due to toxicity. The primary endpoint was median progression-free survival (PFS); and secondary endpoints were median overall survival, objective response rate, and safety. Non-inferiority required the upper confidence interval (CI) limit to not exceed a hazard ratio (HR) of 1.5 (one-sided α = 0.075, 80% power).

Results: A total of 170 patients were randomly allocated to arm A or arm B (n = 85 each). The median follow-up was 12.2 versus 10.9 months in arm A versus arm B. Most patients died (83.5% versus 88.2% in arm A versus arm B), mainly from disease progression. PFS non-inferiority was met (HR = 0.78, 95% CI 0.566-1.076, P = 0.131) with a median PFS of 6.1 versus 5.5 months in arm A versus arm B. Median overall survival was similar in arms A and B (12.2 and 11.5 months, respectively) (HR = 0.89, 95% CI 0.640-1.227, P = 0.467). During the maintenance phase, severe asthenia (4.5% versus 21.6%, P = 0.038), serious adverse events (SAEs) (17.8% versus 37.8%, P = 0.049), and treatment-related SAEs (6.7% versus 10.8%, P = 0.695) were reduced in arm A versus arm B.

Conclusion: In older adults, induction with six cycles of FOLFIRI-A plus maintenance with 5-FU/LV-A was non-inferior to FOLFIRI-A until progression. Severe asthenia, SAEs, and treatment-related SAEs were reduced with 5-FU/LV-A maintenance.

Keywords: 5-FU; FOLFIRI; aflibercept; maintenance treatment; metastatic colorectal cancer.

Figure 1

Study design. A total of 45 patients in arm A and 37 patients in arm B initiated the maintenance phase. 5-FU, 5-fluorouracil; LV, leucovorin; mCRC, metastatic colorectal cancer; Q2W, once every 2 weeks.

Figure 2

Patient flow chart. 5-FU, 5-fluorouracil; AE, adverse event; LV, leucovorin; PFS, progression-free survival; PP per protocol. ^aComputerized tomography scan >35 days. ^bSeven patients were excluded from the PP [in all of them the reason was that they did not have response evaluation criteria in solid tumors (RECIST) v1.1 assessment done before end of treatment]. ^cA total of 13 patients were excluded from the PP (12 patients did not have RECIST v1.1 assessment done before end of treatment and 1 patient had a protocol deviation ‘previous tumor diagnosed <5 years ago’).

Figure 3

Progression-free survival and overall survival during the treatment with by arm A or arm B (ITT population). Arm A, FOLFIRI-aflibercept (six cycles) followed by maintenance treatment with 5-FU/LV-aflibercept; arm B, FOLFIRI-aflibercept. 5-FU, 5-fluorouracil; CI, confidence interval; Cumulative survival, Kaplan–Meier cumulative survival curve; HR, hazard ratio; LV, leucovorin; OS, overall survival; PFS, progression-free survival.