A little bit of background – MGMT promoter methylation is associated with a greater efficacy of temozolomide in glioblastoma patients but is also found in about one-third of colorectal cancers. Previous phase II non-randomised trials showed an overall response rate to single agent temozolomide of about 10% in refractory metastatic colorectal cancer and MGMT methylation detected by a qualitative assay which is methylation specific PCR, or MSP.
The use of temozolomide and its efficacy may be improved by the use in earlier treatment lines in combination with other active agents and also by refining the selection, the molecular selection, beyond MSP. So the trial was a randomised phase II study that compared second line treatment with capecitabine and temozolomide, the CAPTEM regimen, versus standard FOLFIRI as second line treatment for patients with RAS mutated and MGMT methylated metastatic colorectal cancer. The aim of the study was to demonstrate a superiority of the CAPTEM regimen in terms of progression free survival over FOLFIRI. In the trial design we enrolled metastatic colorectal cancer patients with measurable disease, ECOG PS 0-1, after failure of prior FOLFOX or CAPOX plus or minus bevacizumab regimen with locally assessed RAS mutation and centrally confirmed MGMT methylation. Patients were then randomised on a one to one basis to either fully oral four weekly capecitabine and temozolomide, the experimental arm, or standard FOLFIRI that is given bi-weekly intravenously.
So the results – the primary study endpoint was not met since CAPTEM was not superior to FOLFIRI in terms of progression free survival. But actually the two regimens achieved similar progression free survival, overall survival, overall response rate and disease control rate. The CAPTEM regimen was associated with a more favourable toxicity profile, compliance and quality of life.
We also examined whether the efficacy of the two treatment arms was different according to specific biomarkers such as MGMT immunohistochemistry. Surprisingly, patients with positive MGMT immunohistochemistry who were receiving CAPTEM achieved a significantly worse outcome in terms of both progression free survival and disease control rate as compared to those patients receiving FOLFIRI. In the subgroup of patients with negative MGMT immunohistochemistry there was no difference between the two arms. The p interaction test was 0.07 for progression free survival and 0.031 for disease control rate, suggesting a potential predictive utility of MGMT immunohistochemistry.
In conclusion, our trial was a phase II study so the use of temozolomide should be further investigated by phase III studies, ideally restricted to an MGMT negative population. We believe that our hospital will design future trials for expanding the use of this agent for this population of colorectal cancer patients that have a real unmet medical need, the RAS mutated one. This study was a non-profit study conducted in Italy and there was no financial support from big pharma companies, so it was an honour to present it here in Barcelona. Thank you.
