ONCAlert | 2017 San Antonio Breast Cancer Symposium

Second-Line Chemotherapy Doublet Proves Noninferior to FOLFIRI in mCRC

Lisa Astor
Published Online: Jan 12,2018
According to the results of the randomized phase III AXEPT clinical trial, a chemotherapy doublet has proved noninferior to treatment with standard FOLFIRI (folinic acid [leucovorin], fluorouracil [5-FU], and irinotecan) for patients with previously treated metastatic colorectal cancer (mCRC).1

Modified XELIRI (mXELIRI; capecitabine and irinotecan) with or without bevacizumab (Avastin) demonstrated similar overall survival (OS) rates to FOLFIRI with or without bevacizumab in the second line, but mXELIRI also showed an improved safety profile.

“Modified XELIRI is effective and well tolerated. This regimen is a more convenient alternative to FOLFIRI as a second-line backbone therapy for mCRC,” said Tae Won Kim, MD, director of the Clinical Research Center and the Center for Personalized Cancer Medicine, Asan Medical Center Cancer Institute, University of Ulsan College of Medicine, in Seoul, Korea. He presented findings on behalf of the AXEPT trial investigators during the 2017 ESMO Asia Congress.

XELIRI has generally been excluded from guidelines as a recommended backbone for patients with mCRC because of a higher rate of toxicities seen with the regimen in clinical trials, Kim noted. In the BICC-C study, which compared the FOLFIRI, XELIRI, and irinotecan plus bolus fluorouracil/leucovorin regimens, XELIRI demonstrated higher rates of severe vomiting, diarrhea, and dehydration.2 However, more recent trials have shown favorable efficacy and tolerability with a modified version of the XELIRI regimen: irinotecan 200 mg/m2 on day 1 and capecitabine 1600 mg/m2 on days 1 to 14 every 3 weeks.


In the phase III AXEPT trial, 650 patients with mCRC from Japan, Korea, and China who had progressed during or after first-line chemotherapy were randomized 1:1 to either FOLFIRI or mXELIRI, both with or without added bevacizumab. In each arm, 310 patients were treated.

The primary endpoint was OS, and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Kim explained that the upper margin of the noninferiority hypothesis was a hazard ratio (HR) of 1.3.

In the FOLFIRI arm, 5-FU was given intravenously at 400 mg/m2 with 200 mg/m2 of leucovorin and 180 mg/m2 of irinotecan, all on day 1, which was followed by 2400 mg/m2 of 5-FU through day 3. Added bevacizumab was administered at 5 mg/kg on day 1 of the 2-week cycle. When added to the mXELIRI regimen, bevacizumab was given at 7.5 mg/kg; the regimen was administered every 3 weeks. In both arms, the dose of irinotecan was lowered to 150 mg/m2 for patients with UGT1A1 *28 or *6 homozygotes or double-heterozygotes. 

In the intent-to-treat (ITT) population, characteristics were mostly well balanced between the 2 arms, Kim noted. The median age was 60 in the FOLFIRI arm and 61 in the mXELIRI arm. A majority of the patients had an ECOG performance status of 0 or 1 (99%) and left-sided primary tumors (76%) and had received prior oxaliplatin (97%).

Capecitabine had been received by 42.9% of patients in the FOLFIRI arm and 36.8% in the mXELIRI arm. Prior anti-EGFR therapy had been given to 15.1% and 17.2% in the FOLFIRI and mXELIRI arms, respectively.

“When this study was planned, targeted therapy was not reimbursed in Korea and in China, [so] less than 30% of the patients were exposed to prior bevacizumab,” Kim said. As a result, 83% received concomitant bevacizumab in the trial.

KRAS mutations were found in 31.2% of patients in the FOLFIRI arm and among 28.5% in the mXELIRI arm; 8% in the FOLFIRI arm and 7.4% in the mXELIRI arm had UGT1A1 *28 or *6 double-heterozygotes or homozygotes.

Median OS was 15.4 months with FOLFIRI with or without bevacizumab in the ITT population and 16.8 months with XELIRI (HR, 0.85; 95% CI, 0.71-1.02; P = .088). Per protocol, the median OS was 15.4 and 16.8 months with the FOLFIRI and mXELIRI regimens, respectively (HR, 0.85; 95% CI, 0.71-1.03). Median PFS in the ITT group was 7.2 months with FOLFIRI and 8.4 months with mXELIRI, which did not achieve statistical significance (HR, 0.95; 95% CI, 0.81-1.11; P = .5078).

The FOLFIRI arm demonstrated an ORR of 18.4%, and the mXELIRI arm had an ORR of 24.2% (P = .0951), with 2 complete responses from FOLFIRI and 13 from mXELIRI; the DCR was 71.9% and 77.4%, respectively (P = .1394).

Subgroup analyses of OS showed that lower performance status favored treatment with FOLFIRI. No prior treatment with oxaliplatin also favored FOLFIRI. “Overall survival with the modified XELIRI arm was noninferior to the FOLFIRI arm in patients with or without bevacizumab,” Kim noted.

The rate of grade 3/4 adverse events (AEs) was significantly higher with FOLFIRI compared with mXELIRI (72.3% vs 53.9%; P <.0001). Grade 3/4 neutropenia was especially higher in the FOLFIRI arm (42.9% vs 16.8%; P <.0001). AEs of increased frequency with mXELIRI included nausea, diarrhea, digestive tract perforation, and grade 2 hand-foot syndrome.
  1. Park Y, Muro K, Xu R, et al. Randomized, non-inferiority, phase III trial of second-line chemotherapy for metastatic colorectal cancer, comparing the efficacy and safety of XELIRI ± bevacizumab vs FOLFIRI ± bevacizumab (AXEPT). Presented at: 2017 ESMO Asia Congress; November 17-19, 2017; Singapore. Abstract LBA3_PR. oncologypro.esmo.org/Meeting-Resources/ESMO-Asia-2017Congress/Randomized-non-inferiority-phase-III-trial-of-second-line-chemotherapy-for-metastatic-colorectal-cancer-mCRC-comparing-the-efficacy-and-safety-of-XELIRI-bevacizumab-versus-FOLFIRI-bevacizumab-AXEPT-LBA3_PR.
  2. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C study. J Clin Oncol. 2007;25(30):4779-4786. doi: 10.1200/JCO.2007.11.3357.

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Second-Line Chemotherapy Doublet Proves Noninferior to FOLFIRI in mCRC
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