A randomised trial in 650 patients has confirmed the safety and efficacy of a new second line treatment for metastatic colorectal cancer, researchers report at the ESMO Asia 2017 Congress.

Oral fluorinated pyrimidines have been investigated to replace intravenous 5FU in colorectal cancer (CRC).

Capecitabine combined with oxaliplatin (XELOX) has demonstrated comparable efficacy and safety to FOLFOX for the management of metastatic and adjuvant CRC.

However, the combined capecitabine and irinotecan (XELIRI) regimen failed to replace FOLFIRI due to concerns over safety and efficacy.

A modified XELIRI (mXELIRI) regimen was subsequently developed with reduced doses of irinotecan (200 mg/m2 on day 1) and capecitabine (1600 mg/m2 on days 1–14).

In combination with bevacizumab it has shown favourable tolerability and efficacy comparable to XELOX plus bevacizumab in the first and second line settings.

Following these two trials, the Asian XELIRI ProjecT (AXEPT) was designed.

This multicentre, open-label, randomised phase 3 trial assessed the efficacy and safety of mXELIRI versus FOLFIRI, with or without bevacizimab, as second line treatment for patients with metastatic CRC.

It was designed to demonstrate non-inferiority of the capecitabine containing regimen in terms of overall survival, with 95% confidence interval (CI) upper limit of the hazard ratio (HR) pre-specified as less than 1.3.

The trial enrolled 650 patients aged 20 years or older with histologically confirmed unresectable colorectal adenocarcinoma.

Patients had been withdrawn from first line chemotherapy for mCRC due to intolerable toxicity, disease progression or relapse fewer than 180 days after the final dose of adjuvant chemotherapy.

Patients were randomly assigned in a 1:1 ratio to receive either mXELIRI with or without bevacizumab every three weeks or FOLFIRI with or without bevacizumab every two weeks.

Patients were stratified according to the following factors:

1. country (Japan versus South Korea versus China)
2. Eastern Cooperative Oncology Group (ECOG) performance status (0–1 versus 2)
3. number of metastatic sites (one versus more than one)
4. prior oxaliplatin treatment (yes versus no)
5. concurrent bevacizumab treatment (with versus without).

After a median follow-up of 15.8 months, the median overall survival was 16.8 and 15.4 months in the mXELIRI and FOLFIRI arms, respectively (HR 0.85, 95% CI 0.71–1.02, non-inferiority test p<0.0001).

Similarly, there was no statistical difference in terms of median progression-free survival between the two arms: 8.4 months (95% CI, 7.1−9.1) for patients treated with mXELIRI compared with 7.2 months (95% CI, 6.6−8.5) for those treated with FOLFIRI (HR=0.95; 95% CI, 0.81−1.11; p=0.5078).

The incidence of grade 3/4 adverse events was significantly lower in the mXELIRI arm than the FOLFIRI arm (167 [53.9%] versus 224 [72.3%] of 310 patients; p<0.0001).

The most common grade 3/4 adverse event was neutropaenia (52 [16.8%] and 133 [42.9%] patients in the mXELIRI and FOLFIRI arms, respectively; p<0.0001).

The incidences of grade 3/4 diarrhoea were low in both arms (7.1% and 3.2%, respectively; p=0.0443).

The efficacy and safety results were similar across all prespecified subgroups.

Lead author Tae Won Kim, Professor of the Department of Oncology, Asan Medical Centre, Seoul, Korea, said “The AXEPT trial demonstrates that modified XELIRI with or without bevacizumab has a non-inferior efficacy to FOLFIRI with or without bevacizumab and is well tolerated. The modified XELIRI regimen could be an alternative to the standard FOLFIRI regimen as a second line backbone therapy for metastatic colorectal cancer.”

Commenting on the study, Dr Rodrigo Dienstmann, principal investigator of the Oncology Data Science (ODysSey) Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain, and research scientist at the Computational Oncology Group, Sage Bionetworks, Seattle, US, said “Capecitabine is given orally and is more convenient for patients compared to infusional 5FU. However, at the maximum doses the combination of capecitabine and irinotecan (XELIRI) can be quite toxic.”

“The main objective of AXEPT was to assess whether a reduced dose-intensity of the chemotherapy (the modified XELIRI regimen) would not negatively impact overall survival,” he continued. “As the trial met the primary endpoint, we can say that mXELIRI is non-inferior to standard FOLFIRI (with or without bevacizumab). The toxicity profile was quite favourable for the modified regimen, with less neutropaenia. The investigators observed slightly more diarrhoea, as expected, but still acceptable. This study supports the use of mXELIRI in the second line setting, with the potential to increase patient convenience.”

Regarding the need for further research, Dienstmann said “Quality of life data will be critical to understanding the value of this regimen. We also need biomarker analysis, such as the impact of RAS status and emerging biomarkers on response to chemotherapy with or without bevacizumab and prognosis. This would help clinicians who have to optimise the sequence of chemotherapy/targeted therapy in metastatic CRC. 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. In addition, some early studies have found a favourable safety profile with modified XELIRI given every two weeks and this deserves further study.”

Source: ESMO