Modified dose XELIRI shows potential as second-line alternative for metastatic CRC

Roshini Claire Anthony
21 Nov 2017
Modified dose XELIRI shows potential as second-line alternative for metastatic CRC
Prof Tae Won Kim

A modified dose of XELIRI with or without bevacizumab may be an alternative second-line chemotherapy treatment for patients with metastatic colorectal cancer (CRC), according to results of the noninferiority phase III AXEPT* trial.

“Modified XELIRI is an effective, well-tolerated, and more convenient alternative to FOLFIRI as a second-line backbone therapy for metastatic CRC,” presented lead author Professor Tae Won Kim from the Asan Medical Centre, Seoul, Korea, at ESMO Asia 2017 in Singapore.

According to Kim, XELIRI is not recommended by major guidelines in the treatment of mCRC due to the toxicity demonstrated by this regimen in the BICC-C trial. [J Clin Oncol 2007;25:4779-4786] However, a modified XELIRI dose (irinotecan dose reduced from 250 to 200 mg/m2 and capecitabine from 2,000 to 1,600 mg/m2/day) plus bevacizumab demonstrated favourable efficacy and tolerability in previous studies. [Oncologist 2014;19:1131-1132; Ann Oncol 2013;24:1580-1587]

As such, researchers randomized 650 patients from 98 sites in Japan, Korea, and China to FOLFIRI (irinotecan [180 mg/m2 on day 1] plus 5-FU [400 mg/m2 IV bolus on day 1 and 2,400 mg/m2 IV infusion on days 1–3] plus I-LV  [200 mg/m2 on day 1]) with or without bevacizumab (5 mg/kg on day 1) every 2 weeks or modified XELIRI (irinotecan [200 mg/m2 on day 1] plus capecitabine [1,600 mg/m2/day on days 1–14]) with or without bevacizumab (7.5 mg/kg on day 1) every 3 weeks to compare the safety and efficacy of these regimens in patients with metastatic CRC who had progressed during or after first-line chemotherapy.

A lower dose of irinotecan (150 mg/m2) was administered in both groups for patients with UGT1A1 *28 or *6 homo or double heterozygotes.

A majority of patients were ECOG 0–1 and had previous exposure to oxaliplatin (97.8 and 97.2 percent of patients on FOLFIRI and modified XELIRI, respectively).

After a median 15.8-month follow-up period, modified XELIRI was noninferior to FOLFIRI in terms of overall survival (median, 16.8 vs 15.4 months; hazard ratio [HR], 0.85, 95 percent confidence interval [CI], 0.71–1.02; p<0.001 for noninferiority [prespecified margin upper limit HR, 1.3] and p=0.088 for superiority). [ESMO Asia 2017, abstract LBA 3]

Progression-free survival was comparable between patients on modified XELIRI and FOLFIRI (median, 8.4 vs 7.2 months; HR, 0.95, 95 percent CI, 0.81–1.11; p=0.5078).

The overall response rate was 24.2 and 18.4 percent in the modified XELIRI and FOLFIRI arms, respectively, while disease control rate was 77.4 and 71.9 percent, respectively.

The incidence of grade 3–4 adverse events was lower in the modified XELIRI compared with the FOLFIRI arm (53.9 percent vs 72.3 percent; p<0.0001), primarily due to the lower incidence of grade 3–4 neutropenia in the modified XELIRI vs FOLFIRI arm (16.8 percent vs 42.9 percent; p<0.0001). The incidence of febrile neutropenia was comparable between groups (p=0.6718), while the incidence of diarrhoea was higher in the modified XELIRI vs FOLFIRI arm (7.1 percent vs 3.2 percent; p=0.0443).

Based on the results of the AXEPT study, modified XELIRI with or without bevacizumab can replace FOLFIRI with or without bevacizumab especially in the Korean/Japanese/Chinese population using the dose schedule that was utilized in AXEPT, said discussant Dr Ian Chau, consultant medical oncologist from The Royal Marsden, Sutton, UK.

As the dose schedule was previously used in a German study, the regimen might also work in a Western population, he said.

However, Chau did not rule out the possibility that post-trial treatments such as cetuximab, regorafenib, and/or trifluridine/tipiracil, which was given to these patients, may have influenced the survival results.

Dr Rodrigo Dienstmann from the Vall d’Hebron Institute of Oncology, Barcelona, Spain, also pointed to the importance of biomarker analysis and quality of life data pertaining to this regimen.

“Pharmacogenetic studies can also be insightful. There are known genetic variations within the UGT1A1 gene across Asian and non-Asian populations, which may impact on irinotecan toxicity profile … some early studies have [also] found a favourable safety profile with modified XELIRI given every 2 weeks and this deserves further study,” he added.


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